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EXHIBIT 10.14
NORTHWEST BIOTHERAPEUTICS, INC.
CLINICAL TRIAL AGREEMENT
This Clinical Trial Agreement (the "Agreement"), is made as of the 16th
day of December, 1999, (the "Effective Date") by and between Northwest
Biotherapeutics, Inc., a Delaware corporation (the "Sponsor"), and The
University of Texas, M.D. Anderson Cancer Center, a nonprofit educational and
healthcare facility having corporate powers under the laws of the State of Texas
(hereinafter the "Institution"), a component of The University of Texas System
(hereinafter the "System.")
RECITALS
The Sponsor desires to test its therapy of autologous recombinant
prostate specific membrane antigen loaded dendritic cells (the "Product") for
metastatic, hormone refractory prostate cancer in a clinical setting. The
Institution seeks the advancement of health care through research and clinical
investigation, and as such is willing to permit testing of the Product in
accordance with the terms of this Agreement.
AGREEMENT
In consideration of the foregoing and of the mutual promises contained
in this Agreement, the parties agree as follows:
1. STATEMENT OF WORK. The Institution agrees to conduct a clinical study
of the Product in accordance with study protocol No. DC1-HRPC attached hereto as
Exhibit A (the "Study"). In the event of any conflict between Exhibit A and the
provisions of this Agreement, the provisions of this Agreement shall govern.
2. PRINCIPAL INVESTIGATOR. The Study will be conducted under the direct
supervision of Christos Papandreou, M.D., Ph.D., Study Chairman (hereinafter the
"Principal Investigator") with the participation of other Institution clinical
and research personnel to be identified or approved by Sponsor. The Institution
agrees to conduct the Study in strict accordance with the protocol and all
applicable federal, state, and local laws and regulations. If Principal
Investigator becomes permanently unavailable, for any reason, the Sponsor may,
at its sole discretion, appoint another Principal Investigator or terminate this
Agreement.
3. IRB APPROVAL. The Institution's obligations to conduct the Study are
expressly conditional upon the approval of its Investigational Review Board,
which the parties and the Principal Investigator will cooperate to obtain. The
implementation of DC1-HRPC at the Institution is embodied in the IRB approved
Institutional Protocol ID99-333 attached hereto as Exhibit B. The Sponsor and
the Study Chair will closely coordinate to insure the FDA approved IND protocol
governing this trial (DC1-HRPC as approved by the FDA as described in the
"Investigator's Brochure," section V of the IND) and the ID99-333 protocol are
executed, maintained and amended in accordance with applicable Federal, State
and Institutional Regulations.
CONFIDENTIAL
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4. REPORTS AND CONFERENCES.
A. The Principal Investigator will make informal verbal reports
to the Sponsor (or the Sponsor's representatives) at least monthly, and will
meet with the Sponsor's representatives upon reasonable request at the
Institution's facilities to discuss the progress of the Study. A final written
report shall be submitted to the Sponsor within thirty (30) days after
completion of, or any premature termination of, the Study and, if requested, the
Principal investigator shall assist the Sponsor in interpreting such report.
Copies of all clinical data, including copies of case report forms,
questionnaires, other records identified in the Protocol and other relevant
information generated during the Study will be promptly and fully provided to
the Sponsor (or the Sponsor's representative), and shall be freely usable by the
Sponsor consistent with good business judgment.
B. The Institution agrees to notify the Sponsor within
twenty-four (24) hours after learning of any serious and/or unexpected adverse
Product reaction affecting any patient in the Study. The Institution further
agrees to follow up such notification of adverse Product reaction with
appropriate reports in compliance with the Protocol and all applicable legal and
regulatory requirements.
C. The Institution agrees to notify the Sponsor within
twenty-four hours in the event that the FDA or any other regulatory authority
notifies the Institution of a pending inspection/audit. In addition, the
Principal Investigator will forward to the Sponsor any written communication
related to the use of the Sponsor's Product received as a result of the
inspection/audit within twenty-four (24) hours of receipt of such communication
and will allow the Sponsor to assist in responding to any citations. Such
responses shall be made within two (2) weeks of issuance of any citations or
within any earlier deadline set by the issuing regulatory authority. The
Principal Investigator shall also provide to the Sponsor copies of any documents
provided to any inspector or auditor. In the event of the FDA or other
regulatory authority requests or requires any action to be taken to address any
citations, the Institution agrees, following consultation with the Sponsor, to
take such action as necessary to address such citations, and agree to cooperate
with the Sponsor with respect to any such citation and/or action taken.
5. PAYMENTS. The Sponsor will pay, to the Institution, as the
Institution's total compensation under this Agreement, the amounts and in
accordance with the schedule set forth in Exhibit C attached hereto.
6. PUBLICITY. Neither party shall use the name of the other party,
including any trademark, trade name, or any contraction, abbreviation,
simulation, or adaptation thereof of the other party, or the name of the party's
employees, in any publicity, advertising or news release without the prior
written approval of an authorized officer of the other party.
7. CONFIDENTIAL INFORMATION. During the performance of the Study and
during the term of this Agreement, the Institution or the Principal Investigator
may receive confidential or trade secret information, including information
concerning the Sponsor's present and future business, marketing plans,
regulatory submissions, product fines, product plans, date testing and research
techniques, inventions, processes, practices, trade secrets, and like
information
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(collectively, "Confidential Information") from the Sponsor. The Institution
agrees to hold in confidence all such Confidential Information and not to
disclose or make such Confidential information available to any third parties
without the Sponsor's written permission, for a period of five (5) years from
the termination of this Agreement. This obligation will apply only to
information which the Sponsor has designated in writing as "confidential" and
will not apply to any such information which:
(i) was known to the Institution prior to its receipt from the
Sponsor, as evidenced by written documentation;
(ii) was or becomes a matter of public information or publicly
available through no fault on the part of the Institution.
(iii) is acquired from a third party entitled to disclose the
information to the Institution; or
(iv) was developed independently by the Institution, as evidenced
by written documentation.
(v) is required by law or regulation to be disclosed. In the
event that information is required to be disclosed pursuant to subsection v, the
party required to make disclosure shall notify the other to allow that party to
assert whatever exclusions or exemptions may be available to it under such law
or regulation.
8. PUBLICATION RIGHTS. The Sponsor acknowledges that the Institution is
dedicated to free scholarly exchange and to public dissemination of the results
of their scholarly activities. The Principal Investigator and the Institution
shall retain the right to publish research results in pursuit of educational and
scientific purposes. However, the Institution expressly agrees that all drafts
of any publications or oral presentations, including without limitation
manuscripts, abstracts, posters, and visual works based on the Study or any
results of the Study shall be submitted to the Sponsor at least thirty (30) days
prior to the proposed submission of such drafts for publication or presentation.
Such publications and presentations shall not divulge any of the Sponsor's
Confidential Information without prior written approval of the Sponsor, and the
Institution shall promptly remove any Confidential Information identified and
requested by the Sponsor. If requested by the Sponsor, the Principal
Investigator and the Institution shall delay the submission of any publication
or presentation up to sixty (60) days from the date of the Sponsor's request for
such a delay to permit the preparation and filing of related patent
applications. in addition, the Sponsor shall have the right to require that any
publication or presentation concerning the work performed hereunder acknowledge
the Sponsor's support.
9. INVENTIONS. "Invention" shall mean any discovery, concept, or idea,
whether or not patentable, made during the conduct of the study, and arising
directly from the performance of the study, including but not limited to
processes, methods, software, tangible research products, formulas and
techniques, improvements thereto, and know-how related thereto.
Institution agrees that the Principal Investigator will promptly
disclose to its Intellectual Property Committee and to Sponsor any Inventions
made by the Institution and/or the Principal
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Investigator. It is agreed that all Inventions and any information with respect
thereto shall be subject to confidentiality obligations commensurate with those
set forth in Section 7 herein.
Any Inventions that originate solely with the Principal Investigator, or
any other Institution agent or employee associated with this study (jointly or
severally referred to as "Inventor") shall be the property of Institution. If
Inventor is a co-inventor with Sponsor, its agents or employees, Institution and
Sponsor shall jointly own the Invention. Any Inventions that originate solely
with any agent or employee of Sponsor shall be the property of Sponsor. To the
extent that Sponsor pays all patent expenses for an Invention, Institution does
hereby grant to Sponsor an exclusive option to negotiate an exclusive, worldwide
royalty-bearing license to any Invention in which Institution has an ownership
interest. Sponsor shall indicate its intention to exercise its option to license
by notifying Institution in writing within forty-five (45) days of each
Invention's disclosure to Sponsor. If Sponsor decides to exercise its option,
the terms shall be negotiated in good faith within one-hundred twenty (120) days
of the date the option is exercised, or within such time as the parties may
mutually agree in writing.
If negotiations between Sponsor and the Institution terminate and the
Institution thereafter negotiates a license agreement with a third party on
substantially better terms than those last offered to Sponsor, Sponsor shall be
given the first right to refuse such terms for a period of sixty (60) days from
the date of Sponsors receipt of a draft of such license agreement from
Institution.
10. INDEMNIFICATION BY SPONSOR. The Sponsor will indemnify, hold
harmless and defend the System, Institution, their Regents, officers, agents,
and employees (collectively the "Indemnitees") against all actions, suits,
claims, demands and prosecutions (hereinafter a "Claim") that may be brought or
instituted, and all judgments, damages, liabilities, costs and expenses
resulting therefrom, arising out of the activities to be carried out pursuant to
the obligations under this Agreement, including but not limited to the use by
Sponsor of the results obtained from the activities performed by Institution
under this Agreement, but only to the extent that any such Claim is not caused
by or the result of: (a) any negligence or willful act or omission of any
Indemnitees; or (b) failure to adhere to the terms of the protocol provided by
the Sponsor hereunder. The Sponsor's indemnification obligations under this
Section 10 only arise if: (i) the Institution notifies the Sponsor within (30)
thirty days after it becomes aware of a Claim; (ii) the Institution, subject to
the Statutory duties of the Texas Attorney General permits the Sponsor control
the defense and settlement, at the Sponsor's expense, of any such Claim; (iii)
the Institution and Principal Investigator fully cooperate with the Sponsor in
the defense of any such claim, and (iv) the Institution does not settle any such
Claim without the prior written approval and consent of the Sponsor.
11. INDEMNIFICATION BY INSTITUTION. Institution shall to the extent
authorized under the Constitution and laws of the State of Texas, indemnify and
hold Sponsor harmless from liability resulting from the negligent acts or
omissions of Institution, its agents or employees pertaining to the activities
to be carried out pursuant to the obligations of this Agreement; provided,
however, that Institution shall not hold Sponsor harmless from claims arising
out of the negligence or willful malfeasance of Sponsor, its officers, agents,
or employees, or any person or entity not subject to Institutions supervision or
control.
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12. LIABILITY INSURANCE. The Sponsor will maintain during the term of
this Agreement liability insurance with minimum limits of not less than
$1,000,000. As soon as practicable upon execution of this Agreement, the Sponsor
will deposit with the Institution certificates of insurance evidencing this
coverage. Such coverage may not be changed or terminated except upon at least
thirty (30) days prior written notice to the Institution. In addition, the
Sponsor will at all times comply with all statutory workers' compensation and
employers' liability requirements covering its employees with respect to
activities performed under this Agreement.
13. RELATIONSHIP OF THE PARTIES. The Institution and the Principal
Investigator shall both be deemed to be independent contractors for all purposes
and for all services to be provided under this Agreement, and neither the agent
nor the employee of the Sponsor. The Institution shall have no authority to make
any statements, representations or commitments of any kind, or to take any
action, which shall be binding upon the Sponsor, except as expressly provided
for in this Agreement or authorized in Writing by the Sponsor.
14. REPRESENTATIONS AND WARRANTIES OF INSTITUTION. Institution
represents that the Principal Investigator and all other investigators that may
perform services hereunder are its employees and shall abide by the terms of
this Agreement as if each were a party hereto.
15. WARRANTIES; LIMITATION OF LIABILITY. THE SPONSOR MAKES NO
WARRANTIES, EXPRESS OR IMPLIED, AS TO ANY PRODUCT OR OTHER MATERIALS OR
PROCESSES PROVIDED HEREUNDER. EXCEPT AS EXPRESSLY STATED HEREIN, THE SPONSOR
SHALL NOT BE LIABLE FOR ANY DIRECT, CONSEQUENTIAL, PUNITIVE, INDIRECT, OR OTHER
DAMAGES SUFFERED BY THE INSTITUTION OR THE PRINCIPAL INVESTIGATOR AS A RESULT OF
THE STUDY.
16. TERM. This Agreement shall be effective from the Effective Date of
this Agreement and shall expire thirty (30) days after receipt by Sponsor of the
final summary of work accomplished during the Study. This Agreement may be
terminated by either party upon fourteen (14) weeks written notice.
17. RETURN OF PRODUCT. Upon termination of this Agreement, the
Institution will return to the Sponsor all non-disposable Product, test kits,
and packaging materials as well as all copies of drawings, specifications,
manuals and other printed or reproduced material (including information stored
on machine-readable media) provided by the Sponsor to the Institution or the
Principal Investigator. The Sponsor may, at the Sponsor's option, request that
such materials be destroyed. All equipment purchased with funds under this
Agreement will become the property of Institution.
18. MISCELLANEOUS.
A. AMENDMENTS AND WAIVERS. Any term of this Agreement may be
amended or waived only with the written consent of the parties or their
respective successors and assigns. Any amendment or waiver effected in
accordance with this Section 18(a) shall be binding upon the parties and their
respective successors and assigns.
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B. NOTICE. Any notice required or Permitted by this Agreement
shall be in writing and shall be deemed sufficient upon receipt, when delivered
personally or by courier, overnight delivery service or confirmed facsimile, or
forty-eight (48) hours after being deposited in the regular mail as certified or
registered mail (airmail if sent internationally) with postage prepaid, if such
notice is addressed to the party to be notified at such party's address or
facsimile number as set forth below, or as subsequently modified by written
notice.
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INSTITUTION: SPONSOR:
University of Texas Northwest Bio therapeutics, Inc.
M.D. Anderson Cancer Center 120 Northgate Plaza, Suite 200
1515 Holcombe Blvd., Box 202 Seattle, WA 98125
Houston, Texas 77030
ATTENTION: Donna Gilberg, C.P.A. ATTENTION: Daniel O. Wilds
Manager, Grants & President and CEO
Contracts Accounting
If by FAX: (713) 796-0381 If by FAX: (206) 368-3026
If by express mail: same as address above If by express mail: same address
as above
C. ASSIGNMENT. The Institution agrees not to assign any of its
rights or obligations under this Agreement to any other party without first
obtaining the Sponsor's written approval. The terms and conditions of this
Agreement shall inure to the benefit of and be binding upon the respective
permitted successors and assigns of the parties. Nothing in this Agreement,
express or implied, is intended to confer upon any party other than the parties
hereto or their respective successors and assigns any rights, remedies,
obligations, or liabilities under or by reason of this Agreement, except as
expressly provided in this Agreement.
D. GOVERNING LAW; JURISDICTION. This Agreement shall be construed
in accordance with the laws of the State of Texas.
E. SEVERABILITY. If one or more provisions of this Agreement are
held to be unenforceable under applicable law, the parties agree to renegotiate
such provision in good faith, in order to maintain the economic position enjoyed
by each party as close as possible to that under the provision rendered
unenforceable. In the event that the parties cannot reach a mutually agreeable
and enforceable replacement for such provision, then (i) such provision shall be
excluded from this Agreement, (ii) the balance of the Agreement shall be
interpreted as if such provision were so excluded and (iii) the balance of the
Agreement shall be enforceable in accordance with its terms.
F. FORCE MAJEURE. Performance of this Agreement by each party
shall be pursued with due diligence in all requirements hereof, however, neither
party shall be liable to the other for any loss or damages for delay or for
nonperformance due to causes not reasonably within its control. The party
affected shall promptly notify the other in writing of the nature, cause, date
of commencement thereof, the anticipated extent of such delay.
G. ENTIRE AGREEMENT. This Agreement is the product of both of the
parties hereto, and constitutes the entire agreement between such parties
pertaining to the subject matter hereof, and merges all prior negotiations and
drafts of the parties with regard to the transactions contemplated herein. Any
and all other written or oral agreements existing between the parties hereto
regarding such transactions are expressly canceled.
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The parties hereto have caused this Agreement to be executed on their
behalf by their duly authorized representatives to he effective on the year and
date first above written.
NORTHWEST BIOTHERAPEUTICS, INC.
By: /s/ Daniel O. Wilds
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Name: Daniel O. Wilds
Title: President and Chief Executive
Officer
Date: 12-16-99
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THE UNIVERSITY OF TEXAS, M.D.
ANDERSON CANCER CENTER
By: /s/ Leonard A. Zwelling
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Name: Leonard A. Zwelling, M.D., M.B.A.
Title: Associate Vice President,
Research Administration
Date: 12-28-99
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I have read this agreement and understood my obligations hereunder:
/s/ Christos Papandreou Date: 12-20-99
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Christos Papandreou, M.D., Ph.D.
PRINCIPAL INVESTIGATOR,
STUDY CHAIRMAN
/s/ Christopher Logothetis Reviewed and Approved
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Christopher Logothetis, M.D.
Chairman, Department of Genitourinary
Medical Oncology
Date: 12-28-99
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/s/ Robert C. Bast
--------------------------------------
Robert C. Bast, Jr., M.D.
Head, Division of Medicine
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EXHIBIT A
Northwest Biotherapeutics, Inc. Study Protocol No. DC1-HRPC
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CONFIDENTIAL
Northwest Biotherapeutics, Inc.
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NORTHWEST BIOTHERAPEUTICS, INC.
PHASE I CLINICAL TRIAL OF RECOMBINANT PROSTATE SPECIFIC MEMBRANE
ANTIGEN (rPSMA)-LOADED MATURE AUTOLOGOUS DENDRITIC CELLS (CaPVax)
FOR THE TREATMENT OF METASTATIC HORMONE REFRACTORY PROSTATE
CANCER
1. OVERVIEW OF CAPVAX PHASE I CLINICAL TRIAL .................................. 3
2. INTRODUCTION................................................................ 5
3. OBJECTIVES.................................................................. 16
4. PATIENT ELIGIBILITY......................................................... 16
5. TREATMENT PLAN.............................................................. 18
6. PRE-TREATMENT EVALUATION.................................................... 19
7. ON STUDY EVALUATION (SEE APPENDIX A FOR SCHEDULING)......................... 20
8. PATIENT DISCONTINUATION .................................................... 24
9. CONCOMITANT MEDICATIONS .................................................... 24
10. ADVERSE EVENTS ............................................................. 25
11. CRITERIA FOR DISEASE EVALUATION AND ENDPOINTS .............................. 28
12. STATISTICAL CONSIDERATIONS ................................................. 29
13. INVESTIGATOR OBLIGATIONS ................................................... 31
14. ADMINISTRATIVE CONSIDERATIONS .............................................. 32
15. REFERENCES ................................................................. 34
APPENDIX A: STUDY DIAGRAM ...................................................... 40
APPENDIX B: PERFORMANCE STATUS ................................................. 41
APPENDIX C: SKIN TESTING PROCEDURE ............................................. 42
APPENDIX D: QUALITY OF LIFE QUESTIONAIRE ....................................... 44
APPENDIX E: BRIEF PAIN INVENTORY ............................................... 47
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APPENDIX F: PATIENT REGISTRATION FORM........................................... 49
APPENDIX G: NPCP CRITERIA....................................................... 51
APPENDIX H: OFF STUDY FORM...................................................... 53
APPENDIX I: OFF STUDY PATIENT RE-ENTRY FORM..................................... 54
APPENDIX J: LEUKAPHERESIS PROCEDURE INFORMATION................................. 55
APPENDIX K: INFORMED CONSENT.................................................... 57
APPENDIX L: NCI COMMON TOXICITY CRITERIA ....................................... 61
APPENDIX M: TOXICITY MODULE .................................................... 64
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1. OVERVIEW OF CaPVax PHASE I CLINICAL TRIAL
OBJECTIVE:
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The purpose of this study is to assess the safety of and to monitor patient
response to CaPVax, mature, autologous dendritic cells (DC) loaded ex vivo with
recombinant prostate specific membrane antigen (rPSMA; Medarex Corporation,
Annandale, NJ), in the treatment of patients with metastatic, hormone refractory
prostate cancer (HRPC).
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ELIGIBILITY:
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1. Histologic proof of prostate carcinoma, progressing hormone refractory
disease after antiandrogen withdrawal trial, in the presence of castrate
serum testosterone levels (<30 ng/dl). Hormone therapy, with the
exception of antiandrogens, to maintain androgen ablation must continue
(e.g. Luteinizing hormone-releasing hormone (LHRH) agonists).
Progression can manifest itself as:
a) A 50% increase in prostate specific antigen (PSA) level from the
nadir PSA level confirmed twice and measured at least two weeks
apart,
b) new bone lesion on bone scan, or
c) progression of soft tissue disease as evidenced by standard
radiographic methods i.e. CT or MRI.
2. Age greater than 18 years old, life expectancy of at least 1 year,
Zubrod performance status: 0-1.
3 Patients must have limited bone disease, if any, less than/equal to 3
metastatic lesions on bone scan, and minimal symptoms.
4 Adequate hematological function, i.e. Hemoglobin > 12.5mg/dl, ALC >
500/MM(3), ANC>1,000/mm(3), Platelets > 150,000/mm(3)
5. Adequate hepatic and renal functions, i.e. bilirubin < 1.5mg/dl,
SGOT/SGPT < 2 times the upper limit of normal, and serum creatinine
< 2.5mg/dl.
6. Patients must not have received prior chemotherapy, radiation therapy
for metastatic disease, including Strontium-89, or other investigational
therapy.
7 Patients who received any immunosuppressives, such as Prednisone,
Hydrocortisone, or Ketoconazole in the four (4) weeks prior to
enrollment into the study are not eligible.
8. Patients with brain metastases, uncontrolled heart, liver or renal
diseases, or other serious intercurrent illness (including known HIV or
hepatitis positive) are not eligible. Patients with prior splenectomy,
history of severe asthma, anaphylaxis or other serious adverse reactions
to vaccines are not eligible. Patients with autoimmune disease such as
rheumatoid arthritis, systemic lupus erythematosus, scleroderma,
polymyositis-dermatomyositis, juvenile onset insulin dependent diabetes
or vasculitis are not eligible.
9. Patients with a positive protein purified derivative (PPD) skin test or
history of
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previous bacillus Calmette-Guerin (BCG) vaccination, Tuberculosis (TB)
exposure, or adverse reactions to vaccines or skin tests are not
eligible.
10. Patients may not take any medication that may affect immune function,
with the following exceptions: nonprescription strength doses of
non-steroidal anti-inflammatory drugs (NSAIDS), acetaminophen or
aspirin, low doses of antihistamine therapy, normal range doses of
vitamins and H2 blockers.
11. Signed informed consent, in keeping with the institutional policies,
indicating that the patient is aware of the investigational nature of
this study. The consent form is appended to this protocol.
TREATMENT PLAN:
Peripheral blood mononuclear cells (PBMC) are isolated by leukapheresis from the
patient. These cells are cryopreserved for further ex vivo expansion. Adherent
cells are then cultured in with Interleukin-4 (IL-4; Schering-Plough
Corporation, Madison, NJ) and Leukine(R), also known as granulocyte-macrophage
colony-stimulating factor (GM-CSF; Immunex Corporation, Seattle, WA) to generate
DC. Heat-inactivated BCG (Organon Teknika, Durham, NC) mycobacteria is added to
the dendritic cell cultures to facilitate maturation of the cells and to enhance
a carrier immune response. The DC are loaded with rPSMA. Patients receive four
treatments at monthly intervals (26-32 days) of 5 million, 10 million, or 20
million rPSMA-loaded mature, autologous DC (CaPVax) by intradermal injection
followed by 2 hours of close observation.
STATISTICAL CONSIDERATION:
Please refer to Section 12.0
PATIENT EVALUATION: (Pretreatment and Interim Testing)
A complete history and physical exam to include performance status, recent
weight loss, concurrent nonmalignant disease and therapy is performed prior to
entry into study and every month A skin prick test panel with control and 3
common recall antigens to be read at 15 minutes after inoculation for
immediate-type hypersensitivity and reevaluated at 48 hours after
administration. Laboratory studies at study entry shall include CBC,
differential, platelets, urinalysis, sodium, potassium, chloride, bicarbonate,
BUN, creatinine, magnesium, calcium, phosphorus, glucose, SGPT, total bilirubin,
albumin, total alkaline phosophatase, lactate dehydrogenase, PSA, prostatic acid
phosphatase (PAP), and testosterone. A bone scan, chest x-ray, CT of the abdomen
and pelvis and EKG are performed at screening. Repeat evaluation including
complete history and physical exam, performance status, recent weight loss, CBC,
differential, platelet count, urinalysis, sodium, potassium, chloride,
bicarbonate, BUN, creatinine, magnesium, calcium, phosphorus, glucose, SGPT,
total bilirubin, albumin, total alkaline phosophatase, lactate dehydrogenase,
PSA, PAP, ESR, and ANA are performed at various intervals throughout the study
(see Appendix A, Study Diagram). Bone scan, chest x-ray, and CT scan of abdomen
and pelvis are repeated eight weeks after the last
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injection (week 20) and six weeks following the week 20 visit (week 26).
ESTIMATED ACCRUAL:
It is estimated that accrual will be 10-15 participants per month. The total
accrual is 60 patients, 30 patients at each study center.
LENGTH OF STAY:
This is an outpatient regimen.
RETURN VISITS: (HOW OFTEN MUST PARTICIPANTS VISIT THE PRINCIPAL INVESTIGATOR'S
SITE)
Patients will be seen as outpatients every 2-4 weeks.
HOME CARE: (SPECIFY WHAT (IF ANY) TREATMENT MAY BE GIVEN AT HOME)
Please refer to Section 9.0, Concomitant Medications
NAME OF SPONSOR/FUNDING SOURCE:
Northwest Biotherapeutics, Inc., Seattle, Washington.
2. INTRODUCTION
2.1 REVIEW OF PROSTATE CANCER
Prostate cancer is the most common form of cancer currently diagnosed in
American men. In 1999, 179,300 new cases are expected to be diagnosed with
37,000 deaths resulting from the disease, making prostate cancer second only to
lung cancer as the leading cancer cause of death among men in the United States
[1].
Although the majority of incident prostate cancer cases are localized to the
prostate, nearly a third of all newly diagnosed prostate cancer patients may
present with locally advanced or metastatic disease [1]. At this time,
available treatments for metastatic prostate cancer -- including hormonal,
chemotherapeutic, and radiation strategies -- have failed to demonstrate
curative potential [2]. In addition, prostatectomy and radiation therapy--the
standard therapies employed against early-stage, localized prostate cancer--can
exhibit failure rates between 20 and 50% [3]. As a result, an ever-increasing
number of treated patients accumulate who either manifest metastatic disease or
are at very high risk for the development of such disease. The treatment
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options for these primary treatment failures, as with the primary metastatic
cases, are few in number and severely limited in terms of safety and efficacy.
Hormonal treatment of metastatic prostate cancer has improved only marginally
because nearly all cases ultimately result in hormone refractory disease.
Although there are occasional dramatic and long term disease-free survivors with
hormonal therapy, the median survival range of these particular patients remains
at 2 1/2 - 3 years [4, 5]. Once hormonal therapy fails, there are no curative
options and few options for pain relief. No cytotoxic agent has been able to
change consistently the natural history of HRPC. The median survival of HRPC is
less than one year and no agent has yet been shown to improve the median
survival of such patients. There is a great need for new treatment modalities
that can be given safely with a potential to improve the late stage life of the
37,000 men who are estimated to die of the disease in 1999 [1].
2.2 TUMOR SPECIFIC IMMUNOTHERAPY
One alternative to widely used conventional cancer treatments is to utilize the
ability of the immune system to target and eliminate tumor cells. The potential
therapeutic benefit of eliciting an anti-tumor immune response in cancer
patients was first suggested over a decade ago when the direct association
between immunosuppression and increased incidence of melanoma was initially
observed. The original tumor vaccines consisted of irradiated, allogeneic
melanoma cells. Some patients enjoyed prolonged survival following treatment,
although high serum IgM titers were elicited which reacted with cell membrane
antigens and likely decreased clinical responses. In a phase II report, Morton
et al. treated 136 patients with a vaccine consisting of 3 melanoma lines
expressing large amounts of melanoma-associated antigens. Overall survival
increased in several patients, and correlated with a positive skin test against
the immunogen [6].
New strategies for tumor immunotherapy are designed to increase tumor vaccine
immunogenicity, resulting in enhanced specific T cell responses. Some procedures
involve genetically altered tumor vaccines; introducing genes coding for
cytokines, costimulatory molecules, or components of the major
histocompatibility complex (MHC) into tumor cells [7, 8].
Conversely, other approaches to tumor vaccination utilize altered autologous
antigen-presenting cells to present tumor associated antigens [9, 10]. Since the
mechanism of the molecular events involved in immune recognition is now
elucidated, new and exciting strategies in anticancer therapeutics are emerging.
Researchers now understand some of the crucial portions of primary and secondary
signaling pathways that are activated when T and B lymphocytes produce an immune
response to a tumor cell [reviewed in 11-13]. T cell recognition of antigen
requires the formation of a trimolecular complex comprised of: 1) the major
histocompatibility complex (MHC); 2)
16
the T cell receptor (TCR); and 3) a short segment of intracellularly-processed
protein associated with the MHC. Antigen presentation of cell-surface peptides
to T cells can occur in association with either MHC class I or II molecules; the
former associated with CD8+ T cell responses (usually cytolytic T cells [CTL]),
and the latter associated with CD4+ T cell responses (usually helper T cells
[TH]). Since most tumors do not express MHC class II, it is generally accepted
that the enhancement of CD8+ mediated immune responses is of paramount
importance in anti-cancer immunotherapeutics. Tumor specific proteins are
proteolytically cleaved into fragments of 8-12 amino acids in length, the
peptides are presented on the cell surface in association with MHC class I, and
the complex is recognized by the TCR of naive T cells [11, 13].
Significant progress in the discovery and characterization of tumor-associated
antigens (TAA), beginning with the identification of melanoma antigen (MAGE)
earlier in this decade, is evident [14, 15]. Intensive research into these
moieties as potential targets of immune-based cancer treatment is continuous.
These TAA targets can be classified into four general groups:
1. "Cancer/testis" antigens, including the MAGE gene family
[16-21], whose expression in normal tissues is limited to testis
and whose genes have been mapped to the X chromosome;
2. Antigens derived from viruses such as Human Papilloma Virus [22,
23] and Epstein-Barr Virus [24];
3. Differentiation antigens such as PSA [25, 26], prostate-specific
membrane antigen (PSMA) [27-29], Melan-A/MART-1 [30], and gp100
[31],
4. Antigens existing in a modified or mutated state in tumors as
compared to normal tissue, such as ras [32, 33] and p53 [34,
35].
Favorable results continue to be reported as compared with standard treatments
such as chemotherapy and radiotherapy, and so hold promise for decreasing
patient mortality.
2.3 CAPVAX: A DENDRITIC CELL/RECOMBINANT PROSTATE SPECIFIC MEMBRANE ANTIGEN
IMMUNOTHERAPY FOR PROSTATE CANCER
CaPVax is an autologous cellular immunotherapy being studied for the treatment
of hormone refractory metastatic prostate cancer. CaPVax is based on mature
autologous DC loaded ex vivo with rPSMA. The rPSMA-DC are prepared ex vivo
wherein the patient's leukapheresed peripheral blood mononuclear cells (PBMC)
are processed in a 7-day incubation procedure, including an overnight incubation
period with inactivated
17
BCG and same-day osmotic loading with rPSMA. This methodology produces mature
rPSMA-loaded autologous DC that are then injected back into the patient. The
pharmacologic rationale for CaPVax is to elicit a potent anticancer T cell
response as a result of the efficient presentation by the DC of rPSMA in the
form of a complex of antigen and MHC molecules to T cells. The goal is to elicit
a specific antigen-specific immune response in HRPC patients.
2.3.1 PROSTATE SPECIFIC MEMBRANE ANTIGEN
PSMA is a 750 amino acid type II transmembrane membrane glycoprotein containing
10 potential N-linked glycosylation sites [36]. PSMA is composed of a 19 amino
acid intracellular portion, a 24 amino acid transmembrane portion, and a 707
amino acid extracellular portion [37].
The expression of PSMA in human tissues has been extensively studied [27, 36,
38-40]. Evidence from immunohistochemical studies using the anti-PSMA antibody
7E11.C5 indicates that PSMA is highly, but not exclusively, specific for
prostatic epithelial cells [29, 36, 38, 40-41]. Immunohistochemical and Western
blot studies indicate weak but detectable PSMA expression in salivary gland,
brain, and small intestine [27, 36, 39, 42]. In contrast, these studies
confirmed the highest expression of PSMA in prostatic tissues. Similarly,
results from ribonuclease protection assays utilizing prostatic and 11 other
human tissue types indicated strong prostatic expression and weak expression in
brain and salivary tissues. In collaboration with Hybritech, Inc. (San Diego,
CA), quantitative ELISA assays were performed for PSMA presence in the membrane
and cytosol fractions of a variety of tissues. Results again point to the high
degree of prostate specificity of PSMA (Table 1).
TABLE 1: PSMA LEVELS IN HUMAN TISSUE SPECIMENS
--------------------------------------------------------------------------------------------------------------
TISSUE PROTEIN (mg/ml) PSMA (ng/ml) PSMA/PROTEIN x 10(-6)
--------------------------------------------------------------------------------------------------------------
PROSTATE (NORMAL)
Membrane 10.2 10,492 1,029
Cytosol 7.8 138 18
--------------------------------------------------------------------------------------------------------------
PROSTATE (BENIGN)
Membrane 7.7 4,701 611
Cytosol 9 267 30
--------------------------------------------------------------------------------------------------------------
PROSTATE (CANCER)
Membrane 19.6 69,789 3,561
Cytosol 11.3 718 64
--------------------------------------------------------------------------------------------------------------
BREAST (NORMAL)
Membrane 3.8 79 21
Cytosol 2.9 1.1 0.4
--------------------------------------------------------------------------------------------------------------
BREAST (CANCER)
Membrane 20.4 884 43
Cytosol 11.6 23.5 2
--------------------------------------------------------------------------------------------------------------
18
--------------------------------------------------------------------------------------------------------------
TISSUE PROTEIN (mg/ml) PSMA (ng/ml) PSMA/PROTEIN x 10 (-6)
--------------------------------------------------------------------------------------------------------------
SMALL INTESTINE 4.5 4.6 1
--------------------------------------------------------------------------------------------------------------
LARGE INTESTINE
Membrane 8.6 71.3 8.3
Cytosol 6.2 2.3 0.4
--------------------------------------------------------------------------------------------------------------
KIDNEY
Membrane 17.2 31.5 1.8
Cytosol 10.9 0.7 0.1
--------------------------------------------------------------------------------------------------------------
OVARY
Membrane 4.8 244 51
Cytosol 6.4 21.3 3.3
--------------------------------------------------------------------------------------------------------------
LIVER
Membrane 24.1 64.3 2.7
Cytosol 18.9 1.9 0.1
--------------------------------------------------------------------------------------------------------------
BONE
Membrane 8.5 21.7 2.6
Cytosol 3.4 0.9 0.3
--------------------------------------------------------------------------------------------------------------
SKIN
Membrane 2.1 17 8.1
Cytosol 6.2 2.3 0.4
--------------------------------------------------------------------------------------------------------------
Detailed studies of PSMA expression in prostatic tissues were conducted on 184
whole mount step-sectioned prostate specimens after radical prostatectomy [38].
In this study, intense immunoreactivity for PSMA with 7E11.C5 was observed in
all cases. The mean number of cells staining in benign epithelium and prostatic
intraepithelial neoplasia (PIN) was lower than in adenocarcinoma. Staining was
highly specific for epithelial cells and adenocarcinomas were most intensely
stained with the highest grade cancers showing intense staining of almost every
cell. This observation is consistent with biochemical studies showing that PSMA
mRNA expression is downregulated by steroids such as
5-(alpha)-dihydrotestosterone and is upregulated by BFGF, TGF-(alpha), and EGF
[27]. This behavior corresponds to the elevated expression of PSMA in hormone
refractory tumors. Thus, its expression patterns from normal tissue to advanced
cancer makes PSMA a very useful marker for treatment and prediction of outcome
in patients with prostatic cancer.
In summary, these studies combine to indicate that PSMA is an excellent target
for immunotherapy, having the required tissue specificity. For this phase I
clinical trial rPSMA is contract manufactured through Medarex, Inc. (Annandale,
NJ).
2.3.2 DENDRITIC CELL-BASED IMMUNOTHERAPY
T cells are the major immune system component largely responsible for the
recognition and destruction of tumor cells based on expression of specific
tumor-associated antigens. As the specific mechanisms underlying the immune
response were revealed, this information was utilized to elicit or amplify
antitumor immune response.
19
T cell immune responses begin with the interaction of the T cell receptor with
antigenic peptides bound to MHC proteins. If this interaction is accompanied by
binding of costimulatory receptors (e.g. CD28) to their ligands (CD80 and CD86),
then an intracellular cascade of biochemical events is triggered that results in
T cell activation and proliferation. Activated T cells are able to lyse target
cells, e.g. tumor cells, which express the stimulating antigen and the
appropriate MHC protein. Antigen-presenting cells are specialized cells that
express the required molecules involved in T cell activation events. DC are
considered the most potent antigen presenting cell (APC), capable of initiating
primary T cell responses [11-13, 43,44].
DC express high levels of MHC class I and II molecules, as well as abundant
levels of costimulatory factors. In their immature state, they display
phagocytic and macropinocytotic activity. As they mature, surface receptors
involved in antigen uptake undergo down-regulation. Concurrently, DC enhance
their ability to process and present antigen to naive T cells. DC stimulate
naive T cells to become antigen-specific effectors more effectively than any
other APC, and they do so following their migration to primary lymphoid tissue
where such T cells are predominantly located [45]. The ability of each dendritic
cell to stimulate as many as 100 T cells in vitro provided the scientific
rationale for our approach using the adoptive transfer of DC.
DC are found in low abundance in various tissues, and obtaining sufficient
numbers of DC from prostate cancer patients can be difficult in light of the
patients' past cancer therapy, which may have compromised their immune system.
DC were successfully isolated and cultured from PBMC from such prostate cancer
patients [46]. After incubation of adherent PBMC in the presence of Leukine(R),
and IL-4 (each 500 U/mL) for 7 days, the majority of cells have dendritic
morphology and possess cell surface markers characteristics of DC (CD3(-),
CD14(-), CD19(-), CD1a(+), CD4(+), CD11c(+), and HLA-DR(+)) [46]. These culture
methods allow for ex vivo expansion of autologous DC from tumor-bearing patients
in sufficient numbers for use in immunotherapeutic studies. Autologous DC are
charged with tumor antigens, and introduced back into patients as a cancer
vaccine. Several clinical trials involving readministration of autologous DC
pulsed with tumor antigens have been conducted with positive clinical outcomes
(Table 2).
The majority of the trials are for the treatment of several different types of
malignancy with a single exception treating HIV. The only consistent finding
from all the reports is the absence of serious adverse reactions. Regardless of
the route of injection, dose or source of antigen, administration of DC is well
tolerated and does not induce autoimmune disease [47]. The only adverse events
that have been reported are mild fever and swelling of the lymph node when cells
are introduced intranodally.
From the clinical trials reported to date, it is difficult to reach a consensus
on any variable, such as dose, route of administration, antigen, etc., other
than safety because
20
of the large differences in trial design. It is also uncertain the extent to
which the DC immunotherapy is therapeutic because the number of patients treated
thus far is small. However, the responses reported thus far are encouraging and
warrant further investigation.
TABLE 2: SUMMARY OF CLINICAL TRIALS UTILIZING DC
---------------------------------------------------------------------------------------------------------------------------
NUMBER OF ROUTE OF NUMBER OF ADVERSE CLINICAL
DISEASE ANTIGEN PATIENTS ADMINISTRATION DC REACTIONS RESPONSE
---------------------------------------------------------------------------------------------------------------------------
B Cell Tumor 4 i.v.* 2-32 million None 3
Lymphoma(9) Specific Responders
Idiotype
---------------------------------------------------------------------------------------------------------------------------
CEA Expressing CEA Peptide 11 i.v. 10-30 None 2
Tumors[47] million Responders
8 i.v./i.d.** 100 million/
1 million
---------------------------------------------------------------------------------------------------------------------------
Prostate PSMA 95 i.v. 5-30 million None 28
Cancer[48-49] Peptides Responders
---------------------------------------------------------------------------------------------------------------------------
Melanoma Tumor Lysate 16 Intranodal 1 million None 5
or MAGE Responders
peptides
---------------------------------------------------------------------------------------------------------------------------
HIV[51] Gp 160 or 6 i.v. None No
Env, gag and Responders
pol peptides
---------------------------------------------------------------------------------------------------------------------------
Renal Cell Tumor Lysate 4 i.v. 5-10 None 1
Carcinoma[52] million Responder
---------------------------------------------------------------------------------------------------------------------------
Multiple Tumor 12 i.v. 0.5-11 None 3
Mylemona[53] Specific million Responders
Idiotype
---------------------------------------------------------------------------------------------------------------------------
* Intravenous administration
** Intradermal administration
2.3.3 DC LOADED WITH PSMA ACTIVATE ANTIGEN SPECIFIC CD4(+) AND CD8(+)
T CELLS FROM PROSTATE CANCER PATIENTS
The ability of DC from prostate cancer patients to activate autologous T cells
was evaluated in vitro. Prostate cancer patients' DC were loaded with PSMA
using methods to enhance immunologic potency: 1) inclusion of inactivated BCG
mycobacteria to elevate CD83 and CD86 expression on the DC; and 2) osmotic
loading using hypertonic medium to promote the engulfing of exogenous PSMA.
DC from several prostate cancer patients were loaded with rPSMA or PSMA
purified from LNCaP cells (LnPSMA). The LNCaP cell line was derived from a
needle aspiration biopsy of the left supraclavicular lymph node of a man with
confirmed metastatic prostate adenocarcinoma and expresses several prostate
specific characteristics, including expression of PSMA. The DC were osmotically
loaded with either LnPSMA or
21
rPSMA in the presence of BCG. These PSMA loaded DC were then co-cultured with
autologous PBMC. The T cells stimulated by the DC during the 10 day co-culture
were isolated and co-cultured a second time with PSMA loaded autologous DC.
Beginning seven days after the second co-culture, T cell reactivity to PSMA was
determined on a weekly basis using an enzyme-linked immunoadsorbent assay
(ELISA) to measure interferon-(greek gamma) (IFN((greek gamma)) secretion. At
various time-points, most of the patients' T cells studied had reactivity to
PSMA. In one typical assay, PSMA-specific T cells were generated from the PBMC
of patient 105 (Figure 1). Three in vitro stimulations with DC loaded with
either LnPSMA or rPSMA were performed. Following this, T cells were reactive
with autologous DC osmotically loaded with either LnPSMA (Figure 1a) or rPSMA
(Figure 1b). Both rPSMA and LnPSMA loaded DC that were matured with BCG produced
activated, antigen specific T cells.
In another experiment, DC were loaded with different amounts of LnPSMA to
define the optimum amount of antigen for T cell stimulation (Figure 2). Two
different concentrations of DC (2 x 10)(7) or 1 x 10(7)) were osmotically
loaded with 15 to 60 ug PSMA in a 0.2 mL volume. (~75-300 ug/mL). 1 x 10(7) DC
were osmotically loaded with 60 ug ovalbumin (OVA) in a 0.2 mL volume (~300
ug/mL) as a specificity control. These DC were mixed with autologous
PSMA-reactive T cells. Cultured T cells were washed and added to 96-well plates
at 5 x 10(4) cells/well in duplicate. Autologous DC pulsed with PSMA, OVA, or
unpulsed were added to the autologous T cells at 5 x 10(4) cells/well. After 24
hours incubation, 150 ul of supernatant was removed from each culture. An ELISA
using paired antibodies from the manufacturer (Endogen, Inc. , Woburn, MA)
measured the amount of IFN(greek gamma) present. When 1 x 10(7) DC were loaded
with PSMA, IFN(greek gamma) secretion was observed maximally with 30 ug PSMA.
When 2 x 10(7) DC were loaded with PSMA, a slight dose-dependent decrease in
IFN(greek gamma) secretion was observed with minimum IFN(greek gamma) secretion
at 60 ug PSMA. However, the amount of IFN(greek gamma) secretion was greater -
and more highly specific - when 2 x 10(7) versus 1 x 10(greek gamma)(7) DC were
loaded with PSMA. Therefore, we chose to load 30ug PSMA in order to achieve
strong immunoreactivity.
In a subsequent experiment, a constant amount of LnPSMA (60 ug) was osmotically
loaded into various concentrations of DC - from 2 x 10(6) to 2 x 10(7) - to
define the optimum number of DC (per a given amount of antigen) for T cell
stimulation (Figure 3). Four different concentrations of DC were osmotically
loaded with LnPSMA as before in a 0.2 mL volume. DC were osmotically loaded with
60 ug ovalbumin (OVA) in a 0.2 mL volume as a specificity control. These DC were
mixed with autologous PSMA-reactive T cells. IFN(greek gamma) secretion was
measured after 24 hours. Standard ELISAs were performed to assess IFN(greek
gamma) secretion. Immunoreactivity was comparable, regardless of the amount of
DC; a true dose-dependent effect of DC concentration of IFN(greek gamma)
secretion was not observed. This assay demonstrated that 2 x 10(7) DC could be
loaded with a LnPSMA concentration nearly approximating that used in our
clinical methodology.
22
We propose to include inactivated BCG in the final 18-24 hours of dendritic cell
culture because of its ability to stimulate maturation of DC and thereby to
enhance T cell activation. BCG treatment upregulates the expression of several
surface molecules crucial to the enhanced function of a dendritic cell as an
APC, including CD40, CD54, CD80, CD83 and CD86 (Figure 4).
[Figure 1: Specific cytokine secretion by PT 105 T cells stimulated with PSMA
osmotically loaded into BCG-treated DC.]
[Figure 2: Specific cytokine secretion by PT 112 T cells stimulated with
BCG-treated DC osmotically loaded with PSMA.]
[Figure 3: Specific cytokine secretion by PT 66 T cells stimulated with
BCG-treated DC.]
[Figure 4: Dendritic cell characterization.]
23
3. OBJECTIVES
The primary objective of this study is to assess the safety of immunization with
CaPVax, mature autologous DC loaded with rPSMA, in the treatment of patients
HRPC. The secondary objective is to monitor the potential clinical response of
administering CaPVax.
The study hypotheses represent primary objectives. Each primary objective is
addressed by endpoint measures which provide objective criteria for evaluating
the hypothesis. Secondary objectives are addressed with statistical methods that
evaluate other benefits of treatment.
3.1 STUDY HYPOTHESIS AND ENDPOINTS
HYPOTHESIS 1: Serious adverse events (AEs) which are either probably or possibly
related to treatment with CaPVax injections will rarely occur among study
subjects.
ENDPOINT 1: A subject is coded as having experienced a serious AE provided at
least one of the AEs listed in Section 10.2 occurs anytime during the study
period. The AE must be at least possibly related to treatment, as defined in
Section 10.1.
HYPOTHESIS 2: As a result of treatment, a significant proportion of patents will
experience either a partial or a complete response to their HRPC.
ENDPOINT 2: A patient is coded as having a partial or a complete response
provided he satisfies the "response evaluation" criteria defined in section
11.2.
4. PATIENT ELIGIBILITY
4.1 INCLUSION CRITERIA
1. Histologic proof of prostate carcinoma, progressing hormone
refractory disease after antiandrogen withdrawal trial, in the
presence of castrate serum testosterone levels (<30 ng/dl).
Progression can manifest as:
- A 50% increase in PSA level from the nadir PSA level
confirmed twice and measured at least two weeks apart;
- new bone pain, or new lesion on bone scan; or,
- progression of soft tissue disease as evidenced by standard
radiographic methods of evaluation, i.e. CT or MRI.
24
Hormone therapy, with the exception of antiandrogens (e.g. LHRH)
to maintain androgen ablation must continue.
2. Age greater than 18 years old.
3. Life expectancy of at least 1 year.
4. Zubrod or Eastern Cooperative Oncology Group (ECOG) performance
status of 0-1.
5. Patients must have limited bone disease defined as less than or
equal to 3 metastatic sites on a bone scan and minimal symptoms.
6. Adequate hematological function i.e. Hemoglobin > 12.5mg/dl,
absolute lymphocyte count (ALC) > 500/ mm(3), absolute neutrophil
count (ANC) > 1,000/mm(3), Platelets> 150,000/mm(3).
7. Adequate hepatic and renal functions, i.e. bilirubin < 1.5mg/dl,
SGOT/SGPT < 2 times the upper limit of normal, serum creatinine <
2.5mg/dl, or creatinine clearance > 50ml/min.
8. Signed informed consent before any study procedure, keeping with
the institutional policies, indicating that the patient is aware
of the investigational nature of this study. The consent form is
appended to this protocol (see Appendix K).
4.2 EXCLUSION CRITERIA
1. History of prior malignancy other than prostate cancer, clinically
evident within the 24 months preceding enrollment into the study,
except curatively-treated basal cell or squamous cell carcinoma of
the skin.
2. Patients must NOT have received prior chemotherapy, radiation
therapy for metastatic disease, including Strontium-89, or other
investigational therapy that may result in a compromised immune
system.
3. Patients who received any immunosuppressives such as Prednisone,
Hydrocortisone, or Ketoconazole in the four weeks prior to
enrollment in the study are not eligible.
25
4. Patients with brain metastases, uncontrolled heart, liver or renal
diseases, or other serious intercurrent illness (including known
HIV or hepatitis positive) are NOT eligible.
5. Prior splenectomy.
6. History of severe asthma, anaphylaxis or other serious adverse
reactions to vaccines or any of the antigens included in the skin
test.
7. History of immunodeficiency or autoimmune disease such as
rheumatoid arthritis, systemic lupus erythematosus, scleroderma,
polymyositisdermatomyositis, Juvenile onset insulin dependent
diabetes, or vasculitis.
8. Impending untreated spinal cord compression or urinary outlet
obstruction.
9. Patients with a positive2-step Purified Protein Derivative (PPD)
skin test or history of previous BCG vaccination or Tuberculosis
(TB) exposure.
10. Positive virology screening test (Hepatitis B surface Antigen
(HbsAg), Anti-Hepatitis core Antigen (a-HBc), Liver enzyme
(ALT)-surrogate marker for non A, B, C hepatitis virus, Anti-HIV 1
Antibody (a-HIV-1), Anti-HIV 2 Antibody (a-HIV-2), Anti-human T
lymphotropic virus 1(a-HTLV-1), Syphilis, HIV Antigen (HIV-1
p24Ag), Anti-Hepatitis C Virus (a HCV)).
11. Patients may NOT take any medication that may affect immune
function, with the following exceptions: nonprescription strength
doses of NSAIDS, acetaminophen or aspirin, low doses of
antihistamine therapy, normal range doses of vitamins and H2
blockers.
5. TREATMENT PLAN
PBMC are isolated by leukapheresis from the patient before treatment begins. An
aliquot of these cells is cryopreserved for further ex vivo culture. After
thawing and culturing PBMC, adherent cells are cultured ex vivo for six days
with IL-4 and Leukine(R) to generate DC. Inactivated BCG is added to the
dendritic cell cultures to facilitate maturation of the cells and to stimulate a
strong carrier immune response after intradermal administration. Eighteen to
twenty-four (18-24) hours after BCG treatment, rPSMA is added under hypertonic
conditions. Patients receive four injections of 5 million, 10 million, or 20
million rPSMA loaded autologous DC by intradermal injection [one dose is
administered every month (26-32 days)]. Each patient is observed for 2 hours
after administration. Some patients may need to have a second leukapheresis
(between 4-12 weeks after the first one), depending on the yield of the first
leukapheresis and ex vivo expansion.
26
The interval one month (26-32 days) between injections was selected to avoid
excess loss of any beneficial immunological response. Four injections were
selected to achieve sufficient restimulations to generate a maximum T cell
response.
At the study center, all CaPVax injections are given intradermally into one
thigh followed by intradermal injections in alternating thighs at subsequent
injections (refer to section 7.5.2). Three patients are enrolled first in the 5
x 10(6) DC dose level. If no adverse reactions occur 48 hours after the first
injection, the dose will be escalated to 10 x 10(6) DC in another three
patients. If no adverse reactions occur 48 hours after the first injection,
three patients are enrolled at the highest dose, 20 x 10(6) DC. The rest of the
patients are randomized for one DC dose level such that there are 10 patients
per dose level at each study center (see section 12 for sample size
considerations).
If there is evidence of an AE in at least one patient in any dose level, then
the committee for AEs determines if this is a favorable response or an AE
(please refer to Section 10). If it is determined that it is an AE, then 3 more
patients are enrolled at that same dose before escalation to a higher dose.
6. PRE-TREATMENT EVALUATION
6.1 SCREENING
Screening of patients for participation in this clinical trial takes place
within 4 weeks prior to enrollment in order to verify that each patient meets
all study criteria (see section 4.0). Patients failing the initial screening due
to out of range laboratory values may be rescreened at the investigator's
discretion. All patients screened should be documented using a screening log.
Each patient enrolled in the study must sign the consent form (see Appendix K)
and fill out a patient registration form (see Appendix F).
6.1.1 PROCEDURES AND TESTS
Prior to the first vaccination, Day 1, the following procedures and tests are
performed or administered (see Appendix A):
1. The patient's medical history and complete physical examination
including vital signs, height and weight, and Zubrod performance
score (see Appendix B).
2. A skin prick test panel provided by the sponsor with control and 3
common recall antigens (Candida Albicans, Mumps, PPD). These tests
are read at 15 minutes after inoculation for immediate-type
hypersensitivity to any of the antigens and approximately 48-72
hours after administration for delayed type hypersensitivity
(DTH). Palpable indurations of 5mm or more indicate a positive
reaction. The
27
absence of induration less than 5mm is considered negative. The
widest diameter of distinctly palpable induration is measured and
a Polaroid photograph will be taken (see Appendix C). The PPD skin
test is administered as a two-step test. If the first test is
negative, the test is repeated one week later to rule out any
false negative result. This ensures a PPD naive patient
population.
3. 12 lead EKG. EKG is read and the report signed by the
cardiologist.
4. Chest x-rays (PA and lateral views).
5. Blood and urine are collected for the following:
- Hematology (Complete blood count (CBC) &
differential);
- Blood Chemistry parameters (Chemistry 22) Chem-22
profile includes the following specific
measurements: sodium, potassium, chloride,
bicarbonate, BUN, creatinine, magnesium, calcium,
phosphorus, glucose, SGPT, total bilirubin, albumin,
total alkaline phosophatase, lactate dehydrogenase;
- Serum Markers (PSA & PAP);
- Serum Markers of autoimmune disease [Erythrocytic
sedimentation rate (ESR) and Antinuclear antibodies
(ANA)];
- Testosterone;
- Urinalysis with microscopic examination.
6.1.2 TUMOR IMAGING
Bone scan, Chest x-ray, and CT of the abdomen and pelvis are performed at
screening. Measurable disease is defined in Section 11.0. Follow up bone scan,
chest x-ray, and CT scans are repeated at Week 20 and Week 26.
6.1.3 ASSESSMENT OF PATIENT'S QUALITY OF LIFE (SEE APPENDIX D) AND BRIEF
PAIN INVENTORY (SEE APPENDIX E)
7. ON STUDY EVALUATION (SEE APPENDIX A FOR SCHEDULING)
7.1 LABORATORY PROCEDURES AND MEASUREMENTS
1. Routine Safety Laboratory Tests
28
- Safety-related hematology, blood chemistry, and
physical examinations are performed at various
intervals throughout the study. Testosterone level
and urinalysis are performed at screening and week
14 (see Appendix A, Study Diagram).
2. Hematology Parameters
- Hematology testing consists of CBC, differential,
and platelets.
3. Blood Chemistry Parameters (Chem-22)
4. Urinalysis with microscopic examination
5. Physical Examinations
- Physical examinations include monitoring vital signs
to observe a generalized systemic reaction,
examining the vaccination site for any local or
regional reaction, reviewing any quality of life
changes, and discussing degree of pain (see
Appendices D and E, respectively).
7.2 SPECIAL LABORATORY TESTS
1. Serum PSA is measured.
2. Serum PAP is measured.
3. Serum testosterone is measured.
4. Serum markers of autoimmune disease are measured (ESR and ANA).
7.3 IMMUNOLOGY DETERMINATIONS
The tests described in this section are performed at Northwest Biotherapeutics,
Inc. Blood for immune monitoring is drawn prior to the first leukapheresis,
prior to each injection, and at weeks 14, 20, and 26 (see Appendix A). PBMC are
isolated and utilized for the following immunological determinations:
1. Nonspecific immune response: stimulation of PBMC with anti-CD3
measured by proliferation;
29
2. BCG specific cellular response: stimulation of PBMC with
Tuberculin-purified protein derivative (PPD), a component obtained
from human strains of Mycobacterium tuberculosis, measured by
proliferation;
3. PSMA specific antibodies: measured in serum by ELISA;
4. PSMA specific cellular response: stimulation of PBMC by autologous
DC loaded with rPSMA measured by cytokine production (ELISA or
ELISPOT).
7.4 SKIN TESTS
1. Nonspecific cellular immune response: skin test using 2 additional
common recall antigens (Candida albicans, Mumps).
2. PPD specific DTH response: skin test using PPD.
7.5 TREATMENT DEFINITIONS
7.5.1 LEUKAPHERESIS AND BLOOD DRAW
Prior to beginning CaPVax immunotherapy, patients are leukapheresed at the
Apheresis Unit of the study center. Another leukapheresis may be performed
between the first and fourth treatments depending on the DC yield from the first
leukapheresis.
Prior to each leukapheresis, a blood work-up is done at the study center to
include CBC, platelet count, and Chem-22. Blood is drawn for immune monitoring
prior to the CaPVax injections and on follow-up at weeks 14, 20, and 26. The
blood is shipped to the sponsor.
7.5.2 CAPVAX INJECTIONS
Five, ten, or twenty million mature, autologous rPSMA-loaded DC are injected
intradermally in a shaved, clean area of the thigh. The CaPVax injections are
given in alternating thighs once every month (26-32 days) for a total of 4
treatment cycles.
Mature DC are defined as CD11c positive, CD14 negative cells as determined using
flow cytometry. The percentage of CD14 positive cells varies from patient to
patient and thus requires an adjustment in the number and volume of cells
injected to achieve the
30
originally planned dose of DC. The following is an example of how the injection
volume is determined:
FORMULA FOR CALCULATING INJECTION VOLUME:
Cell count per vial / 0.25mL = Cells per mL
Dose to be administered / Percent CD14 negative, CD11c positive cells = cell
number to inject
Cell number to Inject / cells per mL = Injection volume
FOR EXAMPLE:
If the cell count per vial is 10 x 10(6) and the percent CD14 negative, CD11c
positive cells is 67%, and the dose to be administered is 10 x 10(6) cells,
THEN:
10 x 10(6) (cells per vial) / 0.25mL = 40 x 10(6) cells per mL
10 x 10(6) / 0.67 = 14.9 x 10(6) = cell number to inject
14.9 x 10(6) / (40 x 10(6) cells per mL) = 0.37mL
Volume to inject = 0.37mL
Instructions for injection are provided with each shipment of CaPVax. Each
patient has lot specific injection instructions that is provided by the sponsor.
These instructions clearly indicate how much vaccine is injected. It is expected
that the number of injections given per dose of DC will not exceed 8 injections
for one round of treatment.
7.5.3 CLINICAL EVALUATION
Patients are evaluated every month by one of the study physicians. Aside from
the above listed blood tests, CBC and Chem-22 studies are obtained at every
interval. Physical examination at each follow-up visit is documented (see
Appendix A). Quality of life, pain score assessments, and monitoring for
autoimmune disease are evaluated as well.
7.5.4 TOXICITY MONITORING
Both acute and chronic toxicity are monitored. Monitoring for acute toxicity
takes place during and immediately following injection for a period of two
hours. Patients are
31
observed for the development of an immediate localized allergic reaction or
anaphylactic reaction during this time. Chronic toxicity is evaluated at the
monthly physical examination. Although the nature of chronic toxicity following
injection of CaPVax is unknown, physical examination, history, and quality of
life assessments are recorded along with all pertinent laboratory tests.
8. PATIENT DISCONTINUATION
8.1 OFF-STUDY CRITERIA
Patients who require other treatments for prostate cancer or for a complication
of the cancer (e.g. vertebral collapse) are taken off study. They will be
included in the follow-up analysis. Such patients are considered as failures and
will be followed by one of the participating physicians and the data center,
with information collected periodically.
Non-compliance with the protocol or a patient's refusal to continue with the
study are also reasons for discontinuation.
8.2 PATIENT DISCONTINUATION DUE TO SEVERE ADVERSE EVENT
See Section 10, Adverse Events.
9. CONCOMITANT MEDICATIONS
Medications taken by the patient within seven days prior to the first
vaccination and throughout the study is recorded on the appropriate case report
form. A potential patient is not eligible to enter the study if they are taking
any medication that may affect immune function, with the following exceptions:
- Patients may take doses of nonprescription strength NSAIDS,
acetaminophen, ibuprofen or aspirin for non-chronic headache,
muscle pain, trauma or prophylaxis as long as their dosing regimen
complies with the recommended dose as found on the product
label/package insert.
- Patients may receive antihistamine therapy for colds or allergies
at low doses.
- Patients must continue LHRH agonists, if they were on LHRH
agonists at the initiation of the trial.
- Patients may take vitamin supplements within a dose range not
associated with toxicity.
32
- Patients may take cimetidine or other H(2) blockers.
- Patients may receive a maximum of two short courses (not more than
10 days per course) of antibiotics for treatment of minor
infection, but not more frequently than twice in a 45 day span.
Any other medications that may affect immune function are contraindicated for
the duration of the patient's study participation. The same exceptions as above
apply during the study.
10. ADVERSE EVENTS
10.1 ADVERSE EVENT RECORDING
An objective of this study is to evaluate the safety of CaPVax. Therefore,
clinical AEs occurring during and after vaccine treatment must be recorded.
An AE is defined as any change in signs or symptoms, and may include a single
symptom or sign, a set of related symptoms or signs, or a disease. An AE must be
recorded even if it is unlikely to be causally related to the study drug.
Patients are instructed to report any AE to the investigator. On each day of
evaluation, the patient is questioned in a general way regarding any new medical
problems and new or changed medications. All AEs are documented in the source
document and on the AE form.
The intensity of all AEs not localized to the CaPVax injection site are graded
according to the National Cancer Institute (NCI) Common Toxicity Criteria (see
Appendix L). AEs that are considered by the investigator to be localized or
related to the injection site will be graded according to the Injection Site
Reaction section of the NCI Common Toxicity Criteria (see Appendix L).
The relationship to study treatment is characterized as not related, possibly
related, or probably related and is determined according to the following
guidelines:
PROBABLY RELATED: a direct cause and effect relationship between the
study treatment and the AE is likely;
POSSIBLY RELATED: a cause and effect relationship between the study
treatment and the AE has not been demonstrated at this time and is not
probable, but is also not impossible;
33
NOT RELATED: there is no question that the AE is definitely not
associated with the study treatment (comment on other etiology in
comments section of the clinical report form).
Any patients withdrawn from the study should have the end-of-study (week 14 or
week 20) procedures performed at that time, unless patient declines.
10.2 SERIOUS ADVERSE EVENT REPORTING
The Ambulatory Unit of the Principal Investigator's site is contacted during a
serious AE in order to determine the physician on call, who is notified and
apprised of the situation. A serious AE is defined as one of the following:
- Death
- An event which is life threatening. In the opinion of the
investigator, the patient was at immediate risk of death due to
the event as it occurred.
- An event which results in persistent or significant
disability/incapacity.
- An event which requires inpatient hospitalization or prolongs
hospitalization.
- A laboratory abnormality which meets any of the above criteria.
- An important medical event that, based upon appropriate medical
judgement, may jeopardize the patient or subject and may require
medical or surgical intervention to prevent one of the outcomes
listed above.
10.3 MANAGEMENT OF A BCG-RELATED ADVERSE EVENT
Repeated intradermal injection of attenuated BCG is safely used for the
treatment of bladder cancer (54), colon cancer (55, 56), prostate cancer (57),
and melanoma (58). Inactivated BCG is used in the production of CaPVax for the
purposes of maturing the DC ex vivo. However unlikely, inactivated BCG may
trigger a hypersensitivity reaction including symptoms of persistent fever or
skin ulceration. These adverse reactions will be treated as follows:
- Cold packs or topical steroid preparation may be used for
symptomatic relief of associated skin discomfort.
- For low grade fever (<39 degrees Celsius). Administer oral
paracetamol.
34
- For high grade fever (>39 degrees Celsius) perform all of the
following:
1. Draw blood for standard blood culture set (x 2).
2. Draw blood for Mycobacterial blood culture.
3. Test the residual sample of the CaPVax (i.e. DC vial
retained from previous vaccination) for: gram stain,
culture/sensitivity, AFB stain and culture, fungal
smear and culture.
4. Administer one gram (1g) of ampicillin every four
hours (IV).
5. Administer 5mg/kg of gentamicin daily (IV).
6. Or, if the patient is allergic to penicillin,
administer one gram (1g) of vancomycin every 12
hours and 5mg/kg of gentamicin (IV).
7. Administer three-drug antituberculous therapy: 300mg
of isoniazid once daily, 600mg rifampicin once
daily, orally, and ethambutol (15mg/kg) once daily.
8. Administer 100mg of hydrocortisone 4 times daily
(IV).
10.4 SERIOUS ADVERSE EVENT COMMITTEE
A designated committee is formed to evaluate any AEs. The committee is comprised
of a physician and nurse from the site, a physician from the sponsor, and the
sponsor's RA/QA Manager. The committee is responsible for handling any AEs that
may occur during the course of treatment. For instance, a patient develops a
severe local skin reaction after the second or third intradermal injection of
CaPVax. Regardless of the type of reaction (favorable immune response or
unfavorable adverse event) the committee determines the course of treatment, if
necessary, and the study status of the patient, i.e. is the patient able to
continue CaPVax therapy. If the patient is allowed to continue on-study, the
committee may decide to tailor the dose or modify the dose interval or remove
the patient from the study.
10.5 STOPPING CRITERIA
The dose level is discontinued if two serious adverse events are observed within
the first ten patients treated. These adverse events must be deemed by the
Serious Adverse Event Committee to be probably or possibly related to the study
drug.
35
If the dose level is discontinued due to two SAEs occurring, the remaining
patients are randomized to the remaining dose levels. There are two advantages
of this strategy: 1) it is ethically desirable for the patients, since they are
less likely to be treated at unsafe dose levels; and 2) it is scientifically
desirable since it provides more information for the dose levels not terminated.
10.6 REPORTING AN ADVERSE EVENT TO THE FDA
The sponsor is responsible for reporting AEs to the FDA as described in 21 CFR
Section 312.32 (IND Safety Reports).
11. CRITERIA FOR DISEASE EVALUATION AND ENDPOINTS
All patients who receive CaPVax are evaluated primarily for safety. Patients are
followed for a longer period of time (26 weeks) to monitor potential clinical
response using NPCP criteria for evaluating patient response (see Appendix G).
11.1 DEFINITIONS
11.1.1 MEASURABLE DISEASE
Requires bidimensionally measurable lesion with clearly defined margins by at
least one of the following criteria:
1. photographs or plain x-ray with at least one diameter > 0.5
cm.
2. CT/MRI/or other imaging scans with at least one diameter >
1 cm (or the minimal limit of resolution of the technique,
and/or
3. palpable lesion with both diameters measuring at least 2
cm.
11.1.2 EVALUABLE DISEASE
Masses with margins not clearly defined, palpable lesion with either diameter <
2 cm, and lesion with both diameters < 0.5 cm by x-ray, CT, or MRI. Serum PSA
values are also considered evaluable. Bone scan lesions are considered
evaluable.
11.2 RESPONSE EVALUATION
11.2.1 RESPONSE FOR BIDIMENSIONALLY MEASURABLE DISEASE
COMPLETE RESPONSE: disappearance of all measurable disease for at least
six weeks (weeks 20-26).
36
PARTIAL RESPONSE: reduction by at least 50% of the sum of two
perpendicular diameters of measurable disease for at least six weeks
(weeks 20-26).
11.2.2 RESPONSE WITH EVALUABLE DISEASE (BONE SCAN ONLY)
COMPLETE RESPONSE: disappearance of all bone scan lesions for at least
six weeks (weeks 20-26).
PARTIAL RESPONSE: partial regression or stabilization of bone scan
lesions for at least six weeks (weeks 20-26).
11.2.3 RESPONSE WITH EVALUABLE DISEASE (ELEVATED PSA VALUE ONLY)
COMPLETE RESPONSE: undetectable PSA on three successive determinations
spaced at least two weeks apart (weeks 12-26).
PARTIAL RESPONSE: decline in PSA by at least 50% with maintenance of the
decline on at least two consecutive determinations spaced at least two
weeks apart (weeks 12-26).
11.3 PROGRESSION
Progression is defined as progression of CT or bone scan lesions (an increase in
number and/or intensity) on consecutive bone scans, increase in the sum of the
perpendicular diameters of measurable disease by at least 25%, a rise in PSA of
greater than 50% from basline (on day 1 prior to the first CaPVax injection) on
two consecutive determinations spaced at least two weeks apart, or new bone
lesions on plain film and/or bone scan in the presence of a stable PSA.
11.4 STABLE DISEASE
Stable disease is defined as when a patient fails to qualify for either a
response or progressive disease.
12. STATISTICAL CONSIDERATIONS
This is a two-center study, with equal numbers of patients treated at each site.
All patients receive CaPVax injections and act as their own controls. The
treatment plan is presented in Section 5.0.
37
12.1 STUDY DESIGN
Three patients per dose level are evaluated for toxicity. If these patients do
not experience grade 3 or 4 toxicity, the study continues with the planned dose
escalation. Descriptive statistics are used in the Phase I part of the protocol.
Given results of PSA that is collected during the study, the generalized
estimating equation (GEE) is used for statistical evaluation of response. Based
on previous experience with a similar product, we chose sixty (60) patients to
achieve a 95% probability of not missing an adverse event and to observe an
actual response rate of about 20%.
12.2 SAMPLE SIZE CONSIDERATIONS AND STATISTICAL METHODS FOR PRIMARY OUTCOMES
The studies by Murphy et al [48, 49] together evaluated 109 different patients
with treatment regimens similar to the ones of this proposal. Twenty-eight of
the 109 patients (26%) had either a complete or partial response to treatment.
There were no AEs reported among these 109 subjects related to treatment.
We chose the sample size (n) to be sufficiently large to provide a reasonable
chance of detecting a serious AE, even if it is relatively rare in occurrence,
and to provide an estimate of the efficacy of treatment. Using the Poisson
probability distribution, there is 95% probability that AT LEAST one AE is
observed for any event with a "true" occurrence rate of at least 5%, provided
n=60. With n=60 and assuming the observed complete/partial response rate equals
25%, the 95% two-sided confidence interval for the "true" response rate among
patients with HRPC equals 10% to 41%. Stated as a one-sided interval, with 95%
confidence the "true" response rate would equal or exceed 14%.
Summary estimates of AE rates and their standard deviations are presented in
tabular format. All AEs are reported and described on a case-by-case basis.
Exact binomial probability calculations are used to estimate and provide the 95%
confidence interval for the response rate, and a P-value quantifies the level of
statistical significance of the data for this primary outcome.
12.3 STATISTICS FOR SECONDARY STUDY OBJECTIVES
SECONDARY OBJECTIVE 1: Test the hypothesis that, on average over the study
period, patients' PSA values will trend downward compared to screening
values. Each subject is assayed eight times at various times between day 1
and week 26. Regression analysis using Generalized Estimating Equations
(GEE) is used to test for trend of improvement over the study period.
38
SECONDARY OBJECTIVE 2: Describe how the patient's experiences of pain,
physical functioning and quality-of-life measures change during the course
of treatment and during the follow-up period. For each patient over the
study period pain is assessed five times using the Brief Pain Inventory,
physical functioning is measured six times using both the Karnofsky and
Zubrod Performance Scales, and quality of life assessments are obtained five
times using the FACT-P questionnaire. Patient averages at screening and
during the study weeks is graphed and the trends and tempos of these
repeated measurements is modeled and analyzed using GEE.
SECONDARY OBJECTIVE 3: Describe how the patient's skin test and other lab
results change during the course of treatment and during the follow-up
period. For each patient over the study period skin tests are assessed four
times using four recall antigens (Candida, Mumps, and PPD) and CBC,
differential blood chemistry and serum markers are measured nine times.
Patient averages at screening and during the study weeks are graphed and the
trends of these repeated measurements are modeled and analyzed using GEE.
12.4 STUDY ASSESSMENTS
12.4.1 DATA CONTROL MEASURES
In order to assure adequate control and provide study data that are consistent
and of the highest quality, the following measures are employed:
1. Each clinical procedure (i.e. physical examination) for a
particular patient is conducted by the same person if possible
throughout the patient's study participation.
2. Each clinical laboratory procedure is conducted by the same
laboratory throughout the study.
3. Data generated automatically is reviewed by the appropriate
specialist, i.e. computer generated EKG interpretation is
reviewed and signed off by a cardiologist.
13. INVESTIGATOR OBLIGATIONS
As indicated on FDA Form 1572, the Principal Investigator is responsible for the
conduct of the clinical trial at the site and is responsible for personally
overseeing the treatment of all study patients. The Principal Investigator must
assure that all study site personnel, including Sub-investigators and other
study staff members, adhere to the study protocol and to all FDA regulations and
guidelines regarding clinical trials both during and after study completion.
39
13.1 INFORMED CONSENT
All subjects will be informed of the nature of the program, its possible hazards
and their right to withdraw at any time, and will sign a form indicating their
consent to participate prior to receiving any study-related procedures.
13.2 INSTITUTIONAL REVIEW BOARD
This protocol and relevant substantive data must be submitted to the appropriate
Institutional Review Board (IRB) for review and approval before the study can be
initiated. Amendments to the protocol are also submitted to the IRB prior to
implementation of the change. A letter documenting IRB approval must be received
by the Sponsor prior to initiation of the study. The Principal Investigator is
also responsible for informing the IRB of the progress of the study and for
obtaining annual IRB renewal. The IRB must be informed at the time of completion
of the study and should be provided with a summary of the results of the study
by the Principal Investigator. The Principal Investigator must notify the IRB in
writing of any significant adverse reactions.
14. ADMINISTRATIVE CONSIDERATIONS
14.1 PRESTUDY DOCUMENTATION
The following documentation must be received by the study Sponsor prior to
initiation of the trial: FDA Form 1572; curricula vitae of the Principal
Investigator and all Sub-investigators; signed Protocol Agreement; copy of the
correspondence from the IRB indicating approval of the protocol and consent
form, signed by the IRB chairperson or designee; an IRB membership list
containing the names and occupations of the IRB members; copy of the Informed
Consent Form that was reviewed and approved by the IRB; clinical laboratory
reference ranges for all tests required in the protocol and a copy of the
laboratory license or accreditation.
14.2 STUDY DOCUMENTATION
The Investigator and study staff have responsibility for maintaining a
comprehensive and centralized filing system containing all study-related
documentation. These files must be suitable for inspection by the Sponsor or the
FDA at any time, and should consist of the following elements: patient files
(complete medical records, laboratory data, supporting source documentation, and
the Informed Consent); study files (the protocol with all amendments, copies of
all pre-study documentation, and all correspondence between the IRB, site, and
Sponsor); and drug accountability files, containing a complete account of the
receipt and disposition of the study drug.
40
14.3 DATA COLLECTION
Case Report Forms (CRFs) must be submitted to the Sponsor for each patient
enrolled in the study. CRFs are to be completed in a neat, legible manner, using
a black pen to ensure accurate interpretation of data. Any changes or
corrections made on the CRFs must be dated and initialed by the individual
making the change, and subsequently reviewed and signed by the Investigator.
When corrections are made, the original entry should be crossed out using a
single line. Do not erase, overwrite, or use white-out on the original entry.
All datafields on the CRFs must be filled in.
14.4 PROTOCOL INTERPRETATION AND COMPLIANCE
The procedures defined in the protocol are carefully reviewed by the
Investigator and his/her staff prior to the time of study initiation to ensure
accurate representation and implementation. Protocol amendments, if any, are
reviewed and implemented promptly following IRB approval. The Sponsor is
responsible for submitting protocol amendments to the FDA as described in 21 CFR
Section 312.30 (Protocol Amendments).
14.5 STUDY MONITORING AND DATA COLLECTION
A representative from the Sponsor will visit the study center periodically to
monitor adherence to the protocol and applicable FDA regulations, and the
maintenance of adequate and accurate clinical records. CRFs are reviewed to
ensure that key safety and efficacy data are collected and recorded as specified
by the protocol. The Sponsor's representative (or designate) is permitted to
access patient medical records, laboratory data and other source documentation
as needed to appropriately monitor the trial.
14.6 DISCLOSURE OF DATA/PUBLICATION
Individual patient medical information obtained as a result of this study is
considered confidential and disclosure to third parties other than those noted
below is prohibited. Such medical information may be given to the patient's
personal physician or to other appropriate medical personnel responsible for the
patient's welfare. Data generated as a result of this study are to be available
for inspection on request by the FDA, the Sponsor or Sponsor's representative
and by the Institutional Review Board.
Presentation or publication of the study results is not permitted without prior
submission to the Sponsor. It is anticipated that the final results of this
study will be submitted to a peer-reviewed scientific journal. Authorship on
such a paper will be acknowledged with customary scientific practice.
41
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51. Kundu SK, Engleman E, Benike C, et al: A pilot trial of HIV antigen-pulsed
allogeneic and autologous dendritic cell therapy in HIV-infected patients.
AIDS Res Hum Retroviruses 1998; 14: 551-560.
52. Holtl L, Rieser C, Papesh R, et al: Cellular and humoral immune responses in
patients with metastatic renal cell carcinoma after vaccination with antigen
pulsed dendritic cells. J Urol 1999; 161: 777-782.
53. Reichardt VL, Okadda CY, Liso A, et al: Idiotype vaccination using dendritic
cells after autologous peripheral blood stem cell transplantation for
multiple myeloma-a feasibility study. Blood 1999; 93: 2411-2419.
54. Nseyo UO, Lamm DL: Immunotherapy of bladder cancer. Semin Surg Oncol 1997;
13:342-349.
55. Hoover HC, Brandhorst JS Jr, Peters LC, et al: Adjuvant active specific
immunotherapy for human colorectal cancer: 6.5-year median follow-up of a
phase III prospectively randomized trial. J Clin Oncol 1993; 11: 390-399.
46
56. Vermorken JB, Claessen AM, van Tinteren H, et al: Active specific
immunotherapy for stage II and stage III human colon cancer: a randomized
trial. Lancet 1999; 353: 345-350.
57. Guinan PD, John T, Baumgartner G, et al: Adjuvant immunotherapy (BCG) in
stage D prostate cancer. Am J Clin Oncol 1982; 5: 65-68.
58. Hsueh EC, Gupta RK, Qi K, et al: Correlation of specific immune responses
with survival in melanoma patients with distant metastases receiving
polyvalent melanoma cell vaccine. J Clin Oncol 1998; 16: 2913-2920.
47
APPENDIX A: STUDY DIAGRAM
-------------------------------------------------------------------------------------------------------------------------------
PROCEDURE SCREENING DAY 1 WEEK 4 WEEK 6 WEEK 8 WEEK 12 WEEK 14 WEEK 20 WEEK 23 WEEK 26
-------------------------------------------------------------------------------------------------------------------------------
Study Consent X
-------------------------------------------------------------------------------------------------------------------------------
Chest x-ray X X X
-------------------------------------------------------------------------------------------------------------------------------
Bone Scan X X X
-------------------------------------------------------------------------------------------------------------------------------
CT Pelvis/Abdomen X X X
-------------------------------------------------------------------------------------------------------------------------------
EKG X
-------------------------------------------------------------------------------------------------------------------------------
Testosterone & Urinalysis X X
-------------------------------------------------------------------------------------------------------------------------------
History & Site Orientation X
-------------------------------------------------------------------------------------------------------------------------------
Physical Exam, Weight X X X X X X X X
-------------------------------------------------------------------------------------------------------------------------------
CBC & Differential X X X X X X X X X
-------------------------------------------------------------------------------------------------------------------------------
Blood Chemistry(1) X X X X X X X X X
-------------------------------------------------------------------------------------------------------------------------------
Serum Markers(2) X X X X X X X X X
-------------------------------------------------------------------------------------------------------------------------------
Skin Tests, ANA, ESR(3) X X X X
-------------------------------------------------------------------------------------------------------------------------------
Pain Score Assessment(4) X X* X X X
-------------------------------------------------------------------------------------------------------------------------------
Quality of Life Questionnaire X X* X X X
-------------------------------------------------------------------------------------------------------------------------------
Zubrod Performance Status X X X X X X
-------------------------------------------------------------------------------------------------------------------------------
Virology Testing(5) X
-------------------------------------------------------------------------------------------------------------------------------
Leukapheresis(6) X
-------------------------------------------------------------------------------------------------------------------------------
Blood for Immune Monitoring(7) X X X X X X X
-------------------------------------------------------------------------------------------------------------------------------
I.D. Injection of DC(8) X X X X
-------------------------------------------------------------------------------------------------------------------------------
Vital Sign Monitoring X X X X X
-------------------------------------------------------------------------------------------------------------------------------
AE Assessment X X X X X X X
-------------------------------------------------------------------------------------------------------------------------------
(1) Comprehensive metabolic panel, including hepatic and renal functions.
(2) Includes prostatic acid phosphatase (PAP) and prostate specific antigen
(PSA), using standard enzymatic immune assay.
(3) Skin tests are completed and monitored by the study site physician(s) or
research nurse(s) and include testing for Candida, Mumps, and PPD.
Antinuclear Antibodies (ANA) and Erythrocytic Sedimentation Rate (ESR) are
measured as markers of induced autoimmunity.
(4) Brief Pain Inventory to evaluate pain on a scale from 0-10, i.e. from no
pain to severe pain.
(5) Virology testing is performed at screening and includes the following:
HbsAg, a-HBc, ALT, a-HIV-1, a-HIV-2, a-HTLV-1, STS, HIV-1p24Ag, a-HCV.
(6) Patients are leukapheresed at the apheresis unit at the study site once or
twice prior to the first injection, or between injections, depending on
amount of cells harvested. The cells collected are shipped to Northwest
Biotherapeutics, Inc. for cell processing, DC maturation and rPSMA-loading.
(7) Ten (10) 10mL green-top tubes of whole blood plus one red-top tube are
drawn on Day 1, prior to the first injection, or between injections,
depending on amount of cells harvested. The cells collected are shipped to
Northwest Biotherapeutics, Inc. for cell processing, DC maturation and
rPSMA-loading.
(8) The autologous CaPVax is shipped to the site for intradermal (I.D.)
injection.
* The Brief Pain Inventory and Quality of Life questionnaire is given to the
patient at Week 4, filled out by the patient at Week 6, and returned to
the study site at Week 8.
48
APPENDIX B
KARNOFSKY/ZUBROD PERFORMANCE STATUS SCALE
Kamofsky Performance Scale(1) ECOG or Zubrod Performance Scale(2)
<Table>
<Caption>
POINT DESCRIPTION POINT DESCRIPTION
----- ----------- ----- -----------
100 Normal, no complaints, no 0 Normal activity, asymptomatic
evidence of disease
--------------------------------------------------------------------------------
90 Able to carry on normal 1 Symptomatic, fully ambulatory
activity
--------------------------------------------------------------------------------
80 Normal activity with effort,
some signs or symptoms of
disease
--------------------------------------------------------------------------------
70 Cares for self, unable to carry 2 Symptomatic, in bed less than
on normal activity or do active 50% of normal day
work
--------------------------------------------------------------------------------
60 Requires occasional assistance
but is able to care for most of
his needs
--------------------------------------------------------------------------------
50 Requires considerable
assistance and frequent medical
care
--------------------------------------------------------------------------------
40 Disabled, requires special care 3 Symptomatic, in bed more than 50%
and assistance of time, not bedridden
--------------------------------------------------------------------------------
30 Severely disabled,
hospitalization indicated,
death not imminent
--------------------------------------------------------------------------------
20 Very sick, hospitalization 4 100% bedridden
necessary, active support
treatment necessary
--------------------------------------------------------------------------------
10 Moribund, fatal processes
progressing rapidly
--------------------------------------------------------------------------------
0 Dead 5 Dead
--------------------------------------------------------------------------------
</Table>
References:
1. Karnofsky, DA: Meaningful clinical classification of therapeutic responses
to anticancer drugs. Clin Pharm Ther 2:709-712, 1961.
2. Stanley, KE: Prognostic factors for survival in patients with inoperable
lung cancer. J Nat Can Inst 65:25-32, 1980.
49
APPENDIX C
SKIN TESTING PROCEDURE
Skin testing is a widely used procedure for monitoring specific cellular
immune response and is indicated when detection of delayed-hypersensitivity
reaction is desired. It is standardized procedure with very small risk. All skin
testing procedures are performed according to the manufacturer's instructions
included as a package insert with the skin test antigens. The skin test antigens
(Candida, Mumps, PPD) are approved for use in the US.
ANTIGENS USED AND HOW SUPPLIED:
Candida, Mumps, and PPD (tuberculin purified protein derivative) will be used
for skin testing.
1. Candida albicans skin test antigen for cellular hypersensitivity
(Candin(R)) is a clear, colorless, sterile solution, made from the culture
filtrate of two strains of Candida albicans. It is supplied in a 1 ml
multidoses vial containing ten 0.1 ml doses, stable at 2-8 degrees C (35-40
degrees F), and is distributed by Allermed Laboratories, Inc. (San Diego,
CA).
2. Mumps skin test antigen (MSTA(R)) is a sterile suspension of killed mumps
virus, prepared from the extraembryonic fluid of the virus-infected chicken
embryo. It is supplied in a 1 ml multidoses vial containing ten 0.1 ml
doses, is slightly opalescent in color, stable when stored at 2-8 degrees
C, and is distributed by Connaught Laboratories, Inc. (Swiftwater,
Pennsylvania).
3. Tuberculin PPD (Mantoux)-Tubersol(R), obtained from a human strain of
Mycobacterium tuberculosis, is available in stabilized solutions
bio-equivalent to 5 U.S. units (TU) PPD-S per test dose (0.1 ml) and is
available in 1 ml vials. This Tubersol(R) solution is ready for immediate
use without any further dilution, and remains stable for at least 4 weeks
when stored at 2-8 degrees C. It is distributed by Connaught Laboratories,
Inc. (Swiftwater, Pennsylvania, USA).
METHOD OF ADMINISTRATION
The following procedure is recommended for performing the skin test.
1. The site of the test is the volar surface of the forearm about 2-4 inches
below the bend of the elbow.
2. To eliminate any later identification problems, see figure below for
antigen placement.
[ Candida ] [ Mumps ] [ PPD ]
3. The skin is cleansed with alcohol and allowed to dry.
4. The test dose is administered with a 1 ml syringe calibrated in tenths and
fitted with a short, one half inch, 26 or 27 gauge needle.
5. Disposable sterile syringes and needles must be used.
6. The rubber cap of the vial is wiped with alcohol and allowed to dry. The
needle is then inserted gently through the cap and the required amount of
the antigen is drawn into the syringe.
7. The point of the needle is inserted into the most superficial layers of the
skin with the needle bevel pointing upward. If the intradermal injection is
performed properly, a definite white bleb will rise at the needle point,
about 10 mm (3/8") in diameter. This will disappear within minutes. No
dressing is required. In the event of a subcutaneous injection (i.e. no
bleb formed), the test should be repeated immediately at another site.
50
INTERPRETATION OF SKIN TESTS:
These tests are read at 15 minutes after inoculation for immediate-type
hypersensitivity to any of the antigens and approximately 48-72 hours for
delayed-type hypersensitivity (DTH). Results of the test, or sensitivity, are
indicated by induration, usually accompanied by erythema. The widest diameter of
distinctly palpable induration is recorded in millimeters (mm). Presence of
edema and necrosis is also reported. Palpable induration of 5 mm or more
indicates a positive reaction. Induration of less than 5 mm is considered
negative.
INTERACTIONS:
Reactivity to the skin test may be depressed or suppressed in patients with
impaired immunity, including patients with advanced cancer. Reactivity to PPD
may be temporarily depressed by live mumps vaccine. Therefore, PPD should be
administered either before or simultaneously with the mumps vaccine.
CONTRAINDICATIONS:
PPD is not administered to known positive reactors because of the severity of
reactions that may occur at the test site in highly positive patients. Candida,
Mumps, or PPD is not used with history of allergic reaction to these products.
It is also contraindicated to administer MSTA(R), mumps skin test, to anyone
with history of anaphylactic reaction to eggs or egg product. Individuals with
history of allergy to Thimerosal must not receive MSTA(R).
ADVERSE REACTIONS:
Local reactions consist primarily of rash, pruritus, induration, tenderness,
vesiculation, abscess formation, ulceration or necrosis at the site of
injection, and/or regional lymphadenopathy. Cold packs or topical steroid
preparations are employed for symptomatic relief of the associated skin
discomfort. Immediate hypersensitivity reactions occur in some individuals
approximately 15-20 minutes after intradermal injection and is characterized by
the presence of an edematous hive surrounded by a zone of erythema. Systemic
reactions to Candin(R) and MSTA(R) have not been observed. However, all foreign
antigens have the remote possibility of causing Type 1 anaphylaxis and even
death when injected intradermally. Systemic reactions usually occur within 30
minutes after injection of antigen and may include the following symptoms:
sneezing, coughing, itching, shortness of breath, abdominal cramps, vomiting,
diarrhea, tachycardia, hypotension and respiratory failure in severe cases.
Systemic allergic reactions including anaphylaxis must be immediately treated
with Epinephrine HCL 1:1000.
PRECAUTIONS:
Epinephrine injection (1:1000) must be immediately available to combat
unexpected anaphylactic or other allergic reactions. Vials of the skin test
product is inspected visually for particulate matter or discoloration prior to
administration. If particles or discoloration are observed, the product is not
used and is discarded. The antigens must be given intradermally. If they are
injected subcutaneously, no reaction or an unreliable reaction may occur.
Special care should be taken to ensure the antigen is not injected into a blood
vessel.
51
APPENDIX D
QUALITY OF LIFE QUESTIONNAIRE (FACT-P)
FACT-P (VERSION 4)
Below is a list of statements that other people with your illness have said are
important. By circling one (1) number per line, please indicate how true each
statement has been for you during the past 7 days.
NOT A LITTLE SOME- QUITE VERY
PHYSICAL WELL-BEING AT ALL BIT WHAT A BIT MUCH
GP1 I have a lack of energy.............................. 0 1 2 3 4
GP2 I have nausea........................................ 0 1 2 3 4
GP3 Because of my physical condition, I have
trouble meeting the needs of my family............... 0 1 2 3 4
GP4 I have pain.......................................... 0 1 2 3 4
GP5 I am bothered by side effects of treatment........... 0 1 2 3 4
GP6 I feel ill........................................... 0 1 2 3 4
GP7 I am forced to spend time in bed..................... 0 1 2 3 4
NOT A LITTLE SOME- QUITE VERY
SOCIAL/FAMILY WELL-BEING AT ALL BIT WHAT A BIT MUCH
GS1 I feel close to my friends........................... 0 1 2 3 4
GS2 I get emotional support from my family............... 0 1 2 3 4
GS3 I get support from my friends ....................... 0 1 2 3 4
GS4 My family has accepted my illness.................... 0 1 2 3 4
GS5 I am satisfied with family communication
about my illness..................................... 0 1 2 3 4
GS6 I feel close to my partner (or the person
who is my main support)............................. 0 1 2 3 4
Regardless of your current level of sexual activity,
please answer the following question. If you prefer
not to answer it, please check this box [ ] and go
to the next section.
GS7 I am satisfied with my sex life...................... 0 1 2 3 4
Version 4; 9/4/98
52
FACT-P (VERSION 4) (APPENDIX D, CONTINUED)
By circling one (1) number per line, please indicate how true each statement has
been for you during the past 7 days.
NOT A LITTLE SOME- QUITE VERY
EMOTIONAL WELL-BEING AT ALL BIT WHAT A BIT MUCH
GE1 I feel sad........................................... 0 1 2 3 4
GE2 I am satisfied with how I am coping with my illness.. 0 1 2 3 4
GE3 I am losing hope in the fight against my illness..... 0 1 2 3 4
GE4 I feel nervous....................................... 0 1 2 3 4
GE5 I worry about dying.................................. 0 1 2 3 4
GE6 I worry that my condition will get worse............. 0 1 2 3 4
NOT A LITTLE SOME- QUITE VERY
FUNCTIONAL WELL-BEING AT ALL BIT WHAT A BIT MUCH
GF1 I am able to work (include work at home)............. 0 1 2 3 4
GF2 My work (include work at home) is fulfilling......... 0 1 2 3 4
GF3 I am able to enjoy life.............................. 0 1 2 3 4
GF4 I have accepted my illness........................... 0 1 2 3 4
GF5 I am sleeping well................................... 0 1 2 3 4
GF6 I am enjoying the things I usually do for fun........ 0 1 2 3 4
GF7 I am content with the quality of my life right now... 0 1 2 3 4
53
FACT-P (VERSION 4) (APPENDIX D, CONTINUED)
By circling one (1) number per line, please indicate how true each statement has
been for you during the past 7 days.
NOT A LITTLE SOME- QUITE VERY
ADDITIONAL CONCERNS AT ALL BIT WHAT A BIT MUCH
C2 I am losing weight................................... 0 1 2 3 4
C6 I have a good appetite............................... 0 1 2 3 4
P1 I have aches and pains that bother me................ 0 1 2 3 4
P2 I have certain areas of my body where I
experience significant pain.......................... 0 1 2 3 4
P3 My pain keeps me from doing things I want to do...... 0 1 2 3 4
P4 I am satisfied with my present comfort level......... 0 1 2 3 4
P5 I am able to feel like a man......................... 0 1 2 3 4
P6 I have trouble moving my bowels...................... 0 1 2 3 4
F7 I have difficulty urinating.......................... 0 1 2 3 4
BL2 I urinate more frequently than usual................. 0 1 2 3 4
P8 My problems with urinating limit my activities....... 0 1 2 3 4
BL5 I am able to have and maintain an erection........... 0 1 2 3 4
54
APPENDIX E
BRIEF PAIN INVENTORY (SHORT FORM)
Date: Time:
----------------- ---------------------
Name:
------------------------- ------------------------- --------------
Last First Middle Initial
1. Throughout our lives, most of us have had pain from time to time (such as
minor headaches, sprains, and toothaches). Have you had pain other than these
everyday kinds of pain today?
1. Yes 2. No
2. On the diagram, shade in the ares where you feel pain. Put an X on the area
that hurts the most.
[DIAGRAM OF PAIN LOCATION]
3. Please rate your pain by circling the one number that best describes your
pain at its worst in the last 24 hours.
0 1 2 3 4 5 6 7 8 9 10
No Pain as bad as
Pain you can imagine
4. Please rate your pain by circling the one number that best describes your
pain at its least in the last 24 hours.
0 1 2 3 4 5 6 7 8 9 10
No Pain as bad as
Pain you can imagine
5. Please rate your pain by circling the one number that best describes your
pain the average.
0 1 2 3 4 5 6 7 8 9 10
No Pain as bad as
Pain you can imagine
6. Please rate your pain by circling the one number that tells how much pain you
have right now.
0 1 2 3 4 5 6 7 8 9 10
No Pain as bad as
Pain you can imagine
55
BRIEF PAIN INVENTORY (APPENDIX E, CONTINUED)
7. What treatments or medications are you receiving for your pain?
8. In the last 24 hours, how much relief have pain treatments or medications
provided? Please circle the one percentage that most shows how much
relief
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
No Complete
Relief Relief
9. Circle the one number that described how, during the past 24 hours, pain
has interfered with your:
A. General Activity
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
B. Mood
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
C. Walking Ability
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
D. Normal Work (includes both work outside the home and housework)
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
E. Relations with other people
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
F. Sleep
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
G. Enjoyment of life
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
56
APPENDIX F
PATIENT REGISTRATION FORM
Date Registered - ____/_____/____
Study Identification No. - _______________
Patient Name_____________________________________________
Date of Birth ____/_____/____
Date Original Prostate Cancer Diagnosed ____/_____/____
Diagnosing Physician_____________________________________
City/State_______________________________________________
PRIMARY THERAPY TYPE (CIRCLE WHERE APPROPRIATE) -
1. Surgery Radical Prostatectomy Perineal Prostatectomy Other
2. Radiation External Beam Brachytherapy Other
3. Hormonal Therapy Orchiectomy LHRH angonist
Peripheral Androgen Blockade Other
None
Other (specify)__________________________________________
Date Metastatic Prostate Cancer Diagnosed____/_____/____
Diagnosing Physician_____________________________________
City/State_______________________________________________
Metastatic Site(s)_______________________________________
THERAPY FOR METASTATIC DISEASE (CIRCLE WHERE APPROPRIATE) -
1. Radiation External Beam Strontium-89
2. Hormonal Therapy Orchiectomy LHRH angonist
Peripheral Androgen Blockade Other
None
Other (specify)__________________________________________
57
Date Hormonal Therapy Failure ____/_____/____
Failure based on:
Imaging/Radiographic Evidence (detail)________________________________
PSA Progression (detail)______________________________________________
Is patient currently being treated for metastatic disease (circle one) Y / N
If yes, describe current treatment____________________________________
______________________________________________________________________
CLINICAL DISEASE EXTENT
Total PSA______ng/mI
Bone Scan Results - Positive Negative
If bone scan positive, where is lesion located?______________________
CT/MRI Results - Positive Negative
CLINICAL PRESENTATION
H&P Results / Impression:
Concurrent Medical Conditions:
KNOWN ALLERGIES:
CLINICAL LABS - SCREENING
CBC - Out of Range Values? Y / N If yes, specify:
Chem-22 - Out of Range Values? Y/ N If yes, specify:
Chest X-ray remarkable/unremarkable If yes, specify:
58
APPENDIX G
NPCP CRITERIA FOR EVALUATING PATIENT RESPONSE
NPCP CRITERIA for Evaluating Patient Responses to Treatment Modalities for
Prostatic Cancer (modified) [1]
Complete Response
All of the Following:
1. Tumor masses, if present, totally disappeared and no new lesions appeared.
2. Elevated prostate specific antigen (PSA), if present, returned to normal.
3. Osteolytic lesions, if present, recalcified.
4. Osteoblastic lesions, if present, disappeared with a negative bone scan.
5. If hepatomegaly is a significant indicator, there must be a complete
return in size of the liver to normal (as measured by distention below both
costal margins at mid-clavicular lines and from the tip of the xiphoid
process during quiet respiration without liver movement), and normalization
of all pretreatment abnormalities of liver function, including bilirubin
(mg per dl) and SGOT.
6. No significant cancer-related deterioration in weight (greater than 10%),
symptoms, or performance status.
Partial Regression
Any of the Following:
1. Recalcification of one or more of any osteolytic lesions
2. A reduction by 50% in the number of increased uptake areas on the bone
scan.
3. Decrease of 50% or more in cross-sectional area of any measurable lesion.
4. If hepatomegaly is a significant indicator, there must be at least a 30%
reduction in liver size as indicated by a change in the measurements, and
at least a 30% improvement of all pretreated abnormalities of
liver function, including bilirubin (mg/dI) and SGOT.
All of the Following:
5. No new sites of disease.
6. PSA returned to normal or was reduced by greater than 50%
7. No significant cancer-related deterioration in weight (greater than 10%),
symptoms, or performance status.
59
Objectively Stable
All of the Following:
1. No new lesions occurred and no measurable lesions increased more than 25%
in cross-sectional areas.
2. Elevated PSA, if present, decreased, though need not have returned to
normal or decreased by greater than 50%.
3. Osteolytic lesions, if present, did not appear to worsen.
4. Osteoblastic lesions, if present, did not appear to worsen.
5. Hepatomegaly, if present, did not appear to worsen by more than a 30%
increase in liver measurements, and symptoms of hepatic abnormalities did
not worsen, including bilirubin (mg/dl) and SGOT.
6. No significant cancer-related deterioration in weight (greater than 10%),
symptoms, or performance status.
Objective Progression
Any of the following:
1. Significant cancer-related deterioration in weight (greater than 10%),
symptoms or performance status.
2. Appearance of new areas of malignant disease by bone scan or x-ray or in
soft tissue by other appropriate techniques.
3. Increase in any previously measurable lesion by greater than 25% in
cross-sectional area.
4. Development of recurring anemia secondary to prostatic cancer (not related
to treatment; protocols for patients with metastatic disease who have not
failed hormone therapy).
5. Development of ureteral obstruction (protocols for patients as in No. 4
above).
6. PSA increase of greater than 50%.
NOTE: An increase in acid or alkaline phosphatase alone is not to be considered
an indication of progression. These should be used in conjunction with other
criteria.
1. Murphy GP, Slack NH: Response Criteria for the prostate of the USA
national prostatic cancer project. Prostate 1980; 1: 375-382.
60
APPENDIX H
OFF STUDY FORM
Patient Name_______________________________________
Date___________________________
Physician__________________________________________
The above named patient has been removed from Phase I CaPVax protocol due to:
1. Treatment for disease progression: Specify -
2. Complication(s): Specify -
3. Toxicity: Specify -
4. Other Reason: Specify -
61
APPENDIX I
OFF STUDY PATIENT RE-ENTRY FORM
Patient Name_______________________________________
Date___________________________
Physician__________________________________________
The above named patient, previously removed from the Phase I CaPVax protocol, is
to be reinstated on protocol.
Reason(s) for removal from protocol:
Reason(s) for reinstatement on protocol:
62
APPENDIX J
LEUKAPHERESIS PROCEDURE PATIENT INFORMATION
Apheresis, a Greek term meaning "taking away" is applied to a number of
procedures in which blood is processed to remove a specific component (cells or
plasma). Leukapheresis is removing whole blood cells needed for the clinical
trial study you are participating in. This is accomplished by pumping a donor's
blood through a machine called an automated cell separator.
A cell separator, similar to those used in blood banks and pictured here, is
used to obtain the specific cells needed for study. After blood from you, the
donor, enters the machine, it circulates through a centrifuge. Centrifugal
force caused the different types of blood cells to separate into layers. The
white cell layer is collected while the remaining blood cells and plasma return
to you, the donor.
The collection of white blood cells by apheresis requires the circulation of
large volumes of blood through the apheresis machine. It is possible to do
this by accessing a large vein in each arm. An intravenous needle with tubing
is placed in each arm. The blood moves from the vein in one arm, through the
apheresis machine and is returned to the vein in the other arm.
[PICTURE OF CELL SEPARATOR]
When the collection is completed, the intravenous needles are removed. This
process is repeated each time you have apheresis. Your arm veins will be
assessed by the nursing staff at the Apheresis Unit to make sure you have veins
adequate to perform the procedure. If a patient does not have adequate veins in
the arm for leukapheresis, a specialist at the study center will use a femoral
catheter.
How long does each procedure take?
This varies from one person to another but will generally take about four hours.
What procedures are done for my safety during apheresis?
- Every precaution is taken to ensure your safety:
- You are closely monitored by an apheresis nurse; physicians and other
support staff are on hand.
63
- Your blood never leaves the sterile tubing circuit; supplies are used
for only one collection and then discarded.
- There is only a small volume (approximately one cup) of your blood in
the cell separator at any time; your blood is returning to you at the
same rate it is being removed.
- A solution is added to your blood as it circulates through the apheresis
device to prevent clotting; this solution is quickly inactivated by your
body.
What activities can be done during the procedure?
- You may lie in bed or sit in a recliner chair. With the intravenous
lines for venous access in each arm, you are able to watch television,
listen to audio tapes or any other quiet activities which do not require
use of your arms.
- A companion is welcome to stay with you during this procedure. You may
bring a snack with you to eat during apheresis. If needed, a commode or
urinal may be used at the bedside.
[GRAPHIC OF PATIENT UNDERGOING APHERESIS]
What are the side effects during apheresis?
The insertion of intravenous needles is the only uncomfortable part of the
apheresis process. The apheresis procedure itself is painless; in fact, most
donors report no noticeable or unusual sensations during the procedure. Some,
though, experience mild side effects such as chilling, a tingling sensation on
the face or body, and lightheadedness. Adverse reactions are extremely rare.
What will I feel like when the procedure is over?
Some donors report feeling fatigued following apheresis. The sites of the
intravenous lines will have soreness or tenderness and you will be instructed to
limit your activities for several hours.
If you have any questions or concerns regarding this procedure, please do not
hesitate to contact a member of the apheresis team.
64
APPENDIX K
INFORMED CONSENT
PROTOCOL TITLE: PHASE I CLINICAL TRIAL OF RECOMBINANT PROSTATE SPECIFIC MEMBRANE
ANTIGEN (rPSMA)-LOADED AUTOLOGOUS DENDRITIC CELLS (CaPVax) FOR
THE TREATMENT OF METASTATIC HORMONE REFRACTORY PROSTATE CANCER
1. --------------------------- --------------------------------
Participants Name ID Number
You have the right to know about the procedures that are to be used in your
participation in clinical research so as to afford you an opportunity to make
the decision whether or not to undergo the procedure after knowing the risks and
hazards involved. This disclosure is not meant to frighten or alarm you; it is
simply an effort to make you better informed so that you may give or withhold
your consent to participate in clinical research study. This informed consent
does not supersede other consents you may have signed.
This clinical trial is so designed that no person shall be excluded from
participation in it on the grounds of race, color, gender, or national origin or
be denied the benefits, or be otherwise subjected to discrimination through or
under this study.
2. PURPOSE OF STUDY: The goal of this clinical research study is to assess
the safety of mature, autologous dendritic cells (DC) combined with
recombinant human prostate specific membrane antigen (rPSMA) to treat
patients with metastatic, hormone refractory prostate cancer. Another
goal is to monitor the immune response.
3. DESCRIPTION OF RESEARCH: Patients are leukapheresed to collect white
blood cells. For this process, a needle is inserted into a vein in one
arm. Blood is withdrawn by the needle and passed through a device that
removes only white blood cells. About one cup of blood circulates in the
machine at any time during the procedure. The blood is returned to the
patient through a needle in the other arm. Each session will take about
4 hours. Leukapheresis is performed at the beginning of the study and
may have to be repeated, depending on the yield of the first
leukapheresis and the ex vivo expansion. If necessary, leukapheresis is
repeated between 4 -12 weeks after the first one.
DC are grown in culture from the collected white cells. rPSMA is added
to the cells. The DC plus rPSMA are returned to the patient. It is hoped
that these cells will stimulate the body's immune system to kill
prostate tumor cells.
Patients will receive DC plus rPSMA through an intradermal injection in
the upper thigh once every 4 weeks for 12 weeks. The patient is observed
during and for 2 hours after each treatment
65
Patients are asked about potential side effects during their next
checkup (every month).
During the study, patients are physically examined, including blood
tests, at various intervals. A bone scan, chest x-ray, and CT of the
abdomen and pelvis are performed during week 20 and week 26 of the
study. After the study patients are followed as deemed necessary by
their treating physician. The physician contacts the patient via a phone
call 3 months after their treatment is over to ask about their disease
and their quality of life.
Before treatment starts, patients have a complete exam including blood
and urine tests. A chest x-ray, bone scan, and heart function test (EKG)
are done. CT scans of the abdomen and pelvis are performed to measure
the tumor. A skin-prick test is done to test for reactions to 3 recall
antigens (Candida albicans, Mumps, PPD). For this, small injections are
administered in the forearm. The results of the skin-prick tests are
checked at 15 minutes and 48 hours after the tests are administered.
Treatment of prostate cancer with mature, autologous DC plus rPSMA is
authorized by the U.S. Food and Drug Administration for experimental use
only. As many as 60 patients will take part in the study. All will be
treated as outpatients at a referral cancer center.
4. RISKS, SIDE EFFECTS AND DISCOMFORTS TO THE PARTICIPANTS:
Adverse reactions to leukapheresis are extremely rare because the
patient's own blood never leaves the sterile tubing circuit and every
precaution is taken to ensure safety. The insertion of intravenous
needles is the only uncomfortable part of the apheresis process. Some
patients may experience mild side effects such as chills, tingling
sensation on the face or body, or lightheadedness. All patients are
instructed to limit their activities for several hours. If a patient
does not have adequate veins in the arms for leukapheresis, a specialist
at the site can put in a femoral catheter
The potential presence of inactivated BCG in the CaPVax may cause
ulceration and necrosis of the skin at the site of injection. Mild to
high grade fever may be another side effect secondary to injection of
inactivated BCG. Systemic hypersensitivity reaction is extremely rare.
DC plus rPSMA may cause allergic reactions. Symptoms may include skin
rash, itching, hives, wheezing, shortness of breath, nausea, vomiting,
changes in heart rate, a decrease in blood pressure, and/or fainting.
Taking blood samples may cause pain, redness, swelling, bruising, and/or
infection where the needle enters the skin. Patients may feel faint or
lightheaded when blood is drawn.
Using DC with other drugs may cause other side effects that are not seen
when each drug is given alone. If any doctor other than the study doctor
prescribes other drugs, the patient must tell the study nurse right
away.
This clinical research study may involve unforeseeable risks to the
participant.
5. POTENTIAL BENEFITS
66
CaPVax may stimulate a specific immune response and may cause the
prostate cancer to stop growing or shrink. This treatment may improve
the quality of life and ease the pain for this advanced stage of
disease. There may be no benefits at all for patients in the study What
is learned in this study may benefit future cancer patients.
6. ALTERNATE PROCEDURES OR TREATMENTS
Patients may choose to be treated in other ways. These include treatment
with chemotherapy (adriamycin, ketoconazole, vinblastine, estramustine)
or other investigational agents. Patients may choose not to have
treatments at ail. In all cases, patients will receive care for symptoms
and pain.
UNDERSTANDING THE PARTICIPANTS
7. I have been given an opportunity to ask any questions concerning the
treatment involved and the investigator has been willing to reply to my
inquiries. This treatment is administered under the above number, titled
and described clinical research protocol at this institution. I hereby
authorize Dr.________________ , the attending physician and designated
associates to administer the treatment.
8. I have been told and understand that my participation in this clinical
research study is voluntary. I may decide not to participate, or
withdraw my consent and discontinue my participation at any time. Such
action will be without prejudice and there shall be no penalty or loss
of benefits to which I may otherwise be entitled, and I will continue to
receive treatment by my physician at this institution.
Should I decide not to participate or withdraw my consent from
participation in this clinical research, I have been advised that I
should discuss the consequences or effects of my decision with my
physician
In addition, I understand that the investigator may discontinue the
clinical research study if, in the sole opinion and discretion of the
investigator, the study or treatment offers me little or no future
benefit, or the supply of medication ceases to be available or other
causes prevent continuation of the clinical research study. The
investigator will notify me should such circumstances arise and my
physician will advise me about which available treatments may be of
benefit at that time, I will be informed of any new findings developed
during the course of this clinical research study as related to my
willingness to continue participation in this study.
9. I have been assured that confidentiality will be preserved except that
qualified monitors from the Food and Drug Administration (FDA) may
review my medical records where appropriate and necessary. Qualified
monitors shall include assignees authorized by the Surveillance
Committee of this institution provided that confidentially is assured
and preserved. My name will not be revealed in any reports or
publications resulting from this study, without my expressed consent. In
special circumstances, the FDA might be required to reveal the names of
the participants.
10. I have been informed that should I suffer any injury as a result of
participation in the research activity, reasonable medical facilities
are available for treatment at this institution. I understand, however,
that I cannot expect to receive any credit or
67
reimbursement for expenses from this institution for such injury.
11. I have been informed that should I inquire of the attending physician
whether or not there are any services, investigational agents or
devices, and/or medications being offered by the sponsor of this
clinical research project at a reduced cost or without cost. Should the
investigational agent become commercially available during the course of
the study, I understand that I may be required to cover the cost of
subsequent doses.
Costs related to my medical care including expensive drugs, tests or
procedures that may be specifically required by this clinical research
study shall be my responsibility unless the sponsor or other agencies
contribute toward said costs. I have been given the opportunity to
discuss the expenses or costs associated with my participation in this
research activity.
12. It is possible that this research project will result in the development
of beneficial treatments, devices, new drugs, or possible patentable
procedures, in which event I understand that I cannot expect to receive
any compensation in this research project.
13. I may discuss any questions or problems during or after this study with
the Principal Investigator, Sub-investigators, or Research nurse.
CONSENT: Based upon the above, I consent to participate in the research and have
received a copy of the consent form.
----------------------------------- ---------------------------------
DATE SIGNATURE OF PARTICIPANT
----------------------------------- ---------------------------------
WITNESS OTHER THAN PHYSICIAN SIGNATURE OF PERSON RESPONSIBLE
OR INVESTIGATOR AND RELATIONSHIP
I have discussed this clinical research study with the participant and/or his or
her authorized representative, using a language which is understandable and
appropriate. I believe that I have fully informed this participant of the nature
of this study and its possible benefits and risks and I believe the participant
understood this explanation.
--------------------------------
PHYSICIAN/INVESTIGATOR
I have translated the above informed consent into___________________ for this
patient.
----------------------------------- ---------------------------------
Name of Translator Signature of Translator and Date
68
APPENDIX L
NCI COMMON TOXICITY CRITERIA
FINAL 1/30/98
CTC VERSION 2.0
COMMON TOXICITY CRITERIA (CTC)
<Table>
<Caption>
-----------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------------
Allergic reaction/ none transient rash drug urticaria, drug fever symptomatic Anaphylaxis
hypersensitivity fever < 38 degrees C *38 degrees C (*100.4 bronchospasm to
(including drug fever) (< 100.4 degrees F) degrees F), and/or requiring parenteral
asymptomatic medication(s), with
bronchospasm or without urticaria;
allergy-related
edema/angioedema
Note: Isolated urticaria, in the absence of other manifestations of an allergic or hypersensitivity reaction, is graded in
the DERMATOLOGY/SKIN category.
-----------------------------------------------------------------------------------------------------------------------------
Autoimmune reaction none serologic or other evidence of reversible Autoimmune
evidence of autoimmune autoimmune reaction causing
autoimmune reaction involving a reaction involving major grade 4
reaction but patient non-essential function of a major organ dysfunction;
is asymptomatic organ or function organ or other progressive and
(e.g., vitiligo), all (e.g., toxicity (e.g., irreversible
organ function is hypothyroidism), transient colitis or reaction; long-term
normal and no requiring treatment anemia), requiring administration of
treatment is other than short-term high-dose immuno-
required immunosuppressive immunosuppressive suppresive
drug treatment therapy required
Urticaria is graded in the DERMATOLOGY/SKIN category if it occurs as an isolated symptom. If it occurs with other manifestations of
allergic or hypersensitivity reaction, grade as Allergic reaction/hypersensitivity above.
-----------------------------------------------------------------------------------------------------------------------------
Allergy/Immunology- None Mild moderate severe life-threatening or
Other disabling
(Specify, _________)
-----------------------------------------------------------------------------------------------------------------------------
BLOOD/BONE MARROW
-----------------------------------------------------------------------------------------------------------------------------
Hemoglobin (Hgb) WNL < LLN - 10.0 g/dl 8.0 - < 10.0 g/dl 6.5 - < 8.0 g/dl < 6.5 g/dl
< LLN - 100 g/L 80 - < 100 g/L 65 - < 80 g/L < 65 g/L
< LLN - 6.2 mmol/L 4.9 - < 6.2 mmol/L 4.0 - < 4.9 mmol/L < 4.0 mmol/L
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the protocol so
specifies.
For leukemia studies or WNL 10 - < 25% 25 - < 50% 50 - < 75% * 75% decrease
bone marrow decrease from decrease from decrease from from pretreatment
infiltrative/ pretreatment pretreatment pretreatment
myelophthisic
processes
-----------------------------------------------------------------------------------------------------------------------------
Leukocytes (total WNL < LLN - 3.0 x 10(9)/L * 2.0 - < 3.0 x 10(9)/L * 1.0 - < 2.0 x 10(9)/L < 1.0 x 10(9)/L
WBC) < LLN - 3000/mm(3) * 2000 - < 3000/mm(3) * 1000 - < 2000/mm(3) < 1000/mm(3)
-----------------------------------------------------------------------------------------------------------------------------
Neutrophils/granulocytes WNL * 1.5 - < 2.0 x 10(9)/L * 1.0 - < 1.5 x 10(9)/L * 0.5 - < 1.0 x 10(9)/L < 0.5 x 10(9)/L
(ANC/AGC) * 1500 - < 2000/mm(3) * 1000 - < 1500/mm(3) * 500 - < 1000/mm(3) < 500/mm(3)
-----------------------------------------------------------------------------------------------------------------------------
</Table>
* Greater than or equal to
69
<Table>
<Caption>
GRADE
--------------------------------------------------------------------------------------------------------
TOXICITY 0 1 2 3 4
-------------------- --------- --------------------- --------------------- --------------------- ---------------------
For BMT: WNL *1.0 - < 1.5 x 10(9) *0.5 - < 1.0 x 10(9) *0.1 - < 0.5 x 10(9) < 0.1 x 10(9)/L
/L *1000 - /L *500 - /L *100 - < 500/mm(3) < 100/mm(3)
< 1500/mm(3) < 1000/mm(3)
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the protocol so
specifies.
For leukemia studies WNL 10 - < 25% 25 - < 50% 50 -< 75% *75% decrease
or bone marrow decrease from decrease from decrease from from screening
infiltrative/ screening screening screening
myelophthisic process
------------------------------------------------------------------------------------------------------------------------------------
Platelets WNL < LLN - 75.0 X 10(9) *50.0 - < 75.0 x 10(9) *10.0 - < 50.0 x 10(9) < 10.0 x 10(9)/L
/L /L /L < 10000/mm(3)
< LLN - 75000/mm(3) *50000 - *10000 -
< 75000/mm(3) < 50000/mm(3)
------------------------------------------------------------------------------------------------------------------------------------
CONSTITUTIONAL SYMPTOMS
------------------------------------------------------------------------------------------------------------------------------------
Fatigue none increased fatigue moderate (e.g., severe (e.g., bedridden or
(lethargy, malaise, over screening, but decrease in decrease in disabling
asthenia) not altering normal performance status performance status
activities by 1 ECOG level or by *2 EDOG levels
20% Karnofsky or or 40% Karnofsky or
Lansky) or causing Lansky) or loss of
difficulty performing ability to perform
some activities some activities
Note: See Appendix of the protocol for performance status scales.
------------------------------------------------------------------------------------------------------------------------------------
Fever (in the absence none 38.0 - 39.0 degrees C 39.1 - 40.0 degrees C > 40.0 degrees C > 40.0 degrees C
of neutropenia, where (100.4 - 102.2 (102.3 - 104.0 ( > 104.0 degrees F) ( > 104.0 degrees F)
neutropenia is degrees F) degrees F) for < 24 hrs for > 24 hrs
defined as AGC
< 1.0 x 10(9)/L
Also consider Allergic reaction/hypersensitivity.
Note: The temperature measurements listed above are oral or tympanic.
------------------------------------------------------------------------------------------------------------------------------------
Rigors, chills none mild, requiring severe and/or not responsive to -
symptomatic prolonged, narcotic medication
treatment (e.g., requiring narcotic
blanket) or non- medication
narcotic medication
------------------------------------------------------------------------------------------------------------------------------------
Weight loss < 5% 5 - < 10% 10 - < 20% * 20% -
Also consider Vomiting, Dehydration, Diarrhea.
------------------------------------------------------------------------------------------------------------------------------------
Constitutional none mild moderate severe life-threatening or
Symptoms - Other disabling
(Specify, )
------------------------------------------------------------------------------------------------------------------------------------
DERMATOLOGY/SKIN
------------------------------------------------------------------------------------------------------------------------------------
Injection site none pain or itching or pain or swelling, ulceration or -
reaction erythema with inflammation necrosis that is
or phelebitis severe or prolonged,
or requiring surgery
------------------------------------------------------------------------------------------------------------------------------------
Urticaria none Requiring no requiring PO or requiring IV -
(hives, welts, medication topical treatment or medication or
wheals) IV medication or steroids for
steroids for *24 hours
< 24 hours
------------------------------------------------------------------------------------------------------------------------------------
Dermatology/Skin - none Mild moderate severe life-threatening or
Other disabling
(Specify, )
------------------------------------------------------------------------------------------------------------------------------------
</Table>
----------
* greater than or equal to
** less than or equal to
70
<Table>
<Caption>
------------------------------------------------------------------------------------------------------------------------------------
GASTROINTESTINAL
------------------------------------------------------------------------------------------------------------------------------------
Anorexia none loss of appetite oral intake requiring IV fluids requiring feeding
significantly tube or parenteral
decreased nutrition
------------------------------------------------------------------------------------------------------------------------------------
HEPTIC
------------------------------------------------------------------------------------------------------------------------------------
Alkaline phosphatase WNL >ULN - 2.5 x ULN >2.5 - 5.0 x ULN >5.0 - 20.0x ULN >20.0 x ULN
------------------------------------------------------------------------------------------------------------------------------------
Bilirubin WNL >ULN - 1.5 x ULN >1.5 - 3.0 x ULN >3.0 - 10.0x ULN >10.0 x ULN
------------------------------------------------------------------------------------------------------------------------------------
SGOT (AST) WNL >ULN - 2.5 x ULN >2.5 - 5.0 x ULN >5.0 - 20.0x ULN >20.0 x ULN
(serum glutamic
oxaloacetic
transaminase)
------------------------------------------------------------------------------------------------------------------------------------
SGPT (ALT) WNL >ULN - 2.5 x ULN >2.5 - 5.0 x ULN >5.0 - 20.0x ULN >20.0 x ULN
(serum glutamic
pyruvic transaminase)
------------------------------------------------------------------------------------------------------------------------------------
Hepatic-Other none Mild moderate severe life-threatening or
(Specify, ) disabling
------------------------------------------------------------------------------------------------------------------------------------
LYMPHATICS
------------------------------------------------------------------------------------------------------------------------------------
Lymphatics normal mild lymphedema moderate severe severe
lymphedema lymphedema lymphedema
requiring limiting function; limiting function
compression; lymphocyst with ulceration
lymphocyst requiring surgery
------------------------------------------------------------------------------------------------------------------------------------
Lymphatics-Other none Mild moderate severe life-threatening or
(Specify, ) disabling
------------------------------------------------------------------------------------------------------------------------------------
RENAL/GENITOURINARY
------------------------------------------------------------------------------------------------------------------------------------
CREATININE WNL >ULN - 1.5 x ULN >1.5 - 3.0 x ULN >3.0 - 6.0 x ULN >6.0 x ULN
Note: Adjust to age-appropriate levels for pediatric patients.
------------------------------------------------------------------------------------------------------------------------------------
Urinary retention normal hesitancy or hesitancy requiring requiring frequent bladder rupture
dribbling, but no medication or in/out
significant residual occasional in/out catheterization
urine; retention catheterization (<4 (*4 x per week) or
occurring during x per week) or urological
the immediate operative bladder intervention (e.g.,
postoperative atony requiring TURP, suprapubic
period indwelling catheter tube, urethrotomy)
beyond immediate
postoperative
period but for <6
weeks
------------------------------------------------------------------------------------------------------------------------------------
Urine color change normal asymptomatic,
(not related to other change in urine
dietary or physiologic color
causes e.g., bilirubin,
concentrated urine,
hematuria)
------------------------------------------------------------------------------------------------------------------------------------
Vaginal bleeding is graded in the HEMORRHAGE category.
------------------------------------------------------------------------------------------------------------------------------------
Vaginitis none mild, not requiring moderate, relieved severe, not relieved ulceration requiring
(not due to treatment with treatment with treatment, or surgery
infection) ulceration not
requiring surgery
------------------------------------------------------------------------------------------------------------------------------------
Renal/Genitourinary- none mild moderate severe life-threatening or
Other (Specify, disabling
)
------------------------------------------------------------------------------------------------------------------------------------
</Table>
* greater than or equal to
71
APPENDIX M
TOXICITY MODULE
To be implemented at the request of the study sponsor or principal investigator
in the protocol or by protocol amendment when more detailed information is
considered pertinent.
-------------------------------------------------------------------------------------------------
Toxicity: Date of Treatment: Course Number:
-------------------------------------------------------------------------------------------------
Date of onset: Grade at onset:
-------------------------------------------------------------------------------------------------
Date of first change in grade: Grade:
-------------------------------------------------------------------------------------------------
Date of next change in grade: Grade:
-------------------------------------------------------------------------------------------------
Date of next change in grade: Grade:
-------------------------------------------------------------------------------------------------
Date of next change in grade: Grade:
-------------------------------------------------------------------------------------------------
Date of next change in grade: Grade:
-------------------------------------------------------------------------------------------------
Date of next change in grade: Grade:
-------------------------------------------------------------------------------------------------
Did toxicity resolve? Yes_____ No_____
If so, date of resolution of toxicity:
-------------------------------------------------------------------------------------------------
Date of last observation (if prior to
recovery):
-------------------------------------------------------------------------------------------------
Reason(s) observations stopped (if
prior to recovery):
-------------------------------------------------------------------------------------------------
Was patient retreated? Yes_____ No_____
If yes, was treatment delayed for
recovery? YES_____ NO_____
Date of next treatment?
Dose reduced for next treatment? Yes_____ No_____
-------------------------------------------------------------------------------------------------
Additional Comments:
-------------------------------------------------------------------------------------------------
-------------------------------------------------------------------------------------------------
If module is being activated for new toxicity, not currently in CTC, please
provide definitions for toxicity grading:
Grade 0 = __________________________________________________________________________________
Grade 1 = __________________________________________________________________________________
Grade 2 = __________________________________________________________________________________
Grade 3 = __________________________________________________________________________________
Grade 4 = __________________________________________________________________________________
72
EXHIBIT B
M.D. Anderson Cancer Center Study Protocol No. ID99-333
-10-
73
PROTOCOL ABSTRACT
PHASE I CLINICAL TRIAL OF RECOMBINANT PROSTATE SPECIFIC MEMBRANE ANTIGEN
(rPSMA)-LOADED MATURE AUTOLOGOUS DENDRITIC CELLS (CaPVax) FOR THE TREATMENT OF
METASTATIC HORMONE REFRACTORY PROSTATE CANCER
STUDY CHAIRMAN:
Christos Papandreou, M.D., Ph.D.
OBJECTIVE:
The purpose of this study is to assess the safety of and to monitor patient
response to CaPVax, mature, autologous dendritic cells (DC) loaded ex vivo with
recombinant prostate specific membrane antigen (rPSMA; Medarex Corporation,
Annandale, NJ), in the treatment of patients with metastatic, hormone refractory
prostate cancer (HRPC).
ELIGIBILITY:
1. Histologic proof of prostate carcinoma, progressing hormone refractory
disease after antiandrogen withdrawal trial, in the presence of castrate
serum testosterone levels (<30 ng/dl).
Hormone therapy, with the exception of antiandrogens, to maintain androgen
ablation must continue (e.g. Luteinizing hormone-releasing hormone (LHRH)
agonists). Progression can manifest itself as:
a) A 50% increase in prostate specific antigen (PSA) level from the nadir
PSA level confirmed twice and measured at least two weeks apart,
b) New bone lesion on bone scan, or
c) Progression of soft tissue disease as evidenced by standard radiographic
methods i.e. CT or MRI.
2. Age greater than 18 years old, life expectancy of at least 1 year, Zubrod
performance status 0-1.
3. Patients must have limited bone disease, if any, < or = 3 metastatic lesions
on bone scan, and Minimal symptoms.
4. Adequate hematological function, i.e. Hemoglobin > 12.8 mg/dl, WBC < or =
11,000, ANC>1,000/mm(3), Platelets> 100,000/mm(3)
5. Adequate hepatic and renal functions, i.e. bilirubin <1.5mg/dl, SGOT/SGPT <
2 times the Upper limit of normal, and serum creatinine <2.5mg/dl.
6. Patients must not have received prior Ketoconazole, chemotherapy, radiation
therapy for Metastatic disease, including Strontium-89, or other
investigational therapy.
7. Patients who received any immunosuppressives, such as Prednisone, or
Hydrocortisone in the Four (4) weeks prior to enrollment into the study are
not eligible.
8. Patients with brain metastases, uncontrolled heart, liver or renal diseases,
or other serious Intercurrent illness (including known HIV or hepatitis
positive) are not eligible. Patients with Prior splenectomy, history of
severe asthma, anaphylaxis or other serious adverse reactions to Vaccines
are not eligible. Patients with autoimmune disease such as rheumatoid
arthritis, Systemic lupus erythematosus, scleroderma, polymyositis-
dermatomyositis, juvenile onset Insulin dependent diabetes or vasculitis are
not eligible.
74
9. Patients with a positive protein purified derivative (PPD) skin test or
history of previous bacillus Calmette-Guerin (BCG) vaccination, Tuberculosis
(TB) exposure, or adverse reactions to vaccines or skin tests are not
eligible.
10. Patients may not take any medication that may affect immune function, with
the following exceptions: nonprescription strength doses of non-steroidal
anti-inflammatory drugs (NSAIDS), acetaminophen or aspirin, low doses of
antihistamine therapy, normal range doses of vitamins and H2 blockers.
11. Signed informed consent, in keeping with the institutional policies,
indicating that the patient is aware of the investigational nature of this
study. The consent form is appended to this protocol.
TREATMENT PLAN:
Peripheral blood mononuclear cells (PBMC) are isolated by leukapheresis from the
patient. These cells are cryopreserved for further ex vivo expansion. Adherent
cells are then cultured in with Interleukin-4 (IL-4; Schering-Plough
Corporation, Madison, NJ) and Leukine(R), also known as granulocyte-macrophage
colony-stimulating factor (GM-CSF; Immunex Corporation, Seattle, WA) to generate
DC. Inactivated BCG (Organon Teknika, Durham, NC) mycobacteria is added to the
dendritic cell cultures to facilitate maturation of the cells and to enhance a
carrier immune response. The DC are loaded with rPSMA. Patients receive four
monthly treatments of 5 million, 10 million, or 20 million rPSMA-loaded mature,
autologous DC (CaPVax) by intradermal injection followed by 2 hours of close
observation.
STATISTICAL CONSIDERATIONS:
This is a two-center study, with equal numbers of patients treated at each site.
All patients receive CaPVax injections and act as their own controls. The
treatment plan is presented in Section 5.0.
Safety Monitoring
A serious adverse event (AE) has been defined on page 19. Consider the patients
treated at one of the dose levels (DLs). Denote the probability of an adverse
event (AE) at this DL by (theta). The maximum acceptable probability of an AE in
a population of patients treated at any DL is .05. We assume that, a priori,
(theta) follows a beta distribution with parameters (.10,1.9), which in
particular has mean .05. The early stopping criterion is that the DL will be
terminated if at any point in the trial Pr[(theta) > .05 / data] > .90. Applying
this criterion in sequence will terminate that DL if [# patients with an AE ]/
[# patients evaluated] is > or = 2/10, 3/22, 4/35, or 5/50. To apply this rule,
note that the boundary "2/10" means that the DL will be discontinued if 2 AEs
are observed at any point among the first 10 patients treated at that DL and
evaluated, hence 2/2, 2/3, ..., up to 2/10 will cause the DL to be terminated.
Similarly, for example, if there are 1/10 and then 2/11 AEs, so that the trial
continues to treat patients at that DL at that point, but subsequently one more
AE is observed in any patient thereafter up to the 22nd patient evaluated, then
that DL is stopped. These rules pertain to all patients evaluated at that DL,
including patients in the dose escalation stage. Thus, for example, a DL will be
terminated if 2 patients among the first 3 or 6 treated in the dose escalation
stage have an AE.
75
For a single dose level with up to 20 patients, this rule has the following
operating characteristics:
True Prob[AE] Prob[Early Termination] Sample Size 25th, 50th 75th
Percentiles
------------- ----------------------- ---------------------------
.01 .005 20 20 20
.05 .11 20 20 20
.10 .37 10 20 20
.20 .80 5 9 18
.25 .91 4 7 10
Although at most 20 patients will be treated at each dose level if none of the
three DLs are terminated early, in the case that a DL is terminated early the
remaining patients among the 60 in the trial will be randomized to the remaining
dose levels. In this case, more than 20 patients may be treated on each of the
remaining DLs. This is a simple "play the winners" strategy. It has the
advantage that it is ethically desirable for the patients, since they are less
likely to be treated at unsafe DLs, and it is scientifically desirable since it
provides more information for the DLs not terminated, compared to what would be
the case if the sample size were limited to a maximum of 20 per dose level.
PATIENT EVALUATION: (Pretreatment and Interim Testing)
A complete history and physical exam to include performance status, recent
weight loss, concurrent nonmalignant disease and therapy is performed prior to
entry into study and every month. A skin prick test panel with control and 3
common recall antigens to be read at 15 minutes after inoculation for
immediate-type hypersensitivity and reevaluated at 48 hours after
administration. Delayed-type hypersensitivity (DTH) skin test to measure
patient's response to rPSMA is performed at screening, four weeks after the
second injection, two weeks after the fourth injection, and fourteen weeks after
the last injection (week 26). LABORATORY studies at study entry shall include
CBC, differential, platelets, urinalysis, sodium, potassium, chloride,
bicarbonate, BUN, creatinine, magnesium, calcium, phosphorus, glucose, SGPT,
total bilirubin, albumin, total alkaline phosophatase, lactate dehydrogenase,
PSA, prostatic acid phosphatase (PAP), and testosterone. A bone scan, chest
x-ray, CT of the abdomen and pelvis and EKG are performed at screening. Repeat
evaluation including complete history and physical exam, performance status,
recent weight loss, CBC, differential, platelet count, urinalysis, sodium,
potassium, chloride, bicarbonate, BUN, creatinine, magnesium, calcium,
phosphorus, glucose, SGPT, total bilirubin, albumin, total alkaline
phosophatase, lactate dehydrogenase, PSA, PAP, ESR, and ANA are performed at
various intervals throughout the study (see Appendix A, Study Diagram), Bone
scan, chest x-ray, and CT scan of abdomen and pelvis are repeated eight weeks
after the last injection (week 20) and six weeks following the week 20 visit
(week 26).
76
ESTIMATED ACCRUAL:
It is estimated that accrual will be 10-15 participants per month. The total
accrual is 60 Patients, 30 patients at each study center.
SITE OF STUDY:
This study is performed on an:
Inpatient OUTPATIENT
LENGTH OF STAY:
This is an outpatient regimen.
RETURN VISITS: (How often must participants visit the Principal
Investigator's Site?)
Patients will be seen as outpatients every 2-4 weeks.
HOME CARE: (SPECIFY WHAT (IF ANY) TREATMENT MAY BE GIVEN AT HOME)
Please refer to Section 9.0, Concomitant Medications
WHERE WILL STUDY BY CONDUCTED:
Only at MDACC
NAME OF SPONSOR/FUNDING SOURCE:
Northwest Biotherapeutics, Inc., 120 Northgate Plaza, Suite 200, Seattle,
Washington, 98125, Sponsor contact: Dr. Elgamal, Sponsor's phone: 206-368-3036,
Fax: 206-368-3026
COMPETING PROTOCOLS:
DM98-066, (This protocol will be the number one priority of the Department of
Genitourinary Medical Oncology)
NAME OF RESEARCH NURSE/DATA MANAGER RESPONSE FOR PROTOCOL:
Rachel Cox
PUBLIC DISPLAY OF PROTOCOL ON THE OFFICE OF PROTOCOL RESEARCH WEB SITE:
The Office of Protocol Research maintains a website (www.clinicaltrials.org)
listing protocols actively accruing patients. No information is given about drug
dose or schedule. Would you like this protocol listed on this website?
Yes No
77
STUDY COLLABORATORS:
/s/ CHRISTOPHER LOGOTHETIS /s/ LANCE PAGLIARO
----------------------------------- ------------------------------------
Christopher Logothetis, M.D. Lance Pagliaro, M.D.
GU Medical Oncology GU Medical Oncology
/s/ DANAI DALIANI /s/ RICHARD E. GILES
----------------------------------- ------------------------------------
Danai Daliani, M.D. Richard Giles, Ph.D., B.S.
GU Medical Oncology GU Medical Oncology
/s/ RANDALL MILLIKAN /s/ SHI-MING TU
----------------------------------- ------------------------------------
Randall Millikan, Ph.D., M.D. Shi-Ming Tu, M.D.
GU Medical Oncology GU Medical Oncology
/s/ BENJAMIN LICHTIGER /s/ LORI WOOD
----------------------------------- ------------------------------------
Benjamin Lichtiger, M.D., Ph.D. Lori Wood, M.D.MSc
Laboratory Medicine--Patient Care GU Medical Oncology
Services
/s/ JERI KIM /s/ AIDA B. NARVIOS
----------------------------------- ------------------------------------
Jeri Kim, M.D. Aida B. Narvios, M.D.
GU Medical Oncology Laboratory Medicine--Patient Care
Services
/s/ KIUM ANH DO PETER F. THALL
----------------------------------- ------------------------------------
Kim-Anh Do, Ph.D. Peter Thall, Ph.D.
Department of Biomathmatics Department of Biomethmatics
The Department of Genitourinary Medical Oncology and Laboratory Medicine--
Patient Care Services, The University of Texas M.D. Anderson Cancer Center,
1515 Holcombe Blvd, Box 13, Houston, TX 77030. Telephone: 713-792-2830 -- Fax
713-745-1625
78
1.0 INTRODUCTION
1.1 Review of Prostate Cancer
Prostate cancer is the most common form of cancer currently
diagnosed in American men. In 1999, 179,300 new cases are
expected to be diagnosed with 37,000 deaths resulting from the
disease, making prostate cancer second only to lung cancer as
the leading cancer cause of death among men in the United States
[1].
Although the majority of incident prostate cancer cases are
localized to the prostate, nearly a third of all newly diagnosed
prostate cancer patients may present with locally advanced or
metastatic disease [1]. At this time, available treatments for
metastatic prostate cancer - including hormonal,
chemotherapeutic, and radiation strategies - have failed to
demonstrate curative potential [2]. In addition, prostatectomy
and radiation therapy--the standard therapies employed against
early-stage, localized prostate cancer---can exhibit failure
rates between 20 and 50% [3]. As a result, an everincreasing
number of treated patients accumulate who either manifest
metastatic disease or are at very high risk for the development
of such disease. The treatment options for these primary
treatment failures, as with the primary metastatic cases, are
few in number and severely limited in terms of safety and
efficacy.
Hormonal treatment of metastatic prostate cancer has improved
only marginally because nearly all cases ultimately result in
hormone refractory disease. Although there are occasional
dramatic and long term disease-free survivors with hormonal
therapy, the median survival range of these particular patients
remains at 2 1/2 - 3 years [4, 5]. Once hormonal therapy fails,
there are no curative options and few options for pain relief.
No cytotoxic agent has been able to change consistently the
natural history of HRPC. The median survival of HRPC is less
than one year and no agent has yet been shown to improve the
median survival of such patients. There is a great need for new
treatment modalities that can be given safely with a potential
to improve the late stage life of the 37,000 men who are
estimated to die of the disease in 1999 [1].
1.2 Tumor Specific Immunotherapy
One alternative to widely used conventional cancer treatments is
to utilize the ability of the immune system to target and
eliminate tumor cells. The potential therapeutic benefit of
eliciting an anti-tumor immune response in cancer patients was
first suggested over a decade ago when the direct association
between immunosuppression and increased incidence of melanoma
was initially observed. The original tumor vaccines consisted of
irradiated, allogeneic melanoma cells. Some patients enjoyed
prolonged survival following treatment, although high serum IgM
titers were elicited which reacted with cell membrane antigens
and likely decreased clinical responses. In a phase II report,
Morton et al. treated 136 patients with a vaccine consisting of
3 melanoma lines expressing large amounts of melanoma-associated
antigens. Overall survival increased in several patients, and
correlated with a positive skin test against the immunogen [6].
79
New strategies for tumor immunotherapy are designed to increase
tumor vaccine immunogenicity, resulting in enhanced specific T
cell responses. Some procedures involve genetically altered
tumor vaccines; introducing genes coding for cytokines,
costimulatory molecules, or components of the major
histocompatibility complex (MHC) into tumor cells [7, 8].
Conversely, other approaches to tumor vaccination utilize
altered autologous antigen-presenting cells to present tumor
associated antigens [9, 10]. Since the mechanism of the
molecular events involved in immune recognition is now
elucidated, new and exciting strategies in anticancer
therapeutics are emerging. Researchers now understand some of
the crucial portions of primary and secondary signaling pathways
that are activated when T and B lymphocytes produce an immune
response to a tumor cell [reviewed in 11-13]. T cell recognition
of antigen requires the formation of a trimolecular complex
comprised of: 1) the major histocompatibility complex (MHC); 2)
the T cell receptor (TCR); and 3) a short segment of
intracellularly-processed protein associated with the MHC.
Antigen presentation of cell-surface peptides to T cells can
occur in association with either MHC class I or II molecules;
the former associated with CD8(+) T cell responses (usually
cytolytic T cells [CTL]), and the latter associated with CD4(+)
T cell responses (usually helper T cells [T(H)]). Since most
tumors do not express MHC class II, it is generally accepted
that the enhancement of CD8(+) mediated immune responses is of
paramount importance in anti-cancer immunotherapeutics. Tumor
specific proteins are proteolytically cleaved into fragments of
8-12 amino acids in length, the peptides are presented on the
cell surface in association with MHC class I, and the complex is
recognized by the TCR of naive T cells [11, 13].
Significant progress in the discovery and characterization of
tumor-associated antigens (TAA), beginning with the
identification of melanoma antigen (MAGE) earlier in this
decade, is evident [14, 15]. Intensive research into these
moieties as potential targets of immune-based cancer treatment
is continuous. These TAA targets can be classified into four
general groups;
1. "Cancer/testis" antigens, including the MAGE
gene family [16-21], whose expression in normal
tissues is limited to testis and whose genes
have been mapped to the X chromosome;
2. Antigens derived from viruses such as Human
Papilloma Virus [22, 23] and Epstein-Barr Virus
[24];
3. Differentiation antigens such as PSA [25, 26],
prostate-specific membrane antigen (PSMA)
[27-29], Melan-A/MART-1 [30], and gp100 [31];
4. Antigens existing in a modified or mutated state
in tumors as compared to normal tissue, such as
ras [32, 33] and p53 [34, 35].
Favorable results continue to be reported as compared with
standard treatments such as chemotherapy and radiotherapy, and
so hold promise for decreasing patient mortality.
80
1.3 CaPVax: A Dendritic Cell/recombinant Prostate Specific Membrane
Antigen Immunotherapy for Prostate Cancer
CaPVax is an autologous cellular immunotherapy being studied for
the treatment of hormone refractory metastatic prostate cancer.
CaPVax is based on mature autologous DC loaded ex vivo with
rPSMA. The rPSMA-DC are prepared ex vivo wherein the patient's
leukapheresed peripheral blood mononuclear cells (PBMC) are
processed in a 7-day incubation procedure, including an
overnight incubation period with inactivated BCG and same-day
osmotic loading with rPSMA. This methodology produces mature
rPSMA-loaded autologous DC that are then injected back into the
patient. The pharmacologic rationale for CaPVax is to elicit a
potent anticancer T cell response as a result of the efficient
presentation by the DC of rPSMA in the form of a complex of
antigen and MHC molecules to T cells. The goal is to elicit a
specific antigen-specific immune response in HRPC patients.
1.3.1 Prostate Specific Membrane Antigen
PSMA is a 750 amino acid type II transmembrane membrane
glycoprotein containing 10 potential N-linked
glycosylation sites [36]. PSMA is composed of a 19 amino
acid intracellular portion, a 24 amino acid
transmembrane portion, and a 707 amino acid
extracellular portion [37].
The expression of PSMA in human tissues has been
extensively studied [27, 36, 38-40]. Evidence from
immunohistochemical studies using the anti-PSMA antibody
7E11.C5 indicates that PSMA is highly, but not
exclusively, specific for prostatic epithelial cells
[29, 36, 38, 40-41]. Immunohistochemical and Western
blot studies indicate weak but detectable PSMA
expression in salivary gland, brain, and small intestine
[27, 36, 39, 42]. In contrast, these studies confirmed
the highest expression of PSMA in prostatic tissues.
Similarly, results from ribonuclease protection assays
utilizing prostatic and 11 other human tissue types
indicated strong prostatic expression and weak
expression in brain and salivary tissues. In
collaboration with Hybritech, Inc. (San Diego, CA),
quantitative ELISA assays were performed for PSMA
presence in the membrane and cytosol fractions of a
variety of tissues. Results again point to the high
degree of prostate specificity of PSMA (Table 1).
81
TABLE 1: PSMA LEVELS IN HUMAN TISSUE SPECIMENS
TISSUE PROTEIN (MG/ML) PSMA (NG/ML) PSMA/PROTEIN (NG/MG)
------ -------------- ----------- -------------------
PROSTATE (NORMAL)
Membrane 10.2 10,492 1,029
Cytosol 7.8 138 18
PROSTATE (BENIGN)
Membrane 7.7 4,701 611
Cytosol 9 267 30
PROSTATE (CANCER)
Membrane 19.6 69,789 3,561
Cytosol 11.3 718 64
BREAST (NORMAL)
Membrane 3.8 79 21
Cytosol 2.9 1.1 0.4
BREAST (CANCER)
Membrane 20.4 884 43
Cytosol 11.6 23.5 2
SMALL INTESTINE 4.5 4.6 1
LARGE INTESTINE
Membrane 8.6 71.3 8.3
Cytosol 6.2 2.3 0.4
KIDNEY
Membrane 17.2 31.5 1.8
Cytosol 10.9 0.7 0.1
OVARY
Membrane 4.8 244 51
Cytosol 6.4 21.3 3.3
LIVER
Membrane 24.1 64.3 2.7
Cytosol 18.9 19 0.1
BONE
Membrane 8.5 21.7 2.6
Cytosol 3.4 0.9 0.3
SKIN
Membrane 2.1 17 8.1
Gytosol 6.2 2.3 0.4
Detailed studies of PSMA expression in prostatic tissues
were conducted on 184 whole mount step-sectioned
prostate specimens after radical prostatectomy [38]. In
this study, intense immunoreactivity for PSMA with
7E11.C5 was observed in all cases. The mean number of
cells staining in benign epithelium and prostatic
intraepithelial neoplasia (PIN) was lower than in
adenocarcinoma. Staining was highly specific for
epithelial cells and adenocarcinomas were most intensely
stained with the highest grade cancers showing intense
staining of almost every cell. This observation is
consistent with biochemical studies showing that PSMA
mRNA expression is downregulated by steroids such as
5a-dihydrotestosterone and is upregulated by BFGF,
TGF-a, and EGF [27]. This behavior corresponds to the
elevated expression of PSMA in hormone refractory
tumors. Thus, its expression patterns from normal tissue
to advanced cancer makes PSMA a very useful marker for
treatment and prediction of outcome in patients with
prostatic cancer.
82
Protocol ID99-333
November 5, 1999
Page 5
In summary, these studies combine to indicate that PSMA
is an excellent target for immunotherapy, having the
required tissue specificity. For this phase I clinical
trial rPSMA is contract manufactured through Medarex,
Inc. (Annandale, NJ).
1.3.2 Dendritic Cell-Based Immunotherapy
T cells are the major immune system component largely
responsible for the recognition and destruction of tumor
cells based on expression of specific tumor-associated
antigens. As the specific mechanisms underlying the
immune response were revealed, this information was
utilized to elicit or amplify antitumor immune response.
T cell immune responses begin with the interaction of
the T cell receptor with antigenic peptides bound to MHC
proteins. If this interaction is accompanied by binding
of costimulatory receptors (e.g. CD28) to their ligands
(CD80 and CD86), then an intracellular cascade of
biochemical events is triggered that results in T cell
activation and proliferation. Activated T cells are able
to lyse target cells, e.g. tumor cells, which express
the stimulating antigen and the appropriate MHC protein.
Antigen-presenting cells are specialized cells that
express the required molecules involved in T cell
activation events. DC are considered the most potent
antigen presenting cell (APC), capable of initiating
primary T cell responses [11-13, 43,44].
DC express high levels of MHC class I and II molecules,
as well as abundant levels of costimulatory factors. In
their immature state, they display phagocytic and
macropinocytotic activity. As they mature, surface
receptors involved in antigen uptake undergo
down-regulation. Concurrently, DC enhance their ability
to process and present antigen to naive T cells. DC
stimulate naive T cells to become antigen-specific
effectors more effectively than any other APC, and they
do so following their migration to primary lymphoid
tissue where such T cells are predominantly located
[45]. The ability of each dendritic cell to stimulate as
many as 100 T cells in vitro provided the scientific
rationale for our approach using the adoptive transfer
of DC.
DC are found in low abundance in various tissues, and
obtaining sufficient numbers of DC from prostate cancer
patients can be difficult in light of the patients' past
cancer therapy, which may have compromised their immune
system. DC were successfully isolated and cultured from
PBMC from such prostate cancer patients [46]. After
incubation of adherent PBMC in the presence of
Leukine(R), and IL-4 (each 500 U/mL) for 7 days, the
majority of cells have dendritic morphology and possess
cell surface markers characteristics of DC (CD3-, CD14-,
CD19-, CD1a+, CD4+, CD11c+, and HLA-DR+) [46]. These
culture methods allow for ex vivo expansion of
autologous DC from tumor-bearing patients in sufficient
numbers for use in immunotherapeutic studies. Autologous
DC are charged with tumor antigens, and introduced back
into patients as a cancer vaccine. Several clinical
trials involving
83
readministration of autologous DC pulsed with tumor antigens have been
conducted with positive clinical outcomes (Table 2).
The majority of the trials are for the treatment of several different
types of malignancy with a single exception treating HIV. The only
consistent finding from all the reports is the absence of serious
adverse reactions. Regardless of the route of injection, dose or source
of antigen, administration of DC is well tolerated and does not induce
autoimmune disease [47]. The only adverse events that have been
reported are mild fever and swelling of the lymph node when cells are
introduced intranodally.
From the clinical trials reported to date, it is difficult to reach a
consensus on any variable, such as dose, route of administration,
antigen, etc., other than safety because of the large differences in
trial design. It is also uncertain the extent to which the DC
immunotherapy is therapeutic because the number of patients treated
thus far is small. However, the responses reported thus far are
encouraging and warrant further investigation.
TABLE 2: SUMMARY OF CLINICAL TRIALS UTILIZING DC
<Table>
<Caption>
----------------------------------------------------------------------------------------------
NUMBER OF ROUTE OF NUMBER OF ADVERSE CLINICAL
DISEASE ANTIGEN PATIENTS ADMINISTRATION DC REACTIONS RESPONSE
----------------------------------------------------------------------------------------------
B Cell Tumor 4 i.v.* 2-32 million None 3
Lymphoma[9] Specific Responders
Idiotype
----------------------------------------------------------------------------------------------
CEA Expressing CEA Peptide 11 i.v. 10-30 None 2
Tumors[47] million Responders
8 i.v./i.d.** 100 million/
1 million
----------------------------------------------------------------------------------------------
Prostate PSMA 95 i.v. 5-30 million None 28
Cancer[48-49] Peptides Responders
----------------------------------------------------------------------------------------------
Melanoma[50] Tumor Lysate 16 Intranodal 1 million None 5
or MAGE Responders
peptides
----------------------------------------------------------------------------------------------
HIV[51] Gp 160 or Env, 6 i.v. None No
gag and pol Responders
peptides
----------------------------------------------------------------------------------------------
Renal Cell Tumor Lysate 4 i.v. 5-10 None 1
Carcinoma[52] million Responder
----------------------------------------------------------------------------------------------
Multiple Tumor 12 i.v. 0.5-11 None 3
Mylemona[53] Specific million Responders
Idiotype
----------------------------------------------------------------------------------------------
</Table>
* Intravenous administration
** Intradermal administration
1.3.3 DC Loaded with PSMA Activate Antigen Specific CD4(+) and CD8(+) T cells
from Prostate Cancer Patients
The ability of DC from prostate cancer patients to activate autologous
T cells was evaluated in vitro. Prostate cancer patients' DC were
loaded with PSMA using methods to enhance immunologic potency: 1)
inclusion of inactivated
84
BCG mycobacteria to elevate CD83 and CD86 expression on
the DC; and 2) osmotic loading using hypertonic medium
to promote the engulfing of exogenous PSMA.
DC from several prostate cancer patients were loaded
with rPSMA or PSMA purified from LNCaP cells (LnPSMA).
The LNCaP cell line was derived from a needle aspiration
biopsy of the left supraclavicular lymph node of a man
with confirmed metastatic prostate adenocarcinoma and
expresses several prostate specific characteristics,
including expression of PSMA. The DC were osmotically
loaded with either LnPSMA or rPSMA in the presence of
BCG. These PSMA loaded DC were then co-cultured with
autologous PBMC. The T cells stimulated by the DC during
the 10 day co-culture were isolated and co-cultured a
second time with PSMA loaded autologous DC. Beginning
seven days after the second co-culture, T cell
reactivity to PSMA was determined on a weekly basis
using an enzyme-linked immunoadsorbent assay (ELISA) to
measure interferon-y (IFNy) secretion. At various
time-points, most of the patients' T cells studied had
reactivity to PSMA. In one typical assay, PSMA specific
T cells were generated from the PBMC of Patient 105
(Figure 1). Three in vitro stimulations with DC loaded
with either LnPSMA or rPSMA were performed. Following
this, T cells were reactive with autologous DC
osmotically loaded with either LnPSMA (Figure 1a) or
rPSMA (Figure lb). Both rPSMA and LnPSMA loaded DC that
were matured with BCG produced activated antigen
specific T cells.
In another experiment, DC was loaded with different
amounts of LnPSMA to define the optimum amount of
antigen for T cell stimulation (Figure 2). Two different
concentrations of DC (2 x 10(7) or 1 x 10(7)) were
osmotically loaded with 15 to 60 ug PSMA in a 0.2 mL
volume. (approx. 75-300 ug/mL). 1 x 10(7) DC were
osmotically loaded with 60 ug ovalbumin (OVA) in a 0.2
mL volume (approx. 300 ug/mL) as a specificity control.
These DC were mixed with autologous PSMA-reactive T
cells. Cultured T cells were washed and added to 96-well
plates at 5 x 10(4) cells/well in duplicate. Autologous
DC pulsed with PSMA, OVA, or unpulsed were added to the
autologous T cells at 5 x 10(4) cells/well. After 24
hours incubation, 150 ul of supernatant was removed from
each culture. An ELISA using paired antibodies from the
manufacturer (Endogen, Inc., Woburn, MA) measured the
amount of IFNy present. When 1 x 10(7) DC were loaded
with PSMA, IFNy secretion was observed maximally with 30
ug PSMA. When 2 x 10(7) DC were loaded with PSMA, a
slight dose-dependent decrease in IFNy secretion was
observed with minimum IFNy secretion at 60 ug PSMA.
However, the amount of IFNy secretion was greater - and
more highly specific - when 2 x 10(7) versus 1 x 10(7)
DC were loaded with PSMA. Therefore, we chose to load
30ug PSMA in order to achieve strong immunoreactivity.
In a subsequent experiment, a constant amount of LnPSMA
(60 ug) was osmotically loaded into various
concentrations of DC - from 2 x 10(6) to 2 x 10(7) - to
define the optimum number of DC (per a given amount of
antigen) for T cell stimulation (Figure 3). Four
different concentrations of DC were osmotically
85
loaded with LnPSMA as before; in a 0.2 mL volume. DC
were osmotically loaded with 60 mg ovalbumin (OVA) in a
0.2 mL volume as a specificity control. These DC were
mixed with autologous PSMA-reactive T cells. IFNy
secretion was measured after 24 hours. Standard ELISAs
were performed to assess IFNy secretion.
Immunoreactivity was comparable, regardless of the
amount of DC; a true dose-dependent effect of DC
concentration of IFNy secretion was not observed. This
assay demonstrated that 2 x 10(7) DC could be loaded
with a LnPSMA concentration nearly approximating that
used in our clinical methodology.
We propose to include inactivated BCG in the final 18-24
hours of dendritic cell culture because of its ability
to stimulate maturation of DC and thereby to enhance T
cell activation. BCG treatment upregulates the
expression of several surface molecules crucial to the
enhanced function of a dendritic cell as an APC,
including CD40, CD54, CD80, CD83 and CD86 (Figure 4).
86
Protocol ID99-333
November 5, 1999
Page 9
SPECIFIC CYTOKINE SECRETION BY
PT 105 T CELLS STIMULATED WITH
PSMA OSMOTICALLY LOADED INTO BCG-TREATED DC
[DIAGRAM]
FIGURE 1: PBMC from a prostate cancer patient were stimulated in vitro with
BCG-treated, autologous DC osmotically loaded with either (2 different T-cell
lines were tested, 1 against LnPSMA, 1 against rPSMA (A) 15 ug LnPSMA or (B) 15
ug rPSMA at an effector:stimulator ratio of 10:1. Three days after initial
stimulation, 300 1U/ml IL-2 was added to each 24-well culture. Cultures were
restimulated with PSMA-loaded DC at day 10 of culture, and at weekly intervals
thereafter. IL-2 was subsequently added one day after each restimulation,
5x10(5)/ml effector T cells and 5x10(5)/ml DC stimulators were added in
duplicate to 96-well plates in a volume of 100 u1 each. Twenty-four hours later,
the supernatants were harvested and measured for IFN-gamma production in an
ELISA using standard, matched antibody pairs.
SPECIFIC CYTOKINE SECRETION BY PT 112
T CELLS STIMULATED WITH BCG-TREATED DC
OSMOTICALLY LOADED WITH PSMA
[DIAGRAM]
FIGURE 2: PBMC from a prostate cancer patient were stimulated in vitro as
described in the legend to Fig. 1. 5x10(5)/ml effector T cells and 5x10(5)/ml DC
stimulators were added in duplicate to 96-well plates in a volume of 100 u1
each. Ten or twenty million DC were osmotically loaded with various
concentrations of LnPSMA. In addition 1x10(7) DC were either osmotically loaded
with 60ug ovalbumin (OVA) or mock-loaded. Twenty-four hours later, the
supernatants were harvested and measured for IFN-gamma production in an ELISA
using standard, matched antibody pairs.
SPECIFIC CYTOKINE SECRETION BY PT 66
T CELLS STIMULATED WITH BCG-TREATED DC
[DIAGRAM]
FIGURE 3: PBMC from a prostate cancer patient were stimulated in vitro as
described in the legend to Fig. 1. 5x10(5)/ml effector T cells and 5x10(5)/ml DC
stimulators were added in duplicate to 96-well plates in a volume of 100 u1
each. Various amount of DC were osmotically loaded with a standard concentration
of LnPSMA (60ug). In addition 2x10(6) or 5x10(6) DC were either osmotically
loaded with 60ug OVA or mock-loaded. Twenty-four hours later, the supernatants
were harvested and measured for IFN-gamma production in an ELISA using standard,
matched antibody pairs.
87
FIGURE 4: DENDRITIC CELL CHARACTERIZATION
DAY 7 DC DAY 7 DC + 24 Hr BCG
CD40
CD54
[GRAPHS] [GRAPHS] CD80
CD83
CD86
FIGURE 4: Cell surface expression of CD molecules on DC after maturation with
BCG measured by flow cytometry. Adherent PBMC were cultured for six days with
GM-CSF and IL-4. On day six, half the cells were treated with BCG. On day seven,
cells were analyzed by flow cytometry. Isotype controls are indicated by the
broken line and the solid line indicates expression of the CD antigen. CD40 is
expressed on B cells and DC. It is involved in B cell/T cell and DC/T cell
interactions. CD54 is a cell adhesion molecule expressed on B and T lymphocytes,
monocytes, and DC. CD80/CD86 are costimulatory molecules expressed on activated
B cells, macrophages, and DC. CD83 is expressed on mature DC.
2.0 OBJECTIVES
The primary objective of this study is to assess the safety of
immunization with CaPVax, mature autologous DC loaded with rPSMA, in the
treatment of patients HRPC. The secondary objective is to monitor the
potential clinical response of administering CaPVax.
88
The study hypotheses represent primary objectives. Each primary objective is
addressed by endpoint measures which provide objective criteria for evaluating
the hypothesis. Secondary objectives are addressed with statistical methods that
evaluate other benefits of treatment.
2.1 Study Hypothesis and Endpoints
HYPOTHESIS 1: Serious adverse events (AEs) which are either probably or
possibly related to treatment with CaPVax injections will rarely occur
among study subjects.
ENDPOINT 1: A subject is coded as having experienced a serious AE
provided at least one of the AEs listed in Section 10.2 occurs anytime
during the study period. The AE must be at least possibly related to
treatment, as defined in Section 10.1.
HYPOTHESIS 2: As a result of treatment, a significant proportion of
patients will experience either a partial or a complete response to
their HRPC.
ENDPOINT 2: A patient is coded as having a partial or a complete
response provided he satisfies the "response evaluation" criteria
defined in section 11.2.
3.0 PATIENT ELIGIBILITY
3.1 Inclusion Criteria
1. Histologic proof of prostate carcinoma, progressing
hormone refractory disease after antiandrogen withdrawal
trial, in the presence of castrate serum testosterone
levels (<30 ng/dl) Progression can manifest as:
- A 50% increase in PSA level from the nadir PSA
level confirmed twice and measured at least two
weeks apart;
- new bone pain, or new lesion on bone scan; or,
- progression of soft tissue disease as evidenced
by standard radiographic methods of evaluation,
i.e. CT or MRI.
Hormone therapy, with the exception of antiandrogens
(e.g. LHRH) to maintain androgen ablation must continue.
2. Age greater than 18 years old.
3. Life expectancy of at least 1 year.
4. Zubrod performance status : 0-1.
5. Patients must have limited bone disease defined as less
than or equal to 3 metastatic sites on a bone scan and
minimal symptoms.
89
6. Adequate hematological function i.e. Hemoglobin >
12.8mg/dl, WBC < or = 11,000, absolute neutrophil count
(ANC) > 1,000/mm(3), Platelets> 150,000/mm(3).,
7. Adequate hepatic and renal functions, i.e. bilirubin
<1.5mg/dl, SGOT/SGPT < 2 times the upper limit of
normal, serum creatinine < 2.5mg/dl, or creatinine
clearance> 50ml/min.
8. Signed informed consent before any study procedure,
keeping with the institutional policies, indicating that
the patient is aware of the investigational nature of
this study. The consent form is appended to this
protocol (see Appendix K)
3.2 Exclusion Criteria
1. History of prior malignancy other than prostate cancer,
clinically evident within the 24 months preceding
enrollment into the study, except curatively-treated
basal cell or squamous cell carcinoma of the skin.
2. Patients must NOT have received prior Ketoconazole,
chemotherapy, radiation therapy for metastatic disease,
including Strontium-89, or other investigational therapy
that may result in reduced immune competency.
3. Patients who received any immunosuppressives such as
Prednisone or Hydrocortisone in the four weeks prior to
enrollment in the study are not eligible.
4. Patients with brain metastases, uncontrolled heart,
liver or renal diseases, or other serious intercurrent
illness (including known HIV or hepatitis positive) are
NOT eligible.
5. Prior splenectomy.
6. History of severe asthma, anaphylaxis or other serious
adverse reactions to vaccines or any of the antigens
included in the skin test.
7. History of immunodeficiency or autoimmune disease such
as rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, polymyositis- dermatomyositis, juvenile
onset insulin dependent diabetes, or vasculitis.
8. Impending untreated spinal cord compression or urinary
outlet obstruction.
9. Patients with a positive PPD skin test or history of
previous BCG vaccination or Tuberculosis (TB) exposure.
10. Positive virology screening test (Hepatitis B surface
Antigen (HbsAg), Anti-Hepatitis core Antigen (a-HBc),
Liver enzyme (ALT)-surrogate marker for non A, B, C
hepatitis virus, Anti-HIV 1 Antibody (a-HIV-1), Anti-HIV
2 Antibody (a-HIV-2), Anti-human T lymphotropic virus
1(a-HTLV-1), Syphilis, HIV Antigen (HIV-1 p24Ag),
Anti-Hepatitis C Virus (a HCV)).
90
11. Patients may not take any medication that may affect
immune function, with the following exceptions:
nonprescription strength doses of NSAIDS, acetaminophen
or aspirin, low doses of antihistamine therapy, normal
range doses of vitamins and H2 blockers.
4.0 TREATMENT PLAN
PBMC are isolated by leukapheresis from the patient before
treatment begins. An aliquot of these cells is cryopreserved for
further ex vivo culture. After thawing and culturing PBMC,
adherent cells are cultured ex vivo for six days with IL-4 and
Leukine(R) to generate DC. Inactivated BCG is added to the
dendritic cell cultures to facilitate maturation of the cells
and to stimulate a strong carrier immune response after
intradermal administration. Eighteen to twenty-four (18-24)
hours after BCG treatment, rPSMA is added under hypertonic
conditions. Two (2) weeks after BCG treatment and rPSMA loading
of their autologous dendritic cells, patients receive four
injections of 5 million, 10 million, or 20 million rPSMA loaded
autologous DC by intradermal injection [one dose is administered
in 1-4 injections every month (26-32 days)]. Each patient is
observed for 2 hours after administration. Some patients may
need to have a second leukapheresis (between 4-12 weeks after
the first one), depending on the yield of the first
leukapheresis and ex vivo expansion.
The interval one month (26-32 days) between injections was
selected to avoid excess loss of any beneficial immunological
response. Four injections were selected to achieve sufficient
restimulations to generate a maximum T cell response.
At the study center, all CaPVax injections are given
intradermally into one thigh followed by intradermal injections
in alternating thighs at subsequent injections. Each dose of
CaPVax is given as 1-4 injections, each as 0.1 ml, depending on
the dose of DC. Three patients are enrolled first in the 5 x
10(6) DC dose level. If no adverse reactions occur 48 hours
after the first injection, the dose will be escalated to 10 x
10(6) DC in another three patients. If no adverse reactions
occur 48 hours after the first injection, three patients are
enrolled at the highest dose, 20 x 10(6) DC. The rest of the
patients are randomized for one DC dose level such that there
are 10 patients per dose level at each study center (see section
12 for sample size considerations).
If there is evidence of an AE in at least one patient in any
dose level, then the committee for AEs determines if this is a
favorable response or an AE (please refer to Section 10). If it
is determined that it is an AE, then 3 more patients are
enrolled at that same dose before escalation to a higher dose.
5.0 PRE-TREATMENT EVALUATION
5.1 Screening
Screening of patients for participation in this clinical trial
will take place prior to enrollment in order to verify that each
patient meets all study criteria (see section 4.0). Patients
failing the initial screening due to out of range laboratory
values may be rescreened at the investigator's discretion. All
patients screened should be documented using a screening log.
Each patient enrolled in the study must sign the consent form
(see Appendix K) and fill out a patient registration form (see
Appendix F)
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5.1.1 Procedures and Tests
Prior to the first vaccination, Day 1, the following
procedures and tests are performed or administered (see
Appendix A):
1. The patient's medical history and complete
physical examination including vital signs,
height and weight, and Zubrod performance score
(see Appendix B).
2. A skin prick test panel provided by the sponsor
with control and 3 common recall antigens
(Candida Albicans, Mumps, PPD). These tests are
read at 15 minutes after inoculation for
immediate-type hypersensitivity to any of the
antigens and approximately 48 hours after
administration. Palpable indurations of 5mm or
more indicate a positive reaction. The absence
of induration less than 5mm is considered
negative. In case of a negative PPD reaction,
PPD will be repeated in a week to access boost
effect. The widest diameter of distinctly
palpable induration is measured and a Polaroid
photograph will be taken (see Appendix C).
3. DTH skin testing to measure patients' responses
to rPSMA. One tenth ml (0.1ml) dosage of rPSMA
is injected intradermally in distinct sites of
the forearm. Responses are monitored as
described in the above paragraph (skin prick
test). These intradermal challenges are repeated
four weeks after the second injection, two weeks
after the 4th injection, and at week 26.
4. 12 lead EKG. EKG is read and the report signed
by the cardiologist.
5. Chest x-rays (PA and lateral views).
6. Blood and urine are collected for the following:
- Hematology (Complete blood count (CBC) &
differential);
- Blood Chemistry parameters (Chemistry
22) Chem-22 profile includes the
following specific measurements: sodium,
potassium, chloride, bicarbonate, BUN,
creatinine, magnesium, calcium,
phosphorus, glucose, SGPT, total
bilirubin, albumin, total alkaline
phosophatase, lactate dehydrogenase;
- Serum Markers (PSA & PAP);
- Serum Markers of autoimmune disease
[Erythrocytic sedimentation rate (ESR)
and Antinuclear antibodies (ANA)];
- Testosterone;
- Urinalysis with microscopic examination.
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5.1.2 Tumor Imaging
Bone scan, Chest x-ray, and CT of the abdomen and pelvis
are performed at screening. Measurable disease is
defined in Section 11.0. Follow up bone scan, chest
x-ray, and CT scans are repeated at Week 20 and Week 26.
For the responding patients, the radiographic follow-up
will be extended to 9 months and 12 months.
5.1.3 Assessment of patient's Quality of Life (see Appendix D)
and Brief Pain Inventory (see Appendix E)
6.4 ON STUDY EVALUATION (SEE APPENDIX A FOR SCHEDULING)
6.1 Laboratory Procedures and Measurements
1. Routine Safety Laboratory Tests
- Safety-related hematology, blood chemistry, and
physical examinations are performed at various
intervals throughout the study. Testosterone
level and urinalysis are performed at screening
and week 14 (see Appendix A, Study Diagram).
2. Hematology Parameters
- Hematology testing consists of CBC,
differential, and platelets
3. Blood Chemistry Parameters (Chem-22)
4. Urinalysis with microscopic examination
5. Physical Examinations
- Physical examinations include monitoring vital
signs to observe a generalized systemic
reaction, examining the vaccination site for any
local or regional reaction, reviewing any
quality of life changes, and discussing degree
of pain (see Appendices D and E, respectively).
6.2 Special Laboratory Tests
1. Serum PSA is measured.
2. Serum PAP is measured.
3. Serum testosterone is measured.
4. Serum markers of autoimmune disease are measured (ESR
and ANA)
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6.3 Immunology Determinations (To be done by the sponsor)
Blood for immune monitoring is drawn prior to the first
leukapheresis, prior to each injection, and at weeks 2, 14, 20,
and 26 (see Appendix A). PBMC are isolated and utilized for the
following immunological determinations:
1. Nonspecific immune response: stimulation of PBMC with
anti-CD3 measured by proliferation;
2. BCG specific cellular response: stimulation of PBMC with
Tuberculin-purified protein derivative (PPD), a
component obtained from human strains of Mycobacterium
tuberculosis, measured by proliferation;
3. PSMA specific antibodies: measured in serum by ELISA;
4. PSMA specific cellular response: stimulation of PBMC by
autologous DC loaded with rPSMA measured by cytokine
production (ELISA or ELISPOT).
6.4 Skin tests
1. Nonspecific cellular immune response: skin test using 2
additional common recall antigens (Candida albicans,
Mumps).
2. PPD specific DTH response: skin test using PPD.
3. rPSMA specific DTH response: skin test using rPSMA.
6.5 Treatment definitions
6.5.1 Leukapheresis and Blood Draw (See Appendix M)
Prior to beginning CaPVax immunotherapy, patients are
leukapheresed at the Apheresis Unit of the study center.
Another leukapheresis may be performed between the
second and fourth treatments depending on the DC yield
from the first leukapheresis.
Prior to each leukapheresis, a blood work-up is done at
the study center to include CBC, platelet count, and
Chem-22. Blood is drawn for immune monitoring prior to
the first leukapheresis only and is shipped to the
sponsor.
6.5.2 CaPVax Injections
Five, ten, or twenty million mature, autologous
rPSMA-loaded DC are injected intradermally in a shaved,
clean area of the thigh. The CaPVax injections are given
in alternating thighs once every month (26-32 days).
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Each injection contains 5 million DC, thus a patient
receiving twenty million DC receives four injections at
one time.
6.5.3 Clinical Evaluation
Patients are evaluated every month by one of the study
physicians. Aside from the above listed blood tests, CBC
and Chem-22 studies are obtained at every interval.
Physical examination at each follow-up visit is
documented (see Appendix A). Quality of life, pain score
assessments, and monitoring for autoimmune disease are
evaluated as well.
6.5.4 Toxicity Monitoring
Both acute and chronic toxicity are monitored.
Monitoring for acute toxicity takes place during and
immediately following injection for a period of two
hours. Patients are observed for the development of an
immediate localized allergic reaction or anaphylactic
reaction during this time. Chronic toxicity is evaluated
at the monthly physical examination. Although the nature
of chronic toxicity following injection of CaPVax is
unknown, physical examination, history, and quality of
life assessments are recorded along with all pertinent
laboratory tests.
7.0 PATIENT DISCONTINUATION
7.1 Off-study Criteria
Patients who require other treatments for prostate cancer or for
a complication of the cancer (e.g. vertebral collapse) are taken
off study. They will be included in the follow-up analysis. Such
patients are considered as failures and will be followed by one
of the participating physicians and the data center, with
information collected periodically.
7.2 Patient Discontinuation Due to Severe Adverse Event
7.3 Non Compliance With Protocol
7.4 Patients refuse to continue on study
See Section 10, Adverse Events.
8.0 CONCOMITANT MEDICATIONS
Medications taken by the patient within seven days prior to the first
vaccination and throughout the study is recorded on the appropriate case
report form. A potential patient is not eligible to enter the study if
they are taking any medication that may affect immune function, with the
following exceptions:
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- Patients may take doses of nonprescription strength NSAIDS,
acetaminophen, ibuprofen or aspirin for non-chronic headache,
muscle pain, trauma or prophylaxis as long as their dosing
regimen complies with the recommended dose as found on the
product label/package insert.
- Patients may receive antihistamine therapy for colds or
allergies at low doses.
- Patients must continue LHRH agonists, if they were on LHRH
agonists at the initiation of the trial.
- Patients may take vitamin supplements within a dose range not
associated with toxicity.
- Patients may take cimetidine or other H2 blockers.
- Patients may receive a maximum of two short courses (not more
than 10 days per course) of antibiotics for treatment of minor
infection, but not more frequently than twice in a 45 day span.
Any other medications that may affect immune function are
contraindicated for the duration of the patient's study participation.
The same exceptions as above apply during the study.
9.0 ADVERSE EVENTS (SEE APPENDIX P)
9.1 Adverse Event Recording
An objective of this study is to evaluate the safety of CaPVax.
Therefore, clinical AEs occurring during and after vaccine
treatment must be recorded.
An AE is defined as any change in signs or symptoms, and may
include a single symptom or sign, a set of related symptoms or
signs, or a disease. An AE must be recorded even if it is
unlikely to be causally related to the study drug.
Patients are instructed to report any AE to the investigator. On
each day of evaluation, the patient is questioned in a general
way regarding any new medical problems and new or changed
medications. All AEs are documented in the source document and
on the AE form.
The intensity of all AEs not localized to the CaPVax injection
site are graded according to the National Cancer Institute (NCI)
Common Toxicity Criteria (see Appendix L). AEs that are
considered by the investigator to be localized or related to the
injection site will be graded according to the Injection Site
Reaction section of the NCI Common Toxicity Criteria (see
Appendix L).
The relationship to study treatment is characterized as not
related, possibly related, or probably related and is determined
according to the following GUIDELINES;
PROBABLY RELATED: a direct cause and effect relationship between
the study treatment and the AE is likely;
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POSSIBLY RELATED: a cause and effect relationship between the
study treatment and the AE has not been demonstrated at this
time and is not probable, but is also not impossible;
NOT RELATED: there is no question that the AE is definitely not
associated with the study treatment (comment on other etiology
in comments section of the clinical report form).
Any patients withdrawn from the study should have the
end-of-study (week 14 or week 20) procedures performed at that
time, unless patient declines.
9.2 Serious Adverse Event Reporting
The Ambulatory Unit of the Principal Investigator's site is
contacted during a serious AE in order to determine the
physician on call, who is notified and apprised of the
situation. A serious AE is defined as one of the following:
- Death
- An event which is life threatening. In the opinion of
the investigator, the patient was at immediate risk of
death due to the event as it occurred.
- An event which results in persistent or significant
disability/incapacity
- An event which requires inpatient hospitalization or
prolongs hospitalization.
- A laboratory abnormality which meets any of the above
criteria.
- An important medical event that, based upon appropriate
medical judgement, may jeopardize the patient or subject
and may require medical or surgical intervention to
prevent one of the outcomes listed above.
9.3 Management of a BCG-related Adverse Event
Repeated intradermal injection of attenuated BCG is safely used
for the treatment of bladder cancer (54), colon cancer (55, 56),
prostate cancer (57), and melanoma. (58). Inactivated BCG is
used in the production of CaPVax for the purposes of maturing
the DC ex vivo. However unlikely, inactivated BCG may trigger a
hypersensitivity reaction including symptoms of persistent fever
or skin ulceration. These adverse reactions will be treated as
follows:
- Cold packs or topical steroid preparation may be used
for symptomatic relief of associated skin discomfort.
- For low grade fever (<39 degreesC): Administer oral
paracetamol.
- For high grade fever (>39 degreesC) perform all of the
following:
97
1. Draw blood for standard blood culture set (x 2).
2. Draw blood for Mycobacterial blood culture.
3. Test the residual sample of the CaPVax (i.e. DC vial
retained from previous vaccination) for: gram stain,
culture/sensitivity, AFB stain and culture, fungal smear
and culture.
4. Administer one gram (1g) of ampicillin every four hours
(IV).
5. Administer 5mg/kg of gentamycin daily (IV).
6. Or, if the patient is allergic to penicillin, administer
one gram (1g) of vancomycin every 12 hours and 5mg/kg
of gentamycin (IV).
7. Administer three-drug antituberculous therapy: 300mg of
isoniazid once daily, 600mg rifampicin once daily,
orally, and ethambutol (15mg/kg) once daily.
8. Administer 100mg of hydrocortisone 4 times daily (IV).
9.4 Serious Adverse Event Committee
A designated committee is formed to evaluate any AEs. The
committee is comprised of a physician and nurse from the site, a
physician from the sponsor, and the sponsor's RA/QA Manager. The
committee is responsible for handling any AEs that may occur
during the course of treatment. For instance, a patient develops
a severe local skin reaction after the second or third
intradermal injection of CaPVax. Regardless of the type of
reaction, the committee determines the course of treatment, if
necessary, and the study status of the patient, i.e. is the
patient able to continue CaPVax therapy. If the patient is
allowed to continue on-study, the committee may decide to tailor
the dose or modify the dose interval, or remove patient from the
study.
9.5 Reporting an Adverse Event to the FDA
The sponsor is responsible for reporting AEs to the FDA as
described in 21 CFR Section 312.32 (IND Safety Reports).
10.0 CRITERIA FOR DISEASE EVALUATION AND ENDPOINTS
All patients who receive CaPVax are evaluated primarily for safety.
Patients are followed for a longer period of time to monitor potential
clinical response using NPCP criteria for evaluating patient response
(see Appendix G). Radiographic evaluation will be performed at 26 weeks
and at the time of maximal PSA response.
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10.1 Definitions
10.1.1 Measurable Disease
Requires bidimensionally measurable lesion with clearly
defined margins by at least one of the following
criteria:
1. photographs or plain x-ray with at least one diameter
> 0.5 cm.
2. CT/MRI/or other imaging scans with at least one diameter
> 1 cm (or the minimal limit of resolution of the
technique, and/or
3. palpable lesion with both diameters measuring at least 2
cm.
10.1.2 Evaluable Disease
Masses with margins not clearly defined, palpable lesion
with either diameter < 2 cm, and lesion with both
diameters < 0.5 cm by x-ray, CT, or MRI. Serum PSA
values are also considered evaluable. Bone scan lesions
are considered evaluable.
10.2 Response Evaluation
10.2.1 Response for bidimensionally measurable disease
COMPLETE RESPONSE: disappearance of all measurable
disease for at least six weeks.
PARTIAL RESPONSE: reduction by at least 50% of the sum
of two perpendicular diameters of measurable disease for
at least six weeks.
10.2.2 Response with evaluable disease (bone scan only)
COMPLETE RESPONSE: disappearance of all bone scan
lesions for at least six weeks.
PARTIAL RESPONSE: partial regression of bone scan
lesions for at least six weeks.
10.2.3 Response with evaluable disease (elevated PSA value
only)
COMPLETE RESPONSE: undetectable PSA on three successive
determinations spaced at least two weeks apart.
PARTIAL RESPONSE: decline in PSA by at least 50% with
maintenance of the decline on at least two consecutive
determinations spaced at least two weeks apart.
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10.3 Progression
Progression is defined as progression of CT or bone scan lesions
(an increase in number and/or intensity) on consecutive bone
scans, increase in the sum of the perpendicular diameters of
measurable disease by at least 25%, a rise in PSA of greater
than 50% from base line level on two consecutive determinations
spaced at least two weeks apart, or new bone lesions on plain
film and/or bone scan in the presence of a stable PSA.
10.4 Stable Disease
Stable disease is defined as when a patient fails to qualify for
either a response or progressive disease.
11.0 STATISTICAL CONSIDERATIONS
This is a two-center study, with equal numbers of patients treated at
each site. All patients receive CaPVax injections and act as their own
controls. The treatment plan is presented in Section 5.0.
Safety Monitoring
A serious adverse event (AE) has been defined on page 19.
Consider the patients treated at one of the dose levels (DLs).
Denote the probability of an adverse event (AE) at this DL by
(theta). The maximum acceptable probability of an AE in a
population of patients treated at any DL is .05. We assume that,
a priori, (theta) follows a beta distribution with parameters
(.10,1.9), which in particular has mean .05. The early stopping
criterion is that the DL will be terminated if at any point in
the trial Pr[(theta) > .05, data] > .90. Applying this criterion
in sequence will terminate that DL if [# patients with an AE ]/
[# patients evaluated] is > or = 2/10, 3/22, 4/35, or 5/50. To
apply this rule, note that the boundary "2/10" means that the DL
will be discontinued if 2 AEs are observed at any point among
the first 10 patients treated at that DL and evaluated, hence
2/2, 2/3, ..., up to 2/10 will cause the DL to be terminated.
Similarly, for example, if there are 1/10 and then 2/11 AEs, so
that the trial continues to treat patients at that DL at that
point, but subsequently one more AE is observed in any patient
thereafter up to the 22nd patient evaluated, then that DL is
stopped. These rules pertain to all patients evaluated at that
DL, including patients in the dose escalation stage. Thus, for
example, a DL will be terminated if 2 patients among the first 3
or 6 treated in the dose escalation stage have an AE.
100
For a single dose level with up to 20 patients, this rule has
the following operating characteristics:
Sample Size 25th, 50th, 75th
True Prob[AE] Prob[Early Termination] Percentiles
------------- ----------------------- ----------------------------
.01 .005 20 20 20
.05 .11 20 20 20
.10 .37 10 20 20
.20 .80 5 9 18
.25 .91 4 7 10
Although at most 20 patients will be treated at each dose level if none of the
three DLs are terminated early, in the case that a DL is terminated early the
remaining patients among the 60 in the trial will be randomized to the remaining
dose levels. In this case, more than 20 patients may be treated on each of the
remaining DLs. This is a simple "play the winners" strategy. It has the
advantage that it is ethically desirable for the patients, since they are less
likely to be treated at unsafe DLs, and it is scientifically desirable since it
provides more information for the DLs not terminated, compared to what would be
the case if the sample size were limited to a maximum of 20 per dose level. (59)
11.3 Statistics for Secondary Study Objectives
SECONDARY OBJECTIVE 1: Test the hypothesis that, on average over
the study period, patients' PSA values will trend downward
compared to screening values. Each subject is assayed eight
times at various times between day 1 and week 26. Regression
analysis using Generalized Estimating Equations (GEE) is used to
test for trend of improvement over the study period.
SECONDARY OBJECTIVE 2: Describe how the patient's experiences of
pain, physical functioning and quality-of-life measures change
during the course of treatment and during the follow-up period.
For each patient over the study period pain is assessed five
times using the Brief Pain Inventory, physical functioning is
measured six times using both the Karnofsky and Zubrod
Performance Scales, and quality of life assessments are obtained
five times using the FACT-P questionnaire. Patient averages at
screening and during the study weeks is graphed and the trends
and tempos of these repeated measurements is modeled and
analyzed using GEE.
SECONDARY OBJECTIVE 3: Describe how the patient's skin test and
other lab results change during the course of treatment and
during the follow-up period. For each patient over the study
period skin tests are assessed four times using four recall
antigens (Candida, Mumps, PPD, and rPSMA) and CBC, differential
blood chemistry and serum markers are measured nine times.
Patient averages at screening and during the study weeks are
graphed and the trends of these repeated measurements are
modeled and analyzed using GEE.
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11.4 Study Assessments
11.4.1 Data control measures
In order to assure adequate control and provide study data
that are consistent and of the highest quality, the following
measures are employed:
1. Each clinical procedure (i.e. physical examination) for a
particular patient is conducted by the same person if
possible throughout the patient's study participation.
2. Each clinical laboratory procedure is conducted by the same
laboratory throughout the study.
3. Data generated automatically is reviewed by the appropriate
specialist, i.e. computer generated EKG interpretation is
reviewed and signed off by a cardiologist.
12.0 INVESTIGATOR OBLIGATIONS
As indicated on FDA Form 1572, the Principal Investigator is responsible
for the conduct of the clinical trial at the site and is responsible for
personally overseeing the treatment of all study patients. The Principal
Investigator must assure that all study site personnel, including
Sub-investigators and other study staff members, adhere to the study
protocol and to all FDA regulations and guidelines regarding clinical
trials both during and after study completion.
12.1 Informed Consent
All subjects will be informed of the nature of the program, its
possible hazards and their right to withdraw at any time, and will
sign a form indicating their consent to participate prior to
receiving any study-related procedures.
12.2 Institutional Review Board
This protocol and relevant substantive data must be submitted to the
appropriate Institutional Review Board (IRB) for review and approval
before the study can be initiated. Amendments to the protocol are
also submitted to the IRB prior to implementation of the change. A
letter documenting IRB approval must be received by the Sponsor prior
to initiation of the study. The Principal Investigator is also
responsible for informing the IRB of the progress of the study and
for obtaining annual IRB renewal. The IRB must be informed at the
time of completion of the study and should be provided with a summary
of the results of the study by the Principal Investigator. The
Principal Investigator must notify the IRB in writing of any
significant adverse reactions.
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13.0 ADMINISTRATIVE CONSIDERATIONS
13.1 Pre-study Documentation
The following documentation must be received by the study Sponsor
prior to initiation of the trial: FDA Form 1572; curricula vitae of
the Principal Investigator and all Sub-investigators; signed
Protocol Agreement; copy of the correspondence from the IRB
indicating approval of the protocol and consent form, signed by the
IRB chairperson or designee; an IRB membership list containing the
names and occupations of the IRB members; copy of the Informed
Consent Form that was reviewed and approved by the IRB; clinical
laboratory reference ranges for all tests required in the protocol
and a copy of the laboratory license or accreditation.
13.2 Study Documentation
The Investigator and study staff have responsibility for
maintaining a comprehensive and centralized filing system
containing all study-related documentation. These files must be
suitable for inspection by the Sponsor or the FDA at any time, and
should consist of the following elements: patient files (complete
medical records, laboratory data, supporting source documentation,
and the Informed Consent); study files (the protocol with all
amendments, copies of all pre-study documentation, and all
correspondence between the IRB, site, and Sponsor); and drug
accountability files, containing a complete account of the receipt
and disposition of the study drug.
13.3 Data Collection
Case Report Forms (CRFs) must be submitted to the Sponsor for each
patient enrolled in the study. CRFs are to be completed in a neat,
legible manner, using a black pen to ensure accurate interpretation
of data. Any changes or corrections made on the CRFs must be dated
and initialed by the individual making the change, and subsequently
reviewed and signed by the Investigator. When corrections are made,
the original entry should be crossed out using a single line. Do
not erase, overwrite, or use white-out on the original entry. All
datafields on the CRFs must be filled in.
13.4 Protocol Interpretation and Compliance
The procedures defined in the protocol are carefully reviewed by
the Investigator and his/her staff prior to the time of study
initiation to ensure accurate representation and implementation.
Protocol amendments, if any, are reviewed and implemented promptly
following IRB approval. The Sponsor is responsible for submitting
protocol amendments to the FDA as described in 21 CFR Section
312.30 (Protocol Amendments).
13.5 Study Monitoring and Data Collection
A representative from the Sponsor will visit the study center
periodically to monitor adherence to the protocol and applicable
FDA regulations, and the maintenance of adequate and accurate
clinical records. CRFs are reviewed to ensure that key safety and
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efficacy data are collected and recorded as specified by the protocol.
The Sponsor's representative (or designate) is permitted to access
patient medical records, laboratory data and other source documentation
as needed to appropriately monitor the trial.
13.6 Disclosure of Data/Publication
Individual patient medical information obtained as a result of this
study is considered confidential and disclosure to third parties other
than those noted below is prohibited. Such medical information may be
given to the patient's personal physician or to other appropriate
medical personnel responsible for the patient's welfare. Data generated
as a result of this study are to be available for inspection on request
by the FDA, the Sponsor or Sponsor's representative and by the
Institutional Review Board.
Presentation or publication of the study results is not permitted
without prior submission to the Sponsor. It is anticipated that the
final results of this study will be submitted to a peer-reviewed
scientific journal. Authorship on such a paper will be acknowledged
with customary scientific practice.
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coding for an antigen recognized by autologous cytolytic T lymphocytes on
a human melanoma. J Exp Med 1995; 182: 689-698.
20. Brandle D, Brasseur F, Weynants P, et al: A mutated HLA-A2 molecule
recognized by autologous cytotoxic T lymphocytes on a human renal cell
carcinoma. J Exp Med 1996; 183: 2501-2508.
21. Sahin U, Tureci O, Schmitt H, et al: Human neoplasms elicit multiple
specific immune responses in the autologous host. Proc Natl Acad Sci USA
1995; 92: 11810-11813.
22. Ressing ME, Sette A, Brandt RM, et al: Human CTL epitopes encoded by human
papillomavirus type 16 E6 and E7 identified through in vivo and in vitro
immunogenicity studies of HLA-A2*0201-binding peptides. J Immunol 1995;
154: 5934-5943.
23. Murakami M, Gurski KJ, Marincola FM, et al: Induction of Specific CD8+
T-Lymphocyte Responses Using a Human Papillomavirus-16 E6/E7 Fusion
Protein and Autologous Dendritic Cells. Cancer Res 1999; 59: 1184-1187.
24. Chen BP, DeMars R, Sondel PM: Presentation of soluble antigen to human T
cells by products of multiple HLA-linked loci: Analysis of antigen
presentation by a panel of cloned autologous, HLA-mutant Epstein-Barr
virus-transformed lymphoblastoid cell lines. Human Immunol 1987; 18: 75-91.
25. Murphy G, Ragde H, Kenny G, et al: Comparison of prostate specific
membrane antigen and prostate specific antigen levels in prostatic cancer
patients. Anticancer Res 1995; 15: 1473-1480.
26. Murphy GP, Barren RJ, Erickson SJ, et al: Evaluation and comparison of two
new prostate carcinoma markers. Free prostate specific antigen and
prostate specific membrane antigen. Cancer 1996; 78: 809-818.
27. Israeli RS, Powell CT, Corr JG, et al: Expression of the prostate-specific
membrane antigen. Cancer Res 1994; 54: 1807-1811.
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28. Murphy GP, Tino WT, Holmes EH et al: Measurement of prostate-specific
membrane antigen in the serum with a new antibody. Prostate 1996; 28:
266-271.
29. Wright GL Jr, Haley C, Beckett ML, et al: Expression of
prostate-specific membrane antigen in normal, benign, and malignant
tissues. Urol Oncol 1995; 1: 18-28.
30. Cox AL, Skipper J, Chen Y, et al: Identification of a peptide recognized
by five melanoma-specific human cytotoxic T cell lines. Science 1994;
264: 716-719.
31. Kawakami Y, Eliyahu S, Delgado CH, et al: Identification of a human
melanoma antigen recognized by tumor-infiltrating lymphocytes associated
with in vivo tumor rejection. Proc Natl Acad Sci USA 1994; 91: 6458-6462.
32. Peace DJ, Smith JW, Disis ML, et al: Induction of T cells specific for
the mutated segment of oncogenic P21 ras protein by immunization in vivo
with the oncogenic protein. J Immunother 1993; 14: 110-114.
33. Cheever MA, Chen W, Disis ML, et al: T cell immunity to oncogenic
proteins including mutated Ras and chimeric Bcr-Abl. Ann NY Acad Sci
1993; 690: 101-112.
34. Yanuck M, Carbone DP, Pendleton CD, et al: A mutant p53 tumor suppressor
protein is a target for peptide induced CD8* cytotoxic T cells. Cancer
Res 1993; 53: 3257-3261.
35. Stuber G, Leder GH, Storkus WJ, et al: Identification of wild-type and
mutant p53 peptides binding to HLA-A2 assessed by a peptide
loading-deficient cell line assay and a novel major histocompatibility
complex class I peptide binding assay. Eur J Immunol 1994; 24: 765-768.
36. Horoszewicz JS, Kawinski E, Murphy GP: Monoclonal antibodies to a new
antigenic marker in epithelial prostatic cells and serum of prostatic
cancer patients. Anticancer Res 1987; 7: 927-935.
37. Israeli RS, Powell CT, Fair WR, et al: Molecular cloning of a
complementary DNA encoding a prostate-specific membrane antigen. Cancer
Res 1993; 53: 227-230.
38. Bostwick DG, Pacelli A, Blute M, et al: Prostate specific membrane
antigen expression in prostatic intraepithelial neoplasia and
adenocarcinoma: a study of 184 cases. Cancer 1998; 82: 2256-2261.
39. Troyer JK, Beckett ML, Wright Gl, et al: Detection and characterization
of the prostate-specific membrane antigen (PSMA) in tissue extracts and
body fluids. Intl J Cancer 1995; 62: 552-558.
40. Murphy GP, Elgamal AA, Su SL, et al: Current evaluation of the tissue
localization and diagnostic utility of prostate specific membrane
antigen. Cancer 1998; 83: 2259-2269.
41. Lopes AD, Davis WL, Rosenstraus MJ, et al: Immunohistochemical and
pharmacokinetic characterization of the site-specific immunoconjugate
CYT-356 derived from antiprostate monoclonal antibody 7E11-C5. Cancer Res
1990; 50: 6423-6429.
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42. Albert ML, Sauter B, Bhardwaj N: Dendritic cells acquire antigen from
apoptotic cells and induce class I-restricted CTLs. Nature 1998; 392:
86-89.
43. Brodsky FM, Lem L, Brenahan PA: Antigen processing and presentation.
Tissue Antigens 1996; 47: 464-471.
44. Siliciano RF, Soloski MJ: MHC class I-restricted processing of
transmembrane proteins. J Immunol 1995; 155: 2.5.
45. Banchereau, J, Steinman RM: Dendritic cells and the control of immunity.
Nature 1998; 392: 245-252.
46. Tjoa B, Erickson S, Barren III R, et al: In vitro propagated dendritic
cells from prostate cancer patients as a component of prostate cancer
immunotherapy. Prostate 1995; 27: 63-69.
47. Morse M, Deng Y, Coleman D, et al: A phase I study of active immunotherapy
with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human
cultured dendritic cells in patients with metastatic malignancies
expressing carcinoembryonic antigen. Clin Cancer Res 1999; 5: 1331-1338.
48. Murphy GP, Tjoa, BA, Simmons, SJ, et al: Infusion of dendritic cells
pulsed with HLA-A2-specific prostate-specific membrane antigen peptides: a
phase II prostate cancer vaccine trial involving patients with
hormone-refractory metastatic disease. Prostate 1999; 38: 73-78.
49. Murphy GP, Tjoa, BA, Ragde H et al: Phase I clinical trial: T cell therapy
for prostate cancer using autologous dendritic cells pulsed with HLA-A0201-
specific peptides from prostate-specific membrane antigen. Prostate 1996;
29: 371-380.
50. Nestle FO, Alijagic S, Gilliet M, et al: Vaccination of melanoma patients
with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 1998; 4:
328-332.
51. Kundu SK, Engleman E, Benike C, et al: A pilot trial of HIV antigen-pulsed
allogenic and autologous dendritic cell therapy in HIV-infected patients.
AIDS Res Hum Retroviruses 1998; 14: 551-560.
52. Holtl L, Rieser C, Papesh R, et al: Cellular and humoral immune responses
in patients with metastatic renal cell carcinoma after vaccination with
antigen dendritic cells. J Urol 1999; 161: 777-782.
53. Reichardt VL, Okadda CY, Liso A, et al: Idiotype vaccination using
dendritic cells after autologous peripheral blood stem cell
transplantation for multiple myeloma--a feasibility study. Blood 1999; 93:
2411-2419.
54. Nseyo UO, Lamm DL: Immunotherapy of bladder cancer. Semin Surg Oncol 1997;
13: 342-349.
55. Hoover HC, Brandhorst JS Jr, Peters LC, et al: Adjuvant active specific
immunotherapy for human colorectal cancer: 6.5-year median follow-up of a
phase III prospectively randomized trial. J Clin Oncol 1993; 11: 390-399.
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56. Vermorken JB, Claessen AM, van Tinteren H, et al: Active specific
immunotherapy for stage II and stage III human colon cancer; a randomized
trial. Lancet 1999; 353: 345-350.
57. Guinan PD, John T, Baumgartner G, et al: Adjuvant immunotherapy (BCG) in
stage D prostate cancer. Am J Clin Oncol 1982; 5: 65-68.
58. Hsueh EC, Gupta RK, Qi K, et al: Correlation of specific immune responses
with survival in melanoma patients with distant metastases receiving
polyvalent melanoma cell vaccine. J Clin Oncol 1998; 16: 2913-2920.
59. Thall, PF and Sung, HG: Some extensions and applications of a Bayesian
strategy for monitoring multiple outcomes in clinical trials. Statistics in
Medicine 17, 1563-1580, 1998.
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APPENDIX A: STUDY DIAGRAM
<Table>
<Caption>
---------------------------------------------------------------------------------------------------------------------------------
Procedure Screening Day 1 Week 2 Week 4 Week 6 Week 8 Week 12 Week 14 Week 20 Week 23 Week 26
---------------------------------------------------------------------------------------------------------------------------------
Study Consent X
Chest x-ray X X X
Bone Scan X X X
CT Pelvis/Abdomen X X X
EKG X
Testosterone & Urinalysis X X
History & Site Orientation X
Physical Exam, Weight X X X X X X X X
CBC & Differential X X X X X X X X X
Blood Chemistry(1) X X X X X X X X X
Serum Markers(2) X X X X X X X X X
Skin Tests, ANA, ESR(3) X X X X
Pain Score Assessment(4) X X* X X X
Quality of Life Questionnaire X X* X X X
Zubrod Performance Status X X X X X X
Virology Testing(5) X
Leukapheresis(6) X X
Blood for Immune Monitoring(7) X# X X X X X X X X
I.D. Injection of DC(8) X X X X
Vital Sign Monitoring X X X X X
AE Assessment X X X X X X X
---------------------------------------------------------------------------------------------------------------------------------
</Table>
(1) Comprehensive metabolic panel, including hepatic and renal functions
(2) Includes prostatic acid phosphatase (PAP) and prostate specific antigen
(PSA), using standard enzymatic immune assay
(3) Skin tests are completed and monitored by the study site physician(s) or
research nurse(s) and include testing for Candida, Mumps, PPD, rPSMA.
Antinuclear Antibodies (ANA) and Erythrocytic Sedimentation Rate (ESR) are
measured as markers of induced autoimmunity.
(4) Brief Pain Inventory to evaluate pain on a scale from 0-10, i.e. from no
pain to severe pain.
(5) Virology testing is performed at screening and includes the following:
HbsAg, a-HBc, ALT, a-HIV-1, a-HIV-2, a-HTLV-1, STS, HIV-1p24Ag, a-HCV.
(6) Patients are leukapheresed at the apheresis unit at the study site once or
twice, depending on amount of cells harvested. The cells collected are
shipped to Northwest Biotherapeutics, Inc. for cell processing, DC
maturation and rPSMA-loading.
(7) 100ml of whole blood is drawn and shipped to the research laboratory of
Northwest Biotherapeutics, Inc., Seattle WA for immune monitoring. This
includes specific and non-specific, cellular and humoral tests.
(8) The autologous CaPVax is shipped to the site for intradermal (I.D.)
injection.
* The Brief Pain Inventory and Quality of Life questionnaire is given
to the patient at Week 4, filled out by the patient at Week 6, and
returned to the study site at Week 8.
# Prior to the first leukapheresis procedure, 100ml of whole blood is drawn
and shipped to the research laboratory Northwest Biotherapeutics Inc. for
immune monitoring.
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APPENDIX B
PERFORMANCE STATUS SCALES
<Table>
<Caption>
Karnofsky Performance Scale(1) Zubrod Performance Scale(2)
Point Description Point Description
--------------------------------------------------------------------------------
100 Normal, no complaints, no 0 Normal activity;
evidence of disease asymptomatic
90 Able to carry on normal activity; 1 Symptomatic; fully
minor signs or symptoms of disease ambulatory
80 Normal activity with effort; some
signs or symptoms of disease
70 Cares for self, unable to carry on 2 Symptomatic; in bed
normal activity or to do active work <50% of time
60 Requires occasional assistance but
is able to care for most of his/her needs
50 Requires considerable assistance
and frequent medical care
40 Disabled, requires special care 3 Symptomatic; in bed
and assistance 50% of time; not
bedridden
30 Severely disabled, hospitalization
indication. Death not imminent
20 Very sick, hospitalization 4 100% Bedridden
indicated. Death not imminent
10 Moribund, fatal processes
progressing rapidly
0 Dead 5 Dead
</Table>
References
1. Karnofsky, D.A.: Meaningful clinical Classification of Therapeutic
Responses to Anti-Cancer Drugs. Editorial. Clin. Pharmacol and
Therapeutics 2:709-712, 1961.
2. Stanley, K.E.: Prognostic Factors for Survival in Patients with
Inoperable Lung Cancer. J. Natl.Can. Inst. 65:25-32, 1980.
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APPENDIX C
SKIN TESTING PROCEDURE
Skin testing is a widely used procedure for monitoring specific cellular immune
response and is indicated when detection of delayed-hypersensitivity reaction is
desired. It is standardized procedure with very small risk. All skin testing
procedures are performed according to the manufacturer's instructions included
as a package insert with the skin test antigens. The skin test antigens
(Candida, Mumps, PPD) are approved for use in the US.
ANTIGENS USED AND HOW SUPPLIED:
Candida, Mumps, PPD (tuberculin purified protein derivative), and rPSMA
(recombinant prostate specific membrane antigen) will be used for skin testing.
1. Candida albicans skin test antigen for cellular hypersensitivity
(Candin(R)) is a clear, colorless, sterile solution, made from the culture
of two strains of Candida albicans. It is supplied in a 1 ml multidoses
vial containing ten 0.1 ml doses, stable at 2-8 degrees C (35-40 degrees
F), and is distributed by Allermed Laboratories, Inc. (San Diego, CA).
2. Mumps skin test antigen (MSTA(R)) is a sterile suspension of skilled mumps
virus, prepared from the extraembryonic fluid of the virus-infected chicken
embryo. It is supplied in a 1 ml multidoses vial containing ten 0.1 ml
doses, is slightly opalescent in color, stable when stored at 2-8 degrees
C, and is distributed by Connaught Laboratories, Inc. (Swiftwater,
Pennsylvania)
3. Tuberculin PPD (Mantoux)-Tubersol(R), obtained from a human strain of
Mycobacterium tuberculosis, is available in stabilized solutions
bio-equivalent to 5 U.S. units (TU) PPD-S per test dose (0.1 ml) and is
available in 1 ml vials. This Tubersol(R) solution is ready for immediate
use without any further dilution, and remains stable for at least 4 weeks
when stored at 2-8 degrees C. It is distributed by Connaught Laboratories,
Inc. (Swiftwater, Pennsylvania, USA).
4. Northwest Biotherapeutics, Inc. (Seattle, Washington) provides cGMP grade
rPSMA for skin testing. rPSMA will be supplied as a sterile, 1 ml,
multidose vial containing ten 0.1 ml doses, after testing for stability at
2-8 degrees C. Each dose will contain about 10 (greek mu)gm of rPSMA, which
is one tenth of the rPSMA dose administered with CaPVax, suspended in 0.1
ml saline.
METHOD OF ADMINISTRATION
The following procedure is recommended for performing the skin test:
1. The site of the test is the volar surface of the forearm about 2-4 inches
below the bend of the elbow.
2. To eliminate any later identification problems, number the antigens
clockwise, starting from the top right with Candida and ending at the top
left with rPSMA. See figure below:
-----------------
rPSMA Candida
-----------------
PPD Mumps
-----------------
3. The skin is cleansed with alcohol and allowed to dry.
4. The test dose is administered with a 1 ml syringe calibrated in tenths and
fitted with a short, one half inch, 26 or 27 gauge needle.
5. Disposable sterile syringes and needles must be used.
6. The rubber cap of the vial is wiped with alcohol and allowed to dry. The
needle is then inserted gently through the cap and the required amount of
the antigen is drawn into the syringe.
7. The point of the needle is inserted into the most superficial layers of the
skin with the needle bevel pointing upward. If the intradermal injection is
performed properly, a definite white bleb will rise at the needle point,
about 10 mm (3/8") in diameter. This will disappear within minutes. No
dressing
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is required. In the event of a subcutaneous injection (i.e. no bleb
formed), the test should be repeated immediately at another site.
INTERPRETATION OF THE TEST:
The skin test is read 48-72 hours after administration. Results of the test, or
sensitivity, are indicated by induration, usually accompanied by erythema. The
widest diameter of distinctly palpable induration is recorded in millimeters
(mm). Presence of edema and necrosis is also reported. Palpable induration of 5
mm or more indicates a positive reaction. Induration of less than 5 mm is
considered negative.
INTERACTIONS:
Reactivity to the skin test may be depressed or suppressed in patients with
impaired immunity, including patients with advanced cancer. Reactivity to PPD
may be temporarily depressed by live mumps vaccine. Therefore, PPD should be
administered either before or simultaneously with the mumps vaccine.
CONTRAINDICATIONS:
PPD is not administered to known positive reactors because of the severity of
reactions that may occur at the test site in highly positive patients. Candida,
Mumps, or PPD is not used with history of allergic reaction to these products.
It is also contraindicated to administer MSTA(R), mumps skin test, to anyone
with history of anaphylactic reaction to eggs or egg product. Individuals with
history of allergy to Thimerosal must not receive MSTA(R).
ADVERSE REACTIONS:
Local reactions consist primarily of rash, pruritus, induration, tenderness,
vesiculation, abscess formation, ulceration or necrosis at the site of
injection, and/or regional lymphadenopathy. Cold backs or topical steroid
preparations are employed for symptomatic relief of the associated skin
discomfort. Immediate hypersensitivity reactions occur in some individuals
approximately 15-20 minutes after intradermal injection and is characterized by
the presence of an edematous hive surrounded by a zone of erythema. Systemic
reactions to Candin(R) and MSTA(R) have not been observed. However, all foreign
antigens have the remote possibility of causing Type 1 anaphylaxis and even
death when injected intradermally. Systemic reactions usually occur within 30
minutes after injection of antigen and may include the following symptoms:
sneezing, coughing itching, shortness of breath, abdominal cramps, vomiting,
diarrhea, tachycardia, hypotension and respiratory failure in severe cases.
Systemic allergic reactions including anaphylaxis must be immediately treated
with Epinephrine HCL 1:1000.
PRECAUTIONS:
Epinephrine injection (1:1000) must be immediately available to combat
unexpected anaphylactic or other allergic reactions. Vials of the skin test
product is inspected visually for particulate manner or discoloration prior to
administration. If particles or discoloration are observed, the product is not
used and is discarded. The antigens must be given intradermally. If they are
injected subcutaneously, no reaction or an unreliable reaction may occur.
Special care should be taken to ensure the antigen is not injected into a blood
vessel.
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APPENDIX D
QUALITY OF LIFE QUESTIONNAIRE (FACT-P VERSION 4)
Below is a list of statements that other people with your illness have said are
important. By circling one (1) number per line, please indicate how true each
statement has been for you during the past 7 days.
<Table>
<Caption>
NOT A LITTLE SOME- QUITE VERY
PHYSICAL WELL-BEING AT ALL BIT WHAT A BIT MUCH
GP1 I have a lack of energy............................. 0 1 2 3 4
GP2 I have nausea....................................... 0 1 2 3 4
GP3 Because of my physical condition, I have
trouble meeting the needs of my family.............. 0 1 2 3 4
GP4 I have pain......................................... 0 1 2 3 4
GP5 I am bothered by side effects of treatment.......... 0 1 2 3 4
GP6 I feel ill.......................................... 0 1 2 3 4
GP7 I am forced to spend time in bed.................... 0 1 2 3 4
</Table>
<Table>
<Caption>
NOT A LITTLE SOME- QUITE VERY
SOCIAL/FAMILY WELL-BEING AT ALL BIT WHAT A BIT MUCH
GS1 I feel close to my friends.......................... 0 1 2 3 4
GS2 I get emotional support from my family.............. 0 1 2 3 4
GS3 I get support from my friends....................... 0 1 2 3 4
GS4 My family has accepted my illness................... 0 1 2 3 4
GS5 I am satisfied with family communication
about my illness.................................... 0 1 2 3 4
GS6 I feel close to my partner (or the person
who is my main support)............................. 0 1 2 3 4
Regardless of your current level of sexual activity,
please answer the following question. If you prefer
not to answer it, please check this box [ ] and go
to the next section
GS7 I am satisfied with my sex life..................... 0 1 2 3 4
</Table>
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By circling one (1) number per line, please indicate how true each statement has
been for you during the past 7 days.
<Table>
<Caption>
NOT A LITTLE SOME- QUITE VERY
EMOTIONAL WELL-BEING AT ALL BIT WHAT A BIT MUCH
GE1 I feel sad............................................ 0 1 2 3 4
GE2 I am satisfied with how I am coping with my illness... 0 1 2 3 4
GE3 I am losing hope in the fight against my illness...... 0 1 2 3 4
GE4 I feel nervous........................................ 0 1 2 3 4
GE5 I worry about dying................................... 0 1 2 3 4
GE6 I worry that my condition will get worse.............. 0 1 2 3 4
</Table>
<Table>
<Caption>
NOT A LITTLE SOME- QUITE VERY
FUNCTIONAL WELL-BEING AT ALL BIT WHAT A BIT MUCH
GF1 I am able to work (include work at home).............. 0 1 2 3 4
GF2 My work (include work at home) is fulfilling.......... 0 1 2 3 4
GF3 I am able to enjoy life............................... 0 1 2 3 4
GF4 I have accepted my illness............................ 0 1 2 3 4
GF5 I am sleeping well.................................... 0 1 2 3 4
GF6 I am enjoying the things I usually do for fun......... 0 1 2 3 4
GF7 I am content with the quality of my life now.......... 0 1 2 3 4
</Table>
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By circling one (1) number per line, please indicate how true each statement
has been for you during the past 7 days.
<Table>
<Caption>
NOT A LITTLE SOME- QUITE VERY
ADDITIONAL CONCERNS AT ALL BIT WHAT A BIT MUCH
C2 I am losing weight.................................. 0 1 2 3 4
C6 I have a good appetite.............................. 0 1 2 3 4
P1 I have aches and pains that bother me............... 0 1 2 3 4
P2 I have certain areas of my body where I
experience significant pain......................... 0 1 2 3 4
P3 My pain keeps me from doing things I want to do..... 0 1 2 3 4
P4 I am satisfied with my present comfort level........ 0 1 2 3 4
P5 I am able to feel like a man........................ 0 1 2 3 4
P6 I have trouble moving my bowels..................... 0 1 2 3 4
F7 I have difficulty urinating......................... 0 1 2 3 4
BL2 I urinate more frequently than usual................ 0 1 2 3 4
P8 My problems with urinating limit my activities...... 0 1 2 3 4
BL5 I am able to have and maintain an erection.......... 0 1 2 3 4
</Table>
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APPENDIX E
BRIEF PAIN INVENTORY (SHORT FORM)
Date: / / Time:
------------------------ -------------------
Name:
---------------------------------------------------------------------------
Last First Middle Initial
1. Throughout our lives, most of us have had pain from time to time (such as
migraine headaches, sprains, and toothaches). Have you had pain other than
these every day kinds of pain today?
1. Yes 2. No
2. On the diagram, shade in the areas where you feel pain. Put an X on the
area that hurts the most.
Right Left Left Right
3. Please rate your pain by circling the one number that best describes your
pain at its worst in the last 24 hours.
0 1 2 3 4 5 6 7 8 9 10
No Pain as bad as
Pain you can imagine
4. Please rate your pain by circling the one number that best describes your
pain at its least in the last 24 hours.
0 1 2 3 4 5 6 7 8 9 10
No Pain as bad as
Pain you can imagine
5. Please rate your pain by circling the one number that best describes your
pain on average.
0 1 2 3 4 5 6 7 8 9 10
No Pain as bad as
Pain you can imagine
6. Please rate your pain by circling the one number that tells how much pain
you have right now.
0 1 2 3 4 5 6 7 8 9 10
No Pain as bad as
Pain you can imagine
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7. What treatments or medications are you receiving for your pain?
8. In the last 24 hours, how much relief have pain treatments or medication
provided? Please circle the one percentage that most shows how much relief
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
No Complete
Relief Relief
9. Circle the one number that described how, during the past 24 hours, pain
interfered with your:
A. General Activity
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
B. Mood
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
C. Walking Ability
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
D. Normal Work (includes both work outside the home and housework)
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
E. Relations with other people
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
F. Sleep
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
G. Enjoyment of life
0 1 2 3 4 5 6 7 8 9 10
Does not Completely
Interfere Interfere
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Failure based on:
Imaging/Radiographic Evidence (detail) _________________________________________
PSA Progression (detail) _______________________________________________________
Is patient currently being treated for metastatic disease (circle one) Y / N
If yes, describe current treatment _____________________________________________
________________________________________________________________________________
CLINICAL DISEASE EXTENT
Total PSA ____ ng/ml
Bone Scan Results - Positive Negative
If bone scan positive, where is lesion located? ________________________________
MRI Results - Positive Negative
CLINICAL PRESENTATION
H&P Results / Impression:
Concurrent Medical Conditions:
KNOWN ALLERGIES:
CLINICAL LABS - SCREENING
CBC - Out of Range Values? Y / N If yes, specify:
Chem-22 - Out of Range Values? Y / N If yes, specify:
Chest X-ray remarkable/unremarkable If yes, specify:
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APPENDIX G
NPCP CRITERIA FOR EVALUATING PATIENT RESPONSE
NPCP Criteria for Evaluating Patient Responses to Treatment Modalities for
Prostatic Cancer (modified)[1]
Complete Response
All of the Following:
1. Tumor masses, if present, totally disappeared and no new lesions
appeared.
2. Elevated prostate specific antigen (PSA), if present, returned to
normal.
3. Osteolytic lesions, if present, recalcified.
4. Osteoblastic lesions, if present, disappeared with a negative bone scan.
5. If hepatomegaly is a significant indicator, there must be a complete
return in size of the liver to normal (as measured by distension below
both costal margins at mid-clavicular lines and from the tip of the
xiphoid process during quiet respiration without liver movement), and
normalization of all pretreatment abnormalities of liver function,
including bilirubin (mg per dl) and SGOT.
6. No significant cancer-related deterioration in weight (greater than
10%), symptoms, or performance status.
Partial Regression
Any of the following:
1. Recalcification of one or more of any osteolytic lesions.
2. A reduction by 50% in the number of increased uptake areas on the bone
scan.
3. Decrease of 50% or more in cross-sectional area of any measurable
lesion.
4. If hepatomegaly is a significant indicator, there must be at least a 30%
reduction in liver size as indicated by a change in the measurements,
and at least a 30% improvement of all pretreated abnormalities of liver
function, including bilirubin (mg/dl) and SGOT.
All of the Following:
5. No new sites of disease.
6. PSA returned to normal or was reduced by greater than 50%.
7. No significant cancer-related deterioration in weight (greater than
10%), symptoms, or performance status.
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Objectively Stable
All of the Following:
1. No new lesions occurred and no measurable lesions increased more than 25% in
cross-sectional areas.
2. Elevated PSA, if present, decreased, though need not have returned to normal
or decreased by greater than 50%.
3. Osteolytic lesions, if present, did not appear to worsen.
4. Osteoblastic lesions, if present, did not appear to worsen.
5. Hepatomegaly, if present, did not appear to worsen by more than a 30%
increase in liver measurements, and symptoms of hepatic abnormalities did
not worsen, including bilirubin (mg/dl) and SGOT.
6. No significant cancer-related deterioration in weight (greater than 10%),
symptoms, or performance status.
Objective Progression
Any of the following:
1. Significant cancer-related deterioration in weight (greater than 10%),
symptoms or performance status.
2. Appearance of new areas of malignant disease by bone scan or x-ray or in
soft tissue by other appropriate techniques.
3. Increase in any previously measurable lesion by greater than 25% in
cross-sectional area.
4. Development of recurring anemia secondary to prostatic cancer (not related
to treatment; protocols for patients with metastatic disease who have not
failed hormone therapy).
5. Development of ureteral obstruction (protocols for patients as in No. 4
above).
6. PSA increase of greater than 50%.
NOTE: An increase in acid or alkaline phosphatase alone is not to be considered
an indication of progression. These should be used in conjunction with other
criteria.
1. Murphy GP, Slack NH: Response Criteria for the prostate of the USA national
prostatic cancer project. Prostate 1980; 1:375-382.
121
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APPENDIX H
OFF STUDY FORM
Patient Name __________________________________
Date _________________________
Physician _____________________________________
The above named patient has been removed from Phase I CaPVax protocol due to:
1. Treatment for disease progression: Specify -
2. Complication(s): Specify -
3. Toxicity: Specify -
4. Other Reason: Specify -
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APPENDIX I
OFF STUDY PATIENT RE-ENTRY FORM
Patient Name __________________________________
Date _________________________
Physician _____________________________________
The above named patient, previously removed from the Phase I CaPVax protocol,
is to be reinstated on protocol.
Reason(s) for removal from protocol:
Reason(s) for reinstatement on protocol:
123
November 16, 1999
Page 47
APPENDIX J
LEUKAPHERESIS PROCEDURE PATIENT INFORMATION
Apheresis, a Greek term meaning "taking away" is applied to a number of
procedures in which blood is processed to remove a specific component (cells or
plasma). Leukapheresis is removing white blood cells needed for the clinical
trial study you are participating in. This is accomplished by pumping a donor's
blood through a machine called an automated cell separator.
A cell separator, similar to those used in blood banks and pictured here, is
used to obtain the specific cells needed for study. After blood from you, the
donor, enters the machine, it circulates through a centrifuge. Centrifugal
force causes the different types of blood cells to separate into layers. The
white cell layer is collected while the remaining blood cells and plasma
return to you, the donor.
The collection of white blood cells by apheresis requires the circulation of
large volumes of blood through the apheresis machine. It is possible to do this
by accessing a large vein in each arm. An intravenous needle with tubing is
placed in each arm. The blood moves from the vein in one arm, through the
apheresis machine and is returned to the vein in the other arm.
When the collection is completed, the intravenous needles are removed. This
process is repeated each time you have apheresis. Your arm veins will be
assessed by the nursing staff at the Apheresis Unit to make sure you have veins
adequate to perform the procedure. If a patient does not have adequate veins in
the arm for leukapheresis, a specialist at the study center will use a femoral
catheter.
How long does each procedure take?
This varies from one person to another but will generally take about four hours.
What procedures are done for my safety during apheresis?
- Every precaution is taken to ensure your safety:
- You are closely monitored by an apheresis nurse; physicians and other
support staff are on hand.
- Your blood never leaves the sterile tubing circuit; supplies are used for
only one collection and then discarded.
- There is only a small volume (approximately one cup) of your blood in the
cell separator at any time; your blood is returning to you at the same
rate it is being removed.
124
November 16, 1999
Page 48
- A solution is added to your blood as it circulates the apheresis device
to prevent clotting; this solution is quickly inactivated by your body.
What activities can be done during the procedure?
- You may lie in bed or sit in a recliner chair. With the intravenous
lines for venous access in each arm, you are able to watch television,
listen to audio tapes or any other quiet activities which do not require
use of your arms.
- A companion is welcome to stay with you during the procedure. You may
bring a snack with you to eat during apheresis. If needed, a commode or
urinal may be used as the bedside.
[GRAPHIC]
What are the side effects during apheresis?
The insertion of intravenous needles is the only uncomfortable part of the
apheresis process. The apheresis procedure itself is painless; in fact, most
donors report no noticeable or unusual sensations during the procedure. Some,
though, experience mild side effects such as chilling, a tingling sensation on
the face or body, and lightheadedness. Adverse reactions are extremely rare.
What will I feel like when the procedure is over?
Some donors report feeling fatigued following apheresis. The sites of the
intravenous lines will have soreness or tenderness and you will be instructed
to limit your activities for several hours.
If you have any question or concerns regarding this procedure, please do not
hesitate to contact a member of the apheresis team.
125
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APPENDIX K
NCI COMMON TOXICITY CRITERIA (CTC) VERSION 2.0
<Table>
<Caption>
------------------------------------------------------------------------------------------------------------------------------------
TOXICITY 0 1 2 3 4
------------------------------------------------------------------------------------------------------------------------------------
ALLERGY/IMMUNOLOGY
------------------------------------------------------------------------------------------------------------------------------------
Allergic reaction/ None Transient rash, drug Urticaria, drug fever Symptomatic Anaphylaxis
hypersensitivity fever (less than) (greater than or equal bronchospasm,
(including drug fever) 38 (degrees) C to) 38 (degrees) C requiring
((less than) 100.4 ((greater than or parenteral
(degrees) F) equal to) 100.4 medication(s), with
(degrees) F), and/or or without
asymptomatic urticaria; allergy-
bronchospasm related edema/
angioedema
Note: Isolated urticaria, in the absence of other manifestations of an allergic
or hypersensitivity reaction, is graded in the DERMATOLOGY/SKIN category.
------------------------------------------------------------------------------------------------------------------------------------
Allergic rhinitis None mild, not requiring Moderate, - -
(including sneezing, treatment requiring treatment
nasal stuffiness,
postnasal drip)
------------------------------------------------------------------------------------------------------------------------------------
Autoimmune reaction None Serologic or other Evidence of reversible autoimmune
evidence of autoimmune autoimmune reaction causing
autoimmune reaction involving reaction involving major grade 4
reaction but patient a non-essential function of a major organ dysfunction;
is asymptomatic organ or function organ or other progressive and
(e.g., vitiligo), all (e.g., hypothyroidism), toxicity (e.g., irreversible
organ function is requiring treatment transient colitis or reaction; long-term
normal and no other than anemia), requiring administration of
treatment is immunosuppressive short-term high-dose
required drugs immunosuppressive immunosuppressive
treatment therapy required
Also consider Hypothyroidism, Colitis, Hemoglobin, Hemolysis.
------------------------------------------------------------------------------------------------------------------------------------
Serum sickness None - - present -
------------------------------------------------------------------------------------------------------------------------------------
Urticaria is graded in the DERMATOLOGY/SKIN category if it occurs as an isolated symptom.
If it occurs with other manifestations of allergic or hypersensitivity reaction, grade
as Allergic reaction/hypersensitivity above.
------------------------------------------------------------------------------------------------------------------------------------
Vasculitis None mild, not requiring symptomatic, requiring steroids ischemic changes
treatment requiring or requiring
medication amputation
------------------------------------------------------------------------------------------------------------------------------------
Allergy/Immunology- None Mild moderate severe life-threatening or
Other disabling
(Specify, )
------------------------------------------------------------------------------------------------------------------------------------
AUDITORY/HEARING
------------------------------------------------------------------------------------------------------------------------------------
Conductive hearing loss is graded as Middle ear/hearing in the AUDITORY/HEARING category.
------------------------------------------------------------------------------------------------------------------------------------
Earache is graded in the PAIN category.
------------------------------------------------------------------------------------------------------------------------------------
External auditory canal Normal External otitis with external otitis with external otitis necrosis of the
erythema or dry moist desquamation with discharge, canal soft tissue
desquamation mastoiditis or bone
Note: Changes associated with radiation to external ear (pinnae) are graded under
Radiation dermatitis in the DERMATOLOGY/SKIN category.
------------------------------------------------------------------------------------------------------------------------------------
</Table>
126
November 16, 1999
Page 50
<Table>
<Caption>
GRADE
TOXICITY 0 1 2 3 4
----------------------------------------------------------------------------------------------------------------------------------
Inner ear/hearing Normal hearing loss on tinnitus or hearing tinnitus or hearing severe unilateral or
audiometry only loss, not requiring loss, correctable bilateral hearing
hearing aid or with hearing aid or loss (deafness), not
treatment treatment correctable
----------------------------------------------------------------------------------------------------------------------------------
Middle ear/hearing Normal serous otitis serous otitis or otitis with necrosis of the
without subjective infection requiring discharge, canal soft tissue or
decrease in hearing medical mastoiditis or bone
intervention; conductive hearing
subjective decrease loss
in hearing; rupture
of tympanic
membrance with
discharge
----------------------------------------------------------------------------------------------------------------------------------
Auditory/Hearing- Normal mild moderate severe life-threatening or
Other disabling
(Specify, )
----------------------------------------------------------------------------------------------------------------------------------
BLOOD/BONE MARROW
----------------------------------------------------------------------------------------------------------------------------------
Bone marrow Normal mildly hypocellular moderately severely aplasia or greater than 6
cellularity for age or 25% reduction hypocellular or hypocellular or weeks to recover
from normal greater than 25 - greater than 50 - of normal bone
cellularity for age less than or equal to less than or equal to marrow cellularity
50% reduction from 75% reduction in
normal cellularity cellularity for age
for age or greater or 4 - 6 weeks to
than 2 but less than recovery of normal
4 weeks to recovery bone marrow
of normal bone marrow cellularity
cellularity
Normal ranges:
children (less than
or equal to 18 years) 90% cellularity
average
younger adults (19-59) 60-70%
cellularity
average
older adults (greater 50% cellularity
than or equal to 60 average
years)
Note: Grade Bone marrow cellularity only for changes related to treatment not disease.
------------------------------------------------------------------------------------------------------------------------------------
CD4 count WNL less than LLN - 500/mm(3) 200 - less than 500/mm(3) 50 - less than 200/mm(3) less than 50/mm(3)
------------------------------------------------------------------------------------------------------------------------------------
Haptoglobin normal decreased absent
------------------------------------------------------------------------------------------------------------------------------------
Hemoglobin (Hgb) WNL less than LLN - 10.0 g/dl 8.0 - less than 10.0 g/dl 6.5 - less than 8.0 g/dl less than 6.5 g/dl
less than LLN - 100 g/L 80 - less than 100 g/L 65 - 80 g/L less than 65 g/L
less than LLN - 6.2 4.9 - less than 6.2 mmol/L 4.0 - less than 4.9 mmol/L less than 4.0 mmol/L
mmol/L
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the protocol so
specifies.
For leukemia studies WNL 10 - less than 25% 25 - less than 50% 50 - less than 75% greater than or equal to
or bone marrow decrease from decrease from decrease from 75% decrease from
infiltrative/ pretreatment pretreatment pretreatment pretreatment
myelophthisic
processes
------------------------------------------------------------------------------------------------------------------------------------
</Table>
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-----------------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------------------
Hemolysis (e.g., none only laboratory evidence of red cell requiring catastrophic
immune hemolytic evidence of destruction and is transfusion and/or consequences of
anemia, drug-related hemolysis [e.g., greater than or equal medical hemolysis (e.g.,
hemolysis, other) direct antiglobulin to 2gm decrease in intervention (e.g., renal failure,
test (DAT, hemoglobin, no steroids) hypotension,
Coombs') transfusion bronchospasm,
schistocytes] emergency
splenectomy)
Also consider Haptoglobin,
Hgb.
-----------------------------------------------------------------------------------------------------------------------------------
Leukocytes (total WNL < LLN - 3.0 x 10(9) * 2.0 - < 3.0 x 10(9) * 1.0 - < 2.0 x 10(9) < 1.0 x 10(9)/L
WBC) /L /L /L < 1000/mm(3)
< LLN - 3000/mm(3) * 2000 - < * 1000 - <
3000/mm(3) 2000/mm(3)
For BMT studies: WNL * 2.0 - < 3.0 X * 1.0 - < 2.0 x 10(9) * 0.5 - < 1.0 x 10(9) < 0.5 x 10(9)/L
10(9)/L /L * 1000 - /L * 500 - < 500/mm(3)
* 2000 - < 2000/mm(3) < 1000/mm(3)
< 3000/mm(3)
Note: The following criteria using age, race and sex normal values may be used for pediatric studies if the protocol so specifies.
* 75 - < 100% LLN * 50 - < 75% LLN * 25 - 50% LLN < 25% LLN
-----------------------------------------------------------------------------------------------------------------------------------
Lymphopenia WNL <LLN - 1.0 x 10(9) * 0.5 - < 1.0 x 10(9) < 0.5 x 10(9)/L
/L /L <500/mm(3)
< LLN - 1000/mm(3) * 500 - < 1000/mm(3)
Note: The following criteria using age, race, and sex normal values may be used for pediatric studies if the protocol so specifies.
* 75 - < 100% LLN * 50 - < 75% LLN * 25 - < 50% LLN < 25% LLN
-----------------------------------------------------------------------------------------------------------------------------------
Neutrophils/granulocytes WNL * 1.5 - < 2.0 x 10(9) * 1.0 - < 1.5 x 10(9) * 0.5 - < 1.0 x 10(9) < 0.5 x 10(9)/L
(ANC/AGC) /L /L /L < 500/mm(3)
* 1500 - * 1000 - * 500 - < 1000/mm(3)
< 2000/mm(3) < 1500/mm(3)
For BMT: WNL * 1.0 - < 1.5 x * 0.5 - < 1.0 x 10(9) * 0.1 - < 0.5 x 10(9) < 0.1 x 10(9)/L
10(9)/L /L /L < 100/mm(3)
* 1000 - * 500 - < 1000/mm(3) * 100 - < 500/mm(3)
< 1500/mm(3)
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the protocol so
specifies.
For leukemia studies WNL 10 - < 25% 25 - < 50% 50 - < 75% * 75% decrease
or bone marrow decrease from decrease from decrease from from baseline
infiltrative/ baseline baseline baseline
myelophthisic process
-----------------------------------------------------------------------------------------------------------------------------------
Platelets WNL < LLN - < 75.0 x * 50.0 - < 75.0 x * 10.0 - < 50.0 x < 10.0 x 10(9)/L
10(9)/L < LLN - 10(9)/L 10(9)/L < 10000/mm(3)
75000/mm(3) * 50000 - < * 10000 - <
75000/mm(3) 50000/mm(3)
For BMT: WNL * 50.0 - < 75.0 x * 20.0 - < 50.0 x * 10.0 - < 20.0 x < 10.0 x 10(9)/L
10(9)/L 10(9)/L 10(9)/L < 10000/mm(3)
* 50000 - * 20000 - * 10000 -
< 75000/mm(3) < 50000/mm(3) < 20000/mm(3)
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative/myelophthisic process if the protocol so
specifies.
For leukemia studies WNL 10 - < 25% 25 - < 50% 50 - < 75% * 75% decrease
or bone marrow decrease from decrease from decrease from from baseline
infiltrative/ baseline baseline baseline
myelophthisic process
-----------------------------------------------------------------------------------------------------------------------------------
* Greater than or equal to
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Page 52
<Table>
<Caption>
---------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
---------------------------------------------------------------------------------------------------------
Transfusion: Platelets none -- -- yes platelet
transfusions and
other measures
required to
improve platelet
increment; platelet
transfusion
refractoriness
associated with
life-threatening
bleeding (e.g.,
HLA or cross
matched platelet
transfusions)
For BMT: none 1 platelet 2 platelet *3 platelet platelet
transfusion in 24 transfusion in 24 transfusion in 24 transfusion and
hours hours hours other measures
required to
improve platelet
increment; platelet
transfusion
refractoriness
associated with
life-threatening
bleeding (e.g.,
HLA or cross
matched platelet
transfusions)
Also consider Platelets
---------------------------------------------------------------------------------------------------------
Transfusion: pRBCs none Yes
For BMT: none **2 u pRBC 3 u pRBC (>15 *4 u pRBC hemorrhage or
(**15cc/kg) in 24 **30cc/kg) in 24 (>30cc/kg) in 24 hemolysis
hours elective or hours elective or hours associated with
planned planned life-threatening
anemia; medical
intervention
required to
improve
hemoglobin
Also consider Hemoglobin
---------------------------------------------------------------------------------------------------------
Blood/Bone Marrow- none mild moderate severe life-threatening or
Other disabling
(Specify, )
---------------------------------------------------------------------------------------------------------
CARDIOVASCULAR (ARRHYTHMIA)
---------------------------------------------------------------------------------------------------------
Conduction none asymptomatic, not symptomatic, but symptomatic and life-threatening
abnormality/ requiring treatment not requiring requiring treatment (e.g., arrhythmia
Atrioventricular heart (e.g., Mobitz type I treatment (e.g., Mobitz type associated with
block second-degree AV II second-degree CHF, hypotension,
block AV block, third- syncope, shock)
Wenckebach) degree AV block)
---------------------------------------------------------------------------------------------------------
* greater than or equal to
** less than or equal to
</Table>
129
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Page 53
<Table>
<Caption>
-----------------------------------------------------------------------------------------------------------------------------------
GRADE
-----------------------------------------------------------------------------------------------------------------------------------
TOXICITY 0 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------------------
Nodal/junctional none asymptomatic, not symptomatic, but symptomatic and life-threatening
arrhythmia/dysrhythmia requiring treatment not requiring requiring treatment (e.g., arrhythmia
treatment associated with
CHF, hypotension,
syncope, shock)
-----------------------------------------------------------------------------------------------------------------------------------
Palpitations none present - - -
Note: Grade palpitations only in the absence of a documented arrhythmia.
-----------------------------------------------------------------------------------------------------------------------------------
Prolonged QTc none asymptomatic, not symptomatic, but symptomatic and life-threatening
interval (QTc >0.48 requiring treatment not requiring requiring treatment (e.g., arrhythmia
seconds) treatment associated with
CHF, hypotension,
syncope, shock)
-----------------------------------------------------------------------------------------------------------------------------------
Sinus bradycardia none asymptomatic, not symptomatic, but symptomatic and life-threatening
requiring treatment not requiring requiring treatment (e.g., arrhythmia
treatment associated with
CHF, hypotension,
syncope, shock)
-----------------------------------------------------------------------------------------------------------------------------------
Sinus tachycardia none asymptomatic, not symptomatic, but symptomatic and -
requiring treatment not requiring requiring treatment
treatment of underlying
cause
-----------------------------------------------------------------------------------------------------------------------------------
Supraventricular none asymptomatic, not symptomatic, but symptomatic and life-threatening
arrhythmias requiring treatment not requiring requiring treatment (e.g., arrhythmia
(SVT/atrial fibrillation/ treatment associated with
flutter) CHF, hypotension,
syncope, shock)
-----------------------------------------------------------------------------------------------------------------------------------
Syncope (fainting) is graded in the NEUROLOGY category.
-----------------------------------------------------------------------------------------------------------------------------------
Vasovagal episode none - present without present with loss of -
loss of consciousness
consciousness
-----------------------------------------------------------------------------------------------------------------------------------
Ventricular arrhythmia none asymptomatic, not symptomatic, but symptomatic and life-threatening
(PVCs/bigeminy/trigeminy/ requiring treatment not requiring requiring treatment (e.g., arrhythmia
ventricular treatment associated with
tachycardia) CHF, hypotension,
syncope, shock)
-----------------------------------------------------------------------------------------------------------------------------------
Cardiovascular/ none asymptomatic, not symptomatic, but symptomatic, and life-threatening
Arrhythmia-Other requiring treatment not requiring requiring treatment (e.g., arrhythmia
(Specify, treatment of underlying associated with
_______________) cause CHF, hypotension,
syncope, shock)
-----------------------------------------------------------------------------------------------------------------------------------
CARDIOVASCULAR (GENERAL)
-----------------------------------------------------------------------------------------------------------------------------------
Acute vascular leak absent - symptomatic, but respiratory life-threatening;
syndrome not requiring fluid compromise or requiring pressor
support requiring fluids support and/or
ventilatory support
-----------------------------------------------------------------------------------------------------------------------------------
Cardiac- none non-specific T- asymptomatic, ST- angina without acute myocardial
ischemia/infarction wave flattening or and T-wave evidence of infarction
changes changes suggesting infarction
ischemia
-----------------------------------------------------------------------------------------------------------------------------------
</Table>
130
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Page 54
<Table>
<Caption>
------------------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
------------------------------------------------------------------------------------------------------------------------------------
Cardiac left ventricular normal asymptomatic asymptomatic but CHF responsive to severe or refractory
function decline of resting resting ejection treatment CHF or requiring
ejection fraction fraction below LLN intubation
of **10% but <20% for laboratory or
of baseline value; decline of resting
shortening fraction ejection fraction
**24% but <30% **20% of
baseline value;
<24% shortening
fraction
------------------------------------------------------------------------------------------------------------------------------------
CNS cerebrovascular ischemia is graded in the NEUROLOGY category.
------------------------------------------------------------------------------------------------------------------------------------
Cardiac troponin I normal - - levels consistent levels consistent with
(cTnI) with unstable myocardial infarction
angina as defined as defined by the
by the manufacturer manufacturer
------------------------------------------------------------------------------------------------------------------------------------
Cardiac troponin T normal **0.03 - <0.05 **0.05 - <0.1 **0.1 - <0.2 ng/ml **0.2 ng/ml
(cTnT) ng/ml ng/ml
------------------------------------------------------------------------------------------------------------------------------------
Edema none asymptomatic, not symptomatic, symptomatic edema anasarca (severe
requiring therapy requiring therapy limiting function generalized edema)
and unresponsive to
therapy or requiring
drug discontinuation
------------------------------------------------------------------------------------------------------------------------------------
Hypertension none asymptomatic, recurrent or requiring therapy hypertensive crisis
transient increase persistent or or more intensive
by >20 mmHg symptomatic therapy than
(diastolic) or to increase by >20 previously
>150/100* if mmHg (diastolic)
previously WNL; not or to >150/100* if
requiring treatment previously WNL; not
requiring treatment
* Note: For pediatric patients, use age and sex appropriate normal values >95th percentile ULN.
------------------------------------------------------------------------------------------------------------------------------------
Hypotension none changes, but not requiring brief requiring therapy shock (associated with
requiring therapy fluid replacement and sustained acidema and impairing
(including transient or other therapy medical attention, vital organ function
orthostatic but not but resolves due to tissue
hypotension) hospitalization; no without persisting hypoperfusion
physiologic physiologic
consequences consequences
Also consider Syncope (fainting)
Note: Angina or MI is graded as Cardiac- ischemia/infarction in the CARDIOVASCULAR (GENERAL) category.
For pediatric patients, systolic BP 65 mmHg or less in infants up to 1 year old and 70 mmHg or less in children older than
1 year of age, use two successive or three measurements in 24 hours.
------------------------------------------------------------------------------------------------------------------------------------
Myocarditis none - - CHF responsive to severe or refractory
treatment CHF
------------------------------------------------------------------------------------------------------------------------------------
Operative injury of none primary suture primary suture vascular occlusion myocardial
vein/artery repair for injury, repair for injury, requiring surgery infarction;
but not requiring but not requiring or bypass for injury resection of organ
transfusion transfusion (e.g., bowel, limb)
------------------------------------------------------------------------------------------------------------------------------------
** greater than or equal to
</Table>
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Page 55
<Table>
<Caption>
-------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
-------------------------------------------------------------------------------------------------------------------------
Pericardial effusion/ none asymptomatic pericarditis (rub, physiologic tamponade
pericarditis effusion ECG changes, consequences (drainage or
requiring treatment and/or chest pain) resulting from pericardial window
symptoms required
-------------------------------------------------------------------------------------------------------------------------
Pericardial arterial/ none brief episode of requiring surgical life-threatening or
ischemia ischemia managed intervention with permanent
non-surgically and functional deficit
without permanent (e.g., amputation)
deficit
-------------------------------------------------------------------------------------------------------------------------
Phlebitis (superficial) none present
Note: Injection site reaction is graded in the DERMATOLOGY/SKIN category.
Thrombosis/embolism is graded in the CARDIOVASCULAR (GENERAL) category.
-------------------------------------------------------------------------------------------------------------------------
Syncope (fainting) is graded in the NEUROLOGY category.
-------------------------------------------------------------------------------------------------------------------------
Thrombosis/embolism none deep vein deep vein embolic event
thrombosis, not thrombosis, including
requiring requiring pulmonary
anticoagulant anticoagulant embolism
therapy
-------------------------------------------------------------------------------------------------------------------------
Vein/artery operative injury is graded as Operative injury of vein/artery in the CARDIOVASCULAR (GENERAL) category.
-------------------------------------------------------------------------------------------------------------------------
Visceral arterial none brief episode of requiring surgical life-threatening or
ischemia (non- ischemia managed intervention with permanent
myocardial) non-surgically and functional deficit
without permanent (e.g., resection of
deficit ileum)
-------------------------------------------------------------------------------------------------------------------------
Cardiovascular/ none mild moderate severe life-threatening or
General-Other disabling
(Specify,
)
-------------------------------------------------------------------------------------------------------------------------
COAGULATION
-------------------------------------------------------------------------------------------------------------------------
Note: See the HEMORRHAGE category for grading the severity of bleeding events.
-------------------------------------------------------------------------------------------------------------------------
DIC Absent laboratory findings laboratory findings
(disseminated present with no and bleeding
intravascular bleeding
coagulation)
Also grade Platelets.
Note: Must have increased fibrin split products or D-dimer in order to grade as DIC.
-------------------------------------------------------------------------------------------------------------------------
Fibrinogen WNL *0.75 - <1.0 x *0.5 - <0.75 x *0.25 - <0.5 x <0.25 - LLN
LLN LLN LLN
Note: The following criteria may be used for leukemia studies or bone marrow infiltrative myelophthisic process if the
protocol so specifies.
For leukemia studies WNL <20% decreased *20 - <40% *40 - <70% <50 mg%
from pretreatment decreased from decrease from
value of LLN pretreatment value pretreatment value
or LLN or LLN
-------------------------------------------------------------------------------------------------------------------------
Partial thromboplastin WNL >ULN - **1.5 x >1.5 - **2 x ULN >2 x ULN
time (PTT) ULN
-------------------------------------------------------------------------------------------------------------------------
Phelbitis is graded in the CARDIOVASCULAR (GENERAL) category.
-------------------------------------------------------------------------------------------------------------------------
Prothrombin time (PT) WNL >ULN - **1.5 x >1.5 - **2 x ULN >2 x ULN
ULN
-------------------------------------------------------------------------------------------------------------------------
Thrombosis/embolism is graded in the CARDIOVASCULAR (GENERAL) category.
-------------------------------------------------------------------------------------------------------------------------
* greater than or equal to
** less than or equal to
</Table>
132
----------------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
----------------------------------------------------------------------------------------------------------------------------------
Thrombotic absent - - laboratory findings laboratory findings
microangiopathy (e.g., present without and clinical
thrombotic clinical consequences,
thrombocytopenic consequences (e.g., CNS
purpura/TTP or hemorrhage/
hemolytic uremic bleeding or
syndrome/HUS) thrombosis/
embolism or renal
failure) requiring
therapeutic
intervention
For BMT evidence of RBC evidence of RBC evidence of RBC evidence of RBC
destruction destruction with destruction with destruction with
(schistocytosis) elevated creatinine creatinine (>3 x renal failure
without clinical (**3 x ULN) ULN) not requiring requiring dialysis
consequences dialysis and/or
encephalopathy
Also consider Hemoglobin (Hgb), Platelets, Creatinine.
Note: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments).
----------------------------------------------------------------------------------------------------------------------------------
Coagulation-Other none mild moderate severe life-threatening or
(Specify, ) disabling
----------------------------------------------------------------------------------------------------------------------------------
CONSTITUTIONAL SYMPTOMS
----------------------------------------------------------------------------------------------------------------------------------
Fatigue none increased fatigue moderate (e.g., severe (e.g., bedridden or
(lethargy, malaise, over baseline, decrease in decrease in disabling
asthenia) but not altering performance statue performance status
normal activities by 1 ECOG level by *2 ECOG levels
or 20% Karnofsky or 40% Karnofsky
or Lansky) or or Lansky) or loss
causing difficulty of ability to
performing some perform some
activities activities
Note: See Appendix III for performance status scales.
----------------------------------------------------------------------------------------------------------------------------------
Fever (in the none 38.0 - 39.0 39.1 - 40.0 >40.0 degrees C >40.0 degrees C
absence of degrees C degrees C (>104.0 degrees F) (>104.0 degrees F)
neutropenia, where (100.4 - 102.2 (102.3 - 104.0 for < 24hrs for > 24 hrs
neutropenia is degrees F degrees F
defined as AGC
< 1.0 x 10(9)/L)
Also consider Allergic reaction/hypersensitivity.
Note: The temperature measurements listed above are oral or tympanic.
----------------------------------------------------------------------------------------------------------------------------------
Hot flashes/flushes are graded in the ENDOCRINE category.
----------------------------------------------------------------------------------------------------------------------------------
Rigors, chills none mild, requiring severe and/or not responsive to --
symptomatic prologned, narcotic
treatment (e.g., requiring narcotic medication
blanket) or non- medication
narcotic
medication
----------------------------------------------------------------------------------------------------------------------------------
Sweating normal mild and frequent or -- --
(diaphoresis) occasional drenching
----------------------------------------------------------------------------------------------------------------------------------
Weight gain <5% 5 - <10% 10 - <20% **20% --
Also consider Ascites, Edema, Pleural effusion.
----------------------------------------------------------------------------------------------------------------------------------
Weight gain - veno-
occlusive disease
(VOD)
Note: The following criteria is to be used ONLY for weight gain associated with Veno-Occlusive Disease.
----------------------------------------------------------------------------------------------------------------------------------
* greater than or equal to
** less than or equal to
133
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Page 57
<Table>
<Caption>
-----------------------------------------------------------------------------------------------------------------------------------
GRADE
-----------------------------------------------------------------------------------------------------------------------------------
TOXICITY 0 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------------------
<2% *2 - <5% *5 - <10% *10% or as ascities *10% or fluid
retention resulting
in pulmonary
failure
-----------------------------------------------------------------------------------------------------------------------------------
Weight loss <5% 5 - <10% 10 - <20% *20% -
Also consider Vomiting, Dehydration, Diarrhea.
-----------------------------------------------------------------------------------------------------------------------------------
Constitutional none mild moderate severe life-threatening or
Symptoms-Other disabling
(Specify, _______________)
-----------------------------------------------------------------------------------------------------------------------------------
DERMATOLOGY/SKIN
-----------------------------------------------------------------------------------------------------------------------------------
Alopecia normal mild hair loss pronounced hair - -
loss
-----------------------------------------------------------------------------------------------------------------------------------
Bruising none localized or in generalized - -
(in absence of grade 3 dependent area
or 4 thrombocytopenia)
Note: Bruising resulting from grade 3 or 4 thrombocytopenia is graded as Petechiae/purpura and Hemorrhage/bleeding with grade 3 or
4 thrombocytopenia in the HEMORRHAGE category, not in the DERMATOLOGY/SKIN category.
-----------------------------------------------------------------------------------------------------------------------------------
Dermatitis, focal none faint erythema or moderate to brisk confluent moist skin necrosis or
(associated with high- dry desquamation erythema or a desquamation, *1.5 ulceration of full
dose chemotherapy patchy moist cm diameter, not thickness dermis;
and bone marrow desquamation, confined to skin may include
transplant) mostly confined to folds; pitting spontaneous
skin folds and edema bleeding not
creases; moderate induced by minor
edema trauma or abrasion
-----------------------------------------------------------------------------------------------------------------------------------
Dry skin normal controlled with not controlled with - -
emollients emollients
-----------------------------------------------------------------------------------------------------------------------------------
Erythema multiforme absent - scattered, but not severe or requiring life-threatening
(e.g., Stevens-Johnson generalized IV fluids (e.g., (e.g., exfoliative
syndrome, toxic eruption generalized rash or or ulcerating
epidermal necrolysis) painful stomatitis) dermatitis or
requiring enteral
or parenteral
nutritional
support)
-----------------------------------------------------------------------------------------------------------------------------------
Flushing absent present - - -
-----------------------------------------------------------------------------------------------------------------------------------
Hand-foot skin none skin changes or skin changes with skin changes with -
reaction dermatitis without pain, not pain, interfering
pain (e.g., interfering with with function
erythema, peeling) function
-----------------------------------------------------------------------------------------------------------------------------------
Injection site reaction none pain or itching or pain or swelling, ulceration or -
erythema with inflammation necrosis that is
or phlebitis severe or prolonged,
or requiring surgery
-----------------------------------------------------------------------------------------------------------------------------------
Nail changes normal discoloration or partial or complete - -
ridging loss of nail(s) or
(koilonychia) or pain in nailbeds
pitting
-----------------------------------------------------------------------------------------------------------------------------------
Petechiae is graded in the HEMORRHAGE category.
-----------------------------------------------------------------------------------------------------------------------------------
Photosensitivity none painless erythema painful erythema erythema with -
desquamation
-----------------------------------------------------------------------------------------------------------------------------------
* greater than or equal to
</Table>
134
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Page 58
<Table>
<Caption>
------------------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
------------------------------------------------------------------------------------------------------------------------------------
Pigmentation changes none localized generalized - -
(e.g., vitiligo) pigmentation pigmentation
changes changes
------------------------------------------------------------------------------------------------------------------------------------
Pruritus none mild or localized, intense or intense or -
relieved widespread, widespread and
spontaneously or relieved poorly controlled
by local measures spontaneously or despite treatment
by systemic measures
------------------------------------------------------------------------------------------------------------------------------------
Purpura is graded in the HEMORRHAGE category
------------------------------------------------------------------------------------------------------------------------------------
Radiation dermatitis none faint erythema or moderate to brisk confluent moist skin necrosis or
dry desquamation erythema or a desquamation, *1.5 ulceration of full
patchy moist cm diameter, not thickness dermis, may
desquamation, mostly confined to skin include bleeding not
confined to skin folds; pitting induced by minor
folds and creases; edema trauma or abrasion
moderate edema
Note: Pain associated with radiation dermatitis is graded separately in the PAIN category as Pain due to radiation.
------------------------------------------------------------------------------------------------------------------------------------
Radiation recall none faint erythema or moderate to brisk confluent moist skin necrosis or
reaction (reaction dry desquamation erythema or a desquamation, *1.5 ulceration of full
following chemotherapy patchy moist cm diameter, not thickness dermis, may
in the absence of desquamation, mostly confined to skin include bleeding not
additional radiation confined to skin folds; pitting induced by minor
therapy that occurs in folds and creases; edema trauma or abrasion
a previous radiation moderate edema
port
------------------------------------------------------------------------------------------------------------------------------------
Rash/desquamation none macular or papular macular or papular symptomatic generalized exfoliative
eruption or eruption or generalized dermatitis or
erythema without erythema with erythroderma or ulcerative dermatitis
associated symptoms pruritus or other macular, papular
associated or vesicular
symptoms eruption or
covering < 50% of desquamation
body surface or covering *50% of
localized body surface area
desquamation or
other lesions
covering < 50% of
body surface area
For BMT: none macular or papular macular or papular symptomatic generalized exfoliative
eruption or eruption or generalized dermatitis or
erythema covering erythema with erythroderma or ulcerative dermatitis
< 25% of body pruritus or other symptomatic macular, or bullous formation
surface area associated papular or vesicular
without associated symptoms eruption, with
symptoms covering *25 - bullous formation,
< 50% of body or desquamation
surface or localized covering * 50% of
desquamation or body surface area
other lesions
covering *25 -
< 50% of
body surface area
------------------------------------------------------------------------------------------------------------------------------------
* greater than or equal to
</Table>
135
Protocol ID99-333
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Page 59
<Table>
<Caption>
-----------------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------------------
Also consider Allergic reaction/hypersensitivity.
Note: Erythema multiforme (Stevens-Johnson syndrome) is graded separately as Erythema multiforme.
-----------------------------------------------------------------------------------------------------------------------------------
Urticaria none requiring no requiring PO or requiring IV -
(hives, welts, wheals) medication topical treatment or medication or
IV medication or steroids for (less
steroids for (less than) 24 hours
than) 24 hours
-----------------------------------------------------------------------------------------------------------------------------------
Wound-infectious none cellulitis superficial infection requiring necrotizing fascitis
infection IV antibiotics
-----------------------------------------------------------------------------------------------------------------------------------
Wound-non-infectious none incisional incisional hernia fascial disruption fascial disruption
separation without evisceration with evisceration
-----------------------------------------------------------------------------------------------------------------------------------
Dermatology/Skin- none mild moderate severe life-threatening or
Other disabling
(Specify, )
-----------------------------------------------------------------------------------------------------------------------------------
ENDOCRINE
-----------------------------------------------------------------------------------------------------------------------------------
Cushingoid appearance absent - present - -
(e.g., moon face with or
without buffalo hump,
centripetal obesity,
cutaneous striae)
Also consider Hyperglycemia, Hypokalemia.
-----------------------------------------------------------------------------------------------------------------------------------
Feminization of male absent - - present -
-----------------------------------------------------------------------------------------------------------------------------------
Gynecomastia none mild pronounced or pronounced or -
painful painful and
requiring surgery
-----------------------------------------------------------------------------------------------------------------------------------
Hot flashes/flushes none mild or no more moderate and - -
than 1 per day greater than 1 per
day
-----------------------------------------------------------------------------------------------------------------------------------
Hypothyroidism absent asymptomatic, TSH symptomatic or patient hospitalized myxedema coma
elevated, no thyroid for manifestations
therapy given replacement of hypothyroidism
treatment given
-----------------------------------------------------------------------------------------------------------------------------------
Masculinization of absent - - present -
female
-----------------------------------------------------------------------------------------------------------------------------------
SIADH (syndrome of absent - - present -
inappropriate
antidiuretic hormone)
-----------------------------------------------------------------------------------------------------------------------------------
Endocrine-Other none mild moderate severe life-threatening or
(Specify, ) disabling
-----------------------------------------------------------------------------------------------------------------------------------
GASTROINTESTINAL
-----------------------------------------------------------------------------------------------------------------------------------
Amylase is graded in the METABOLIC/LABORATORY category.
-----------------------------------------------------------------------------------------------------------------------------------
Anorexia none loss of appetite oral intake requiring IV fluids requiring feeding
significantly tube or parenteral
decreased nutrition
-----------------------------------------------------------------------------------------------------------------------------------
Ascites (non- none asymptomatic symptomatic, symptomatic, life-threatening
malignant) requiring diuretics requiring therapeutic physiologic
paracentesis consequences
-----------------------------------------------------------------------------------------------------------------------------------
</Table>
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<Table>
<Caption>
-------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
-------------------------------------------------------------------------------------------------------------------------
Colitis none - abdominal pain abdominal pain, perforation or
with mucus and/or fever, change in requiring surgery
blood in stool bowel habits with or toxic megacolon
ileus or peritoneal
signs, and
radiographic or
biopsy
documentation
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4
thrombocytopenia, Melena/GI bleeding, Rectal bleeding/hematochezia, Hypotension.
---------------------------------------------------------------------------------------------------------------------------
Constipation none requiring stool requiring laxatives obstipation obstruction or toxic
softener or requiring manual megacolon
dietary modification evacuation or enema
---------------------------------------------------------------------------------------------------------------------------
Dehydration none dry mucous requiring IV fluid requiring IV fluid physiologic
membranes and/or replacement (brief) replacement consequences
diminished skin (sustained) requiring intensive
turgor care; hemodynamic
collapse
Also consider Hypotension, Diarrhea, Vomiting, Stomatitis/pharyngitis (oral/pharyngeal mucositis).
---------------------------------------------------------------------------------------------------------------------------
Diarrhea none increase of <4 increase of 4-6 increase of *7 physiologic
Patients without stools/day over stools/dayk, or stools/day or consequences
colostomy: pre-treatment nocturnal stools incontinence; or requiring intensive
need for parenteral care; or
support for hemodynamic
dehydration collapse
Patients with a none mild increase in moderative increase severe increase in physiologic
colostomy: loose, watery in loose, watery loose, watery consequences,
colostomy output colostomy output colostomy output requiring intensive
compared with compared with compared with care; or
pretreatment pretreatment, but pretreatment, hemodynamic
not interfering with interfering with collapse
normal activity normal activity
For BMT none >500 - **1000ml of >1000 - **1500ml >1500ml of severe abdominal
diarrhea/day of diarrhea/day diarrhea/day pain with or
without ileus
For Pediatric BMT: >500 - **10ml/kg of >1000 - **15ml/kg >15ml/kg of -
diarrhea/day of diarrhea/day diarrhea/day
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4
thrombocytopenia, Pain, Dehydration, Hypotension.
---------------------------------------------------------------------------------------------------------------------------
Duodenal ulcer none - requiring medical uncontrolled by perforation or
(requires radiographic management or outpatient medical bleeding, requiring
or endoscopic non-surgical management emergency surgery
documentation) treatment requiring
hospitalization
---------------------------------------------------------------------------------------------------------------------------
Dyspepsia/heartburn none mild moderate severe -
---------------------------------------------------------------------------------------------------------------------------
Dysphagia, none mild dysphagia, dysphagia, dysphagia, complete
esophagitis, but can eat regular requiring requiring IV obstruction (cannot
odynophagia (painful) diet predominantly hydration swallow saliva)
swallowing) pureed, soft, or requiring enteral or
liquid diet parenteral
nutritional support,
or perforation
-------------------------------------------------------------------------------------------------------------------------
</Table>
* greater than or equal to
** less than or equal to
137
Protocol ID99-333
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Page 61
<Table>
<Caption>
GRADE
--------------------------------------------------------------------------------------------------------
TOXICITY 0 1 2 3 4
----------------------- --------- ------------------- ------------------- ------------------- ---------------------
Note: If toxicity is radiation-related, grade either under Dysphagia- esophageal related to radiation or Dysphagia- pharyngeal
related to radiation.
------------------------------------------------------------------------------------------------------------------------------------
Dysphagia- esophageal none mild dysphagia, but dysphagia, requiring dysphagia, requiring complete obstruction
related to radiation can eat regular diet predominantly feeding tube, IV (cannot swallow
liquid, pureed or hydration or saliva); ulceration
soft diet hyperalimentation with bleeding not
induced by minor
trauma or abrasion
or perforation
Also consider Pain due to radiation, Mucositis due to radiation
Note: Fistula is graded separately as Fistula- esophageal
------------------------------------------------------------------------------------------------------------------------------------
Dysphagia - none mild dysphagia, dysphagia dysphagia, requiring complete obstruction
pharyngeal related to but can eat requiring feeding tube, IV (cannot swallow
radiation regular diet predominantly hydration or saliva); ulceration
pureed, soft, or hyperalimentation with bleeding not
liquid diet induced by minor
trauma or abrasion
or perforation
Also consider Pain due to radiation, Mucositis due to radiation.
Note: Fistula is graded separately as Fistula- pharyngeal.
------------------------------------------------------------------------------------------------------------------------------------
Fistula- esophageal none - - present requiring surgery
------------------------------------------------------------------------------------------------------------------------------------
Fistula- intestinal none - - present requiring surgery
------------------------------------------------------------------------------------------------------------------------------------
Fistula- pharyngeal none - - present requiring surgery
------------------------------------------------------------------------------------------------------------------------------------
Fistula- rectal/anal none - - present requiring surgery
------------------------------------------------------------------------------------------------------------------------------------
Flatulence none mild moderate - -
------------------------------------------------------------------------------------------------------------------------------------
Gastric ulcer none - requiring medical bleeding without perforation or
(requires radiographic management or perforation, bleeding, requiring
or endoscopic non-surgical uncontrolled by emergency surgery
documentation) treatment outpatient medical
management;
requiring
hospitalization or
surgery
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia.
------------------------------------------------------------------------------------------------------------------------------------
Gastritis none - requiring medical uncontrolled by life-threatening
management or outpatient medical bleeding, requiring
non-surgical management; emergency surgery
treatment requiring
hospitalization or
surgery
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia.
------------------------------------------------------------------------------------------------------------------------------------
Hematemesis is graded in the HEMORRHAGE category.
------------------------------------------------------------------------------------------------------------------------------------
Hematochezia is graded in the HEMORRHAGE category as Rectal bleeding/hematochezia.
------------------------------------------------------------------------------------------------------------------------------------
Ileus (or none - intermittent, not requiring non- requiring surgery
Neuroconstipation) requiring surgical
intervention intervention
------------------------------------------------------------------------------------------------------------------------------------
Mouth dryness normal mild moderate - -
------------------------------------------------------------------------------------------------------------------------------------
Mucositis
------------------------------------------------------------------------------------------------------------------------------------
</Table>
138
\
Protocol ID99-333
November 16, 1999
Page 62
<Table>
<Caption>
-----------------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------------------
Note: Mucositis not due to radiation is graded in the GASTROINTESTINAL category for specific sites: Colitis, Esophagitis, Gastritis,
Stomatitis/pharyngitis (oral/pharyngeal mucositis), and Typhlitis; or the RENAL/GENITOURINARY category for Vaginititis.
Radiation-related mucositis is graded as Mucositis due to radiation.
-----------------------------------------------------------------------------------------------------------------------------------
Mucositis due to none erythema of the patchy confluent necrosis or deep
radiation mucosa pseudomembranous pseudomembranous ulceration, may
reaction (patches reaction (contiguous include bleeding
generally ** 1.5 cm patches generally > not induced by
in diameter and 1.5 cm in diameter) minor trauma or
non-contiguous) abrasion
Also consider Pain due to radiation.
Note: Grade radiation mucositis of the larynx here.
Dysphagia related to radiation is also graded as either Dysphagia- esophageal related to radiation or Dysphagia- pharyngeal
related to radiation, depending on the site of treatment.
-----------------------------------------------------------------------------------------------------------------------------------
Nausea none able to eat oral intake no significant -
significantly intake, requiring
decreased IV fluids
-----------------------------------------------------------------------------------------------------------------------------------
Pancreatitis none - - abdominal pain complicated by
with pancreatic shock (acute
enzyme elevation circulatory
failure)
Also consider Hypotension.
Note: Asymptomatic amylase and Amylase are graded in the METABOLIC/LABORATORY category.
-----------------------------------------------------------------------------------------------------------------------------------
Pharyngitis is graded in the GASTROINTESTINAL category a Stomatitis/pharyngitis (oral/pharyngeal mucositis).
-----------------------------------------------------------------------------------------------------------------------------------
Proctitis none increased stool increased stool increased stool perforation,
frequency, occasional frequency, bleeding, frequency/diarrhea, bleeding or
blood-streaked stools, mucus discharge, or requiring parenteral necrosis or other
or rectal discomfort rectal discomfort support; rectal life-threatening
(including requiring medication; bleeding, requiring complication
hemorrhoids), not anal fissure transfusion; or requiring surgical
requiring medication persistent mucus intervention (e.g.,
discharge, colostomy)
necessitating pads
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia,
and Pain due to radiation.
Note: Fistula is graded separately as Fistula- rectal/anal.
Proctitis occurring more than 90 days after the start of radiation therapy is graded in the RTOG/EORTC Late Radiation
Morbidity Scoring Scheme. (See Appendix IV)
-----------------------------------------------------------------------------------------------------------------------------------
Salivary gland changes none slightly thickened thick, ropy, sticky - acute salivary
saliva/may have saliva; markedly gland necrosis
slightly altered altered taste;
taste (e.g., alteration in diet
metallic); required
additional fluids
may be required
-----------------------------------------------------------------------------------------------------------------------------------
</Table>
** Less than or equal to
139
Protocol ID99-333
November 16, 1999
Page 63
<Table>
<Caption>
GRADE
TOXICITY 0 1 2 3 4
Sense of smell normal slightly altered markedly altered -- --
Stomatitis/pharyngitis none painless ulcers, painful erythema, painful erythema, sever ulceration
(oral/pharyngeal erythema, or mild edema, or ulcers, edema, or ulcers or requires
mucositis) soreness in the but can eat or requiring IV parenteral or
absence of lesions swallow hydration enteral nutritional
support or
prophylactic
intubation
For BMT none painless ulcers, painful erythema, painful erythema, severe ulceration
erythema, or mild edema or ulcers edema, or ulcers requiring
soreness in the but can swallow preventing prophylactic
absence of lesions swallowing or intubation or
requiring resulting in
hydration or documented
parenteral (or aspiration
enteral) pneumonia
nutritional
support
Note: Radiation-related mucositis is graded as Mucositis due to radiation.
Taste disturbance normal slightly altered markedly altered -- --
(dysgeusia)
Typhlitis none -- -- abdominal pain, perforation,
(inflammation of the diarrhea, fever, bleeding or
cecum) or radiographic necrosis or other
documentation life-threatening
complication
requiring surgical
intervention (e.g.,
colostomy)
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4
thrombocytopenia, Hypotension, Febrile/neutropenia.
Vomiting none 1 episode in 24 2-5 episodes in 24 > 6 episodes in 24 Requiring
hours over hours over hours over parenteral
pretreatment pretreatment pretreatment; or nutrition; or
need for IV fluids physiologic
consequences
requiring intensive
care; hemodynamic
collapse
Also consider Dehydration.
Weight gain is graded in the CONSTITUTIONAL SYMPTOMS category.
Weight loss is graded in the CONSTITUTIONAL SYMPTOMS category.
Gastrointestinal-Other none mild moderate severe life-threatening
(Specify, ) disabling
HEMORRHAGE
Note: Transfusion in this section refers to pRBC infusion:
For any bleeding with grade 3 or 4 platelets (less than 50,000), always
grade Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia. Also
consider platelets, transfusion- pRBCS, and transfusion-platelets in
addition to the grade that incorporates the site or type of bleeding.
If the site or type of hemorrhage/bleeding is listed, also use the grading
that incorporates the site of bleeding: CNS hemorrhage/bleeding,
Hematuria, Hematemesis, Hemoptysis, Hemorrhage/bleeding with surgery,
Melena/lower GI bleeding, Petechiae/purpura (Hemorrhage/bleeding into
skin), Rectal bleeding/hematochezia, Vaginal bleeding.
If the platelet count is greater than 50,000 and the site or type of
bleeding is listed, grade the specific site. If the site or type is not
listed and the platelet count is greater than 50,000, grade
Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia and specify the
site or type in the OTHER category.
</Table>
140
Protocol ID99 - 333
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Page 64
<Table>
<Caption>
----------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
----------------------------------------------------------------------------------------------------------------
Hemorrhage/bleeding none mild without requiring catastrophic
with grade 3 or 4 transfusion transfusion bleeding, requiring
thrombocytopenia major non-elective
intervention
Also consider Platelets, Hemoglobin, Transfusion-platelet, Transfusion-pRBCs.
Note: This toxicity must be graded for any bleeding with grade 3 or 4 thrombocytopenia. Also grade the site or
type of hemorrhage/bleeding. If the site is not listed, grade as Other in the HEMORRHAGE category.
----------------------------------------------------------------------------------------------------------------
Hemorrhage/bleeding none mild without requiring catastrophic
without grade 3 or 4 transfusion transfusion bleeding requiring
thrombocytopenia major non-elective
intervention
Also consider Platelets, Hemoglobin, Transfusion-platelet, Transfusion-pRBCs.
Note: Bleeding in the absence of grade 3 or 4 thrombocytopenia is graded here only if the specific site or type
of bleeding is not listed elsewhere in the HEMORRHAGE category. Also grade as Other in the HEMORRHAGE
category.
----------------------------------------------------------------------------------------------------------------
CNS none -- -- bleeding noted on hemorrhagic stroke
hemorrhage/bleeding CT or other scan or hemorrhagic
with no clinical vascular event
consequences (CVA) with
neurologic signs
and symptoms
----------------------------------------------------------------------------------------------------------------
Epistaxis none mild without -- requiring catastrophic
transfusion transfusion bleeding, requiring
major non-elective
intervention
----------------------------------------------------------------------------------------------------------------
Hematemesis none mild without -- requiring catastrophic
transfusion transfusion bleeding, requiring
major non-elective
intervention
----------------------------------------------------------------------------------------------------------------
Hematuria none microscopic only intermittent gross persistent gross open surgery or
(in the absence of bleeding, no clots bleeding or clots; necrosis or deep
vaginal bleeding) may require bladder ulceration
catheterization or
instrumentation, or
transfusion
----------------------------------------------------------------------------------------------------------------
Hemoptysis none mild without -- requiring catastrophic
transfusion transfusion bleeding, requiring
major non-elective
intervention
----------------------------------------------------------------------------------------------------------------
Hemorrhage/bleeding none mild without -- requiring catastrophic
associated with transfusion transfusion bleeding, requiring
surgery major non-elective
intervention
Note: Expected blood loss at the time of surgery is not graded as a toxicity.
----------------------------------------------------------------------------------------------------------------
Melena/GI bleeding none mild without -- requiring catastrophic
transfusion transfusion bleeding, requiring
major non-elective
intervention
----------------------------------------------------------------------------------------------------------------
Petechiae/purpura none rare petechiae of petechiae or generalized --
(hemorrhage/bleeding skin purpura in petechiae or
into skin or mucosa) dependent areas of purpura of skin or
skin petechiae of any
mucosal site
----------------------------------------------------------------------------------------------------------------
</Table>
141
Protocol ID99-333
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Page 65
GRADE
<Table>
<Caption>
TOXICITY 0 1 2 3 4
------------------------------------------------------------------------------------------------------------------------------------
Rectal bleeding/ none mild without persistent, requiring requiring catastrophic
hematochezia transfusion or medication, (e.g., transfusion bleeding, requiring
medication steroid suppositories) major non-elective
and/or break from intervention
radiation treatment
------------------------------------------------------------------------------------------------------------------------------------
Vaginal bleeding none spotting, requiring requiring greater than requiring catastrophic
< 2 pads per day or equal to 2 transfusion bleeding, requiring
padsper day, but not major non-elective
requiring transfusion intervention
------------------------------------------------------------------------------------------------------------------------------------
Hemorrhage -- Other none mild without -- requiring catastrophic
Specify site, transfusion transfusion bleeding, requiring
_____________) major non-elective
intervention
------------------------------------------------------------------------------------------------------------------------------------
HEPATIC
------------------------------------------------------------------------------------------------------------------------------------
Alkaline phosphatase WNL > ULN - 2.5 x ULN > 2.5 - 5.0 x ULN > 5.0 - 20.0 x ULN > 20.0 x ULN
------------------------------------------------------------------------------------------------------------------------------------
Bilirubin WNL > ULN - 1.5 x ULN > 1.5 - 3.0 x ULN > 3.0 - 10.0 x ULN > 10.0 x ULN
------------------------------------------------------------------------------------------------------------------------------------
Bilirubin -- graft versus host disease (GVHD)
Note: The following criteria are used for only for bilirubin associated with graft versus host disease.
normal greater than or equal greater than or equal to greater than or equal greater than or
to 2 - < 3 mg/100 ml 3 - < 6 mg/100 ml to 6 - < 15 mg/100 ml equal to 15 mg/
100 ml
------------------------------------------------------------------------------------------------------------------------------------
GGT WNL > ULN - 2.5 x ULN > 2.5 - 5.0 x ULN > 5.0 - 20.0 x ULN > 20.0 x ULN
(y - Glutamyl
transpeptidase)
------------------------------------------------------------------------------------------------------------------------------------
Heptic enlargement absent -- -- present --
Note: Grade Hepatic enlargement only for changes related to VOD or other treatment related toxicity.
------------------------------------------------------------------------------------------------------------------------------------
Hypoalbuminemia WNL < LLN - 3g/dl greater than or equal to < 2 g/dl --
2 - < 3 g/dl
------------------------------------------------------------------------------------------------------------------------------------
Liver normal -- -- asterixis encephalopathy or
dysfunction/failure coma
(clinical)
Note: Documented viral hepatitis is graded in the INFECTION category.
------------------------------------------------------------------------------------------------------------------------------------
Portal vein flow normal -- decreased portal reversal/retrograde --
vein flow portal vein flow
------------------------------------------------------------------------------------------------------------------------------------
SGOT (AST) WNL > ULN - 2.5 x ULN > 2.5 - 5.0 x ULN > 5.0 - 20.0 x ULN > 20.0 x ULN
(serum glutamic
oxaloacetic
transaminase)
------------------------------------------------------------------------------------------------------------------------------------
SGPT (ALT) WNL > ULN - 2.5 x ULN > 2.5 - 5.0 x ULN > 5.0 - 20.0 x ULN > 20.0 x ULN
(serum glutamic
pyruvic transaminase)
------------------------------------------------------------------------------------------------------------------------------------
Hepatic - Other none mild moderate severe life-threatening
(Specify,___________) or disabling
------------------------------------------------------------------------------------------------------------------------------------
INFECTION/FEBRILE NEUTROPENIA
------------------------------------------------------------------------------------------------------------------------------------
Catheter-related none mild, no active moderate, localized severe, systemic life-threatening
infection treatment infection, requiring infection, requiring sepsis, (e.g., septic
local or oral IV antibiotic or shock)
treatment antifungal treatment
or hospitalization
</Table>
142
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Page 66
<Table>
<Caption>
GRADE
------------------------------------------------------------------------------------------------------------------------------
TOXICITY 0 1 2 3 4
------------------------------------------------------------------------------------------------------------------------------
Febrile neutropenia none -- -- Present Life-threatening
(fever of unknown sepsis (e.g., septic
origin without shock)
clinically or
microbiologically
documented infection)
(ANC < 1.0 x 10(to the power of 9)/L,
fever greater than or equal to 38.5 degrees Celsius)
Note: Hypothermia instead of fever may be associated with neutropenia and is graded here.
------------------------------------------------------------------------------------------------------------------------------
Infection (documented none -- -- present life-threatening
clinically or sepsis (e.g., septic
microbiologically) shock)
with grade 3 or 4
neutropenia
(ANC < 1.0 x 10(to the power of 9)/L)
Note: Hypothermia instead of fever may be associated with neutropenia and is graded here. In the absence of documented infection
with grade 3 or 4 neutropenia, grade as Febrile neutropenia.
------------------------------------------------------------------------------------------------------------------------------
Infection with none -- -- present life-threatening
unknown ANC sepsis (e.g., septic
shock)
Note: This toxicity criterion is used in the rare case when ANC is unknown.
------------------------------------------------------------------------------------------------------------------------------
Infection without none mild, no active moderate, localized severe, systemic life-threatening
neutropenia treatment infection, requiring infection, requiring sepsis (e.g., septic
local or oral IV antibiotic or shock)
treatment antifungal
treatment, or
hospitalization
------------------------------------------------------------------------------------------------------------------------------
Infection/Febrile none mild moderate severe life-threatening
Neuropenia-Other or disabling
(Specify, )
------------------------------------------------------------------------------------------------------------------------------
Wound-infectious is graded in the DERMATOLOGY/SKIN category.
------------------------------------------------------------------------------------------------------------------------------
LYMPHATICS
------------------------------------------------------------------------------------------------------------------------------
Lymphatics normal mild lymphedema moderate severe severe
lymphedema lymphedema lymphedema
requiring limiting function; limiting function
compression; lymphocyst with ulceration
lymphocyst requiring surgery
------------------------------------------------------------------------------------------------------------------------------
Lymphatics-Other none mild moderate severe life-threatening or
(Specify, ____) disabling
------------------------------------------------------------------------------------------------------------------------------
METABOLIC/LABORATORY
------------------------------------------------------------------------------------------------------------------------------
Acidosis normal pH < normal, but -- pH < 7.3 pH < 7.3 with life-
(metabolic or greater than or threatening
respiratory) equal to 7.3 physiologic
consequences
------------------------------------------------------------------------------------------------------------------------------
Alkalosis normal pH > normal, but -- pH > 7.5 pH > 7.5 with life-
(metabolic or less than or threatening
respiratory) equal to 7.5 physiologic
consequences
------------------------------------------------------------------------------------------------------------------------------
Amylase WNL > ULN - 1.5 x > 1.5 - 2.0 x ULN > 2.0 - 5.0 x ULN > 5.0 x ULN
ULN
------------------------------------------------------------------------------------------------------------------------------
Bicarbonate WNL < LLN - 16 mEq/dl 11 - 15 mEq/dl 8 - 10 mEq/dl < 8 mEq/dl
------------------------------------------------------------------------------------------------------------------------------
</Table>
143
Protocol ID99 -- 333
November 16, 1999
Page 67
<Table>
<Caption>
------------------------------------------------------------------------------------------------------------------------------------
Grade
Toxicity 0 1 2 3 4
------------------------------------------------------------------------------------------------------------------------------------
CPK WNL >ULN-2.5x >2.5-5xULN >5-10xULN >10xULN
(creatine ULN
phosphokinase)
------------------------------------------------------------------------------------------------------------------------------------
Hypercalcemia WNL >ULN-11.5 >11.5-12.5 mg/dl >12.5-13.5 mg/dl >13.5 mg/dl
mg/dl >2.9-3.1 mmol/L >3.1-3.4 mmol/L >3.4 mmol/L
>ULN-2.9
mmol/L
------------------------------------------------------------------------------------------------------------------------------------
Hypercholesterolemia WNL >ULN-300mg/dl >300-400 mg/dl >400-500 mg/dl >500 mg/dl
>ULN-7.75 >7.75-10.34 >10.34-12.92 >12.92 mmol/L
mmol/L mmol/L >mmol/L
------------------------------------------------------------------------------------------------------------------------------------
Hyperglycemia WNL >ULN-160 mg/dl >160-250 mg/dl >250-500 mg/dl >500 mg/dl
>ULN-8.9 >8.9-13.9 >13.9-27.8 >27.8 mmol/L or
mmol/L mmol/L mmol/L ketoacidosis
------------------------------------------------------------------------------------------------------------------------------------
Hyperkalemia WNL >ULN-5.5 >5.5-6.0 mmol/L >6.0-7.0 mmol/L >7.0 mmol/L
mmol/L
------------------------------------------------------------------------------------------------------------------------------------
Hypermagnesemia WNL >ULN-3.0 mg/dl - >3.0-8.0 mg/dl >8.0 mg/dl
>ULN-1.23 >1.23-3.30 >3.30 mmol/L
mmol/L mmol/L
------------------------------------------------------------------------------------------------------------------------------------
Hypernatremia WNL >ULN-150 >150-155 >155-160 >160 mmol/L
mmol/L mmol/L mmol/L
------------------------------------------------------------------------------------------------------------------------------------
Hypertriglyceridemia WNL >ULN-2.5x >2.5-5.0xULN >5.0-10xULN >10xULN
ULV
------------------------------------------------------------------------------------------------------------------------------------
Hyperuricemia WNL >ULN-less than or - >ULN-less than or equal >10mg/dl
equal to 10 mg/dl to 10 mg/dl >0.59 mmol/L
less than or equal less than or equal to
to 0.59 mmol/L 0.59 mmol/L with
without physiologic physiologic consequences
consequences
Also consider Turnor lysis syndrome, Renal failure, Creatinine, Potassium
-----------------------------------------------------------------------------------------------------------------------------------
Hypocalcemia WNL <LLN-8.0 mg/dl 7.0-<8.0 mg/dl 6.0-<7.0 mg/dl <6.0 mg/dl
<LLN-2.0 1.75-<2.0 1.5<1.75 <1.5 mmol/L
mmol/L mmol/L mmol/L
-----------------------------------------------------------------------------------------------------------------------------------
Hypoglycemia WNL <LLN-55 mg/dl 40-<55 mg/dl 30-<40 mg/dl <30mg/dl
<LLN-3.0 2.2-<3.0 mmol/L 1.7-<2.2 mmol/L <1.7 mmol/L
mmol/L
------------------------------------------------------------------------------------------------------------------------------------
Hypokalemia WNL <LLN-3.0 - 2.5-<3.0 mmol/L <2.5 mmol/L
mmol/L
------------------------------------------------------------------------------------------------------------------------------------
Hypomagnesemia WNL <LLN-1.2 mg/dl 0.9-<1.2 mg/dl 0.7-<0.9 mg/dl <0.7 mg/dl
<llN-0.5 0.4-<0.5 mmol/L 0.3-<0.4 mmol/L <0.3 mmol/L
mmol/L
------------------------------------------------------------------------------------------------------------------------------------
Hyponatremia WNL <LLN-130 - 120-<130 <120 mmol/L
mmol/L mmol/L
------------------------------------------------------------------------------------------------------------------------------------
Hypophosphatemia WNL <LLN-2.5 mg/dl less than or equal to less than or equal to >1.0 mg/dl
2.0-<2.5 mg/dl 1.0-<2.0 mg/dl
<LLN-0.8 less than or equal to less than or equal to <0.3 mmol/L
mmol/L 0.6-<0.8 mmol/L 0.3-<0.6 mmol/L
------------------------------------------------------------------------------------------------------------------------------------
Hypothyroidism is graded in the ENDOCRINE category.
------------------------------------------------------------------------------------------------------------------------------------
Lipase WNL >ULN-1.5x >1.5-2.0xULN >2.0-5.0xULN >5.0xULN
ULN
------------------------------------------------------------------------------------------------------------------------------------
Metabolic/ none mild moderate severe life-threatening
Laboratory- or disabling
Other
(Specify )
------------------------------------------------------------------------------------------------------------------------------------
MUSCULOSKELETAL
------------------------------------------------------------------------------------------------------------------------------------
Arthralgia is graded in the PAIN category.
------------------------------------------------------------------------------------------------------------------------------------
</Table>
144
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<Table>
<Caption>
-----------------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------------------
Arthritis none mild pain with moderate pain severe pain with disabling
inflammation, with inflammation, inflammation,
erythema or joint erythema, or joint erythema, or joint
swelling but not swelling interfering swelling and
interfering with with function, but interfering with
function not interfering activities of daily
with activities of living
daily living
-----------------------------------------------------------------------------------------------------------------------------------
Muscle weakness normal asymptomatic symptomatic and symptomatic and bedridden or
(not due to with weakness on interfering with interfering with disabling
neuropathy) physical exam function, but not activities of
interfering with daily living
activities of
daily living
-----------------------------------------------------------------------------------------------------------------------------------
Myalgia is graded in the PAIN category.
-----------------------------------------------------------------------------------------------------------------------------------
Myositis
(inflammation/ none mild pain, not pain interfering pain interfering bedridden or
damage of interfering with with function, but with function and disabling
muscle) function not interfering interfering with
with activities of activities of
daily living daily living
Also consider CPK.
Note: Myositis implies muscle damage (i.e., elevated CPK).
-----------------------------------------------------------------------------------------------------------------------------------
Osteonecrosis none asymptomatic and symptomatic and symptomatic and symptomatic; or
(vascular detected by interfering with interfering with disabling
necrosis) imaging only function, but not activities of
interfering with daily living
activities of
daily living
-----------------------------------------------------------------------------------------------------------------------------------
Musculoskeletal- none mild moderate severe life-threatening
Other or disabling
(Specify, )
-----------------------------------------------------------------------------------------------------------------------------------
NEUROLOGY
-----------------------------------------------------------------------------------------------------------------------------------
Aphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category.
-----------------------------------------------------------------------------------------------------------------------------------
Arachnoiditis/ absent mild pain not moderate pain severe pain unable to function
meningi arbus/ interfering with interfering with interfering with or perform activities
radiculitis function function, but not activities of of daily living;
interfering with daily living bedridden; paraplegia
activities of
daily living
Also consider Headache, Vomiting, Fever.
-----------------------------------------------------------------------------------------------------------------------------------
Ataxia normal asymptomatic but mild symptoms moderate symptoms bedridden or
(incoordination) abnormal on interfering with interfering with disabling
physical exam, and function, but not activities of
not interfering interfering with daily living
with function activities of
daily living
-----------------------------------------------------------------------------------------------------------------------------------
CNS none -- -- transient ischemic permanent event
cerebrovascular event or attack (e.g., cerebral
ischemia (TIA) vascular accident)
-----------------------------------------------------------------------------------------------------------------------------------
CNS hemorrhage/bleeding is graded in the HEMORRHAGE category.
-----------------------------------------------------------------------------------------------------------------------------------
</Table>
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<Table>
<Caption>
--------------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
--------------------------------------------------------------------------------------------------------------------------------
Cognitive disturbance/ none cognitive cognitive cognitive inability to
learning problems disability; not disability; disability work/frank
interfering with interfering with resulting in mental retardation
work/school work/school significant
performance performance, impairment of
preservation of decline of 1 SD work/school
intelligence (Standard performance;
Deviation) or loss cognitive decline>
of developmental 2 SD
milestones
--------------------------------------------------------------------------------------------------------------------------------
Confusion normal confusion or confusion or confusion or harmful to others
disorientation or disorientation or delirium interfering or self; requiring
attention deficit of attention deficit with activities of hospitalization
brief duration; interfering with daily living
resolves function, but not
spontaneously with interfering with
no sequelae activities of daily
living
--------------------------------------------------------------------------------------------------------------------------------
Cranial neuropathy is graded in the NEUROLOGY category as Neuropathy-cranial.
--------------------------------------------------------------------------------------------------------------------------------
Delusions normal -- -- present toxic psychosis
--------------------------------------------------------------------------------------------------------------------------------
Depressed level of normal somnolence or somnolence or obtundation or coma
consciousness sedation not sedation interfering stupor; difficult to
interfering with with function, but arouse; interfering
function not interfering with with activities of
activities of daily daily living
living
Note: Syncope (fainting) is graded in the NEUROLOGY category.
--------------------------------------------------------------------------------------------------------------------------------
Dizziness/lightheadedn none not interfering with interfering with interfering with bedridden or
ess function function, but not activities of daily disabling
interfering with living
activities of daily
living
--------------------------------------------------------------------------------------------------------------------------------
Dysphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category.
--------------------------------------------------------------------------------------------------------------------------------
Extrapyramidal/ none mild involuntary moderate severe involuntary bedridden or
involuntary movement/ movements not involuntary movements or disabling
restlessness interfering with movements torticollis
function interfering with interfering with
function, but not activities of daily
interfering with living
activities of daily
living
--------------------------------------------------------------------------------------------------------------------------------
Hallucinations normal -- -- present toxic psychosis
--------------------------------------------------------------------------------------------------------------------------------
Headache is graded in the PAIN category.
--------------------------------------------------------------------------------------------------------------------------------
Insomnia normal occasional difficult sleeping frequent difficulty --
difficulty sleeping interfering with sleeping,
not interfering with function, but not interfering with
function interfering with activities of daily
activities of daily living
living
Note: This toxicity is graded when insomnia is related to treatment. If pain or other symptoms interfere with sleep do NOT grade
as insomnia.
--------------------------------------------------------------------------------------------------------------------------------
</Table>
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<Table>
<Caption>
-----------------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------------------
normal mild; easily moderate; severe; -
IRRITABILITY consolable requiring inconsolable
(children < 6 years of increased attention
age)
-----------------------------------------------------------------------------------------------------------------------------------
Leukoencephalapathy none mild increase in moderate increase severe increase in severe increase in
associated SAS (subarachnoid in SAS and/or SAS; severe SAS; severe
radiological findings space) and/or mild moderate ventriculomegaly; ventriculomegaly;
ventriculomegaly; ventriculomegaly; near total white diffuse low
and/or small (+/- and/or focal T2 matter T2 attenuation with
multiple) focal T2 hyperintensities hyperintensities or calcification (CT)
hyperintensities, extending into diffuse low diffuse white
involving centrum ovale, or attenuation (CT), matter necrosis
periventricular involving 1/3 to 2/3 focal white matter (MRI)
white matter or < of susceptible necrosis (cystic)
1/3 or susceptible areas of cerebrum
areas of cerebrum
-----------------------------------------------------------------------------------------------------------------------------------
Memory loss normal memory loss not memory loss memory loss anemsia
interfering with interfering with interfering with
function function, but not activities of daily
interfering with living
activities of daily
living
-----------------------------------------------------------------------------------------------------------------------------------
Mood alteration- normal mild mood moderate mood severe mood suicidal ideation or
anxiety agitation alteration not alteration alteration danger to self
interfering with interfering with interfering with
function function, but not activities of daily
interfering with living
activities of daily
living
-----------------------------------------------------------------------------------------------------------------------------------
Mood alteration- normal mild mood moderate mood severe mood suicidal ideation or
depression alteration not alteration alteration danger to self
interfering with interfering with interfering with
function function, but not activities of daily
interfering with living
activities of daily
living
-----------------------------------------------------------------------------------------------------------------------------------
Mood alteration- normal mild mood moderate mood severe mood danger to self
euphoria alteration not alteration alteration
interfering with interfering with interfering with
function function, but not activities of daily
interfering with living
activities of daily
living
-----------------------------------------------------------------------------------------------------------------------------------
Neuropathic pain is graded in the PAIN category.
-----------------------------------------------------------------------------------------------------------------------------------
Neuropathy-cranial absent - present, not present, interfering life-threatening,
interfering with with activities of disabling
activities of daily daily living
living
-----------------------------------------------------------------------------------------------------------------------------------
</Table>
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<Table>
<Caption>
---------------------------------------------------------------------------------------------------------------------------------
GRADE
Toxicity 0 1 2 3 4
---------------------------------------------------------------------------------------------------------------------------------
Neuropathy-motor normal subjective mild objective objective weakness paralysis
weakness but no weakness interfering with
objective findings interfering with activities of daily
function, but not living
interfering with
activities of daily
living
---------------------------------------------------------------------------------------------------------------------------------
Neuropathy-sensory normal loss of deep tendon objective sensory sensory loss or permanent sensory
reflexes or loss of paresthesia paresthesia loss that interferes
paresthesia (including interfering with with function
(including tingling) tingling), activities of daily
but not interfering interfering with living
with function function, but not
interfering with
activities of daily
living
---------------------------------------------------------------------------------------------------------------------------------
Nystagmus absent present -- -- --
Also consider Vision-double vision.
---------------------------------------------------------------------------------------------------------------------------------
Personality/behavioral normal change, but not disruptive to disruptive to harmful to others
disruptive to patient or family patient and family; or self; requiring
patient or family requiring mental hospitalization
health intervention
---------------------------------------------------------------------------------------------------------------------------------
Pyramidal tract normal asymptomatic with symptomatic or interfering with bedridden or
dysfunction (e.g., abnormality on interfering with activities of daily disabling; paralysis
tone, hyperreflexia physical function but not living
positive Babinski, examination interfering with
fine motor activities of daily
coordination) living
---------------------------------------------------------------------------------------------------------------------------------
Seizure(s) none -- seizure(s) self- seizure(s) in which seizures of any
limited and consciousness is type which are
consciousness if altered prolonged,
preserved repetitive, or
difficult to control
(e.g., status
epilepticus,
intractable
epilepsy)
---------------------------------------------------------------------------------------------------------------------------------
Speech impairment normal -- awareness of receptive or inability to
(e.g., dysphasia or receptive or expressive communicate
aphasia) expressive dysphasia
dysphasia, not impairing ability to
impairing ability to communicate
communicate
---------------------------------------------------------------------------------------------------------------------------------
Syncope (fainting) absent -- -- present --
Also consider CARDIOVASCULAR (ARRHYTHMIA), Vasovagal episode, CNS cerebrovascular ischernia.
---------------------------------------------------------------------------------------------------------------------------------
Tremor none mild and brief or moderate tremor severe tremor --
intermittent but interfering with interfering with
not interfering function, but not activities of daily
with function interfering with living
activities of daily
living
---------------------------------------------------------------------------------------------------------------------------------
</Table>
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<Table>
<Caption>
-----------------------------------------------------------------------------------------------------
GRADE
Toxicity 0 1 2 3 4
-----------------------------------------------------------------------------------------------------
Vertigo none not interfering interfering with interfering with bedridden or
with function function, but activities of disabling
not interfering daily living
with activities
of daily living
-----------------------------------------------------------------------------------------------------
Neurology-Other none mild moderate severe life-threatening
(Specify, ) or disabling
-----------------------------------------------------------------------------------------------------
OCULAR/VISUAL
-----------------------------------------------------------------------------------------------------
Cataract none asymptomatic symptomatic, symptomatic, --
partial visual visual loss
loss requiring
treatment or
interfering with
function
-----------------------------------------------------------------------------------------------------
Conjunctivitis none abnormal symptomatic and symptomatic and --
ophthalmologic interfering with interfering with
changes, but function, but activities of
asymptomatic or not interfering daily living
symptomatic with activities
without visual of daily living
impairment
(i.e., pain and
irritation)
-----------------------------------------------------------------------------------------------------
Dry eye normal mild, not moderate or -- --
requiring requiring
treatment artificial tears
-----------------------------------------------------------------------------------------------------
Glaucoma none increase in increase in visual unilateral or
intraocular intraocular impairment bilateral loss
pressure but no pressure with of vision
visual loss retinal changes (blindness)
-----------------------------------------------------------------------------------------------------
Keratitis none abnormal symptomatic and symptomatic and unilateral or
(corneal inflammation/ ophthalmologic interfering with interfering with bilateral loss
corneal ulceration) changes but function, but activities of of vision
asymptomatic or not interfering daily living (blindness)
symptomatic with activities
without visual of daily living
impairment
(i.e., pain and
irritation)
-----------------------------------------------------------------------------------------------------
Tearing (watery eyes) none mild: not moderate: interfering with --
interfering with interfering with activities of
function function, but daily living
not interfering
with activities
of daily living
-----------------------------------------------------------------------------------------------------
Vision -- blurred normal -- symptomatic and symptomatic and --
vision interfering with interfering with
function, but activities of
not interfering daily living
with activities
of daily living
</Table>
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<Table>
<Caption>
GRADE
TOXICITY 0 1 2 3 4
-------- --- --- --- --- ---
Vision-double vision normal -- symptomatic and symptomatic and --
(diplopia) interfering with interfering with
function, but not activities of daily
interfering with living
activities of
daily living
Vision-flashing normal mild, not symptomatic and symptomatic and --
lights/floaters interfering with interfering with interfering with
function function, but not activities of daily
interfering with living
activities of
daily living
Vision-night normal abnormal electro- symptomatic and symptomatic and --
blindness retinography but interfering with interfering with
(nyctalopia) asymptomatic function, but not activities of daily
interfering with living
activities of
daily living
Vision-photophobia normal -- symptomatic and symptomatic and --
interfering with interfering with
function, but not activities of daily
interfering with living
activities of
daily living
Ocular/Visual-Other normal mild moderate severe unilateral or
(Specify, ________) bilateral loss of
vision (blindness)
PAIN
Abdominal pain or none mild pain not moderate pain; severe pain; pain or disabling
cramping interfering with pain or analgesics analgesics severely
function interfering with interfering with
function, but not activities of daily
interfering with living
activities of
daily living
Arthralgia none mild pain not moderate pain; severe pain; pain or disabling
(joint pain) interfering with pain or analgesics analgesics severely
function interfering with interfering with
function, but not activities of daily
interfering with living
activities of
daily living
Arthritis (joint pain with clinical signs of inflammation) is graded in the MUSCULOSKELETAL category.
Bone pain none mild pain not moderate pain; severe pain; pain or disabling
interfering with pain or analgesics analgesics severely
function interfering with interfering with
function, but not activities of daily
interfering with living
activities of
daily living
</Table>
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<Table>
<Caption>
---------------------------------------------------------------------------------------------------------------------------------
Grade
Toxicity 0 1 2 3 4
---------------------------------------------------------------------------------------------------------------------------------
Chest pain none mild pain not moderate pain: severe pain: pain or disabling
(non-cardiac and non- interfering with pain or analgesics analgesics severely
pleuritic) function interfering with interfering with
function, but not activities of daily
interfering with living
activities of
daily living
---------------------------------------------------------------------------------------------------------------------------------
Dysmenorrhea none mild pain not moderate pain: severe pain: pain or disabling
interfering with pain or analgesics analgesics severely
function interfering with interfering with
function, but not activities of daily
interfering with living
activities of daily
living
---------------------------------------------------------------------------------------------------------------------------------
Dyspareunia none mild pain not moderate pain: severe pain -
interfering with interfering with preventing sexual
function sexual activity activity
---------------------------------------------------------------------------------------------------------------------------------
Dysuria is graded in the RENAL/GENITOURINARY category.
---------------------------------------------------------------------------------------------------------------------------------
Earache (otalgia) none mild pain not moderate pain: severe pain: pain or disabling
interfering with pain or analgesics analgesics severely
function interfering with interfering with
function, but not activities of daily
interfering with living
activities of daily
living
---------------------------------------------------------------------------------------------------------------------------------
Headache none mild pain not moderate pain: severe pain: pain or disabling
interfering with pain or analgesics analgesics severely
function interfering with interfering with
function, but not activities of daily
interfering with living
activities of daily
living
---------------------------------------------------------------------------------------------------------------------------------
Hepatic pain none mild pain not moderate pain: severe pain: pain or disabling
interfering with pain or analgesics analgesics severely
function interfering with interfering with
function, but not activities of daily
interfering with living
activities of daily
living
---------------------------------------------------------------------------------------------------------------------------------
Myalgia none mild pain not moderate pain: severe pain: pain or disabling
(muscle pain) interfering with pain or analgesics analgesics severely
function interfering with interfering with
function, but not activities of daily
interfering with living
activities of daily
living
---------------------------------------------------------------------------------------------------------------------------------
Neuropathic pain none mild pain not moderate pain: severe pain: pain or disabling
(e.g., jaw pain, interfering with pain or analgesics analgesics severely
neurologic pain, function interfering with interfering with
phantom limb pain, function, but not activities of daily
post-infectious interfering with living
neuralgia, or painful activities of daily
neuropathies) living
---------------------------------------------------------------------------------------------------------------------------------
</Table>
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<Table>
<Caption>
-----------------------------------------------------------------------------------------------
GRADE
Toxicity 0 1 2 3 4
-----------------------------------------------------------------------------------------------
Pain due to radiation none mild pain nor moderate pain: severe pain: disabling
interfering with pain or pain or
function analgesics analgesics
interfering with severely
function, but interfering with
not interfering activities of
with activities daily living
or daily living
-----------------------------------------------------------------------------------------------
Pelvic pain none mild pain not moderate pain: severe pain: disabling
interfering with pain or pain or
function analgesics analgesics
interfering with severely
function, but interfering with
not interfering activities of
with activities daily living
or daily living
-----------------------------------------------------------------------------------------------
Pleuritic pain none mild pain not moderate pain: severe pain: disabling
interfering with pain or pain or
function analgesics analgesics
interfering with severely
function, but interfering with
not interfering activities of
with activities daily living
or daily living
-----------------------------------------------------------------------------------------------
Rectal or perirectal none mild pain not moderate pain: severe pain: disabling
pain (proctalgia) interfering with pain or pain or
function analgesics analgesics
interfering with severely
function, but interfering with
not interfering activities of
with activities daily living
or daily living
-----------------------------------------------------------------------------------------------
Tumor pain none mild pain not moderate pain: severe pain: disabling
onset or interfering with pain or pain or
exacerbation of function analgesics analgesics
tumor pain due to interfering with severely
treatment) function, but interfering with
not interfering activities of
with activities daily living
or daily living
-----------------------------------------------------------------------------------------------
Tumor flair is graded in the SYNDROME category.
-----------------------------------------------------------------------------------------------
Pain-Other none mild moderate severe disabling
(Specify, )
-----------------------------------------------------------------------------------------------
PULMONARY
-----------------------------------------------------------------------------------------------
Adult Respiratory absent -- -- -- present
Distress Syndrome
(ARDS)
-----------------------------------------------------------------------------------------------
Apnea none -- -- present requiring
intubation
-----------------------------------------------------------------------------------------------
</Table>
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<Table>
<Caption>
GRADE
TOXICITY 0 1 2 3 4
Carbon monoxide greater than greater than or greater than or greater than or <25% of pre-
diffusion capacity or equal to equal to 75 - equal to 50 - equal to 25 - treatment or
(DLco) 90% of pre- <90% of pre- <75% of pre- <50% of pre- normal value
treatment or treatment or treatment or treatment or
normal value normal value normal value normal value
Cough absent mild, relieved by requiring narcotic severe cough or --
non-prescription antitussive coughing spasms,
medication poorly controlled
or unresponsive
to treatment
Dyspnea normal -- dyspnea on dyspnea at normal dyspnea at rest or
(shortness of breath) exertion level of activity requiring ventilator
support
FEV(1) greater than greater than or greater than or greater than or <25% of pre-
or equal to equal to 75 - equal to 50 - equal to 25 - treatment or
90% of pre- <90% of pre- <75% of pre- <50% of pre- normal value
treatment or treatment or treatment or treatment or
normal value normal value normal value normal value
Hiccoughs (hiccups, none mild, not moderate, severe, prolonged, --
singultus) requiring requiring and refractory to
treatment treatment treatment
Hypoxia normal -- decreased O(2) decreased O(2) decreased O(2)
saturation with saturation at saturation
exercise rest, requiring requiring pressure
supplemental support (CPAP) or
oxygen assisted ventilation
Pleural effusion none asymptomatic and symptomatic, symptomatic, life-threatening
(non-malignant) not requiring requiring requiring O(2) or (e.g., requiring
treatment diuretics therapeutic intubation)
thoracentesis
Pleuritic pain is graded in the PAIN category.
Pneumonitis/pulmonary none radiographic radiographic radiographic radiographic
infiltrates changes but changes and changes and changes and
asymptomatic or requiring steroids requiring oxygen requiring assisted
symptoms not or diuretics ventilation
requiring steroids
Pneumothorax none no intervention chest tube sclerosis or life-threatening
required required surgery required
Pulmonary embolism is graded as Thrombosis/embolism in the CARDIOVASCULAR (GENERAL) category.
Pulmonary fibrosis none radiographic requiring steroids requiring oxygen requiring assisted
changes, but or diuretics ventilation
asymptomatic or
symptoms not
requiring steroids
Note: Radiation-related pulmonary fibrosis is graded in the RTOG/EORTC Late Radiation Morbidity Scoring Scheme-Lung.
(See Appendix IV)
Voice normal mild or persistent whispered speech, marked
changes/stridor/larynx intermittent hoarseness, but not able to dyspnea/stridor
(e.g., hoarseness, loss hoarseness able to vocalize; vocalize, may have requiring
of voice, laryngitis) may have mild to marked edema tracheostomy or
moderate edema intubation
Note: Cough from radiation is graded as cough in the PULMONARY category.
Radiation-related hemoptysis from larynx/pharynx is graded as Grade 4 Mucositis due to radiation in the
GASTROINTESTINAL category. Radiation-related hemoptysis from the thoracic cavity is graded as Grade 4 Hemoptysis
in the HEMORRHAGE category.
Pulmonary-Other none mild moderate severe life-threatening or
(Specify, ) disabling
</Table>
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<Table>
<Caption>
Grade
Toxicity 0 1 2 3 4
----------------------------------------------------------------------------------------------------------
RENAL/GENITOURINARY
----------------------------------------------------------------------------------------------------------
Bladder spasms absent mild symptoms, symptoms severe symptoms --
not requiring requiring requiring narcotic
intervention antispasmotic
----------------------------------------------------------------------------------------------------------
Creatinine WNL > ULN - 1.5 x ULN > 1.5 - 3.0 x ULN > 3.0 - 6.0 x ULN > 6.0 x ULN
Note: Adjust to age-appropriate levels for pediatric patients.
----------------------------------------------------------------------------------------------------------
Dysuria none mild symptoms symptoms relieved symptoms not --
(painful urination) requiring no with therapy relieved despite
intervention therapy
----------------------------------------------------------------------------------------------------------
Fistula or GU fistula none -- -- requiring requiring surgery
(e.g., vaginal, intervention
vesicovaginal)
----------------------------------------------------------------------------------------------------------
Hemoglobinuria -- present -- -- --
----------------------------------------------------------------------------------------------------------
Hematuria (in the absence of vaginal bleeding) is graded in the HEMORRHAGE category.
----------------------------------------------------------------------------------------------------------
Incontinence none with coughing, spontaneous, some no control (in the --
sneezing, etc. control absence of fistula)
----------------------------------------------------------------------------------------------------------
Operative injury to none -- injury of bladder sepsis, fistula, or septic obstruction
bladder and/or ureter with primary obstruction of both kidneys or
repair requiring vesicovaginal
secondary surgery; fistula requiring
loss of one kidney; diversion
injury requiring
anastomosis or re-
implantation
----------------------------------------------------------------------------------------------------------
Proteinuria normal or < 1+ or 0.15 - 1.0 2+ to 3+ or 1.0 - 4+ or > 3.5 g/24 nephrotic
0.15 g/24 hours g/24 hours 3.5 g/24 hours hours syndrome
Note: If there is an inconsistency between absolute value and uristix reading, use the absolute value for grading.
----------------------------------------------------------------------------------------------------------
Renal failure none -- -- requiring dialysis, requiring dialysis
but reversible and irreversible
----------------------------------------------------------------------------------------------------------
Ureteral obstruction none unilateral, not -- bilateral, not stent, nephrostomy
requiring surgery requiring surgery tube, or surgery
----------------------------------------------------------------------------------------------------------
Urinary electrolyte none asymptomatic, not mild, reversible reversible but irreversible,
wasting (e.g., requiring and manageable requiring IV requiring continued
Fanconi's syndrome, treatment with oral replacement replacement
renal tubular replacement
acidosis)
Also consider Acidosis, Bicarbonate, Hypocalcemia, Hypophosphatemia.
----------------------------------------------------------------------------------------------------------
Urinary normal increase in increase > 2 x hourly or more --
frequency/urgency frequency or normal but < with urgency, or
nocturia up to hourly requiring catheter
2 x normal
----------------------------------------------------------------------------------------------------------
Urinary retention normal hesitancy or hesitancy requiring frequent bladder rupture
dribbling, but no requiring in/out catheteriza-
significant medication or tion (greater than
residual urine; occasional in/out or equal to 4 x per
retention occurr- catheterization week) or urological
ing during the (<4 x per week), intervention (e.g.,
immediate post- or operative TURP, suprapubic
operative period bladder atony tube, urethrotomy)
requiring
indwelling catheter
beyond immediate
postoperative
period but for
< 6 weeks
----------------------------------------------------------------------------------------------------------
</Table>
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Page 78
<Table>
<Caption>
-----------------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------------------
Urine color change normal asymptomatic, -- -- --
(not related to change in urine
other dietary or color
physiologic cause
e.g., bilirubin,
concentrated urine,
hematuria)
-----------------------------------------------------------------------------------------------------------------------------------
Vaginal bleeding is graded in the HEMORRHAGE category.
-----------------------------------------------------------------------------------------------------------------------------------
Vaginitis none mild, not moderate, relieved severe, not relieved ulceration
(not due to requiring treatment with treatment with treatment, or requiring surgery
infection) ulceration not
requiring surgery
-----------------------------------------------------------------------------------------------------------------------------------
Renal/ none mild moderate severe life-threatening or
Genitourinary- disabling
Other
(Specify, )
-----------------------------------------------------------------------------------------------------------------------------------
SECONDARY MALIGNANCY
-----------------------------------------------------------------------------------------------------------------------------------
Secondary none -- -- -- present
Malignancy-Other
(Specify type,
)
excludes
metastastic
tumors
-----------------------------------------------------------------------------------------------------------------------------------
SEXUAL/REPRODUCTIVE FUNCTION
-----------------------------------------------------------------------------------------------------------------------------------
Dyspareunia is graded in the PAIN category.
-----------------------------------------------------------------------------------------------------------------------------------
Dysmenorrhea is graded in the PAIN category.
-----------------------------------------------------------------------------------------------------------------------------------
Erectile normal mild (erections moderate no erections --
impotence impaired but (erections impaired,
satisfactory) unsatisfactory for
intercourse)
-----------------------------------------------------------------------------------------------------------------------------------
Female sterility normal -- -- sterile --
-----------------------------------------------------------------------------------------------------------------------------------
Femininization of male is graded in the ENDOCRINE category.
-----------------------------------------------------------------------------------------------------------------------------------
Irregular normal occasionally very irregularly, persistent --
menses (change irregular or but continuing amenorrhea
from baseline) lengthened interval, menstrual cycles
but continuing
menstrual cycles
-----------------------------------------------------------------------------------------------------------------------------------
Libido normal decrease in interest severe loss of -- --
interest
-----------------------------------------------------------------------------------------------------------------------------------
Male infertility -- -- Oligospermia Azoospermia --
(low sperm count)
-----------------------------------------------------------------------------------------------------------------------------------
Masculinization of female is graded in the ENDOCRINE category.
-----------------------------------------------------------------------------------------------------------------------------------
Vaginal dryness normal mild requiring treatment -- --
and/or interfering
with sexual function,
dyspareunia
-----------------------------------------------------------------------------------------------------------------------------------
Sexual/ none mild moderate severe disabling
Reproductive
Function-Other
(Specify, )
-----------------------------------------------------------------------------------------------------------------------------------
SYNDROMES (NOT INCLUDED IN THE PREVIOUS CATEGORIES)
-----------------------------------------------------------------------------------------------------------------------------------
Acute vascular leak syndrome is graded in the CARDIOVASCULAR (GENERAL) category.
-----------------------------------------------------------------------------------------------------------------------------------
</Table>
155
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<Table>
<Caption>
------------------------------------------------------------------------------------------------------------------------------------
Grade
Toxicity 0 1 2 3 4
------------------------------------------------------------------------------------------------------------------------------------
ARDS (Adult Respiratory Distress Syndrome) is graded in the PULMONARY category.
------------------------------------------------------------------------------------------------------------------------------------
Autoimmune reactions are graded in the ALLERGY/IMMUNOLOGY category.
------------------------------------------------------------------------------------------------------------------------------------
DIC (disseminated intravascular coagulation) is graded in the COAGULATION category.
------------------------------------------------------------------------------------------------------------------------------------
Fanconi's syndrome is graded as Urinary electrolyte wasting in the RENAL/GENITOURINARY category.
------------------------------------------------------------------------------------------------------------------------------------
Renal tubular acidosis is graded as Urinary electrolyte wasting in the RENAL/GENITOURINARY category.
------------------------------------------------------------------------------------------------------------------------------------
Stevens-Johnson syndrome (erythema multiforme) is graded in the DERMATOLOGY/SKIN category.
------------------------------------------------------------------------------------------------------------------------------------
SLADH (syndrome of inappropriate antidiuretic hormone) is graded in the ENDOCRINE category.
------------------------------------------------------------------------------------------------------------------------------------
Thrombotic microangiopathy (e.g., thromboitic thrombocytopenic purpura/TTP or hemolytic uremic syndrome/HUS) is graded in
the COAGULATION category.
------------------------------------------------------------------------------------------------------------------------------------
Tumor flare none mild pain not moderate pain; severe pain; pain or Disabling
interfering with pain or analgesics analgesics
function interfering with interfering with
function, but not function and
interfering with interfering with
activities of daily activities of daily
living living
Also consider Hypercalcemia.
Note: Tumor flare is characterized by a constellation of symptoms and signs in direct relation to initiation of therapy (e.g., anti-
estrogens/androgens or additional hormones). The symptoms/signs include tumor pain, inflammation of visible tumor,
hypercalcemia, diffuse bone pain, and other electrolyte disturbances.
------------------------------------------------------------------------------------------------------------------------------------
Tumor lysis syndrome absent -- -- present --
Also consider Hyperkalcemia, Creatinine.
------------------------------------------------------------------------------------------------------------------------------------
Urinary electrolyte wasting (e.g., Fanconi's syndrome, renal tubular acidosis) is graded under the RENAL/GENITOURINARY
category.
------------------------------------------------------------------------------------------------------------------------------------
Syndromes-Other none Mild moderate severe life-threatening or
(Specify, ) disabling
------------------------------------------------------------------------------------------------------------------------------------
</Table>
156
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Page 80
Appendix I
Toxicity Module
To be implemented at the request of the study sponsor or principal investigator
in the protocol or by protocol amendment when more detailed information is
considered pertinent.
<Table>
-------------------------------------------------------------------------------------------------
Toxicity: Date of Treatment: Course Number:
-------------------------------------------------------------------------------------------------
Date of onset: Grade at onset:
-------------------------------------------------------------------------------------------------
Date of first change in grade: Grade:
-------------------------------------------------------------------------------------------------
Date of next change in grade: Grade:
-------------------------------------------------------------------------------------------------
Date of next change in grade: Grade:
-------------------------------------------------------------------------------------------------
Date of next change in grade: Grade:
-------------------------------------------------------------------------------------------------
Date of next change in grade: Grade:
-------------------------------------------------------------------------------------------------
Date of next change in grade: Grade:
-------------------------------------------------------------------------------------------------
Did toxicity resolve? Yes____ No____
If so, date of resolution of toxicity:
-------------------------------------------------------------------------------------------------
Date of last observation (if prior
to recovery):
-------------------------------------------------------------------------------------------------
Reason(s) observations stopped (if prior
to recover):
-------------------------------------------------------------------------------------------------
Was patient retreated? Yes____ No____
If yes, was treatment delayed for
recovery? YES____ NO____
Date of next treatment?
Dose reduced for next treatment? Yes____ No____
-------------------------------------------------------------------------------------------------
Additional Comments:
-------------------------------------------------------------------------------------------------
-------------------------------------------------------------------------------------------------
If module is being activated for new toxicity, not currently in CTC, please provide definitions
for toxicity grading:
Grade 0 = ------------------------------------------------------------
Grade 1 = ------------------------------------------------------------
Grade 2 = ------------------------------------------------------------
Grade 3 = ------------------------------------------------------------
Grade 4 = ------------------------------------------------------------
</Table>
157
Protocol ID99 - 333
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Page 81
Appendix II
Infection Module
To be implemented at the request of the study sponsor or principal investigator
in the protocol or by protocol amendment when more detailed information is
considered pertinent.
1. Use the Common Toxicity Criteria definitions to grade the severity of the
infection.
2. Specify type of infection from the following (CHOOSE ONE):
BACTERIAL FUNGAL PROTOZOAL VIRAL UNKNOWN
3. Specify site of infection from the following (CHOOSE ALL THAT APPLY):
BLOOD CULTURE POSITIVE
BONE INFECTION
CATHETER (intravenous)
CATHETER (intravenous), tunnel infection
CENTRAL NERVOUS SYSTEM INFECTION
EAR INFECTION
EYE INFECTION
GASTROINTESTINAL INFECTION
ORAL INFECTION
PNEUMONIA
SKIN INFECTION
UPPER RESPIRATORY INFECTION
URINARY TRACT INFECTION
VAGINAL INFECTION
INFECTION, not otherwise specified (Specify site, ____________)
4. Specify organism, if known: ________________.
5. Prophylactic antibiotic, antifungal, or antiviral therapy administration
Yes _____ No _____
If prophylaxis was given prior to infection, please specify below:
Antibiotic prophylaxis ____________________________________________________
Antifungal prophylaxis ____________________________________________________
Antiviral prophylaxis _____________________________________________________
Other prophylaxis _________________________________________________________
158
Protocol ID99-333
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Page 82
Appendix III
Performance Status Scales/Scores
<Table>
<Caption>
ECOG or Zubrod scale Karnofsky score
-------------------- ---------------
0 Asymptomatic and fully active 100%
1 Symptomatic; fully ambulatory; restricted 80-90%
in physically strenuous activity
2 Symptomatic; ambulatory; capable of self- 60-70%
care; more than 50% of waking hours are
spent out of bed
3 Symptomatic; limited self-care; spends more 40-50%
than 50% of time in bed, but not bedridden
4 Completely disabled; no self-care; bedridden 20-30%
</Table>
159
Protocol ID99 - 333
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Page 83
Appendix IV
RTOG/EORTC Late Radiation Morbidity Scoring Scheme
Use for toxicities occuring greater than 90 days after radiation therapy.
<Table>
<Caption>
-----------------------------------------------------------------------------------------------------------------------
GRADE
Toxicity 0 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------
Bladder- No Slight epithelial Moderate frequency/ Severe frequency and Necrosis/contracted
Late RT Morbidity change atrophy/minor generalized dysuria/severe bladder (capacity
Scoring from telangiectasia telangiectasia/ generalized less than 100
baseline (microscopic intermittent telangiectasia cc)/severe
hematuria) macroscopic (often with hemorrhagic cystitis
hematuria petechiae); frequent
hematuria; reduction
in bladder capacity
(less than 150 cc)
-----------------------------------------------------------------------------------------------------------------------
Bone- No Asymptomatic; no Moderate pain or Severe pain or Necrosis/spontaneous
Late RT Morbidity change growth retardation; tenderness; growth tenderness; complete fracture
Scoring from reduced bone density retardation; arrest of bone
baseline irregular bone growth; dense bone
sclerosis sclerosis
-----------------------------------------------------------------------------------------------------------------------
Brain- No Mild headache; Moderate headache; Severe headaches; Seizures or
Late RT Morbidity change slight lethargy great lethargy severe CNS paralysis; coma
Scoring from dysfunction (partial
baseline loss of power or
dyskinesia)
-----------------------------------------------------------------------------------------------------------------------
Esophagus- No Mild fibrosis; Unable to take solid Severe fibrosis; Necrosis/perforation;
Late RT Morbidity change slight difficulty in food normally; able to swallow only fistula
Scoring from swallowing solids; swallowing liquids; may have
baseline no pain on semi-solid food; paid on swallowing;
swallowing dilatation may be dilation required
indicated
-----------------------------------------------------------------------------------------------------------------------
Heart- No Asymptomatic or mild Moderate angina on Severe angina; Tamponade/severe
Late RT Morbidity change symptoms; transient effort; mild pericardial heart failure/severe
Scoring from T wave inversion and pericarditis; normal effusion; constrictive
baseline ST changes; sinus heart size; constrictive pericarditis
tachycardia greater persistent abnormal pericarditis;
than 110 (at rest) T wave and ST moderate heart
changes; low QRS failure; cardiac
enlargement; EKG
abnormalities
-----------------------------------------------------------------------------------------------------------------------
Joint- No Mild joint Moderate stiffness; Severe joint Necrosis/complete
Late RT Morbidity change stiffness; slight intermittent or stiffness; pain with fixation
Scoring from limitation of moderate joint pain; severe limitation of
baseline movement moderate limitation movement
of movement
-----------------------------------------------------------------------------------------------------------------------
Kidney- No Transient Persistent moderate Severe albuminuria; Malignant
Late RT Morbidity change albuminuria; no albuminuria (2+); severe hypertension; hypertension; uremic
Scoring from hypertension; mild mild hypertension; persistent anemia coma/urea greater
baseline impairment of renal no related anemia; (less than 10 g%); than 100%
function; urea 25 - moderate impairment severe renal
35 mg%; creatinine of renal function; failure; urea
1.5 - 2.0 urea
-----------------------------------------------------------------------------------------------------------------------
</Table>
160
Protocol ID99 -- 333
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Page 84
<Table>
<Caption>
------------------------------------------------------------------------------------------------------------------------------------
Grade
Toxicity 0 1 2 3 4
------------------------------------------------------------------------------------------------------------------------------------
mg%;creatinine >36-60 mg mg%; >60 mg%;
clearance >75% creatinine creatinine >4
clearance >50- mg%; creatinine
74% clearance
<50%
------------------------------------------------------------------------------------------------------------------------------------
Larynx- No change Hoarseness; slight Moderate arytenoid Severe edema; Necrosis
Late RT Morbidity from arytenoid edema edema; chondritis severe chondritis
Scoring baseline
------------------------------------------------------------------------------------------------------------------------------------
161
Protocol ID99-333
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Page 85
APPENDIX IV (CONTINUED)
RTOG/EORTC LATE RADIATION MORBIDITY SCORING SCHEME
USE FOR TOXICITIES OCCURRING GREATER THAN 90 DAYS AFTER RADIATION THERAPY
<Table>
<Caption>
------------------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
------------------------------------------------------------------------------------------------------------------------------------
Liver- No change Mild lassitude; Moderate Disabling hepatic Necrosis/hepatic
Late RT Morbidity from baseline nausea; dyspepsia; symptoms; some insufficiency; liver coma or
Scoring slightly abnormal abnormal liver function tests encephalopathy
liver function function tests; grossly abnormal;
serum albumin low albumin;
normal edema or ascites
------------------------------------------------------------------------------------------------------------------------------------
Lung- No change Asymptomatic or Moderate Severe Severe respiratory
Late RT Morbidity from baseline mild symptoms symptomatic symptomatic insufficiency/
Scoring (dry cough); slight fibrosis or fibrosis or continuous
radiographic pneumonitis pneumonitis; dense O(2)/assisted
appearances (severe cough); radiographic ventilation
low grade fever; changes
patchy
radiographic
appearances
------------------------------------------------------------------------------------------------------------------------------------
Mucous membrane- No change Slight atrophy and Moderate atrophy Marked atrophy Ulceration
Late RT Morbidity from baseline dryness and telangiectasia; with complete
Scoring little mucus dryness; severe
telangiectasia
------------------------------------------------------------------------------------------------------------------------------------
Salivary glands- No change Slight dryness of Moderate dryness Complete dryness Fibrosis
Late RT Morbidity from baseline mouth; good of mouth; poor of mouth; no
Scoring response on response on response on
stimulation stimulation stimulation
------------------------------------------------------------------------------------------------------------------------------------
Skin- No change Slight atrophy; Patchy atrophy; Marked atrophy; Ulceration
Late RT Morbidity from baseline pigmentation moderate gross telangiectasia
Scoring change; some hair telangiectasia; total
loss hair loss
------------------------------------------------------------------------------------------------------------------------------------
Small/Large intestine- No change Mild diarrhea; mild Moderate diarrhea Obstruction or Necrosis/
Late RT Morbidity from baseline cramping; bowel and colic; bowel bleeding, requiring perforation
Scoring movement 5 x movement > 5 x surgery fistula
daily slight rectal daily; excessive
discharge or rectal mucus or
bleeding intermittent
bleeding
------------------------------------------------------------------------------------------------------------------------------------
Spinal cord- No change Mild Lhermitte's Severe Lhermitte's Objective Mono-, para-,
Late RT Morbidity from baseline syndrome syndrome neurological quadriplegia
Scoring findings at or
below cord level
treatment
------------------------------------------------------------------------------------------------------------------------------------
Subcutaneous tissue- No change Slight induration Moderate fibrosis Severe induration Necrosis
Late RT Morbidity from baseline (fibrosis) and loss but asymptomatic; and loss of
Scoring of subcutaneous fat slight field subcutaneous
contracture; < 10% tissue; field
linear reduction contracture > 10%
linear measurement
------------------------------------------------------------------------------------------------------------------------------------
Eye- No change Asymptomatic Symptomatic Severe keratisis; Panophthalmitis;
Late RT Morbidity from baseline cataract; minor cataract; moderate severe retinopathy blindness
Scoring corneal ulceration corneal ulceration; or detachment;
or keratitis minor retinopathy severe glaucoma
------------------------------------------------------------------------------------------------------------------------------------
</Table>
162
November 16, 1999
Page 78
<Table>
<Caption>
-----------------------------------------------------------------------------------------------------------------------------------
GRADE
TOXICITY 0 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------------------
or glaucoma
-----------------------------------------------------------------------------------------------------------------------------------
Radiation-Other None Mild Moderate Severe Life-threatening or
(Specify, ) disabling
-----------------------------------------------------------------------------------------------------------------------------------
</Table>
163
Protocol ID99 -- 333
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Page 87
Appendix V
BMT Complex/Multi-Component Events
<Table>
<Caption>
------------------------------------------------------------------------------------------------------------------------------------
Grade
Toxicity 0 1 2 3 4
------------------------------------------------------------------------------------------------------------------------------------
Note: The grading of Complex/Multi-Component Events in bone marrow transplant will be defined in the protocol. The grading scale
must use the CTC criteria for grading the specific component events (toxicities).
------------------------------------------------------------------------------------------------------------------------------------
Failure to engraft absent mild moderate severe life-threatening
Also consider Hemoglobin (Hgb), Neutrophils/granulocytes (ANC/AGC), Platelets
------------------------------------------------------------------------------------------------------------------------------------
Graft versus host absent mild moderate severe life-threatening
disease
Also consider Fatigue, Rash/desquamation, Diarrhea, Bilirubin-GVHD
------------------------------------------------------------------------------------------------------------------------------------
Stem cell infusion absent mild moderate severe life-threatening
complications
Also consider Allergic reaction/hypersensitivity, Arrhythmia, Hypertension, Hypotension, Fever, Rigors/chills, Sweating,
Rash/desquamation, Urticaria, Diarrhea, Nausea, Vomiting, Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia,
Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Hemoptysis, Alkaline phosphatase, Bilirubin, GGT, SGOT, SGPT,
Infection, Hyperkalemia, Hypernatremia, Hypokalemia, Depressed level of consciousness, Seizures, Abdominal pain, Headache,
Creatinine, Hemoglobinuria
------------------------------------------------------------------------------------------------------------------------------------
Veno-Occlusive absent mild moderate severe life-threatening
Disease (VOD)
Also consider Weight gain-VOD, Bilirubin, Depressed level of consciousness, Hepatic pain, Renal failure, Hepatic enlargement.
------------------------------------------------------------------------------------------------------------------------------------
</Table>
164
EXHIBIT C
Budget
Personnel Salary & Fringe $149,117
Equipment 2,453
Supplies 2,560
Patient Costs (Research Costs Only for 30 Patients) 71,669
Subtotal: Direct Costs 225,799
Indirect Costs 39,294
TOTAL DIRECT + INDIRECT COSTS 265,093
Payment
The Institution will require the Principal Investigator to agree to use
best efforts to complete the Study within the budgeted amount of eight thousand
eight hundred thirty-six Dollars and 43/00 ($8,836.43) per patient up to a
maximum of 30 patients, for a total estimated budget of two hundred sixty-five
thousand ninety-three Dollars ($265,093) (hereinafter referred to as the "Total
Estimated Budget") as itemized and set forth above.
Any expenditure for time and/or materials which is expected to increase
the total amount for the completed Study to be invoiced by the Institution to
Sponsor in excess of the Total Estimated Budget shall be approved in advance in
writing by Sponsor. The Budget is based on a single Leukapheresis per patient.
The Sponsor will pay for any additional Leukapheresis procedures and associated
tests required for Leukapheresis when the Sponsor and Principal Investigator
agree that additional Leukapheresis is required.
The Institution will invoice Sponsor on a calendar quarterly basis for
expenses for work under this Agreement. The initial payment of twenty-five
percent (25%) will be due within thirty (30) days of the signing of this
agreement by the Sponsor and the Institution. Checks payable to the Institution
shall be sent to:
The University of Texas
M.D. Anderson Cancer Center
Attn: Manager, Grants and Contracts Accounting
P.O. Box 297402
Houston, Texas 77297
-11-
165
EXHIBIT D
PAYMENT SCHEDULE
The Company will pay to the Institution a total of eight thousand eight hundred
thirty-six dollars and 43/00 ($8,836,43) for each patient who completes the
Protocol and for whom the Company receives all reports required by the Protocol
(the "Cost per Patient") up to a maximum of thirty (30) patients. The Company
will make an initial payment of sixty-six thousand two hundred seventy-three
dollars and 23/00 ($66,273.23) representing twenty-five percent (25%) of the
Cost per Patient (the "Initial Payment") derived from Exhibit B and payable
thirty (30) days after the execution of this Agreement. The Initial Payment will
be credited toward the first 25% of the Cost per Patient that becomes due and
payable by the Company. The Initial Payment will be refunded to the Company to
the extent, it any, by which the initial Payment exceeds the total Cost per
Patient that becomes due.
The Cost per Patient will become due as follows:
- 25% payable within 30 days of the Sponsor's and the Institution's execution
of this agreement;
- Up to an aggregate of 60% will be payable in quarterly payments due within
30 days of receipt of Institution's detailed invoices;
- And, the final balance within 30 days of Sponsor's receipt of Institution's
final report.
The amount payable by the Company will be pro-rated for any patient who fails to
complete the Protocol. IN ALL CASES, PATIENT EXPENSES ELIGIBLE FOR THIRD-PARTY
REIMBURSEMENT ARE THE RESPONSIBILITY OF THE INSTITUTION AND WILL NOT BE CHARGED
TO THE SPONSOR.
The Company will withhold the final fifteen per cent (15%) of the total Cost per
Patient until all Case Reports and the Clinical Trial summary report have been
delivered to the Company, and both the Company and the Institution's IRB have
been notified that the Clinical Trial has been completed.
Requests for payment must be in the form of a detailed invoice and submitted to
Northwest Biotherapeutics, Inc. Except for the Initial Payment, the Company will
not be obligated to make any payments until a detailed invoice has been
received. All amounts due will be payable within thirty (30) days of receipt of
the Institution's invoice.
Detailed Invoices shall be addressed to:
Dr. A.A. Elgamal
Sr. Manager of Clinical and Medical Affairs
Northwest Biotherapeutics, Inc,
120 Northgate Plaza, Suite 200
Seattle, Washington 98020
-12-