1
EXHIBIT 10.13
CLINICAL TRIAL AGREEMENT
This Clinical Trial Agreement (the "Agreement") is made as of the 7th
day of January, 2000 (the "Effective Date" by and between Northwest
Biotherapeutics, Inc., a Delaware corporation (the "Sponsor"), and THE REGENTS
OF THE UNIVERSITY OF CALIFORNIA, on behalf of its Los Angeles campus, a
California corporation (hereinafter the "Institution").
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
(the "Study") of the Product in accordance with study protocol no. DC1-HRPC
attached hereto as Exhibit A (the "Protocol"). In the event of any conflict
between the Protocol 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 Arie Belldegrun, M.D. (hereinafter the "Principal Investigator")
with the participation of other Institution clinical and research personnel. 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, and a successor
acceptable to both the institution and Sponsor is not available, this Agreement
may be terminated pursuant to Article 17.
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.
4. REPORTS AND CONFERENCES.
A. The Principal Investigator, or his designate, 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 ninety (90) 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. All clinical data as
-1-
2
embodied in the case report forms and questionnaires, other records and reports
required to be submitted under the Protocol will be promptly provided to the,
Sponsor (or the Sponsor's representative), and shall be freely usable by the
Sponsor consistent with good business judgment. Sponsor shall be provided access
to source data and records relating to the Study during normal business hours
and at mutually agreeable times, and, if necessary, may copy same in such a
manner that the privacy of the Study patients is protected, including redacting
the name, address and other individual identifiers prior to copying.
B. The Principal Investigator and the Institution agree 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
Principal Investigator and the Institution further agree 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 Principal Investigator and the Institution agrees to notify
the Sponsor within seventy-two (72) 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 and the Institution 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 seventy-two (72) hours of
receipt of such communication and agrees to allow the Sponsor to assist in
responding to any citations. Such responses shall be made within three (3) weeks
of issuance of any citations or within any earlier deadline set by the issuing
regulatory authority. The Principal Investigator and the Institution 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 Principal
Investigator and the Institution agree, 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 B 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. INSTITUTION NAME. California Education Code section 92000 prohibits
use of the Institution's name to suggest that the Institution endorses a product
or service. The Sponsor will not use the Institution's names, including "UCLA",
without prior written approval, except to identify the Institution as the Study
site or when required to do so by law.
8. CONFIDENTIAL INFORMATION. During the performance of the Study and
during the term of this Agreement, the Institution may receive confidential or
trade secret information, including information concerning the Sponsor's present
and future business, marketing plans, regulatory submissions, product lines,
product plans, date testing and research techniques,
-2-
3
inventions, processes, practices, trade secrets, and like information
(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 or orally 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) which to the best of Institution's knowledge 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 to be disclosed by law.
9. 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 prior to
submission for publication of any manuscript or presentation of any poster,
presentation, abstract or other written or oral material that describes the
results of the Study, Institution and/or Principal Investigator shall provide
Sponsor sixty (60) days to review any such manuscript 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.
10. INVENTIONS. The Sponsor and the Institution do not expect that
inventions will be conceived or reduced to practice during the Study. However,
in the event that inventions are conceived and reduced to practice during the
Study, the Institution agrees that all patentable and unpatentable inventions,
discoveries, and improvements, (a) directly related to the Company's Product or
Confidential Information and (b) conceived, and reduced to practice during
performance of the Study shall be the solo property of the Sponsor. The
Institution agrees that all such inventions, and discoveries will promptly be
disclosed to the Sponsor and will assure and obtain the assistance of the
Principal Investigator in making application for Letters of Patent in any
country in the world at the Sponsor's request and expense. The Institution
agrees to assist
-3-
4
in prosecuting such patent applications, including executing or obtaining the
execution of all papers necessary to transfer to the Sponsor all of
Institution's right, title and interest in such inventions, and discoveries and
all applications patent and letters patent. The obligation to disclose, assist
and execute shall survive the expiration or termination of this Agreement. The
Sponsor shall reimburse the Institution for any reasonable and necessary
expenses actually incurred in the course of such assistance. In no event shall
the Institution obtain or acquire any rights of any kind with respect to the
Product or the Sponsor's Confidential Information, or any other materials or
information provided by the Sponsor in connection with the Study.
11. INDEMNIFICATION BY SPONSOR. The Sponsor will indemnify, hold
harmless and defend the institution, and its trustees, directors, officers,
employees, physicians and agents, including the Principal Investigator
(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 performance of the Study, 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 11 only arise if: (1) the Institution notifies the Sponsor
promptly after Institution's receipt of written notice of any Claim-, (ii) the
Institution 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. The Sponsor will not settle any
claim which admits the fault of Institution without prior written approval of
Institution, which shall not be unreasonably withheld. Institution's policy
requires that research subjects be provided any and all medical treatment
reasonably necessary for any injury sustained as direct result of participation
in the Study. Sponsor agrees that it will reimburse Institution for the
reasonable costs it incurs in providing reasonably necessary medical treatment
to research subjects who are injured as a direct result of participation in the
Study conducted in accordance with the Protocol. Sponsor will not be responsible
for any injuries that are the result of negligence or misconduct of any agent or
employee of Institution.
12. INDEMNIFICATION BY INSTITUTION. The Institution will indemnify, hold
harmless and defend the Sponsor, and its directors, officers, employees, and
agents, (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 any negligence or willful act or omission of
the Institution, or its trustees, directors, officers, employees physicians and
agents, including the Principal Investigator. The Institution's indemnification
obligations under this Section 12 only arise if the Sponsor: (i) notifies the
Institution promptly after Sponsors receipt of written notice of any Claim; (ii)
permits the Institution control the defense and settlement, at the Institution's
expense, of any such Claim; and (iii) does not settle any such Claim without the
prior written approval and consent of the Institution. Institution will not
settle any claim which admits the fault of Sponsor without the prior written
approval of Sponsor, which shall not be unreasonably withheld.
-4-
5
13. 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. Sponsor is to maintain Liability
Insurance in the following amounts:
General Liability:
Comprehensive or Commercial Form (Minimum Limits)
(1) Each Occurrence $ 500,000
(2) Products/Completed Operations
Aggregate $5,000,000
(3) Personal and Advertising Injury $1,000,000
(4) General Aggregate* $5,000,000
*(not applicable to comprehensive form)
14. RELATIONSHIP OF THE PARTIES. The Institution shall be deemed
to be an independent contractor 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, ex get as expressly provided for in this Agreement
or authorized in writing by the Sponsor.
15. REPRESENTATIONS OF INSTITUTION. The Institution represents that the
covenants set forth in this Agreement shall apply to and am binding on any
individual employed to perform the Study under this Agreement.
16. WARRANTIES; LIMITATION OF LIABILITY. Without limiting Sponsor's
obligations under Articles 11, SPONSOR DOES HEREBY DISCLAIM ANY AND ALL
REPRESENTATION AND WARRANTIES, WHETHER WRITTEN OR ORAL, OR EXPRESSED OR IMPLIED.
WITH RESPECT TO THE PRODUCT, INCLUDING WITHOUT LIMITATION, ANY REPRESENTATION OR
WARRANTY OF QUALITY, PERFORMANCE, MERCHANTABILITY OR FITNESS FOR A PARTICULAR
USE OR PURPOSE, OR THAT THE USE OF THE PRODUCT FOR PURPOSES OTHER THAN SPECIFIED
IN THIS AGREEMENT WILL NOT INFRINGE THE RIGHTS, PATENT OR OTHERWISE, OF ANY
THIRD PARTY.
17. 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 the Sponsor upon
-5-
6
thirty (30) days' written notice. Performance under this Agreement may be
terminated upon sixty (60) days' written notice by the Institution. If the Study
should terminate prior to its completion, Institution shall be paid for work
performed to date in accordance with the Protocol and for any reasonable
uncancellable obligations incurred in accordance with the Protocol prior to the
termination date.
18. RETURN OF PRODUCT. Upon termination of this Agreement the
Institution will return to the Sponsor all non-disposable Product, devices and
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 Product, devices,
and materials be destroyed
19. 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.
(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
five (5) days 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.
INSTITUTION: SPONSOR:
University of California Northwest Biotherapeutics, Inc.
Office of Sponsored Research 2203 Airport Way S., Suite 200
10945 Le Conte Avenue, Suite 1401 Seattle, WA 98134
Los Angeles, CA 90095-1406
ATTENTION: Carli V. Rogers ATTENTION: Daniel 0. Wilds
Industry Contract Officer President and CFO
If by FAX: (310) 206-3619 If by FAX: (425) 608-3026
If by express mail: same address as 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.
-6-
7
(d) GOVERNING LAW; JURISDICTION. This Agreement and all acts and
transactions pursuant hereto and the rights and obligations of the parties
hereto shall be governed, construed and interpreted in accordance with the laws
of the State of California, without giving effect to principles of conflicts of
law.
(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 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 a 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 reasonable 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.
-7-
8
The parties hereto have caused this Agreement to be executed on their
behalf by their duly authorized representatives to be effective on the year and
date first above written.
NORTHWEST BIOTHERAPEUTICS, INC.
By: /s/ Daniel O. Wilds
----------------------------
Name: Daniel O. Wilds
Title: President & C.E.O.
------------------
Date: December 29, 1999
-----------------
THE REGENTS OF THE UNIVERSITY OF
CALIFORNIA
By: /s/ Carli V. Rogers
----------------------------
Name: Carli V. Rogers
Title: Industry Contract Officer
Date: January 19, 2000
Read and acknowledged:
/s/ Arie Belldegrun 1/18/00
--------------------------------------- ----------------------------
Arie Belldegrun, M.D. Date
PRINCIPAL INVESTIGATOR
-8-
9
EXHIBIT A
Northwest Biotherapeutics, Inc. Study Protocol No. DC1-HRPC
-9-
CONFIDENTIAL
Northwest Biotherapeutics, Inc.
10
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
11
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
12
1. OVERVIEW OF CaPVax PHASE I CLINICAL TRIAL
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, 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
-------------------------------------------------------------------------------
13
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
14
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
15
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
15. REFERENCES
1. Landis SH, Murray T, Bolden S, et al: Cancer Statistics, 1999. CA Cancer
J Clin 1999; 49: 8-31.
2. Mettlin CJ, Murphy GP, Cunnigham MP, el al: The national cancer data
base report on race, age, and region variations in prostate cancer
treatment. Cancer 1997; 80: 1261-1266.
3. Ragde H, Elgamal AA, Snow P, et al:: Ten-year disease free survival
after transperineal sonography-guided Iodine-125 brachytherapy with or
without 45-gray external beam Irradiation in the treatment of patients
with clinically localized, low to high Gleason grade prostate carcinoma.
Cancer 1998; 83: 989-1001.
4. Schellhammer P, Sharifi R, Block N, et al: A controlled trial of
bicalutamide versus flutamide, each in combination with leutinizing
hormone-releasing hormone analogue therapy, in patients with advanced
prostate cancer. Urology 1995; 45: 745-752.
5. Vogelzang NJ: One hundred thirteen men with hormone-refractory prostate
cancer died today. J Clin Oncol 1996; 14: 1753-1755.
6. Morton DL, Foshag W, Hoon DSB: Prolongation of survival in metastatic
melanoma after active specific immunotherapy with a new polyvalent
melanoma vaccine. Ann Surg 1992; 216: 463-482.
7. Pardoll D: New strategies for active immunotherapy with genetically
engineered tumor cells. Curr Opin Immunol 1992; 4: 619-623.
8. Simons JW, Mikhak B: Ex vivo therapy using cytokine-transduced tumor
vaccines: molecular and clinical pharmacology. Semin Oncol 1998; 25
661-676.
9. Hsu FJ, Benike C, Fagnoni F, et al: Vaccination of patients with B-cell
lymphoma using autologous antigen-pulsed dendritic cells. Nature Med
1996; 2: 52-58.
10. Mukherji B, Chakraborty NG, Yamasaki S, et al: Induction of
antigen-specific cytolytic T cells in situ human melanoma by
immunization with synthetic peptide-pulsed autologous antigen presenting
cells. Proc Natl Acad Sci USA 1995; 92: 8078-8082.
11. Townsend A, Bodmer H: Antigen recognition by class I-restricted T
lymphocytes. Annu Rev Immunol 1989; 7: 601-624.
42
12. Germain RN, Margulies DH: The biochemistry and cell biology of antigen
processing and presentation. Annu Rev Immunol 1993; 11: 403-450.
13. Jondal M, Schrimbeck R, Reimann J: MHC class-I-restricted CTL responses to
exogenous antigens. Immunity 1996; 5: 295-302.
14. Traversari C, van der Bruggen P, Van den Eynde B, et al. Transfection and
expression of a gene coding for a human melanoma antigen recognized by
autologous cytolytic T lymphocytes. Immunogenetics 1992; 35: 145-152
15. van der Bruggen P, Traversari C, Chomez P, et al: A gene encoding an antigen
recognized by cytolytic T lymphocytes on a human melanoma. Science 1991;
254: 1643-1647.
16. Boon T, Cerottini JC, van den Eynde B, et al: Tumor antigens recognized by T
lymphocytes. Annu Rev Immunol, 1994; 12: 337-365.
17. Gaugler B, van den Eynde B, van der Bruggen P, et al: Human gene MAGE-3
codes for an antigen recognized on a melanoma by autologous cytolytic T
lymphocytes. J Exp Med 1994; 179: 921-930.
18. Boel P, Wildmann C, Sensi ML, et al: BAGE: a new gene encoding an antigen
recognized on human melanomas by cytolytic T lymphocytes. Immunity 1995;
2: 167-175.
19. van den Eynde B, Peeters O, De Backer O, et al: A new family of gene 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 lymphoyctes 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 stuides of HLA-A2*0201-binding peptides. J Immunol 1995;
154: 5934-5943.
43
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.
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.
44
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 GI, 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.
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
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 1 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 ll
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
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
PAYMENT SCHEDULE
The Sponsor will pay to the Institution a total of sixteen thousand two hundred
two and 50/00 dollars ($16,202.50) based on the attached budget itemization for
each patient who completes the Protocol and for whom the Sponsor receives and
approves all reports required by the Protocol (the "Cost per Patient") up to a
maximum of thirty (30) patients. The Sponsor will make an initial payment of
twenty thousand and 00/00 dollars ($20,000,00), equal to five hundred forty and
00/00 dollars ($540.00) per patient (the "Initial Payment") within thirty (30)
days of the execution of this Agreement. The Initial Payment will be credited
toward the first twenty-five percent (25%) [per patient amount] of the Cost per
Patient(s) that becomes due and payable by the Sponsor. The Initial Payment will
be refunded to the Sponsor to the extent, if any, by which the Initial Payment
exceeds the total Cost per Patient which becomes due. The Cost per Patient will
become due as follows:
- [25%] when the patient is registered
- [55%] when the completed Case Report for that patient is delivered
to and accepted by the Company for the primary study endpoint; and
- [20%] when the patient has completed the followup period specified
in the Protocol.
The amount payable by the Sponsor 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. SPONSOR UNDERSTANDS THAT COSTS OF RESEARCH PROCEDURES DONE IN
ACCORDANCE WITH THE PROTOCOL WILL NOT BE BILLED TO A PATIENT'S INSURANCE
COMPANY.
The Sponsor will withhold the final five hundred and 00/00 dollars ($500.00) of
the total Cost per Patient(s) until all Case Reports and the Clinical Trial
summary report have been delivered to and accepted by the Company, and both the
Company and the Institution's IRB have been notified that the Clinical Trial has
been completed.
The Institution will invoice Sponsor on a calendar monthly basis for expenses
for work under this Agreement. Except for the Initial Payment; the Sponsor will
not be obligated to make any payments until an invoice has been received. All
amounts due will be payable within thirty (30) days of receipt.
Checks Payable to THE REGENTS OF THE UNIVERSITY OF CALIFORNIA and mailed to:
UCLA Remittance Center
10920 Wilshire Boulevard, Suite 107
Los Angeles, California 90024-6503
Reference:
Protocol number: DC1 -HRPC
UCLA Project number 023496
Tax ID: 95-6006143
-10-
73
PROTOCOL TITLE : 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.
PRINCIPAL INVESTIGATOR : ARLE BELLDEGRUN, M.D., DEPARTMENT OF UROLOGY, UCLA SCHOOL
OF MEDICINE
PROTOCOL # : DC1-HRPC
SPONSOR : NORTHWEST BIOTHERAPEUTICS, INC.
BUDGET ITEMIZATION
--------------------------------------------------------------------------------------------------------------------------------
-B-
-A- CLINICAL -C- -A + O
PROFESSIONAL SERVICES FIXED COST COST CLINICAL COSTS TOTAL STUDY
(1 YEAR) (PER PT.) (X30 PATIENTS) COST
--------------------------------------------------------------------------------------------------------------------------------
Pharmacy
PRN Medication(1)
--------------------------------------------------------------------------------------------------------------------------------
IRB 2,000.00
--------------------------------------------------------------------------------------------------------------------------------
Radiation Safety Administrative Service Fee(2) 100.00
--------------------------------------------------------------------------------------------------------------------------------
Clinical Research Center (CRC)
Skin Tests NW Biotherapeutics Provides Antigens 400.00 12,000.00
I.D. Injection of DCs and 2 hours of observation 600.00 18,000.00
--------------------------------------------------------------------------------------------------------------------------------
Clark Urology Clinic
Room Charge 400.00 12,000.00
Blood for Immune Monitoring, 100 ml each 125.00 3,750.00
Shipment costs (x 8)(3)
--------------------------------------------------------------------------------------------------------------------------------
Clinical Laboratory tests
Testosterone, total @ wk 14 40.00 1,200.00
CBC/Differential/Platelet(4) 120.00 3,600.00
Chemistry Panel Chem 22(4) 180.00 5,400.00
PAP(4) 105.00 3,150.00
PSA(4) 120.00 3,600.00
ANA 140.00 4,200.00
Erythrocytic Sedimentation Rate 60.00 1,800.00
Urinalysis(4) 20.00 600.00
Virology 125.00 3,750.00
--------------------------------------------------------------------------------------------------------------------------------
Page 1 of 2
74
--------------------------------------------------------------------------------------------------------------------------------
-B-
-A- CLINICAL -C- -A + O
PROFESSIONAL SERVICES FIXED COST COST CLINICAL COSTS TOTAL STUDY
(1 YEAR) (PER PT.) (X30 PATIENTS) COST
--------------------------------------------------------------------------------------------------------------------------------
Radiology
Chest X-Ray ($125.00 @ week 26) 125.00 3,750.00
Bone Scan ($1,000.00 @ week 26) 1,000.00 30,000.00
CT Scan abdomen/pelvis ($2,000.00 @ week 26) 2,000.00 60,000.00
--------------------------------------------------------------------------------------------------------------------------------
Procedures
Leukapheresis; includes supplies(5) 1,200.00 36,000.00
Femoral Catheter Insertion, to include procedure and supplies(6)
Specimen processing and shipping(3)
EKG 125.00 3,750.00
--------------------------------------------------------------------------------------------------------------------------------
Miscellaneous 1,000.00
Advertising; done only after IRB approval
--------------------------------------------------------------------------------------------------------------------------------
Principal Investigator 1,500.00 45,000.00
--------------------------------------------------------------------------------------------------------------------------------
Clinical Research Nurse Coordinator 2,000.00 60,000.00
--------------------------------------------------------------------------------------------------------------------------------
Data Manager 2,000.00 60,000.00
--------------------------------------------------------------------------------------------------------------------------------
Sub-Total: 3,100.00 12,385.00 371,550.00 374,650.00
--------------------------------------------------------------------------------------------------------------------------------
Indirect Costs (22.5%): 697.50 2,786.63 83,598.75 84,296.25
--------------------------------------------------------------------------------------------------------------------------------
TOTAL: 3,797.50 15,171.63 455,148.75 458,946.25
--------------------------------------------------------------------------------------------------------------------------------
------------
(1) PRN Medication charged to sponsor.
(2) Annual Renewal Fee of $50.00 charged to sponsor.
(3) Shipment costs paid for by sponsor.
(4) Charges for Day 1, Week 14, and Week 23. All clinical labs paid for by
sponsor if not covered by insurance.
(5) If second procedure needed, additional related costs will be charged to
sponsor.
(6) If femoral catheter needed, all related costs will be charged to sponsor.
Page 2 of 2