Ignyta 8-K Ignyta Announces Phase 1 Clinical Trial Data for Entrectinib

Entrectinib (formerly RXDX-101) is a potent, selective, small molecule inhibitor of the tyrosine kinases TrkA (coded

by the gene NTRK1), TrkB (coded by the gene NTRK2), TrkC (coded by the gene NTRK3), ROS1 (coded by the gene

ROS1),

and

ALK

(coded

by

the

gene

ALK).

Molecular

alterations

to

these

targets

are

present

in

several

different

tumor types, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), papillary thyroid cancer,

pancreatic cancer, and neuroblastoma, among others. 

Potent in vitro and in vivo antitumor effects have been observed in several TRK, ROS1 and ALK-dependent tumor

models. Antitumor effects in the preclinical models were associated with apoptosis and downstream signaling

effects, leading to MAPK and AKT modulation.

In the First-In-Human Study ALKA-372-001, entrectinib demonstrated early clinical activity (1 CR, 5 PRs among 25

patients) when given intermittently under fasting conditions (ASCO 2014; updated data abstract 2517).  Here

we report on the ongoing Phase 1 portion of a companion Phase 1/2a study (STARTRK-1) where entrectinib was

administered on a continuous daily dosing regimen under fed conditions.

STARTRK-1: Phase 1/2a Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Manish

R.

Patel

1

,

Todd

M.

Bauer²,

Stephen

V.

Liu³,

Alexander

Drilon

4

,

Jennifer

Wheler

5

,

Alice

Shaw

6

,

Anna

Farago

6

,

Sai-Hong

I.

Ou

7

,

David

Luo

8

,

Litain

Yeh

8

,

Zachary

Hornby

8

,

Adrian

Senderowicz

8

,

and

Jonathan

E.

Lim

8

1

Sarah

Cannon

Research

Institute/Florida

Cancer

Specialists,

Sarasota,

FL;

2

Sarah

Cannon

Research

Institute/Tennessee

Oncology,

PLLC,

Nashville,

TN;

3

Georgetown

Lombardi

Comprehensive

Cancer

Center,

Washington,

D.C.;

4

Memorial

Sloan

Kettering

Cancer

Center,

New

York,

NY;

5

The

University

of

Texas

MD

Anderson

Cancer

Center,

Houston,

TX;

6

Massachusetts

General

Hospital,

Boston,

MA;

7

Chao

Family

Comprehensive

Cancer

Center,

University

of

California,

Irvine;

8

Ignyta,

Inc.,

San Diego, CA

Abstract

#2596

–

Presented

at

the

American

Society

of

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

29

–

June

2,

2015,

Chicago,

IL.

Thank

you

to

all

the

patients

and

their

families

who

participated

in

this

study.

Background

Exhibit 99.3

STARTRK-1: Phase 1/2a Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Manish

R.

Patel

1

,

Todd

M.

Bauer²,

Stephen

V.

Liu³,

Alexander

Drilon

4

,

Jennifer

Wheler

5

,

Alice

Shaw

6

,

Anna

Farago

6

,

Sai-Hong

I.

Ou

7

,

David

Luo

8

,

Litain

Yeh

8

,

Zachary

Hornby

8

,

Adrian

Senderowicz

8

,

and

Jonathan

E.

Lim

8

1

Sarah

Cannon

Research

Institute/Florida

Cancer

Specialists,

Sarasota,

FL;

2

Sarah

Cannon

Research

Institute/Tennessee

Oncology,

PLLC,

Nashville,

TN;

3

Georgetown

Lombardi

Comprehensive

Cancer

Center,

Washington,

D.C.;

4

Memorial

Sloan

Kettering

Cancer

Center,

New

York,

NY;

5

The

University

of

Texas

MD

Anderson

Cancer

Center,

Houston,

TX;

6

Massachusetts

General

Hospital,

Boston,

MA;

7

Chao

Family

Comprehensive

Cancer

Center,

University

of

California,

Irvine;

8

Ignyta,

Inc.,

San Diego, CA

Abstract

#2596

–

Presented

at

the

American

Society

of

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

29

–

June

2,

2015,

Chicago,

IL.

Thank

you

to

all

the

patients

and

their

families

who

participated

in

this

study.

Patient Population:

Locally advanced or metastatic solid tumors with NTRK1/2/3, ROS1 or ALK molecular alterations, for whom no alternative

effective standard therapy is available or for whom standard therapy is considered unsuitable or intolerable.

Patients were assigned to escalating doses of entrectinib until determination of the

maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) using standard

3+3 criteria.

As of 01 May 2015, 29 patients were enrolled across 4 dose levels.

Table 1. Patient Disposition and Baseline Characteristics, n (%)

100 mg/m²

200 mg/m²

400 mg/m²

800 mg

TOTAL

Enrolled

5

5

10

9

29

Discontinued

5

5

7 (70)

4 (44)

21 (72)

Primary reason for discontinuation

Disease Progression

Adverse Event

Consent Withdrawn

4

0

1

4

1

0

6

0

1

3

0

1

17 (59)

1 (3)

3 (10)

Age, years, median (range)

68 (28-73)

63 (45-70)

50 (42-66)

54 (38-76)

55 (28-76)

Sex, male/female (%)

100/0

20/80

30/70

11/89

34/66

ECOG performance status

0

1

2

2 (40)

3 (60)

0

2 (40)

3 (60)

0

2 (20)

5 (50)

3 (30)

2 (22)

7 (78)

0

8 (28)

18 (62)

3 (10)

Cohort

Total Dose

(QD)

1

100 mg/m²

2

200 mg/m²

3

400 mg/m²

4

800 mg

The MTD and/or RP2D was defined as the dose with

1 out of 6 patients with DLT (Dose Limiting Toxicity)

DLTs were evaluated during Cycle 1 and graded according to the NCI CTCAE v4.03

Phase 1 Trial Design

Controlled asymptomatic CNS involvement was allowed, with steroids at a stable or decreasing dose for at least 2 weeks prior to

entrectinib treatment

ECOG performance status

2

STARTRK-1: Phase 1/2a Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Manish

R.

Patel

1

,

Todd

M.

Bauer²,

Stephen

V.

Liu³,

Alexander

Drilon

4

,

Jennifer

Wheler

5

,

Alice

Shaw

6

,

Anna

Farago

6

,

Sai-Hong

I.

Ou

7

,

David

Luo

8

,

Litain

Yeh

8

,

Zachary

Hornby

8

,

Adrian

Senderowicz

8

,

and

Jonathan

E.

Lim

8

1

Sarah

Cannon

Research

Institute/Florida

Cancer

Specialists,

Sarasota,

FL;

2

Sarah

Cannon

Research

Institute/Tennessee

Oncology,

PLLC,

Nashville,

TN;

3

Georgetown

Lombardi

Comprehensive

Cancer

Center,

Washington,

D.C.;

4

Memorial

Sloan

Kettering

Cancer

Center,

New

York,

NY;

5

The

University

of

Texas

MD

Anderson

Cancer

Center,

Houston,

TX;

6

Massachusetts

General

Hospital,

Boston,

MA;

7

Chao

Family

Comprehensive

Cancer

Center,

University

of

California,

Irvine;

8

Ignyta,

Inc.,

San Diego, CA

Abstract

#2596

–

Presented

at

the

American

Society

of

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

29

–

June

2,

2015,

Chicago,

IL.

Thank

you

to

all

the

patients

and

their

families

who

participated

in

this

study.

Three treatment-related Grade 3 AEs were observed: neutropenia

(400 mg/m

2

, reported at Cycle 2 and resolved with dose reduction

to 200 mg/m

2

) and 2 DLTs at a fixed daily dose of 800 mg:

cognitive impairment and worsened fatigue; both resolved upon

study drug interruption.  As such, the MTD was exceeded at 800

mg and 400 mg/m

2

per day was selected as the BSA-based RP2D

for both studies.  Further exploration of a fixed daily dose regimen

is ongoing.

No treatment-related SAEs have been reported.

Table 3. Most Common (>10%), Treatment-Related, All Grades, Adverse

Events, n (%)

100

mg/m²

(n=5)

200

mg/m²

(n=5)

400

mg/m²

(n=9)

800 mg

(n=8)

TOTAL

(n=27

a

)

Fatigue

1 (20)

2 (40)

5 (56)

1 (13)

9 (33)

Dysgeusia

0

2 (40)

4 (44)

1 (13)

7 (26)

Constipation

1 (20)

2 (40)

2 (22)

1 (13)

6 (22)

Nausea

1 (20)

3 (60)

2 (22)

0

6 (22)

Paresthesia

1 (20)

0

4 (44)

1 (13)

6 (22)

Dizziness

0

1 (20)

3 (33)

1 (13)

5 (19)

Cognitive disorder

0

0

1 (11)

3 (38)

4 (15)

Vomiting

0

2 (40)

1 (11)

1 (13)

4 (15)

Arthralgia

0

0

2 (22)

1 (13)

3 (11)

Asthenia

0

0

2 (22)

1 (13)

3 (11)

Diarrhea

0

1 (20)

1 (11)

1 (13)

3 (11)

Attention disturbance

0

0

2 (22)

1 (13)

3 (11)

Peripheral neuropathy

0

1 (20)

1 (11)

1 (13)

3 (11)

a

total excluded 2 patients currently in Cycle 1 with no AE reporting

Table 2. Tumor Type and Molecular Alterations (n=29)

Primary Diagnosis

Molecular Alteration

N

Acinic cell carcinoma

NTRK3

fusion

1

Breast

NTRK3

ALK

SNP

SNP

1

1

CRC

NTRK1

NTRK3

ALK

SNP

SNP

SNP

2

2

1

Cholangiocarcinoma

NTRK3

SNP

1

Endometrial

ALK

fusion

1

Esthesioneuroblastoma

NTRK1

amplification

1

Large cell neuroendocrine

No NTRK1/2/3, ROS1, or ALK

alterations

1

NSCLC (70% prior ALK/ROS1 inhibitor)

NTRK1

NTRK1

NTRK3

ROS1

ROS1

ALK

ALK

amplification

fusion

SNP

amplification

fusion

fusion

SNP

1

1

1

1

2

6

1

Ovarian

ALK/NTRK

amplification

1

Pancreatic

No NTRK1/2/3, ROS1, or ALK

alterations

1

Renal cell carcinoma

NTRK2

SNP

1

Squamous cell carcinoma

ALK

amplification

1

RESULTS

Safety

STARTRK-1: Phase 1/2a Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Manish

R.

Patel

1

,

Todd

M.

Bauer²,

Stephen

V.

Liu³,

Alexander

Drilon

4

,

Jennifer

Wheler

5

,

Alice

Shaw

6

,

Anna

Farago

6

,

Sai-Hong

I.

Ou

7

,

David

Luo

8

,

Litain

Yeh

8

,

Zachary

Hornby

8

,

Adrian

Senderowicz

8

,

and

Jonathan

E.

Lim

8

1

Sarah

Cannon

Research

Institute/Florida

Cancer

Specialists,

Sarasota,

FL;

2

Sarah

Cannon

Research

Institute/Tennessee

Oncology,

PLLC,

Nashville,

TN;

3

Georgetown

Lombardi

Comprehensive

Cancer

Center,

Washington,

D.C.;

4

Memorial

Sloan

Kettering

Cancer

Center,

New

York,

NY;

5

The

University

of

Texas

MD

Anderson

Cancer

Center,

Houston,

TX;

6

Massachusetts

General

Hospital,

Boston,

MA;

7

Chao

Family

Comprehensive

Cancer

Center,

University

of

California,

Irvine;

8

Ignyta,

Inc.,

San Diego, CA

Abstract

#2596

–

Presented

at

the

American

Society

of

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

29

–

June

2,

2015,

Chicago,

IL.

Thank

you

to

all

the

patients

and

their

families

who

participated

in

this

study.

Exposures of entrectinib administered on a

continuous daily dosing regimen increased in a

dose proportional manner and reached steady-

state within a week of dosing

Plasma half-life is estimated to be ~ 20-24 hours,

compatible with QD dosing

At the RP2D (400 mg/m

2

QD), the plasma protein

binding corrected mean C

trough

is ~ 2.5X to 3X

that of concentrations observed in animal tumor

models with complete tumor growth inhibition

RESULTS

Pharmacokinetics

100

1000

10000

0

6

12

18

24

Time (hr)

100 mg/m

2

200 mg/m

2

400 mg/m

2

Target Conc.

STARTRK-1: Phase 1/2a Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Manish

R.

Patel

1

,

Todd

M.

Bauer²,

Stephen

V.

Liu³,

Alexander

Drilon

4

,

Jennifer

Wheler

5

,

Alice

Shaw

6

,

Anna

Farago

6

,

Sai-Hong

I.

Ou

7

,

David

Luo

8

,

Litain

Yeh

8

,

Zachary

Hornby

8

,

Adrian

Senderowicz

8

,

and

Jonathan

E.

Lim

8

1

Sarah

Cannon

Research

Institute/Florida

Cancer

Specialists,

Sarasota,

FL;

2

Sarah

Cannon

Research

Institute/Tennessee

Oncology,

PLLC,

Nashville,

TN;

3

Georgetown

Lombardi

Comprehensive

Cancer

Center,

Washington,

D.C.;

4

Memorial

Sloan

Kettering

Cancer

Center,

New

York,

NY;

5

The

University

of

Texas

MD

Anderson

Cancer

Center,

Houston,

TX;

6

Massachusetts

General

Hospital,

Boston,

MA;

7

Chao

Family

Comprehensive

Cancer

Center,

University

of

California,

Irvine;

8

Ignyta,

Inc.,

San Diego, CA

Abstract

#2596

–

Presented

at

the

American

Society

of

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

29

–

June

2,

2015,

Chicago,

IL.

Thank

you

to

all

the

patients

and

their

families

who

participated

in

this

study.

Patients who would have qualified for future

Phase 2 studies based on fusion, dose, and

treatment history; response as per RECIST

v1.1 and based upon local assessment.

*

10 responses among 11 patients

treated at or above the RP2D, leading

to a combined 91% response rate; 9

patients remain on study treatment

with durable responses for up to 16

cycles

Phase 2-eligible patients* (n=11)

Among the other 50 non-Phase 2 eligible patients (e.g., non-fusion alterations,

ALKi-

or ROS1i-resistant), 13 patients (26%) remain on study:

RESULTS

STARTRK-1 and ALKA-372-001 Studies (n=67) Show Preliminary Antitumor Activity of 

Entrectinib in ALKi and ROS1i-Naïve Patients (n=17) with NTRK1/2/3, ROS1, or ALK Fusions

NTRK1/2/3 SNPs, IHC+, amplifications: n=15 (6 ongoing)

ROS1 fusions, ROS1i-resistant: n=3 (1 ongoing)

ROS1 amplifications, deletions: n=4

ALK fusions, ALKi-resistant: n=17 (4 ongoing)

ALK SNPs, amplifications, deletions: n=7 (2 ongoing; 1 patient with

neuroblastoma had a PR for 9 cycles and remains on study)

False positives: n=2

No alterations: n=2

STARTRK-1: Phase 1/2a Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Manish

R.

Patel

1

,

Todd

M.

Bauer²,

Stephen

V.

Liu³,

Alexander

Drilon

4

,

Jennifer

Wheler

5

,

Alice

Shaw

6

,

Anna

Farago

6

,

Sai-Hong

I.

Ou

7

,

David

Luo

8

,

Litain

Yeh

8

,

Zachary

Hornby

8

,

Adrian

Senderowicz

8

,

and

Jonathan

E.

Lim

8

1

Sarah

Cannon

Research

Institute/Florida

Cancer

Specialists,

Sarasota,

FL;

2

Sarah

Cannon

Research

Institute/Tennessee

Oncology,

PLLC,

Nashville,

TN;

3

Georgetown

Lombardi

Comprehensive

Cancer

Center,

Washington,

D.C.;

4

Memorial

Sloan

Kettering

Cancer

Center,

New

York,

NY;

5

The

University

of

Texas

MD

Anderson

Cancer

Center,

Houston,

TX;

6

Massachusetts

General

Hospital,

Boston,

MA;

7

Chao

Family

Comprehensive

Cancer

Center,

University

of

California,

Irvine;

8

Ignyta,

Inc.,

San Diego, CA

Abstract

#2596

–

Presented

at

the

American

Society

of

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

29

–

June

2,

2015,

Chicago,

IL.

Thank

you

to

all

the

patients

and

their

families

who

participated

in

this

study.

Entrectinib was well tolerated in patients with relapsed or refractory

metastatic cancers harboring NTRK1/2/3, ROS1, or ALK molecular

alterations. 

A

BSA-based

RP2D

has

been

defined

as

400

mg/m

2

QD,

which

provides exposure consistent with complete tumor inhibition in

animal tumor models.  

Pharmacokinetic profile showed linear dose increases from 100 to

400 mg/m

2

.

Among

patients

with

ALK

inhibitor-

or

ROS1

inhibitor-naïve

NTRK1/2/3,

ROS1,

or

ALK

fusions,

10/11

(91%)

patients

treated

at or above the RP2D exhibited objective responses as early as

Cycle 1 with durable responses for up to 16 cycles.

These preliminary data support further development of entrectinib.

42 year-old female (MSKCC)

4 prior therapies, ECOG PS 1

Acinic cell carcinoma with NTRK3 fusion

entrectinib 400 mg/m²

QD

46 year-old male (MGH)

4 prior therapies, ECOG PS 2

NSCLC with NTRK1 fusion

entrectinib 400 mg/m²

QD

Jan 2015

Mar 2015

Mar 2015

Apr 2015

Copies of this poster obtained through QRC are for personal

use and may not be reproduced without permission from ASCO

and the author of this poster.

RESULTS

Conclusions

Exploration of a fixed daily dose regimen is ongoing.