Ignyta, Inc. - FORM 8-K - EX-99.2 - EXHIBIT 99.2

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8-K - FORM 8-K - Ignyta, Inc.	d933944d8k.htm
EX-99.3 - EXHIBIT 99.3 - Ignyta, Inc.	d933944dex993.htm
EX-99.4 - EXHIBIT 99.4 - Ignyta, Inc.	d933944dex994.htm
EX-99.1 - EXHIBIT 99.1 - Ignyta, Inc.	d933944dex991.htm

ALKA-372-001: First-in-Human Phase 1 Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Filippo G. De Braud¹, Monica Niger¹, Silvia Damian¹, Benedetta Bardazza¹, Antonia Martinetti¹, Giuseppe Pelosi¹, Giovanna Marrapese², Laura Palmeri², Giulio Cerea², Emanuele Valtorta², Silvio Veronese²,

Andrea

Sartore-Bianchi²,

Elena

Ardini³,

Antonella

Isacchi³,

Marcella

Martignoni

Arturo

Galvani³,

David

Luo

Litain

Yeh

Adrian

Senderowicz

and

Salvatore

Siena²

Fondazione

IRCCS

Istituto

Nazionale

dei

Tumori,

Milan,

Italy;

Ospedale

Niguarda

Ca'

Granda,

Milan,

Italy;

Nerviano

Medical

Sciences,

Nerviano,

Italy;

CLInical

Organization

for

Strategies

Solutions

(CLIOSS),

NMS

Group,

Nerviano, Italy;

Ignyta, Inc., San Diego, CA

Background

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

MAPK

and

AKT

modulation.

the

First-In-Human

Study

ALKA-372-001,

different

schedules

administration

entrectinib

have

been

assessed.

Schedule

(fasted,

days

on/3

days

off

for

weeks,

week

rest)

demonstrated

significant

antitumor

activity

(ASCO

2014).

Here

report

the

completion

Schedule A

as well as on the other 2 ongoing dosing schedules B (QD) and C (4 days on, 3 days off), both under fed conditions. A second Phase 1/2a study is

ongoing (STARTRK-1; abstract 2596) to evaluate ascending doses of entrectinib administered on a once daily dosing regimen, under fed

conditions.

Exhibit 99.2

ABSTRACT

#2517

–

Presented

the

American

Society

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

–

June

2015,

Chicago,

IL.

Thank

you

all

the

patients

and

their

families

who

participated

this

study.

ALKA-372-001: First-in-Human Phase 1 Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Andrea

Sartore-Bianchi²,

Elena

Ardini³,

Antonella

Isacchi³,

Marcella

Martignoni

Arturo

Galvani³,

David

Luo

Litain

Yeh

Adrian

Senderowicz

and

Salvatore

Siena²

Fondazione

IRCCS

Istituto

Nazionale

dei

Tumori,

Milan,

Italy;

Ospedale

Niguarda

Ca'

Granda,

Milan,

Italy;

Nerviano

Medical

Sciences,

Nerviano,

Italy;

CLInical

Organization

for

Strategies

Solutions

(CLIOSS),

NMS

Group,

Nerviano, Italy;

Ignyta, Inc., San Diego, CA

Methods

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

Hematologic

toxicities:

neutropenia

days,

febrile

neutropenia,

neutropenia

infection,

thrombocytopenia

days

associated

with

bleeding

Gastrointestinal

toxicities:

nausea,

vomiting,

diarrhea

despite

maximal

therapy

CNS

toxicities:

and

shift

grades

from

baseline

Other

non-hematological

toxicities:

lipase/amylase

All

other

toxicities

(except

alopecia)

that

fail

recover

baseline

lead

study

drug

interruption

days

Failure

complete

Cycle

with

least

75%

the

planned

dose

Patient Population:

Locally advanced or metastatic solid tumors with TrkA, ROS1 or ALK molecular alterations, for whom no alternative effective standard therapy is available or for

whom standard therapy is considered unsuitable or intolerable.

Dosing schedules and cohorts (Table 1):

Table 1. Dosing Schedules

Schedule

Cohort

Daily Dose Level

# of Patients Treated

# of Patients

Discontinued/

Reason for

Discontinuation

# of Ongoing

Patients

100 mg/m²

200 mg/m²

400 mg/m²

800 mg/m²

1200 mg/m²

1600 mg/m²

3 / PD

2 / PD

4 / PD

3 / PD

1 / PD

3 / PD

200 mg/m²

400 mg/m²

3 / 2PD, 1AE

2/ PD

400 mg/m²

800 mg/m²

1 / PD

2 / PD

TOTAL

PD = progressive disease; AE = adverse event

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

Schedule A: Once daily (fasted) in a 4-day on, 3-day off schedule for 3 weeks, followed by a 7-day rest period, in continuous 28-day cycles. Enrollment is closed.

Schedule B: Once daily (fed) in continuous 28-day cycles. Enrollment is ongoing. At 400 mg/m², additional patients were enrolled once the dose was considered

safe in order to provide additional safety and PK data.

Schedule C:

Once daily (fed) in a 4-day on, 3-day off schedule for 4 weeks without rest, in continuous 28-day cycles. Enrollment is closed.

ABSTRACT

#2517

–

Presented

the

American

Society

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

–

June

2015,

Chicago,

IL.

Thank

you

all

the

patients

and

their

families

who

participated

this

study.

RESULTS

To date, 38 patients have been enrolled as per Table 1. Baseline

characteristics are summarized in Table 2. Data cutoff date (01 May 2015).

Table 2. Baseline Characteristics

Schedule A

(n=19)

Schedule B

(n=13)

Schedule C

(n=6)

TOTAL (n=38)

Age, years, median (range)

50 (22-75)

55 (24-73)

50 (40-63)

52 (22-75)

Sex, male/female (%)

37/63

54/46

50/50

45/55

ECOG performance status, n (%)

10 (53)

8 (42)

1 (5)

8 (62)

5 (39)

1 (17)

5 (83)

19 (50)

18 (47)

1 (3)

Tumor type, n (%)

Gastrointestinal tract (CRC)

Gastrointestinal tract (non-CRC)

Head and neck

NSCLC

Neoplasms of the CNS

Sarcomas

3 (8)

2 (5)

1 (3)

25 (66)

6 (16)

1 (3)

ALKA-372-001: First-in-Human Phase 1 Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Andrea Sartore-Bianchi², Elena Ardini³, Antonella Isacchi³, Marcella Martignoni

, Arturo Galvani³, David Luo

, Litain Yeh

, Adrian Senderowicz

, and Salvatore Siena²

Fondazione

IRCCS

Istituto

Nazionale

dei

Tumori,

Milan,

Italy;

Ospedale

Niguarda

Ca'

Granda,

Milan,

Italy;

Nerviano

Medical

Sciences,

Nerviano,

Italy;

CLInical

Organization

for

Strategies

Solutions

(CLIOSS),

NMS

Group,

Nerviano, Italy;

Ignyta, Inc., San Diego, CA

ABSTRACT

#2517

–

Presented

the

American

Society

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

–

June

2015,

Chicago,

IL.

Thank

you

all

the

patients

and

their

families

who

participated

this

study.

RESULTS

Table 3. Most Common (>10%), Treatment-Related, All Dose Levels, Adverse Events (n, %)

Grade 1

Grade 2

Grade 3

All Grades (n=38)

Paresthesia

16 (42)

Nausea

13 (34)

1 (3)

14 (37)

Myalgia

11 (29)

2 (5)

13 (34)

Asthenia

5 (13)

4 (11)

1 (3)

10 (27)

Dysgeusia

9 (24)

1 (3)

10 (27)

Vomiting

8 (21)

Arthralgia

3 (8)

4 (11)

7 (19)

Diarrhea

5 (13)

2 (5)

7 (19)

Pain in extremity

5 (13)

Attention disturbance

4 (11)

Musculoskeletal pain

3 (8)

1 (3)

4 (11)

Rash

4 (11)

Dizziness

3 (8)

1 (3)

4 (11)

Safety

ALKA-372-001: First-in-Human Phase 1 Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Andrea

Sartore-Bianchi²,

Elena

Ardini³,

Antonella

Isacchi³,

Marcella

Martignoni

Arturo

Galvani³,

David

Luo

Litain

Yeh

Adrian

Senderowicz

and

Salvatore

Siena²

Fondazione

IRCCS

Istituto

Nazionale

dei

Tumori,

Milan,

Italy;

Ospedale

Niguarda

Ca'

Granda,

Milan,

Italy;

Nerviano

Medical

Sciences,

Nerviano,

Italy;

CLInical

Organization

for

Strategies

Solutions

(CLIOSS),

NMS

Group,

Nerviano, Italy;

Ignyta, Inc., San Diego, CA

Two treatment-related Grade 3 AEs were observed: asthenia (1200 mg/m², Schedule A, reported at Cycle 2 and resolved with dose

reduction to 800 mg/m²) and muscular weakness (400 mg/m², Schedule C, reported at Cycle 6 and resolved with dose reduction to

200 mg/m²).

No treatment-related SAEs have been reported.

No DLTs were observed in this study.

2 DLTs occurred in the STARTRK-1 study at a fixed daily dose of 800 mg: Grade 3 cognitive impairment and Grade 3

fatigue; both resolved upon study drug interruption. As such, the MTD was exceeded at 800 mg and 400 mg/m²

per day was selected as the BSA-based RP2D for both studies. Further exploration of a fixed daily dose regimen is

ongoing.

ABSTRACT

#2517

–

Presented

the

American

Society

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

–

June

2015,

Chicago,

IL.

Thank

you

all

the

patients

and

their

families

who

participated

this

study.

RESULTS

Pharmacokinetics

Exposures of entrectinib

administered on a continuous

daily dosing regimen increased

in a dose proportional manner

and reached steady-state within

a week

Plasma half-life is estimated to

be ~ 20-24 hours, compatible

with QD dosing

At the RP2D (400 mg/m²

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

ALKA-372-001: First-in-Human Phase 1 Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Andrea

Sartore-Bianchi²,

Elena

Ardini³,

Antonella

Isacchi³,

Marcella

Martignoni

Arturo

Galvani³,

David

Luo

Litain

Yeh

Adrian

Senderowicz

and

Salvatore

Siena²

Fondazione

IRCCS

Istituto

Nazionale

dei

Tumori,

Milan,

Italy;

Ospedale

Niguarda

Ca'

Granda,

Milan,

Italy;

Nerviano

Medical

Sciences,

Nerviano,

Italy;

CLInical

Organization

for

Strategies

Solutions

(CLIOSS),

NMS

Group,

Nerviano, Italy;

Ignyta, Inc., San Diego, CA

100

1000

10000

Time (hr)

100 mg/m2

200 mg/m2

400 mg/m2

Target Conc.

ABSTRACT

#2517

–

Presented

the

American

Society

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

–

June

2015,

Chicago,

IL.

Thank

you

all

the

patients

and

their

families

who

participated

this

study.

ALKA-372-001

and

STARTRK-1

Studies

(n=67)

Show

Preliminary

Antitumor

Activity

Entrectinib

ALKi

and

ROS1i-Naïve

Patients (n=17) with NTRK1/2/3, ROS1, or ALK Fusions

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

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

ALKi-

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

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 (1 patient had a PR for 9 cycles; she remains on

False positives: n=2

No alterations: n=2

ALKA-372-001: First-in-Human Phase 1 Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Andrea

Sartore-Bianchi²,

Elena

Ardini³,

Antonella

Isacchi³,

Marcella

Martignoni

Arturo

Galvani³,

David

Luo

Litain

Yeh

Adrian

Senderowicz

and

Salvatore

Siena²

Fondazione

IRCCS

Istituto

Nazionale

dei

Tumori,

Milan,

Italy;

Ospedale

Niguarda

Ca'

Granda,

Milan,

Italy;

Nerviano

Medical

Sciences,

Nerviano,

Italy;

CLInical

Organization

for

Strategies

Solutions

(CLIOSS),

NMS

Group,

Nerviano, Italy;

Ignyta, Inc., San Diego, CA

RESULTS

Phase 2-eligible patients*

(n=11)

study for a total of 2 ongoing)

ABSTRACT

#2517

–

Presented

the

American

Society

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

–

June

2015,

Chicago,

IL.

Thank

you

all

the

patients

and

their

families

who

participated

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/m²

QD, which provides exposure consistent

with complete tumor inhibition in animal tumor

models.

Exploration of a fixed daily dose regimen is

ongoing.

Pharmacokinetic profile showed linear dose

increases from 100 to 400 mg/m².

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.

Conclusions

Sep 2014

Nov 2014

Mar 2014

Apr 2014

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.

ALKA-372-001: First-in-Human Phase 1 Study of Entrectinib, an Oral Pan-Trk, ROS1, and ALK Inhibitor,

in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

Andrea

Sartore-Bianchi²,

Elena

Ardini³,

Antonella

Isacchi³,

Marcella

Martignoni

Arturo

Galvani³,

David

Luo

Litain

Yeh

Adrian

Senderowicz

and

Salvatore

Siena²

Fondazione

IRCCS

Istituto

Nazionale

dei

Tumori,

Milan,

Italy;

Ospedale

Niguarda

Ca'

Granda,

Milan,

Italy;

Nerviano

Medical

Sciences,

Nerviano,

Italy;

CLInical

Organization

for

Strategies

Solutions

(CLIOSS),

NMS

Group,

Nerviano, Italy;

Ignyta, Inc., San Diego, CA

RESULTS

75 year-old female

3 prior therapies, ECOG PS 0

mCRC with NTRK1 fusion

entrectinib 1600 mg/m²

Schedule A

67 year-old female

3 prior therapies, ECOG PS 1

NSCLC with ROS1 fusion

entrectinib 400 mg/m²

ABSTRACT

#2517

–

Presented

the

American

Society

Clinical

Oncology

(ASCO)

Annual

Meeting,

May

–

June

2015,

Chicago,

IL.

Thank

you

all

the

patients

and

their

families

who

participated

this

study.

Ignyta, Inc. - FORM 8-K - EX-99.2 - EXHIBIT 99.2 - June 1, 2015

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