Phase 1 Open Label, Dose Escalation Study of RXDX-101, an ...ingytadevsite.kpi.boutique/.../Ignyta_-_ASCO_2014_final_presentation… · Mice were treated orally with RXDX-101 at 120

Phase 1 Open Label, Dose Escalation Study of RXDX-101, an Oral Pan-Trk, ROS1, and ALK Inhibitor, in Patients with Advanced Solid

Tumors with Relevant Molecular AlterationsFilippo G. De Braud1, Lorenzo Pilla1, 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, Marcella Martignoni4, Arturo Galvani3, Paul

Pearson5, David Luo5, James L. Freddo5, and Salvatore Siena2

1Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 2Ospedale Niguarda Ca' Granda, Milan, Italy; 3Nerviano Medical Sciences, Nerviano, Italy;

4CLInical Organization for Strategies & Solutions (CLIOSS), NMS Group, Nerviano, Italy; 5Ignyta, Inc., San Diego, CA

DisclosuresConsultant or Advisory Role• Novartis ; Servier ; Amgen ; Pierre Fabre • Bristol-Myers Squibb ; Boehringer Ingelheim ; • Roche

Research Funding• Nerviano Medical Sciences; Novartis ; Servier ; Amgen ;

Pierre Fabre; Bristol-Myers Squibb ; Boehringer Ingelheim; Roche

Presented by: Filippo De Braud

RXDX-101: Next Generation Kinase Inhibitor

♦ RXDX-101 is a potent, selective, orally available ATP-competitive inhibitor of 5 target oncogenic drivers

♦ In vitro, RXDX-101 demonstrates inhibition of targets as well as downstream effectors in the MAPK and PI3K/AKT pathways

- Active against the most common ALK mutants responsible for crizotinib resistance

♦ In vivo, RXDX-101 demonstrates tumor eradication and tumor growth inhibition in multiple models

- Crosses the blood brain barrier, enabling targeting of CNS lesions

3

Target TrkA TrkB TrkC ROS1 ALKIC50 (nM) 1.7 0.1 0.1 0.2 1.6


Trk Signaling:Activation Drives Cell Growth and Survival

Brodeur GM, et al. Clin Cancer Res 2009

� NTRK1 encodes the TrkA receptor tyrosine kinase

� Trk family of neurotrophin receptors (TrkA, TrkB, TrkC) play a role in development of the central and peripheral nervous system

4

TrkA activates PI3K/AKT, PKC and ERK1/2 pathways, which promote cell growth and survival


Trk Rearrangements in Human MalignancyTM Kinase Domain

NTRK1

MPRIP-NTRK1

CD74-NTRK1NSCLC

TPM3-NTRK1

TFG-NTRK1

TPR-NTRK1

Papillary Thyroid Cancer

TPM3-NTRK1Colorectal Cancer

NTRK1, NTRK2 or NTRK3 fusions have also been identified in Glioblastoma, AML and secretory breast cancer

5Presented by: Filippo De Braud

RXDX-101: Robust Activity In Vitro and In Vivo against TrkA Rearranged Colorectal Cancer

6

RXDX-101

RXDX-101

♦ KM-12 is a human CRC line driven by a constitutively active TrkA fusion protein

♦ RXDX-101 potently inhibits TrkA phosphorylation and downstream signaling

♦ RXDX-101 induces in vivo tumor regression and durable tumor stabilization

RXDX-101

RXDX-101

RXDX-101

Continuous dosing treatments started at Day 9, bid; 21 treatments completed


NCI-H2228 (ALK-driven NSCLC) cells were injected intracranially; Mice were treated orally with RXDX-101 at 120 mg/kg BID for 10 days

RXDX-101 Effective in NSCLC Brain Metastases Model

7

RXDX-101 120 mg/kg os BID

Favorable BBB penetration in three species (brain/blood ratio):•Mouse: 0.4•Rat: 0.6 – 1.0•Dog: 1.4 – 2.2

Vehicle


Pre-Treatment After 10 D of treatment

Median Survival

Control 33.5 days

RXDX-101 56.5 days

P-value: <5x10e-4

ALKA-372-001: Phase I Dose Escalation Study of RXDX-101 in Adult Patients with Advanced Solid Tumors

• Patient population: advanced metastatic solid tumors, with alterations to TrkA, ROS1 or ALK

• Dosing schedule: oral administration once daily 4 days a week (4 days on, 3 days off) for 3 consecutive weeks followed by 1 week of rest, repeated in 28 day cycles

• Dose cohorts: 100, 200, 400, 800, 1200, 1600 mg/m2

• Primary objectives: DLT, MTD, RP2D• Secondary objectives: safety, PK, antitumor activity by

RECIST• N= 20 enrolled, 19 dosed


n = 19Age, mean (range) years 49 (22-75)Male, n (%) 7 (37)Race, %

White 100Histology, n (%)

NSCLCNeuroblastomaCRCPancreaticLeiomyosarcoma

12 (63)3 (16)2 (11)1 (5)1 (5)

Performance status (ECOG)012

991

Prior systemic therapy 12 3 or more

23

14

Demographics and Baseline Characteristics


Primary Diagnosis Molecular Alteration NNSCLC ALK rearrangement

ROS1 2 rearrangements, 1 deletion1 copy number gain

8*

4

CRC TrkA rearrangement ROS1 deletion

11

Neuroblastoma ALK mutationROS1 rearrangement

21

Pancreatic ROS1 deletion 1

Leiomyosarcoma ALK deletion 1

* 7 had failed prior treatment w/ crizotinib

Histology and Molecular Alteration


Adverse Events N (%)Nausea 14 (74)Paresthesia 11(58)Asthenia 9 (47)Vomiting 9 (47)Diarrhea 6 (32)Abdominal pain 5 (26)Dyspnea 4 (21)Back pain 4 (21)Arthralgia 4 (21)

Most Common Adverse Events*

* Frequency > 20%


Adverse Events Grade 3 Grade 4 Grade 5Asthenia 1*Dyspnea 2Lipase increased 1*Anemia 1Pneumonitis 1Confusion 1Ascites 1Respiratory failure 1

Grade 3 / 4 Adverse Events

* Possibly drug related

No DLT observed at any dose levelNo drug related SAEs


RXDX-101 Steady State PK Profile Suitable for Once Daily Dosing

Exposure to RXDX-101 increased in an approximate dose proportional manner up to doses of 800 mg/m2

Mean plasma half-life ranged from 17- 44 hours


Time (Day)

4 5

Con

c (n

M)

100

1000

10000

100 mg/m2

200 mg/m2

400 mg/m2

800 mg/m2

1200 mg/m2

1600 mg/m2

33

4

3

3

3

n

Observed Clinical Responses in Each of TrkA, ROS1 and ALK Patients

Tumor type(Alteration)

Dose (mg/m2)

Treatment Cycles Best Response1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Neuro-blastoma (ALK)

200→400→800→1200 PR*

NSCLC (ALK)

200→400→800 SD

Pancreatic(ROS1) 400→800 SD

NSCLC(ALK) 1200→800 PR*

NSCLC(ROS1) 1200 PR*

CRC(TrkA) 1600 PR*

* Confirmed PR


13 additional patients had progressive disease


Partial Response in Patient with TrkA Rearranged Colorectal Cancer

Patient screened and treated at Ospedale Niguarda Ca’ Granda, Milan, Italy

Cycle 1April 23, 2014

Pre TreatmentMarch 20, 2014

Partial Response in Patient with ALK+ Neuroblastoma


Cycle 15Dose escalated to 1200 mg/m2

Pre Treatment

February 5, 2013 April 14, 2014

RXDX-101: Novel Multi-Kinase Inhibitor with Promising Early Clinical Data

• RXDX-101 is a potent, selective inhibitor of key oncogenic kinases: Trk family, ROS1 and ALK

• Observed partial responses in patients with each of TrkA, ROS1 and ALK alterations

• Well tolerated at doses up to 1600 mg/m2 on an intermittent schedule

• PK profile suitable for appropriate target coverage with once daily dosing

• Currently testing continuous daily dosing


Acknowledgements• Participating patients and their families

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

• Ospedale Niguarda Ca' Granda (PI: Salvatore Siena, MD), Milan, Italy

• Nerviano Medical Sciences, Nerviano, Italy

• Clinical Organization for Strategies & Solutions

• Ignyta, Inc., San Diego, CAPresented by: Filippo De Braud

Documents

Phase 1 Open Label, Dose Escalation Study of RXDX-101, an ...ingytadevsite.kpi.boutique/.../Ignyta_-_ASCO_2014_final_presentation… · Mice were treated orally with RXDX-101 at 120