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A Phase 1b/II Study of Vismodegib, a hedgehog inhibitor in combination with RO4929097, a notch (GSI) inhibitor in metastatic sarcomas. Mrinal Gounder*,

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Presentation on theme: "A Phase 1b/II Study of Vismodegib, a hedgehog inhibitor in combination with RO4929097, a notch (GSI) inhibitor in metastatic sarcomas. Mrinal Gounder*,"— Presentation transcript:

1 A Phase 1b/II Study of Vismodegib, a hedgehog inhibitor in combination with RO , a notch (GSI) inhibitor in metastatic sarcomas. Mrinal Gounder*, Mark Dickson*, Sandra D'Angelo*, Mary Louise Keohan*, Li-Xuan Qin, Richard Carvajal, Ping Chi, Alexander Shoushtari, Mercedes Condy, Yelena Ustoyev, Armando Sanchez, Lanier Tanner, Rita Morales, Joseph Erinjeri, Nian Wu, Cristina Antonescu, Narasimhan Agaram, Samuel Singer, Sam Yoon, Aimee Crago, Robert Maki, S. Percy Ivy1, Naoko Takebe1, William D. Tap* and Gary K. Schwartz *. Sarcoma Medical Oncology Service Memorial Sloan-Kettering Cancer Center, New York, NY

2 Conflict of Interest: None

3 Rationale for study

4 Hedgehog: Embryonic pathway reactivated in cancer
Hedgehog Pathway VISMODEGIB Survival and Growth GLI1 GLI2 Smooth GLI3 Patched Hedgehog

5 Notch: Embryonic pathway reactivated in cancer
NICD MPNST γ-Secretase NICD CSL MAML RO Akt P HES1 HEY1 Survivin Survival and Growth

6 Combination of Cyclopamine (Hedgehog inhibitor) and GSI (Notch Inhibitor)
Cell Viability Gary Schwartz lab, unpublished

7 Hypothesis #1: Combined inhibition of Hedgehog and Notch pathways is a rational therapeutic strategy in patients with advanced sarcoma.

8 Question #1: Are the two drugs safe to combine?

9 FDA approved in metastatic and advanced Basal Cell Carcinoma.
GDC-0449 (Vismodegib) Hedgehog inhibitor FDA approved in metastatic and advanced Basal Cell Carcinoma. 150 mg oral, once daily. RO Notch inhibitor Phase 2 dose: < 20 mg oral, daily. A phase I study of RO , a novel gamma secretase inhibitor, in patients with advanced solid tumors Journal of Clinical Oncology, April 23rd. 2012

10 Key Eligibility Criteria
-- Age > Advanced, metastatic sarcoma -- measurable disease (RECIST 1.1) – 4 prior therapies.

11 Phase Ib: Maximum Administered Dose
3 + 3 design GDC (HH) RO (NCH) DLT Dose Level 1 150 mg daily 10 mg daily None Dose Level 2 15 mg daily -- 9 patients enrolled to Phase I: combination well tolerated. -- Detailed pharmacokinetic data presented at ASCO 2012

12 Question #2: Are the drugs getting into tumor and inhibiting the pathways?

13 Pre- and post- treatment tumor biopsies confirm inhibition of Notch
Myxoid Chondrosarcoma Myxoid Liposarcoma Liposarcoma Epithelioid Clear Cell Desmoid

14 Pre- and Post-treatment biopsy of patients confirms inhibition of Hedgehog pathway
GLI-1 by RT-PCR GLI-1 by RT-PCR

15 Phase II Study Design Stratified : Liposarcoma vs. other
Number of prior 1 vs. >1

16 Primary Endpoint Progression Free Survival
Sample Size: 90 pts (45 in each arm) With a 1-sided alpha of 0.1, this sample size allowed to detect a 75% improvement in the combination arm with a power of 0.9

17 Sarcoma study was closed in April 2014
In 2013, Roche discontinued further development of the Notch inhibitor (RO ) and ~ 15 studies nationwide in many solid tumors was prematurely closed. Sarcoma study was closed in April 2014 67 of the planned 90 pts were enrolled to the study.

18 Final Phase II results: 67 pts (planned 90)
Notch alone Notch + Hedgehog p-value Number enrolled 34 33 Age 56 46 NS Gender - Male 58% 54% ECOG PS 0 88% 87% # Prior therapy 2 3 Liposarcoma 8 9 Other histology 26 24

19

20 TOXICITIES Notch Alone Hedgehog + Notch Grade 1 - 2 Grade 3 -4 Grade 1 -2 Grade 3-4 Anemia 21 (6%) 3 (7%) 22 (5%) 5 (13%) Thrombocytopenia 8 (2%) 11 (3%) Diarrhea 22 (6%) 56 (13%) 1 Metabolic 193 (56%) 24 (57%) 177 (43%) 10 (27%) Fatigue 34 (10%) 51 (12%) 2 Other 10 (3%) 4 (9.5%) 19 (4.6%) 3 Total 343 42 410 37

21 Response No RECIST responses (CR or PR) were seen.
Minor response and stable disease was seen in epithelioid sarcoma, liposarcoma and MFH/UPS.

22 Notch Single Agent: Best response – Duration on study drug
TIME ON STUDY RESPONSE 20 months 11 months 5 months

23 Notch and Hedgehog: Best response – Duration on study drug
TIME ON STUDY 6 months

24 Progression Free Survival
Notch + Hedgehog: mPFS: 12 weeks 6 week PFS: 60% Notch alone mPFS: 8.8 wks 6 week PFS: 60%

25 What can we learn from this study?

26 De-differentiated Liposarcoma
Nov 2012 March 2012 Notch Inhibitor – Single agent

27 PFS: prior drug vs. study drug
12 months 8 months 3 months

28 20% tumor shrinkage – 5 months SD
Epithelioid Sarcoma 1 20% tumor shrinkage – 5 months SD 2 POD – 1 cycle 3 4 NTRK1 and TET2 mutations

29 Desmoid : Wnt pathway -- Cross talk between Wnt, Notch and Hedgehog.
-- Partial responses with PF and OMP54-F28.

30 Desmoid Tumor: No Responses
NOTCH HEDGEHOG + NOTCH

31 Chondrosarcoma Up-regulation of the Hedgehog pathway
5 pts enrolled: No responses or stable disease.

32 Chordoma -- gain of 7q – SHH upregulation
4 patients with chordoma enrolled. No responses or stable disease with the Hedgehog inhibitor or Notch inhibitor.

33 Conclusions The combination of Vismodegib and RO is well tolerated. Notch and Hedgehog was successfully inhibited in tumor tissues. The study did not meet its PFS endpoint Notch inhibition may have a role in a subset of liposarcoma, epithelioid sarcoma and MFH. Hedgehog/Smoothened inhibitors (GDC-0449 and IPI-926) have not shown meaningful clinical activity in chondrosarcoma (or chordoma). Despite pathway inhibition, lack of responses in desmoid tumor cannot be fully explained.

34 Acknowledgements MSKCC William Tap Gary Schwartz Mark Dickson
Mary Louise Keohan Sandra D’Angelo Richard Carvajal Robert Maki Li-Xuan Qin Joseph Erinjeri Mercedes Condy Yelena Usteyov Lanier Tanner Rita Morales NCI Percy Ivy Naoko Takebe FUNDING Gateway Foundation Siskind Family Fund

35 Crosstalk between Hedgehog and Notch pathway
Smooth GLI2 GLI3 GLI1 Patched Hedgehog Hedgehog Pathway NICD Notch γ-Secretase MAML CSL Notch Pathway Akt Pathway Akt mTOR Hes3 Survival and Growth P

36 Fibrosarcoma – MFH/UPS

37 Histology Histology Notch Hedgehog + Notch Liposarcoma 9 10 MFH 5 2
LMS 3 1 Desmoid 4 Epithelioid GIST Chondrosarcoma Chordoma Ewing RMS, Clear cell, DSRCT, Fibrosarcoma, GIST, MPNST, SFT, Synovial Sarcoma, PEComa, Osteosarcoma 7

38 STS and Notch-4 Sam S. Yoon et. al Angiogenic Profile of Soft Tissue Sarcomas Based on Analysis of Circulating Factors and Microarray Gene Expression Journal of Surgical Research, Volume 135, Issue 2, 2006,

39 MPNST

40 Notch inhibition in Liposarcoma
Unpublished. Raymond Meng (Schwartz and Singer lab), MSKCC

41 Notch Inhibition (Ro) and Apoptosis

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