A Phase 1b/II Study of Vismodegib, a hedgehog inhibitor in combination with RO4929097, 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

Conflict of Interest: None

Rationale for study

SmoothGLI2GLI3

GLI1

Patched

Hedgehog

Hedgehog Pathway

Survival and

Growth

Hedgehog: Embryonic pathway reactivated in cancer

VISMODEGIB

NICDNotch

γ-Secretase

Survival andGrowth

HES1HEY1 Survivin

NICDCSLMAML

Notch: Embryonic pathway reactivated in cancer

Akt P

RO4929097

MPNST

Combination of Cyclopamine (Hedgehog inhibitor) and GSI (Notch Inhibitor)

Cell

Viab

ility

Gary Schwartz lab, unpublished

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

advanced sarcoma.

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

• GDC-0449 (Vismodegib)

• Hedgehog inhibitor

• FDA approved in metastatic and advanced Basal Cell Carcinoma.

• 150 mg oral, once daily.

• RO4929097

• Notch inhibitor

• Phase 2 dose: < 20 mg oral, daily.

A phase I study of RO4929097, a novel gamma secretase inhibitor, in patients with advanced solid tumors Journal of Clinical Oncology, April 23rd. 2012

-- Age > 18

-- Advanced, metastatic sarcoma

-- measurable disease (RECIST 1.1)

-- 1 – 4 prior therapies.

Key Eligibility Criteria

Phase Ib: Maximum Administered Dose

3 + 3 design GDC -0449 (HH) RO4929097 (NCH) DLT

Dose Level 1 150 mg daily 10 mg daily None

Dose Level 2 150 mg daily 15 mg daily None

-- 9 patients enrolled to Phase I: combination well tolerated.

-- Detailed pharmacokinetic data presented at ASCO 2012

Question #2:

Are the drugs getting into tumor and inhibiting the pathways?

Pre- and post- treatment tumor biopsies confirm inhibition of Notch

Myx

oid

Lipos

arco

ma

Clea

r Cel

l

Lipos

arco

ma

Myx

oid

Chon

dros

arco

ma

Epith

elio

id

Desm

oid

Pre- and Post-treatment biopsy of patients confirms inhibition of Hedgehog pathway

GLI-1 by RT-PCR GLI-1 by RT-PCR

Phase II Study Design

Stratified : Liposarcoma vs. other Number of prior 1 vs. >1

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

In 2013, Roche discontinued further development of the Notch inhibitor (RO4929097) 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.

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% NS

ECOG PS 0 88% 87% NS

# Prior therapy 2 3 NS

Liposarcoma 8 9 NS

Other histology 26 24

Liposarcoma26%

MFH14%

LMS9%

Desmoid6%

Epithelioid 6%

GIST6%

Chondrosarcoma3%

Chordoma6%

Ewing6%

Other20%

HISTOLOGY

TOXICITIESNotch 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%) 0 11 (3%) 0

Diarrhea 22 (6%) 0 56 (13%) 1

Metabolic 193 (56%) 24 (57%) 177 (43%) 10 (27%)

Fatigue 34 (10%) 3 (7%) 51 (12%) 2

Other 10 (3%) 4 (9.5%) 19 (4.6%) 3

Total 343 42 410 37

Response

• No RECIST responses (CR or PR) were seen.

• Minor response and stable disease was seen in epithelioid sarcoma, liposarcoma and MFH/UPS.

Notch Single Agent: Best response – Duration on study drug

MPNST

MFH/U

PS

Ewing's

Sarco

ma

Chondrosar

coma

Leiomyo

sarco

ma

Ewing's

Sarco

ma

Liposar

coma

Leiomyo

sarco

ma

Extra

skeletal

myx

oid chondro

Liposar

coma

Liposar

coma

Desmoid Tu

morGIST

Chordoma

Liposar

coma

Leiomyo

sarco

ma

MFH/U

PS

MFH/U

PS

Fibro

sarco

ma

Alveolar

Rhabdomyo

sarco

ma

Chordoma

Epith

elioid sa

rcoma

Liposar

coma

Liposar

coma

PEComa

GIST

Desmoid Tu

mor

liposar

coma

MFH/U

PS

Liposar

coma

Epith

elioid sa

rcoma

Liposar

coma

MFH/U

PS

-20

0

20

40

60

80

100

RESPONSE TIME ON STUDY

20 months

11 months

5 months

Liposar

coma

Liposar

coma

Leiomyo

sarco

ma

Osteosar

coma

Liposar

coma

Extra

skelet

al myx

oid chondro

Epith

elioid sa

rcoma

Liposar

coma

Liposar

coma

GIST

Liposar

coma

Desmoplas

tic Small

Round Cell

Chondrosar

coma

Chondrosar

coma

Liposar

coma

Ewing's

Sarco

ma

Liposar

coma

MFH/U

PS

Chondrosar

coma

solita

ry fibro

us tumor

Chordoma

Chordoma

Desmoid Tu

mor

Desmoid Tu

mor

Epith

elioid sa

rcoma

Liposar

coma

MFH/U

PS

solita

ry fibro

us tumor

Clear C

ell

Chondrosar

coma

Desmoid Tu

mor

Liposar

coma

Desmoid Tu

mor

-10

0

10

20

30

40

50

60

10 months

RESPONSE TIME ON STUDY

Notch and Hedgehog: Best response – Duration on study drug

6 months

Progression Free Survival

Notch + Hedgehog: mPFS: 12 weeks6 week PFS: 60%

Notch alonemPFS: 8.8 wks6 week PFS: 60%

p 0.38

What can we learn from this study?

Nov 2012 March 2012

De-differentiated Liposarcoma

Notch Inhibitor – Single agent

PFS: prior drug vs. study drug

recu

rrent d

x untre

ated

recu

rrent d

x, untre

ated

recu

rrent d

x untre

ated

Tem-IGFR

CDK4 prior

CDK4 prior

aurora

kinase

doxoru

bicin

CDK4 prior

CDK4 prior-S

T

CDK4 prior-W

CDK4 prior

CDK4 prior

CDK4 prior

Gem-Doce

CDK4 prior

CDK4 prior

recu

rrent d

x-chro

ns

CDK4 prior

0

50

100

150

200

250

300

350

400

450

500

Individual Liposarcoma Patients: Prior Drug vs. Study drug

Tim

e on

Prio

r Rx

vs. S

tudy

dru

g STUDY DRUG

3 months

8 months

12 months

PRIOR DRUG

NTRK1 and TET2 mutations

Epithelioid Sarcoma1 20% tumor shrinkage – 5 months SD

2 POD – 1 cycle

3 POD – 1 cycle

4 POD – 1 cycle

Desmoid : Wnt pathway

• -- Cross talk between Wnt, Notch and Hedgehog.

• -- Partial responses with PF-03084014 and OMP54-F28.

Progressive Disease Study Terminated Study Terminated Withdrawal Study TerminatedNotch Notch Hedgehog + Notch Hedgehog + Notch Hedgehog + Notch

0

50

100

150

200

250

300

Series1Series2

Tim

e on

Stu

dyDesmoid Tumor: No Responses

HEDGEHOG + NOTCHNOTCH

Chondrosarcoma

• Up-regulation of the Hedgehog pathway

• 5 pts enrolled: No responses or stable disease.

Chordoma• -- gain of 7q – SHH upregulation

4 patients with chordoma enrolled.

No responses or stable disease with the Hedgehog inhibitor or Notch inhibitor.

Conclusions• The combination of Vismodegib and RO4929097 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.

AcknowledgementsMSKCC

William Tap Gary Schwartz Mark Dickson Mary Louise Keohan Sandra D’Angelo Richard CarvajalRobert Maki Li-Xuan Qin Joseph Erinjeri Mercedes Condy Yelena UsteyovLanier TannerRita Morales

NCI

Percy IvyNaoko Takebe

FUNDING

Gateway Foundation Siskind Family Fund

Crosstalk between Hedgehog and Notch pathway

SmoothGLI2GLI3

GLI1

Patched

Hedgehog

Hedgehog PathwayNICDNotch

NICDγ-Secretase

MAML CSLNICD

Notch Pathway

Akt Pathway

Akt

mTOR

Hes3

Survival andGrowth

P

P

Fibrosarcoma – MFH/UPS

HistologyHistology Notch Hedgehog + Notch

Liposarcoma 9 10

MFH 5 2

LMS 3 1

Desmoid 2 4

Epithelioid 2 2

GIST 2 1

Chondrosarcoma 1 4

Chordoma 2 2

Ewing 2 1

RMS, Clear cell, DSRCT, Fibrosarcoma, GIST, MPNST, SFT, Synovial Sarcoma, PEComa,

Osteosarcoma

7 4

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, 282 - 290

MPNST

Notch inhibition in Liposarcoma

Unpublished. Raymond Meng (Schwartz and Singer lab), MSKCC

Notch Inhibition (Ro) and Apoptosis