Results from a Phase 2 Randomized, Placebo-Controlled, Double Blind Study of the Hedgehog Pathway Antagonist IPI-926 in Patients with Advanced Chondrosarcoma Andrew J. Wagner 1 , Peter Hohenberger 2 , Scott Okuno 3 , Mikael Eriksson 4 , Shreyaskumar Patel 5 , Stefano Ferrari 6 , Paolo G. Casali 7 , Sant P. Chawla 8 , Molly Woehr 9 , Robert Ross 9 , Jessica O’Keefe 9 , Amy Hillock 9 , George Demetri 1 , Peter Reichardt 10 1 Dana-Farber Cancer Institute; 2 Universitatsmedizin Mannheim; 3 Mayo Clinic; 4 Skanes Universitetssjukhus i Lund; 5 MD Anderson Cancer Center; 6 IRCCS Istituto Ortopedico Rizzoli; 7 Fondazione IRCCS Istituto Nazionale dei Tumori; 8 Sarcoma Oncology Center; 9 Infinity Pharmaceuticals; 10 Helios Klinikum Bad Saarow CTOS 2013 New York
Results from a Phase 2 Randomized, Placebo-Controlled, Double Blind Study of the Hedgehog Pathway Antagonist IPI-926 in Patients with Advanced Chondrosarcoma. - PowerPoint PPT Presentation
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Results from a Phase 2 Randomized, Placebo-Controlled, Double Blind Study of the Hedgehog Pathway Antagonist IPI-926
in Patients with Advanced ChondrosarcomaAndrew J. Wagner1, Peter Hohenberger2, Scott Okuno3, Mikael
Eriksson4, Shreyaskumar Patel5, Stefano Ferrari6, Paolo G. Casali7, Sant P. Chawla8, Molly Woehr9, Robert Ross9, Jessica O’Keefe9, Amy Hillock9,
George Demetri1, Peter Reichardt10
1Dana-Farber Cancer Institute; 2Universitatsmedizin Mannheim; 3Mayo Clinic; 4Skanes Universitetssjukhus i Lund; 5MD Anderson Cancer Center; 6IRCCS Istituto Ortopedico Rizzoli; 7Fondazione IRCCS Istituto Nazionale dei Tumori; 8Sarcoma
Oncology Center; 9Infinity Pharmaceuticals; 10Helios Klinikum Bad Saarow
CTOS 2013New York
Hedgehog Signaling Pathway
Inactive
Activated
•Plays a critical role in development
•Inactive in most adult cells
•Regulates normal chondrocyte proliferation, terminal differentiation, and endochondral bone development
Nuclear Gli-1
Cases stained Positive Negative
N= 30Conventional 21 (70%) 9 (30%)
Courtesy of Infinity Pharmaceuticals
Hh Pathway in Chondrosarcoma
Maeda et al, 2007; Long et al., 2001; Farquharson et al., 2001; Kimura et al., 2008; Tiet et al., 2006
• Chondrosarcomas express high levels of Hedgehog pathway factors
• Hedgehog increases proliferation of chondrosarcoma cells
No change in Gli-1,Cyclin D1/D2, Myc, or Bcl2
HH Pathway Inhibitors Block SMO
*
Vehicle IPI-926 Vehicle IPI-926 0
0.2
0.4
0.6
0.8
1
1.2
2^ΔΔ
CT
Human Gli-1
Wunder, Alman, et al.
IPI-926 Suppresses Hh Signaling and Chondrosarcoma Growth
IPI-926Control
Courtesy of Infinity Pharmaceuticals
Xenograft Growth Inhibition by IPI-926
Mean 43% (range 37-52%) tumor growth inhibition
Vehicle IPI-926 0
20
40
60
80
100
120
%En
dpoi
nt t
umor
vol
ume
Vehicle IPI-926 0
20
40
60
80
100
120
140%
End
poin
t Tum
or V
olum
e
Vehicle IPI-9260
20
40
60
80
100
120
140
% E
ndpo
int t
umor
wei
ght
Day of implant Established tumors
Tumor from Subject A
p<0.03 p<0.03 p<0.03
Oral, daily treatment of IPI-926, M-F, for 6-10 weeks, n= 8-15/group
Tumor from Subject CTumor from Subject B
Campbell et al. AACR 2011
Mon
ths
On
Trea
tmen
t
PatientCourtesy of Infinity Pharmaceuticals
Phase I study of IPI-926: CS patients
IPI-926-04: Phase 2 Randomized, Double-Blind Study of IPI-926 vs Placebo
in Metastatic/Locally Advanced (Unresectable) Chondrosarcoma
Randomization 2:1
IPI-926160mg QD
N=94
PlaceboQD
N=46
Off study drug
Optionalopen-label
IPI-926
Radiology Review
Confirmed PD
Double-blind Open-Label
Screening
Radiology Review
Confirmed PD
Sponsor: Infinity Pharmaceuticals; NCT01310816 Primary Objectives: Compare PFS of IPI-926 versus placebo; safetySecondary Objectives: TTP, OS, ORR, response duration, PKPreplanned futility analysis after 40% of expected 100 events – DMC met June 15, 2012
Requires RECIST progression in prior 24 weeks
Key Eligibility Criteria• Pathologically-diagnosed conventional chondrosarcoma• Metastasis to at least 1 location or locally advanced disease that
is deemed unresectable by a surgeon• At least 1 measurable target lesion per RECIST 1.1 • Radiographic progression of disease within 24 weeks prior to the
start of screening (date ICF signed), through the screening period• Progression must be based on at least two sets of scans (CT or
MRI), and as defined by RECIST 1.1• At least 18 years of age• ECOG performance status 0 or 1• Life expectancy of at least 3 months