hedgehog signaling pathway
DESCRIPTION
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 PresentationTRANSCRIPT
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
Study AccrualCountry Total N=95
n (%)United States 36 (38)Germany 16 (17)Italy 10 (11)Great Britain 6 (6)Sweden 5 (5)France 4 (4)Poland 4 (4)The Netherlands 4 (4)Australia 3 (3)Canada 3 (3)Norway 2 (2)Russia 2 (2)Jul-1
1
Aug-11
Sep-11
Oct-11
Nov-11
Dec-11
Jan-12
Feb-12
Mar-12
Apr-12
May-12
0
10
20
30
40
50
60
70
80
90
100
Cumulative AccrualMonthly Accrual
IPI-926 N=64
Placebo N=31
Total N=95 IPI-926
N=64Placebo N=31
Total N=95
Age (years) Years since diagnosis
n 64 31 95 <4 41/64 (64) 18/30 (60) 59/94 (63)Mean (SD) 53.7 (12.8) 50.6 (11.5)52.7 (12.4) 4-7 17 (27) 6 (20) 23 (24)Range (min, max) 24, 82 25, 70 24, 82 >8 6 (9) 6 (20) 12 (13)<65 (%) 48/64 (75) 27/31 (87) 75/95 (79)>65 (%) 16 (25) 4 (13) 20 (21) ECOG status
0 24/63 (38) 12/31 (39) 36/94 (38)Female, n (%) 19/64 (30) 11/31 (35) 30/95 (32) 1 39 (62) 19 (61) 58 (62)
Disease Type Baseline disease grade
Metastatic 56 (88) 28 (90) 84 (88) 1 12/43 (28) 4/23 (17) 16/66 (24)Locally Advanced 8 (13) 3 (10) 11 (12) 2 27 (63) 14 (61) 41 (62)
3 4 (9) 5 (22) 9 (14)Systemic TherapyNo prior lines 38 (59) 18 (58) 56 (59)One or more lines 26 (41) 13 (42) 39 (41)
Patient Characteristics
Treatment Emergent Adverse Events in >10% of Patients
IPI-926 N=62 Placebo N=30
Any Grade n (%)
3-4 n (%)
5 n (%) Any Grade
n (%)3-4
n (%)5
n (%)
At least one AE 53 (85) 20 (32) 3 (5) 22 (73) 9 (30) 0
ALT increased 21 (34) 8 (13) 0 0 0 0AST increased 16 (26) 1 (2) 0 0 0 0Constipation 10 (16) 0 0 2 (7) 1 (3) 0Decreased Appetite 10 (16) 1 (2) 0 3 (10) 0 0Muscle Spasms 10 (16) 0 0 2 (7) 0 0Diarrhea 9 (15) 0 0 1 (3) 0 0Vomiting 8 (13) 0 0 0 0 0Alk Phos increased 7 (11) 0 0 1 (3) 0 0Alopecia 6 (10) 0 0 0 0 0Dysguesia 6 (10) 0 0 0 0 0Cough 5 (8) 0 0 3 (10) 0 0
Best Percent Change in Target Lesions (RECIST)
Partial Response
Progressive Disease
PFSIPI-926 Placebo
mPFS (95% CI) 3.7 mos
(1.8, 3.7)2.9 mos
(1.8, 5.6)HR
(95% CI) 1.09 (0.59, 1.99)
OS
IPI-926 PlacebomOS
(95% CI) >8.5 mos (6.2, NE)
>7.5 mos(5.0, NE)
HR (95% CI) 1.01
(0.30, 3.47)
Summary
• Rapid accrual to randomized studies of rare diseases is feasible with world-wide collaboration
• IPI-926 was generally well-tolerated when administered to patients with chondrosarcoma
• There was no apparent improvement in PFS in patients with advanced, progressing chondrosarcoma
• A small subset of patients treated with IPI-926 had minor reductions in tumor size
Additional Investigations
• Gli1 staining of tumor specimens
• Hh pathway mutational analysis
• IDH1/IDH2 mutational analysis, 2HG plasma concentration, and correlation with rate of progression
Tarpey et al. Nature Genetics 2013
Thank YouPatients and their Families
Study Teams
Team at Infinity
Markman AustraliaTattersall AustraliaBrodowicz AustriaSamonigg AustriaBlackstein CanadaBlay FranceDuffaud FranceLe Cesne FranceBompas FranceHohenberger GermanyReichardt GermanyBauer GermanyFerrari ItalyCasali ItalyGelderblom NetherlandsSundby-Hall NorwayMazurkiewicz PolandRutkowski PolandTeplyakov RussiaLichinitser RussiaKudryavtseva RussiaValverde Morales SpainEriksson SwedenBiswas United KingdomWhelan United KingdomGrimer United KingdomCowie United Kingdom
Wagner USAChugh USAOkuno USAPatel USARiedel USARyan USAvon Mehren USAChmielowski USAJones USAMatushansky USAMeyer USASeetharam USABenedetto USAPriebat USAElias USAKraft USAChawla USAStaddon USAVan Tine USAGouw USAAttia USA