Hedgehog Pathway Antagonist IPI926 in Patients with Advanced Chondrosarcoma Andrew J Wagner 1 Peter Hohenberger 2 Scott Okuno 3 Mikael Eriksson 4 Shreyaskumar Patel 5 Stefano Ferrari ID: 1045858
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1. 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 Reichardt101Dana-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 SaarowCTOS 2013New York
2. Hedgehog Signaling PathwayInactiveActivatedPlays a critical role in developmentInactive in most adult cellsRegulates normal chondrocyte proliferation, terminal differentiation, and endochondral bone development
3. Nuclear Gli-1 Cases stainedPositiveNegativeN= 30Conventional21 (70%)9 (30%)Courtesy of Infinity PharmaceuticalsHh Pathway in ChondrosarcomaMaeda et al, 2007; Long et al., 2001; Farquharson et al., 2001; Kimura et al., 2008; Tiet et al., 2006Chondrosarcomas express high levels of Hedgehog pathway factorsHedgehog increases proliferation of chondrosarcoma cells
4. No change in Gli-1,Cyclin D1/D2, Myc, or Bcl2HH Pathway Inhibitors Block SMO
5. *Human Gli-1Wunder, Alman, et al. IPI-926 Suppresses Hh Signaling and Chondrosarcoma GrowthIPI-926ControlCourtesy of Infinity Pharmaceuticals
6. Xenograft Growth Inhibition by IPI-926Mean 43% (range 37-52%) tumor growth inhibitionDay of implantEstablished tumorsTumor from Subject Ap<0.03 p<0.03 p<0.03 Oral, daily treatment of IPI-926, M-F, for 6-10 weeks, n= 8-15/groupTumor from Subject CTumor from Subject BCampbell et al. AACR 2011
7. Months On TreatmentPatientCourtesy of Infinity PharmaceuticalsPhase I study of IPI-926: CS patients
8. IPI-926-04: Phase 2 Randomized, Double-Blind Study of IPI-926 vs Placebo in Metastatic/Locally Advanced (Unresectable) ChondrosarcomaRandomization 2:1IPI-926160mg QDN=94PlaceboQDN=46Off study drugOptionalopen-label IPI-926Radiology ReviewConfirmed PDDouble-blindOpen-LabelScreeningRadiology ReviewConfirmed PDSponsor: 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, 2012Requires RECIST progression in prior 24 weeks
9. Key Eligibility CriteriaPathologically-diagnosed conventional chondrosarcomaMetastasis to at least 1 location or locally advanced disease that is deemed unresectable by a surgeonAt 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 periodProgression must be based on at least two sets of scans (CT or MRI), and as defined by RECIST 1.1At least 18 years of ageECOG performance status 0 or 1Life expectancy of at least 3 months
10. Study AccrualCountryTotal N=95 n (%)United States36 (38)Germany16 (17)Italy10 (11)Great Britain6 (6)Sweden5 (5)France4 (4)Poland4 (4)The Netherlands4 (4)Australia3 (3)Canada3 (3)Norway2 (2)Russia2 (2)
11. IPI-926 N=64Placebo N=31Total N=95 IPI-926 N=64Placebo N=31Total N=95Age (years)Years since diagnosisn643195<441/64 (64)18/30 (60)59/94 (63)Mean (SD)53.7 (12.8)50.6 (11.5)52.7 (12.4)4-717 (27)6 (20)23 (24)Range (min, max)24, 8225, 7024, 82>86 (9)6 (20)12 (13)<65 (%)48/64 (75)27/31 (87)75/95 (79)>65 (%)16 (25)4 (13)20 (21)ECOG status024/63 (38)12/31 (39)36/94 (38)Female, n (%)19/64 (30)11/31 (35)30/95 (32)139 (62)19 (61)58 (62)Disease TypeBaseline disease gradeMetastatic56 (88)28 (90)84 (88)112/43 (28)4/23 (17)16/66 (24)Locally Advanced8 (13)3 (10)11 (12)227 (63)14 (61)41 (62)34 (9)5 (22)9 (14)Systemic TherapyNo prior lines38 (59)18 (58)56 (59)One or more lines26 (41)13 (42)39 (41)Patient Characteristics
12. Treatment Emergent Adverse Events in >10% of PatientsIPI-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 AE53 (85)20 (32)3 (5)22 (73)9 (30)0ALT increased21 (34)8 (13)0000AST increased16 (26)1 (2)0000Constipation10 (16)002 (7)1 (3)0Decreased Appetite10 (16)1 (2)03 (10)00Muscle Spasms10 (16)002 (7)00Diarrhea9 (15)001 (3)00Vomiting8 (13)00000Alk Phos increased7 (11)001 (3)00Alopecia6 (10)00000Dysguesia6 (10)00000Cough5 (8)003 (10) 00
13. Best Percent Change in Target Lesions (RECIST)Partial ResponseProgressive Disease
14. PFSIPI-926PlacebomPFS (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)
15. OSIPI-926PlacebomOS (95% CI)>8.5 mos (6.2, NE)>7.5 mos(5.0, NE)HR (95% CI)1.01 (0.30, 3.47)
16. SummaryRapid accrual to randomized studies of rare diseases is feasible with world-wide collaborationIPI-926 was generally well-tolerated when administered to patients with chondrosarcomaThere was no apparent improvement in PFS in patients with advanced, progressing chondrosarcomaA small subset of patients treated with IPI-926 had minor reductions in tumor size
17. Additional InvestigationsGli1 staining of tumor specimensHh pathway mutational analysisIDH1/IDH2 mutational analysis, 2HG plasma concentration, and correlation with rate of progressionTarpey et al. Nature Genetics 2013
18. Thank YouPatients and their FamiliesStudy TeamsTeam at InfinityMarkmanAustraliaTattersallAustraliaBrodowiczAustriaSamoniggAustriaBlacksteinCanadaBlayFranceDuffaudFranceLe CesneFranceBompasFranceHohenbergerGermanyReichardtGermanyBauerGermanyFerrariItalyCasaliItalyGelderblomNetherlandsSundby-HallNorwayMazurkiewiczPolandRutkowskiPolandTeplyakovRussiaLichinitserRussiaKudryavtsevaRussiaValverde MoralesSpainErikssonSwedenBiswasUnited KingdomWhelanUnited KingdomGrimerUnited KingdomCowieUnited KingdomWagnerUSAChughUSAOkunoUSAPatelUSARiedelUSARyanUSAvon MehrenUSAChmielowskiUSAJonesUSAMatushanskyUSAMeyerUSASeetharamUSABenedettoUSAPriebatUSAEliasUSAKraftUSAChawlaUSAStaddonUSAVan TineUSAGouwUSAAttiaUSA