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Hedgehog Signaling Pathway

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18 diapositives · 816 Views · Jul 21, 2014

Results from a Phase 2 Randomized, Placebo-Controlled, Double Blind Study of the Hedgehog Pathway Antagonist IPI-926 in Patients with Advanced Chondrosarcoma.

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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 Chondrosarcoma Andrew J. Wagner1, Peter Hohenberger2, Scott Okuno3, MikaelEriksson4, 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 Universitetssjukhusi Lund; 5MD Anderson Cancer Center; 6IRCCS IstitutoOrtopedico Rizzoli; 7Fondazione IRCCS IstitutoNazionaledeiTumori; 8Sarcoma Oncology Center; 9Infinity Pharmaceuticals; 10Helios Klinikum Bad Saarow CTOS 2013 New York

  2. Hedgehog Signaling Pathway • Plays a critical role in development • Inactive in most adult cells • Regulates normal chondrocyte proliferation, terminal differentiation, and endochondral bone development Inactive Activated

  3. Hh Pathway in Chondrosarcoma • Chondrosarcomas express high levels of Hedgehog pathway factors • Hedgehog increases proliferation of chondrosarcoma cells Nuclear Gli-1 Maeda et al, 2007; Long et al., 2001; Farquharson et al., 2001; Kimura et al., 2008; Tiet et al., 2006 Courtesy of Infinity Pharmaceuticals

  4. HH Pathway Inhibitors Block SMO No change in Gli-1, Cyclin D1/D2, Myc, or Bcl2

  5. IPI-926 Suppresses Hh Signaling and Chondrosarcoma Growth Control IPI-926 Human Gli-1 * Courtesy of Infinity Pharmaceuticals Wunder, Alman, et al.

  6. XenograftGrowth Inhibition by IPI-926 Oral, daily treatment of IPI-926, M-F, for 6-10 weeks, n= 8-15/group • Day of implant • Established tumors p<0.03 p<0.03 p<0.03 Tumor from Subject C Tumor from Subject A Tumor from Subject B Mean 43% (range 37-52%) tumor growth inhibition Campbell et al. AACR 2011

  7. Phase I study of IPI-926: CS patients Months On Treatment Patient Courtesy of Infinity Pharmaceuticals

  8. IPI-926-04: Phase 2 Randomized, Double-Blind Study of IPI-926 vs Placebo in Metastatic/Locally Advanced (Unresectable) Chondrosarcoma Sponsor: Infinity Pharmaceuticals; NCT01310816 Primary Objectives: Compare PFS of IPI-926 versus placebo; safety Secondary Objectives: TTP, OS, ORR, response duration, PK Preplanned futility analysis after 40% of expected 100 events – DMC met June 15, 2012 Double-blind Open-Label IPI-926160mg QD N=94 Off study drug Radiology Review Confirmed PD Randomization 2:1 Screening PlaceboQD N=46 Optionalopen-label IPI-926 Requires RECIST progression in prior 24 weeks Radiology Review Confirmed PD

  9. 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

  10. Study Accrual

  11. Patient Characteristics

  12. Treatment Emergent Adverse Events in >10% of Patients

  13. Best Percent Change in Target Lesions (RECIST) Progressive Disease Partial Response

  14. PFS

  15. OS

  16. 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

  17. 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

  18. Thank You Patients and their Families Study Teams Team at Infinity