Results from a Phase 2 Randomized, Placebo-Controlled, Double Blind Study of the
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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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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

Hedgehog signaling pathway
Hedgehog Signaling Pathway Double Blind Study of the

  • Plays a critical role in development

  • Inactive in most adult cells

  • Regulates normal chondrocyte proliferation, terminal differentiation, and endochondral bone development



Hh pathway in chondrosarcoma
Hh Double Blind Study of the 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

Hh pathway inhibitors block smo
HH Pathway Inhibitors Block SMO Double Blind Study of the

No change in Gli-1,

Cyclin D1/D2, Myc, or Bcl2

Ipi 926 suppresses hh signaling and chondrosarcoma growth
IPI-926 Suppresses Double Blind Study of the Hh Signaling and Chondrosarcoma Growth



Human Gli-1


Courtesy of Infinity Pharmaceuticals

Wunder, Alman, et al.

Xenograft growth inhibition by ipi 926
Xenograft Double Blind Study of the Growth 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




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

Phase i study of ipi 926 cs patients
Phase I study of IPI-926: Double Blind Study of the CS patients

Months On Treatment


Courtesy of Infinity Pharmaceuticals

IPI-926-04: Double Blind Study of the 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



IPI-926160mg QD


Off study drug

Radiology Review

Confirmed PD

Randomization 2:1




Optionalopen-label IPI-926

Requires RECIST progression in prior 24 weeks

Radiology Review

Confirmed PD

Key eligibility criteria
Key Eligibility Criteria Double Blind Study of the

  • 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 accrual
    Study Accrual Double Blind Study of the

    Patient characteristics
    Patient Characteristics Double Blind Study of the

    Treatment emergent adverse events in 10 of patients
    Treatment Emergent Adverse Events Double Blind Study of the in >10% of Patients

    Best percent change in target lesions recist
    Best Percent Change in Target Lesions (RECIST) Double Blind Study of the

    Progressive Disease

    Partial Response

    PFS Double Blind Study of the

    OS Double Blind Study of the

    Summary Double Blind Study of the

    • 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
    Additional Investigations Double Blind Study of the

    • 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 you
    Thank You Double Blind Study of the

    Patients and their Families

    Study Teams

    Team at Infinity