Hedgehog Signaling Pathway - PowerPoint PPT Presentation

Results from a Phase 2 Randomized, Placebo-Controlled, Double Blind Study of the
1 / 18

  • Uploaded on
  • Presentation posted in: General

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

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.

Download Presentation

Hedgehog Signaling Pathway

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript

Hedgehog signaling pathway

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

  • 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 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

No change in Gli-1,

Cyclin D1/D2, Myc, or Bcl2

Ipi 926 suppresses hh signaling and chondrosarcoma growth

IPI-926 Suppresses Hh Signaling and Chondrosarcoma Growth



Human Gli-1


Courtesy of Infinity Pharmaceuticals

Wunder, Alman, et al.

Xenograft growth inhibition by ipi 926

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




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: CS patients

Months On Treatment


Courtesy of Infinity Pharmaceuticals

Hedgehog signaling pathway

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



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

  • 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

    Patient characteristics

    Patient Characteristics

    Treatment emergent adverse events in 10 of patients

    Treatment Emergent Adverse Events in >10% of Patients

    Best percent change in target lesions recist

    Best Percent Change in Target Lesions (RECIST)

    Progressive Disease

    Partial Response

    Hedgehog signaling pathway


    Hedgehog signaling pathway




    • 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

    • 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

    Patients and their Families

    Study Teams

    Team at Infinity

  • Login