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Phase II Study of Dasatinib (BMS-354825) in Advanced Sarcomas and Chordoma

Phase II Study of Dasatinib (BMS-354825) in Advanced Sarcomas and Chordoma. Coordinating Center: U Michigan. Probability of response to imatinib (95% posterior credible intervals). Rationale for trial: extension of results from imatinib in sarcoma.

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Phase II Study of Dasatinib (BMS-354825) in Advanced Sarcomas and Chordoma

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  1. Phase II Study of Dasatinib (BMS-354825) in Advanced Sarcomas and Chordoma Coordinating Center: U Michigan

  2. Probability of response to imatinib(95% posterior credible intervals)

  3. Rationale for trial:extension of results from imatinib in sarcoma • 30% of liposarcomas and fibrosarcomas showed clinical benefit to gleevec • 2 leiomyosarcomas, 2 MFH and 1 liposarcoma showed objective response by RECIST • Mechanism of response not known • C-kit and PDGFR mutations identified in minority of sarcomas

  4. Chordomas are affected byimatinib - ? inhibition of PDGFR pre post From P.G. Casali et al

  5. Role of src in cancer • V-Src oncogenic protein of Rous sarcoma virus • Src kinases activated by receptor tyrosine kinases • Src elevated expression found in many cancers • May be involved in tissue invasion/metastasis • Involved in osteoblast biology

  6. C-SRC expression in STS Antibody AP7718a (Abgent) 1:50

  7. C-SRC expression in STS Tissue microarray – 181 samples

  8. Dasatinib • Small molecule inhibitor of src-family kinases (src, bcr-abl) and PDGFR • PDGFR inhibition requires higher doses – IC50 30nM • Oral dosing • Short half-life • Overcomes resistance to gleevec in CML

  9. Sarcoma study objectives • Evaluate clinical benefit rate • 4 and 6 month PFS • Time to progression • Objective response rate – confirmed CR and PR • Assess clinical and laboratory toxicities • Characterize mutations in PDGFR • Characterize expression levels of src in tumor

  10. CR PR CR PR SD CR PR SD SD PD PD PD Month 2 Month 6 Month 4 Definition of clinical benefit

  11. Extraskeletal osteosarcoma Fibrosarcoma Liposarcoma (not myxoid) MFH Osteosarcoma Rhabdomyosarcoma Uterine leiomyosarcoma High-grade chondrosarcoma ASPS Chordoma Epithelioid sarcoma GCT Hemangipericytoma Conventional chondrosarcoma Proposed patient groups Slower growth Faster growth

  12. PFS in phase II studies of previously treated soft tissue sarcoma

  13. PFS in phase II studies in untreated soft tissue sarcoma

  14. PFS in slow growth sarcomas

  15. Proposed response threshholds • Target clinical benefit rate at 6 months of at least 20% in “faster growth” group • Target clinical benefit rate at 6 months of at least 40% in “slower growth” group

  16. Patient eligibility • Group 1: Advanced high-grade fibrosarcoma, uterine leiomyosarcoma, liposarcoma, MFH, rhabdomyosarcoma, osteosarcoma treated with 1 or more prior therapies • Group 2: Unresectable or recurrent chondrosarcoma, chordoma, epithelioid sarcoma, alveolar soft part sarcoma, hemangiopericytoma, GCT • Measurable disease • Progressive disease – for Group 1 patients

  17. Treatment plan • Archival tissue to be submitted for PDGFR and c-src analysis (mandatory) • Once-a-day dosing of dasatinib (starting dose pending results of current Phase I study) • Response assessment every 2 months +/- 1 week • Treat until progression or unmanageable toxicity

  18. Implementation timeline • LOI approved by BMS • Protocol in development • Submit to UM PRC/IRB in January • 4-6 month approval process • Distribute to SARC sites after approval

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