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A Proposal for BMS-354825 (Dasatinib) in GIST

A Proposal for BMS-354825 (Dasatinib) in GIST. Jon Trent, MD, PhD Assistant Professor Dept. of Sarcoma Medical Oncology The University of Texas, M. D. Anderson Cancer Center. BMS-354825 (Dasatinib).

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A Proposal for BMS-354825 (Dasatinib) in GIST

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  1. A Proposal for BMS-354825 (Dasatinib) in GIST Jon Trent, MD, PhD Assistant Professor Dept. of Sarcoma Medical Oncology The University of Texas, M. D. Anderson Cancer Center

  2. BMS-354825 (Dasatinib) Thiazolecarboxamide not structurally related to pyrido [2,3-d]-pyrimidine class of molecules Shah. Science 305: 399, 2004

  3. BMS-354825 (Dasatinib) • Mult-targeted oncogenic kinase inhibitor • Fyn, Yes, Src, Lck, Bcr-Abl, Epha-2, Kit, PDGFR, • > 100X potent than imatinib • Binds ABL in active and inactive conformation

  4. Ba/F3 BCR-ABL E255K T315I M351T M244V G250E Q252H Q252R Y253F Y253H E255V F317L E355G F359V H396R F486S BMS-354825 inhibits IR BCR-ABL mutants 1.2 Parental Ba/F3 cells 1 T315I 0.8 Relative growth after 48 hours of drug exposure 0.6 Ba/F3 cell lines in vitro E255K 0.4 “wt” BCR-ABL “wt” BCR-ABL 0.2 M351T M351T 0 0 0 1 1 5 5 10 10 50 50 100 100 Concentration of BMS-354825 (nM) Shah Science. 305: 399 2004

  5. Dasatinib in imatinib-resistant CML CP AP BP Talpaz et al., Sawyers et al., Kantarjian et al., ASCO 2005

  6. Most Commonly Reported Non-Hematologic Toxicity N=40 No QTc prolongation to >500 ms, with no cardiac symptoms

  7. BMS-354825 (Dasatinib) in GIST • Phase I study (N=19, 9 GIST) • Primary Endpoint • Dose/schedule: safe at 90 mg BID 5d/2d • Secondary Endpoint • PET imaging: 1 response • CT imaging: 5 SD 7-17 weeks Evans et al, ASCO 2005

  8. A Proposal for BMS-354825 (Dasatinib) in GIST Jon Trent, MD, PhD Assistant Professor Dept. of Sarcoma Medical Oncology The University of Texas, M. D. Anderson Cancer Center

  9. BMS-354825 (Dasatinib) in GIST: Inclusion Criteria • Histologically confirmed diagnosis of GIST • Refractory or relapsed disease after adequate imatinib. • Imatinib-intolerant • Generalized or limited progression

  10. BMS-354825 (Dasatinib) in GIST: Evaluations • Choi criteria will be used for response endpoints • Tumor size decrease of >10%or tumor density decrease of >15% • RECIST will be recorded for all patients

  11. BMS-354825 (Dasatinib) in GIST: Design • Two-arm phase IIa trial to simultaneously monitor safety and efficacy. • A 20% response rate with less than a 15% rate of toxicity is targeted. • Trial is terminated early if toxicity is high or efficacy is low.

  12. BMS-354825 (Dasatinib) in GIST: Analysis • Safety and Efficacy • Progression-free survival and overall survival • Regression analyses to assess the ability of patient prognostic factors to predict time-to-event outcomes

  13. A Proposal for BMS-354825 (Dasatinib) in GIST Jon Trent, MD, PhD Assistant Professor Dept. of Sarcoma Medical Oncology The University of Texas, M. D. Anderson Cancer Center

  14. Choi Criteia

  15. BMS-354825 (Dasatinib) in Imatinib-resistant CP-CML • N=36 (31 resistant, 5 intolerant) • 15 to 180 mg/d for 5-7 d/wk • 27 pts with mutations • Responses:- Hematologic: 86%- Cytogenetic: 45% Sawyers CL, et al. Blood 104: 4a, 2004

  16. BMS-354825 (Dasatinib) in GIST: Schema Days 1-28: BMS Restage after two cycles Registration Optional core biopsies Hx/PE, CT, Labs

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