1 / 16

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).

fallon
Download Presentation

A Proposal for BMS-354825 (Dasatinib) in GIST

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. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related