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

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

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 BMS (Dasatinib)

Ba/F3 BCR-ABL E255K M351T M244V G250E Q252H Q252R Y253F Y253H E255V F317L E355G F359V H396R F486S T315I Relative growth after 48 hours of drug exposure Concentration of BMS (nM) Parental Ba/F3 cells “wt” BCR-ABL M351T E255K “wt” BCR-ABL M351T T315I Shah Science. 305: BMS inhibits IR BCR-ABL mutants Ba/F3 cell lines in vitro

Dasatinib in imatinib-resistant CML Efficacy (%) CHR87 CGR59 Complete CGR33 CHR50 CGR40 Complete CGR30 CHR28 CGR56 Complete CGR19 CP AP BP Talpaz et al., Sawyers et al., Kantarjian et al., ASCO 2005

Most Commonly Reported Non-Hematologic Toxicity Adverse event Grade 1–2 n (%) Grade 3–4 n (%) Elevated ALT11 (28)0 (0) Elevated creatinine9 (23)1 (3) Diarrhea7 (18)0 (0) Paresthesia4 (10)0 (0) Headache4 (10)0 (0) Nausea2 (5)0 (0) Peripheral edema2 (5)0 (0) Pleural effusion1 (3) GI hemorrhage0 (0)2 (5) N=40 No QTc prolongation to >500 ms, with no cardiac symptoms

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 BMS (Dasatinib) in GIST Evans et al, ASCO 2005

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

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

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 BMS (Dasatinib) in GIST: Evaluations

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. BMS (Dasatinib) in GIST: Design

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 BMS (Dasatinib) in GIST: Analysis

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

Choi Criteia ResponseResponse Definition Complete Response (CR) -Disappearance of all disease -No new lesions Partial Response (PR)-A decrease in size of > or = 10% OR a decrease in CT density (HU) > or = 15% -No new lesions -No obvious progression of non-metastatic disease Stable Disease (SD)-Does not meet criteria for CR, PR, or PD -No symptomatic deterioration attributed to tumor progession Progression of Disease (PD) -An increase in unidimenstional tumor size of > or = 10% AND did not meet criteria for PR by CT density -Any new lesions, including new tumor nodules in a previous cystic tumor

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% BMS (Dasatinib) in Imatinib- resistant CP-CML Sawyers CL, et al. Blood 104: 4a, 2004

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