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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

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
BMS-354825 (Dasatinib)

Thiazolecarboxamide not structurally related to pyrido [2,3-d]-pyrimidine class of molecules

Shah. Science 305: 399, 2004

bms 354825 dasatinib3
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
slide4
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

dasatinib in imatinib resistant cml
Dasatinib in imatinib-resistant CML

CP

AP

BP

Talpaz et al., Sawyers et al., Kantarjian et al., ASCO 2005

most commonly reported non hematologic toxicity
Most Commonly Reported Non-Hematologic Toxicity

N=40

No QTc prolongation to >500 ms, with no cardiac symptoms

bms 354825 dasatinib in gist
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

a proposal for bms 354825 dasatinib in gist8

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 in gist inclusion criteria
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
bms 354825 dasatinib in gist evaluations
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
bms 354825 dasatinib in gist design
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.
slide12
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
a proposal for bms 354825 dasatinib in gist13

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 in imatinib resistant cp cml
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

slide16
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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