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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

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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)

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

Shah. Science 305: 399, 2004


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


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

CP

AP

BP

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


Most Commonly Reported Non-Hematologic Toxicity

N=40

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


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 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

  • Histologically confirmed diagnosis of GIST

  • Refractory or relapsed disease after adequate imatinib.

  • Imatinib-intolerant

  • Generalized or limited progression


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

  • 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-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 GIST

Jon Trent, MD, PhD

Assistant Professor

Dept. of Sarcoma Medical Oncology

The University of Texas,

M. D. Anderson Cancer Center


Choi Criteia


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


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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