Transcript 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)
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
BMS-354825 inhibits IR BCR-ABL mutants
1.2
Relative growth after 48
hours of drug exposure
Parental Ba/F3 cells
1
T315I
0.8
0.6
Ba/F3 cell lines
in vitro
E255K
0.4
“wt” BCR-ABL
0.2
M351T
0
0
1
5
10
50
Concentration of BMS-354825 (nM)
100
Ba/F3
BCR-ABL
E255K
T315I
M351T
M244V
G250E
Q252H
Q252R
Y253F
Y253H
E255V
F317L
E355G
F359V
H396R
F486S
Shah Science. 305: 399 2004
Dasatinib in imatinib-resistant CML
CP
AP
BP
CHR
CGR
Complete CGR
CHR
CGR
Complete CGR
CHR
CGR
Complete CGR
Talpaz et al., Sawyers et al., Kantarjian et al., ASCO 2005
Efficacy (%)
87
59
33
50
40
30
28
56
19
Most Commonly Reported
Non-Hematologic Toxicity
Adverse event
Elevated ALT
Elevated creatinine
Diarrhea
Paresthesia
Headache
Nausea
Peripheral edema
Pleural effusion
GI hemorrhage
N=40
Grade 1–2
n (%)
11 (28)
9 (23)
7 (18)
4 (10)
4 (10)
2 (5)
2 (5)
1 (3)
0 (0)
Grade 3–4
n (%)
0 (0)
1 (3)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (3)
2 (5)
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
Response
Response 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
BMS-354825 (Dasatinib) in Imatinibresistant 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