Phase II Study of Dasatinib in Advanced Sarcomas SARC009
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Transcript of Phase II Study of Dasatinib in Advanced Sarcomas SARC009
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Phase II Study of Dasatinib in Advanced Sarcomas
SARC009Sarcoma PI: Scott Schuetze
GIST PI: Jon TrentRegistration and eCRF: CRAB, Seattle
Drug Supply: Bristol-Myers Squibb
SARC: November 13, 2008
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Dasatinib
Small molecule inhibitor of src-family kinases, c-kit and PDGFR
Preclinical data suggested activity in Ewings & osteosarcoma in cell lines
Lack of activity in PPTP pediatric tumor panel Preclinical data suggests activity in GIST kit and
PDGFR mutants not responsive to imatinib
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Dasatinib study objectives
Primary Evaluate clinical benefit rate = Choi response
or lack of progression for >6 months
Secondary Evaluate 2 and 5 year survival rates Assess clinical and laboratory toxicities Collect tumor for tissue microarray Collect blood samples for drug level and
functional inhibition of SRC phosphorylation
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Patient Eligibility Measurable disease Age > 13 years weight > 50 kg ECOG 0-2 ANC > 1,500, Plt > 75,000 Creatinine < 2x ULN Serum calcium, magnesium and potassium > LLN Pt/PTT < 1.5 x ULN QTc interval < 450 msec LVEF > 45% (if prior treatment with anthracycline)
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Exclusion/prohibitions
Disease curable by multidisciplinary management
Anti-platelet agents Anticoagulants Medications that prolong QT Active cardiac disease within 6 months Antacids – PPI, H-2 blockers IV bisphosphonates CYP 3A4/5 inducers/inhibitors
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Treatment Plan
Tumor tissue submitted to UM (mandatory – all sites) Negative pregnancy test prior to starting drug (for
women of childbearing potential) CBC weekly 1st month, then monthly Serum chemistries including magnesium monthly H&P monthly ECG baseline & after 1st cycle Serum sample pre and post dose (selected sites) Response assessment every 2 months +/- 1 week – on
time reporting of response essential
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SARC009: Imaging
Imaging every 8 weeks +/- 1 week, same method as baseline
Target lesions at least twice the size of slice thickness on CT
Target lesions on MRI should be at least 1cm Size = sum of greatest dimension of targets Density (CT only) = sum of average density of
targets
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Choi criteria
CR = complete disappearance, no new lesions PR = >10% reduction in size or >15% decrease
in density Stable = neither CR, PR or PD PD = >10% increase in size but not >15%
decrease in density, or new lesions >1cm, or unequivocal progression of non-target lesions, or clinical deterioration from sarcoma
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Dose Adjustment
Dasatinib dosing scheme 70 mg bid starting dose 50 mg bid level -1 100 mg once daily level -2
Intolerable grade 2 event, reduce dose without interruption
Significant non-hematologic grade 3 event, hold dose until grade 1 and then restart at reduced dose
Grade 4 non-hematologic event, hold dose until grade 1 and then restart at reduced dose
Grade 3 or 4 neutropenia or thrombocytopenia, hold dose until grade 1 and then restart at reduced dose
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Correlative studies
Sub-type specific tissue microarrays – stored at UM, SARC sites will have access
Plasma sample obtained 2 hours after am dose 2-4 weeks after starting, store -20C or below – collection kits provided by SARC
PBMC lysate from sample pre and post am dasatinib dose 2-4 weeks after starting, store -70C or lower – collection kits provided by SARC
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SARC009: enrollment by site
UM 39 Penn 21 MD Anderson 11 MGH 15 DFCI 14 City of Hope 19 Fox Chase 17 Stanford 17 Kootenai 16
Johns Hopkins 7
Indiana 6 Emory 8 U Pitt 5 WCI 4 SOC 3 Nebraska 2 Cedars-Sinai 2 Arkansas 1
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SARC009: accrual by month
Protocol Accrual to SARC009 Dasatinib (N=207)data as of October 31, 2008
3
6
11
64
8 8
1210
19
57
9
26
1315
29
16
02468
10121416182022242628303234
May07
Jun07
Jul07
Aug07
Sep07
Oct07
Nov07
Dec07
Jan08
Feb08
Mar08
Apr08
May08
Jun08
Jul08
Aug08
Sep08
Oct08
Month/Year of Accrual
Frequency
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SARC009: cumulative accrualProtocol Accrual to SARC009 (N=207)
data as of October 31, 2008
3 920 26 30
38 4658
6887 92 99
108
134147
162
191207
0
25
50
75
100
125
150
175
200
May0
7
Jul0
7
Sep0
7
Nov0
7
Jan0
8
Mar0
8
May0
8
Jul0
8
Sep0
8
Month/Year of Accrual
total patients
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SARC 009: “Aggressive” sub-types
MFH – 34 OPEN Osteosarcoma – 27 On hold Leiomyosarcoma – 48 CLOSED Liposarcoma – 11 CLOSED Ewing’s family – 9 1st stage MPNST – 5 1st stage Rhabdomyosarcoma – 7 1st stage
N = min 9 to max 48 per stratum
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SARC009: “Indolent” stratum
ASPS – 2 Chordoma – 8 Conventional chondrosarcoma – 19 Epithelioid sarcoma – 3 GCT – 0 Hemangiopericytoma – 10
N = 42 (maximum 116)
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SARC009: ineligible
Desmoid/fibromatosis – 1 Extraskeletal myxoid chondrosarcoma - 1
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SARC 009: GIST
Amendment approved May 1, 2008 Imatinib resistance/intolerance +/- sunitinib 22 enrolled to date
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Patient demographics
Prior chemotherapy
yes - 76
no - 66
missing – 54
ECOG
0 – 79
1 – 75
2 – 7
missing - 35
Age
13-25y: 15
25-49y: 61
50-74y: 110
75+y: 10
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Adverse events – all gradesRelatedNot Related
Cardiac Arrhythmia
Cardiac General
Coagulation
Death
Endocrine
Ocular/Visual
Constitutional symptoms
Gastrointestinal
Renal/Genitourinary
Blood/Bone Marrow
0 20 40 60 80 100
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Adverse events – all grades
RelatedNot Related
Hemorrhage/Bleeding
Infection
Pulmonary/Upper Respiratory
Lymphatics
Metabolic/Laboratory
Musculoskeletal/Soft Tissue
Neurology
Pain
Dermatology/Skin
Sexual/Reproductive Function
0 20 40 60 80 100
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Grade >3 AE
RelatedNot Related
Cardiac Arrhythmia
Cardiac General
Coagulation
Death
Endocrine
Ocular/Visual
Constitutional symptoms
Gastrointestinal
Renal/Genitourinary
Blood/Bone Marrow
0 20 40 60 80 100
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Grade >3 AE
RelatedNot Related
Hemorrhage/Bleeding
Infection
Pulmonary/Upper Respiratory
Lymphatics
Metabolic/Laboratory
Musculoskeletal/Soft Tissue
Neurology
Pain
Dermatology/Skin
Sexual/Reproductive Function
0 20 40 60 80 100
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Dasatinib-related SAEs
Cardiac Arrhythmia
Cardiac General
Coagulation
Death
Endocrine
Ocular/Visual
Constitutional symptoms
Gastrointestinal
Renal/Genitourinary
Blood/Bone Marrow
0 20 40 60 80 100
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Dasatinib-related SAEs
Hemorrhage/Bleeding
Infection
Pulmonary/Upper Respiratory
Lymphatics
Metabolic/Laboratory
Musculoskeletal/Soft Tissue
Neurology
Pain
Dermatology/Skin
Sexual/Reproductive Function
0 20 40 60 80 100
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Dasatinib dose
0
10
20
30
40
50
60
70
80
90
100
per
cen
t o
f p
atie
nts
70 mg BID 50 mg BID 100 mg QD
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Reason off treatment
Progressive disease – 88 Clinical progression – 9 Patient withdrew – 9 Death – 12 AE, not related – 6 AE, related – 3 Physician decision – 0 Other - 2
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SARC009: statistical design
Bayesian / dynamic analysis Start analysis after enrollment 9-10 per subtype “aggressive” subtypes - >25% response “indolent” group – 6 month PFS
> 50% = promising <30% = inactive
GIST - 6 month PFS >30% = promising <10% = inactive
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Objective response MFHbaseline 4th cycle
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Evaluable pts clinical benefit rate(CR/PR + > 6 month SD)
0
5
10
15
20
25
30
percent
MFH -
17
Leio
- 33
Osteo
- 13
Lipo -
10
Rhabdo
- 6
Ewings
- 5
MPNST -
3
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MFH treatment duration
0 2 4 6 8 10
cycles
MFH
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LMS – treatment duration
0 2 4 6 8 10 12 14
cycles
LMS
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Osteosarcoma – treatment duration
0 2 4 6 8
cycles
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Liposarcoma – treatment duration
0 2 4 6
cycles
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Progression-free survival – “indolent” & GIST
Progression-Free SurvivalTreated patients with follow-upData as of October 27, 2008
0%
20%
40%
60%
80%
100%
0 3 6 9 12Months after Registration
GISTIndolent
Events / N3 / 10
21 / 36
6-MonthEstimate
58% (22,95)49% (32,65)
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SARC009: summary Close to completing accrual in “aggressive “
sarcomas Preliminary results show activity in “MFH” Results in “indolent” sarcoma allow for continued
accrual GIST too soon to tell 1/3 require dose reduction AEs: hematologic, pulmonary, GI, constitutional,
pain Thanks to many investigators for rapid accrual! Thanks to SARC staff for excellent support!