Phase II Study of Dasatinib in Advanced Sarcomas SARC009 Sarcoma PI: Scott Schuetze GIST PI: Jon Trent Registration and eCRF: CRAB, Seattle Drug Supply: Bristol-Myers Squibb SARC: November 13, 2008
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
SARC009: “Indolent” stratum
ASPS – 2 Chordoma – 8 Conventional chondrosarcoma – 19 Epithelioid sarcoma – 3 GCT – 0 Hemangiopericytoma – 10
N = 42 (maximum 116)
SARC009: ineligible
Desmoid/fibromatosis – 1 Extraskeletal myxoid chondrosarcoma - 1
SARC 009: GIST
Amendment approved May 1, 2008 Imatinib resistance/intolerance +/- sunitinib 22 enrolled to date
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
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
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
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
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
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
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
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
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
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
Objective response MFHbaseline 4th cycle
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
MFH treatment duration
0 2 4 6 8 10
cycles
MFH
LMS – treatment duration
0 2 4 6 8 10 12 14
cycles
LMS
Osteosarcoma – treatment duration
0 2 4 6 8
cycles
Liposarcoma – treatment duration
0 2 4 6
cycles
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)
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!