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

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 1 st month, then monthly  Serum chemistries including magnesium monthly  H&P monthly  ECG baseline & after 1 st 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  UM39  Penn21  MD Anderson11  MGH15  DFCI14  City of Hope19  Fox Chase17  Stanford17  Kootenai16  Johns Hopkins7  Indiana6  Emory8  U Pitt5  WCI4  SOC3  Nebraska2  Cedars-Sinai 2  Arkansas 1

SARC009: accrual by month

SARC009: cumulative accrual

SARC 009: “Aggressive” sub-types  MFH – 34OPEN  Osteosarcoma – 27On hold  Leiomyosarcoma – 48CLOSED  Liposarcoma – 11CLOSED  Ewing’s family – 91 st stage  MPNST – 51 st stage  Rhabdomyosarcoma – 71 st 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: y: y: y: 10

Adverse events – all grades

Grade >3 AE

Dasatinib-related SAEs

Dasatinib dose

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 MFH baseline 4 th cycle

Evaluable pts clinical benefit rate (CR/PR + > 6 month SD)

MFH treatment duration

LMS – treatment duration

Osteosarcoma – treatment duration

Liposarcoma – treatment duration

Progression-free survival – “indolent” & GIST

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!