Phase II Study of Dasatinib in Advanced Sarcomas SARC009

1. Phase II Study of Dasatinib in Advanced SarcomasSARC009 Sarcoma PI: Scott Schuetze GIST PI: Jon Trent Registration and eCRF: CRAB, Seattle Drug Supply: Bristol-Myers Squibb SARC: November 13, 2008

2. 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

3. 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

4. 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)

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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: enrollment by site

12. SARC009: accrual by month

13. SARC009: cumulative accrual

14. 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

15. SARC009: “Indolent” stratum • ASPS – 2 • Chordoma – 8 • Conventional chondrosarcoma – 19 • Epithelioid sarcoma – 3 • GCT – 0 • Hemangiopericytoma – 10 N = 42 (maximum 116)

16. SARC009: ineligible • Desmoid/fibromatosis – 1 • Extraskeletal myxoid chondrosarcoma - 1

17. SARC 009: GIST • Amendment approved May 1, 2008 • Imatinib resistance/intolerance +/- sunitinib • 22 enrolled to date

18. 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 Patient demographics

19. Adverse events – all grades

20. Adverse events – all grades

21. Grade >3 AE

22. Grade >3 AE

23. Dasatinib-related SAEs

24. Dasatinib-related SAEs

25. Dasatinib dose

26. 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

27. 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

28. Objective response MFH 4th cycle baseline

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

30. MFH treatment duration

31. LMS – treatment duration

32. Osteosarcoma – treatment duration

33. Liposarcoma – treatment duration

34. Progression-free survival – “indolent” & GIST

35. 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!