1. Phase II Study of Dasatinib in Advanced Sarcomas SARC 009 Study PI: Scott Schuetze Registration and eCRF: CRAB Drug supply: BMS

2. Dasatinib Small molecule inhibitor of src-family kinases (src, bcr-abl) and PDGFR Oral dosing Short half-life Toxicities: diarrhea, headache, hemorrhage, fatigue, nausea, rash, dyspnea, myelosuppression, hypocalcemia, hypophosphatemia, pleural effusion Rare: prolongation QT, cardiomyopathy

3. Dasatinib study objectives Evaluate clinical benefit rate = objective response or lack of progression for 6 months Evaluate 2 and 5 year survival rates Assess clinical and laboratory toxicities Collect tumor for construction of TMA Collect blood samples for determionation of drug level and functional inhibition of SRC phosphorylation

4. “aggressive” sarcoma sub-types Osteosarcoma - 6 Ewing’s family - 0 Leiomyosarcoma - 9 Liposarcoma - 8 MFH - 4 MPNST - 2 Rhabdomyosarcoma - 2 N = min 9 – max 48 per stratum

5. “Indolent” stratum ASPS - 0 Chordoma - 1 Epithelioid sarcoma - 0 GCT - 0 Hemangiopericytoma - 3 Conventional chondrosarcoma - 3 N = min 10 – max 116

6. 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 < 1.5x ULN QTc interval < 450 msec LVEF > 45%

7. Exclusions/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 St John’s wort

8. Treatment plan Archival tissue to be submitted to UM (mandatory – all sites) Negative pregnancy test prior to starting drug CBC weekly 1 st month, then monthly Serum chemistries monthly H&P monthly ECG after 1 st cycle Serum sample pre and post dose 2-4 weeks after starting (selected sites) Response assessment every 2 months +/- 1 week – on time reporting of response essential

9. Dose adjustment Dasatinib – NEW 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 Clinically 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 Create sub-type specific TMAs – 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. SARC 009: Accrual 10/07 UM – 20 Penn (Staddon) – 8 Washington Cancer I – 2 Stanford – 3 City of Hope – 3 Kootenai ID - 1 Oncology Specialists IL – open Arkansas Childrens - open

12. SARC 009: SAE 20 SAE – 12 related / 8 unrelated Dyspnea – 6 Pleural effusion – 2 Pneumonia – 1 Urinary tract infection - 1 Nausea, vomiting, diarrhea – 3 GI bleeding – 1 Hyponatremia – 1 Sudden cardiac arrest – 1 Tumor related pain - 3