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Phase II Study of Dasatinib in Advanced Sarcomas SARC 009

Phase II Study of Dasatinib in Advanced Sarcomas SARC 009. Study PI: Scott Schuetze Registration and eCRF: CRAB Drug supply: BMS. Dasatinib. Small molecule inhibitor of src-family kinases (src, bcr-abl) and PDGFR Oral dosing Short half-life

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Phase II Study of Dasatinib in Advanced Sarcomas SARC 009

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  1. Phase II Study of Dasatinib in Advanced SarcomasSARC 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 1st month, then monthly • Serum chemistries monthly • H&P monthly • ECG after 1st 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

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