1. Phase II Study of Dasatinib (BMS-354825) in Advanced Sarcomas and Chordoma Coordinating Center: U Michigan

2. Probability of response to imatinib (95% posterior credible intervals)

3. Rationale for trial: extension of results from imatinib in sarcoma 30% of liposarcomas and fibrosarcomas showed clinical benefit to gleevec 30% of liposarcomas and fibrosarcomas showed clinical benefit to gleevec 2 leiomyosarcomas, 2 MFH and 1 liposarcoma showed objective response by RECIST 2 leiomyosarcomas, 2 MFH and 1 liposarcoma showed objective response by RECIST Mechanism of response not known Mechanism of response not known C-kit and PDGFR mutations identified in minority of sarcomas C-kit and PDGFR mutations identified in minority of sarcomas

4. Chordomas are affected by imatinib - ? inhibition of PDGFR prepost From P.G. Casali et al

5. Role of src in cancer V-Src oncogenic protein of Rous sarcoma virus V-Src oncogenic protein of Rous sarcoma virus Src kinases activated by receptor tyrosine kinases Src kinases activated by receptor tyrosine kinases Src elevated expression found in many cancers Src elevated expression found in many cancers May be involved in tissue invasion/metastasis May be involved in tissue invasion/metastasis Involved in osteoblast biology Involved in osteoblast biology

6. C-SRC expression in STS HistologyN01+2+ Leiomyo253175 MFH200155 Lipo162140 Fibrosarc11254 Angiosarc12075 Rhabdo18882 Antibody AP7718a (Abgent) 1:50

7. C-SRC expression in STS Tissue microarray – 181 samples

8. Dasatinib Small molecule inhibitor of src-family kinases (src, bcr-abl) and PDGFR Small molecule inhibitor of src-family kinases (src, bcr-abl) and PDGFR PDGFR inhibition requires higher doses – IC 50 30nM PDGFR inhibition requires higher doses – IC 50 30nM Oral dosing Oral dosing Short half-life Short half-life Overcomes resistance to gleevec in CML Overcomes resistance to gleevec in CML

9. Sarcoma study objectives Evaluate clinical benefit rate Evaluate clinical benefit rate 4 and 6 month PFS 4 and 6 month PFS Time to progression Time to progression Objective response rate – confirmed CR and PR Objective response rate – confirmed CR and PR Assess clinical and laboratory toxicities Assess clinical and laboratory toxicities Characterize mutations in PDGFR Characterize mutations in PDGFR Characterize expression levels of src in tumor Characterize expression levels of src in tumor

10. Definition of clinical benefit SD CR PR PD Month 2 CR PR SD PD Month 6 SD CR PR PD Month 4

11. Proposed patient groups Extraskeletal osteosarcoma Extraskeletal osteosarcoma Fibrosarcoma Fibrosarcoma Liposarcoma (not myxoid) Liposarcoma (not myxoid) MFH MFH Osteosarcoma Osteosarcoma Rhabdomyosarcoma Rhabdomyosarcoma Uterine leiomyosarcoma Uterine leiomyosarcoma High-grade chondrosarcoma High-grade chondrosarcoma ASPS ASPS Chordoma Chordoma Epithelioid sarcoma Epithelioid sarcoma GCT GCT Hemangipericytoma Hemangipericytoma Conventional chondrosarcoma Conventional chondrosarcoma Faster growth Slower growth

12. PFS in phase II studies of previously treated soft tissue sarcoma DrugDisease 3 mo PFS 4 mo PFS 6 mo PFS Gem/TaxLeiomyo47% ET-743STS52%29% ET-743STS44%28% TemodarSTS42%27% TemodarSTS40%22% 9-NCSTS26%22% AP23573STS/bone22% GemSTS/gist15% SU5416STS8%0% ActiveSTS39%30%14% InactiveSTS21%8%

13. PFS in phase II studies in untreated soft tissue sarcoma DrugDisease 6 mo PFS Doxo/avastinSTS50% GemSTS56% EpoBSTS41% DoxilSTS22% ET-743STS24% EORTC trials STS40-55%

14. PFS in slow growth sarcomas DrugDisease 3 mo PFS 6 mo PFS 9-NCChordoma47%33% ABT-510ASPS Docetaxel Low-grade STS 30%

15. Proposed response threshholds Target clinical benefit rate at 6 months of at least 20% in “faster growth” group Target clinical benefit rate at 6 months of at least 20% in “faster growth” group Target clinical benefit rate at 6 months of at least 40% in “slower growth” group Target clinical benefit rate at 6 months of at least 40% in “slower growth” group

16. Patient eligibility Group 1: Advanced high-grade fibrosarcoma, uterine leiomyosarcoma, liposarcoma, MFH, rhabdomyosarcoma, osteosarcoma treated with 1 or more prior therapies Group 1: Advanced high-grade fibrosarcoma, uterine leiomyosarcoma, liposarcoma, MFH, rhabdomyosarcoma, osteosarcoma treated with 1 or more prior therapies Group 2: Unresectable or recurrent chondrosarcoma, chordoma, epithelioid sarcoma, alveolar soft part sarcoma, hemangiopericytoma, GCT Group 2: Unresectable or recurrent chondrosarcoma, chordoma, epithelioid sarcoma, alveolar soft part sarcoma, hemangiopericytoma, GCT Measurable disease Measurable disease Progressive disease – for Group 1 patients Progressive disease – for Group 1 patients

17. Treatment plan Archival tissue to be submitted for PDGFR and c-src analysis (mandatory) Archival tissue to be submitted for PDGFR and c-src analysis (mandatory) Once-a-day dosing of dasatinib (starting dose pending results of current Phase I study) Once-a-day dosing of dasatinib (starting dose pending results of current Phase I study) Response assessment every 2 months +/- 1 week Response assessment every 2 months +/- 1 week Treat until progression or unmanageable toxicity Treat until progression or unmanageable toxicity

18. Implementation timeline LOI approved by BMS LOI approved by BMS Protocol in development Protocol in development Submit to UM PRC/IRB in January Submit to UM PRC/IRB in January 4-6 month approval process 4-6 month approval process Distribute to SARC sites after approval Distribute to SARC sites after approval