1. November 2006 Phase II Study of Dasatinib in Advanced Sarcoma SARC 009 Coordinating site: University of Michigan

2. November 2006 C-SRC expression in STS HistologyN01+2+ Leiomyosarc253175 MFH200155 Liposarcoma162140 Fibrosarcoma11254 Rhabdomyosarc18882 Antibody AP7718a (Abgent) 1:50

3. November 2006 C-SRC expression in STS Tissue microarray – 181 samples

4. November 2006 Dasatinib Small molecule inhibitor of src-family kinases (src, bcr-abl) and PDGFR Oral dosing Short half-life In vitro anti-tumor activity in rhabdomyosarcoma and osteosarcoma cell lines

5. November 2006 Sarcoma study objectives Primary: Response rate Secondary: –Progression-free survival rates –2 and 5 year survival rates –Characterize Src expression –Collect tumor for molecular analysis if warranted

6. November 2006 Definition of Response SD CR PR PD Month 2 CR PR SD PD Month 6 SD CR PR PD Month 4

7. November 2006 Patient Strata 1.Osteosarcoma 2.Leiomyosarcoma 3.Liposarcoma 4.MFH 5.MPNST 6.Rhabdomyosarcoma 7.High-grade chondrosarcoma ASPS Chordoma Epithelioid sarcoma GCT Hemangipericytoma Conventional chondrosarcoma Faster growth Slower growth

8. November 2006 PFS in phase II studies of previously treated soft tissue sarcoma DrugDisease3 mo PFS6 mo PFS Gem/TaxLeiomyo47% ET-743STS50%30% TemodarSTS40%25% 9-NCSTS26%22% GemcitabineSTS15% SU5416STS8%0% TarcevaMPNST0%

9. November 2006 Target activity: higher grade group Target response rate at 6 months of at least 25% in “faster growth” group Minimum 9 subjects accrued to each of 7 sub- groups

10. November 2006 PFS in phase II studies of “indolent” sarcomas DrugDisease6 mo PFS 9-NCChordoma33% ABT-510ASPS40% DocetaxelLow-grade STS30%

11. November 2006 Target activity: indolent group Target response benefit rate at 6 months of at least 50% in “slower growth” group Response rate < 25% will be considered unpromising Minimum of 10 subjects accrued

12. November 2006 Patient eligibility Group 1: Advanced leiomyosarcoma, MFH, liposarcoma, MPNST, rhabdomyosarcoma, osteosarcoma treated with 1 or more prior therapies Group 2: ASPS, chondrosarcoma, chordoma, GCT, epithelioid sarcoma, hemangiopericytoma Measurable disease Age > 13 Weight > 50 kg ECOG score 0-2

13. November 2006 Exclusions Acquired or congenital bleeding disorder Taking anticoagulants or antiplatelet agents On meds with risk of Torsades de Pointes QTc interval >450 msec LVEF <45% (measurement not required in all subjects) Concurrent bisphosphonate therapy not allowed

14. November 2006 Treatment plan Dasatinib 100mg twice daily Q 28 days CBC weekly 1 st month Visits and labs monthly x 6 months, then q 6 weeks x 6 months then q 3 months Tumor imaging every 2 months +/- 1 week x 6 months then q 3 months Treat until progression or unmanageable toxicity

15. November 2006 Dose modification Intolerable Grade 2 toxicity, reduce dose 1 level Grade 3 or 4 toxicity, hold until < Grade 1, then restart at next lower dose Starting doseLevel – 1Level – 2 100 mg bid70 mg bid50 mg bid

16. November 2006 Dasatinib AEs Rash GI disturbance, nausea, vomiting Hypocalcemia Fluid retention, pleural effusions Hemorrhage Cardiomyopathy

17. November 2006 Response assessment Baseline chest imaging required Imaging every 8 weeks Choi criteria 1. > 10% increase in sum of greatest diameter of target lesions or new lesions = progression 2. > 10% decrease in sum of greatest diameter of target lesions = response 3. Neither 1 nor 2 = stable

18. November 2006 Logistics Subjects registered through SARC Local pathologist diagnoses sub-type Dasatinib ordered by site from 3 rd party supplier Archival tumor tissue shipped to UM Electronic data capture (Harvard server?)

19. November 2006 Implementation timeline Protocol approved by BMS, supplying drug Protocol approved by SARC Submit to UM PRC/IRB in December Distribute to SARC sites after approval