1. INTERGROUP COALITION AGAINST SARCOMAS (ICAS) SCIENTIFIC STEERING COMMITTEE: EC Borden, G Demetri, M von Mehren, K Albritton, P Pisters BIOSTATISTICS: C Rankin, J Crowley OPERATIONS: G Goetz (SWOG) A COMMITTEE FOCUSED ON INTERGROUP DEVELOPMENT OF NEW SARCOMA THERAPEUTICS CALGB ECOG NCIC SWOG Collaborations with COG and ACOSOG Communication with SARC and RTOG

2. 2001-2006 INTERGROUP COALITION AGAINST SARCOMAS Goals and Hypotheses Sharpen definition of histologic subtypes to improve therapeutic outcomes and prognosis –Hypothesis: Molecular pathology will better define subtypes and thus improve clinical management and outcomes Emphasize targeted therapeutics –Hypothesis: Signal transduction modulators will be effective and histology specific Facilitate intergroup collaborations –Hypothesis: Increased intergroup collaboration will stimulate sarcoma research State of Science Clin Cancer Research 2003

3. ICAS STUDIES Metastatic Disease: Completed ICAS #SarcomaTarget Inhibitor Prior Rx S0033 GIST KIT imatinib Y S0218 Mesothelioma EGF-R erlotinib N S0330MPNSTEGF-R erlotinib N

4. OVERALL SURVIVAL GIST ON IMATINIB (ICAS S0033) 0% 20% 40% 60% 80% 100% 0246 Years after Registration 400 mg/day 800 mg/day N 345 345 Deaths 168 174 174 MEDIAN (m) 55 51 CR=4% PR=48% 2y=74% 2y(historical)=26%

5. S0502: SCHEMA Imatinib mesylate 400 mg/d po continuously Bevacizumab 15 mg/kg iv q3 weeks Imatinib mesylate 400 mg/d po continuously Incurable GIST RANDOMIZERANDOMIZE Stratify PS 0-1 vs. 2-3

6. S0502: Objectives Primary: PFS of imatinib + bevacizumab vs imatinib alone Secondary: –Compare response between arms –Compare frequency and severity of toxicities –Assess survival differences –Correlative Mutations VEGF and Receptors PET PK

7. Study Coordinators OVERALL CHAIR: Charles Blanke SWOG Translational Medicine: Michael Heinrich SWOG Pathology: Christopher Corless SWOG ECOG: Meg von Mehren CALGB: George Demetri NCIC: Vivien Bramwell Imaging: Janet Eary

8. ICAS STUDIES Metastatic Disease: Active ICAS # Sarcoma Target Inhibitor Prior Rx Accrual S0345 DFSPPDGF-R imatinib Y 7 S0346 SynovialHER2* trastuzumab Y 0 S0505 STSVEGF sorafenib Y 22 S0423 Chondro MTAP pemetrexed Y 11 S0344 Chondro ---- Surgery N 16 CTSU!!!!!!

9. ICAS STUDIES Metastatic Disease: Planned ICAS # Sarcoma Target Inhibitor Prior Rx PI 0405 synovial (neoaj) bcl-2 antisense+AI N Albritton 0502 GIST c-kit  VEGF Imatb  bevamab N Blanke 0612 GIST KIT GW786034 Y Budd 0418 GIST <30y KIT imatinib N Pappo 0631 MFH/Osteo SRC dasatinib Y Chu CTSU!!!!!

10. ICAS STUDIES Metastatic Disease: Proposals for Executive Committee Sarcoma Target Inhibitor Prior Rx PI Desmoid PDGF-Rsunitinib Y Ryan STS VEGF bevacizumab N* Verschraegen * Phase III: AI MFH m-TOR temsirolimus Y TBD

11. CHALLENGES SARCOMAS: 2006 CLINICAL BIOLOGY AND OUTCOMES CURRENT MANAGEMENT AND STANDARDS OF CARE EMPHASIZE CLINICAL PROGRESS

12. CHALLENGES SARCOMAS: 2006 CLINICAL BIOLOGY AND OUTCOMES –What do we know? CURRENT MANAGEMENT AND STANDARDS OF CARE –How are we doing? FUTURE RESEARCH CHALLENGES –Where should we be going?

13. CHALLENGES SARCOMAS: 2006

14. Euramos 1 Phase 3 Trial European and American Osteosarcoma Study Group Collaborators: COG German Austrian Swiss (COSS) European (EOI) Scandinavian (SSG) Trial Mgmt Group Chair M Bernstein Montreal COG Objectives: Improve EFS –Will IE when added to MAP for poor histological responders? –Will PEG-IFN when added to MAP for good histological responders? Eligibility –Resectable axial or extremity osteosarcoma –<40 Registration  2 cycles MAP  surgery  path reveiw  Random  MAPx2  MAPx2 MPx2  PEG-IFNx2y or IEx3 –n=1400 –10% improvement in EFS

15. INTERGROUP COALITION AGAINST SARCOMAS (ICAS) Ernest C. Borden Chair Catherine Rankin Biostatistics SWOG John Crowley Biostatistics SWOG Gretchen Goetz Operations SWOG –SWOG ECOG CALGB NCIC –collaboration with COG ACOSOG M von Mehren G Demetri B Redman V Bramwell K Albritton P Pisters –Communication with SARC A COMMITTEE FOCUSED ON INTERGROUP DEVELOPMENT OF NEW SARCOMA THERAPEUTICS

16. SARCOMAS NEW ERA 2000  MOLECULAR REDEFINITION IMPROVE PRIMARY TREATMENT TARGETED THERAPIES

17. IMPROVING GIST PATIENT OUTCOMES Eliminating GIST stem cell –Few residual clones: ACOSOG #Z9001 –Imatinib with other KIT/PDGF-R tyrosine kinase inhibitors S0612 Targeting of specific mutations –S0033 –S0033 and EORTC combined analysis –new inhibitors: S0612 Inhibition of alternate pathways –Angiogenesis: Bevacizumab S0502 Improved resonse assessement –S0502

18. ICAS HER2 Expression in Synovial Sarcomas Her2/neu

19. S0346 Trastuzumab for Synovial Sarcomas Eligibility –Metastatic Synovial Sarcomas –Central confirmation of her2 expression  2+ –  1 prior treatment Dose/Schedule –IV weekly 4 mg/kg loading, then 2 mg/kg

20. SARCOMAS NEW ERA 2000  MOLECULAR REDEFINITIONMOLECULAR REDEFINITION IMPROVED PRIMARY OUTCOMESIMPROVED PRIMARY OUTCOMES TARGETED THERAPIESTARGETED THERAPIES Case Comprehensive Cancer Center CCF Taussig Cancer Center

21. IMPACT OF DOSE OF IMATINIB ON TOXICITY: ICAS S0033

22. EGF-R EXPRESSION AND INHIBITION IN MPNST Intense membrane staining EGF-R inhibitors DeClue et al JCI 2000 DeClue et al JCI 2000