1. ACOSOG Sarcoma Committee Chair: Peter W.T. Pisters, MD Vice Chairs: Edward Cheng, MD (Orthopedic Oncology) Robert Maki, MD, PhD (Medical Oncology) Brian O’Sullivan, MD (Radiation Oncology) Brian Rubin, MD, PhD (Pathology, Correlative Science) A C O S O G

2. Research Goals and Themes Clinical trials evaluating combined modality management of patients with localized soft tissue sarcomas (STS) Neoadjuvant trials for patients with STS where surgeons are the portal of entry into the cancer care system International network of investigators Correlative science studies facilitated by surgeons as an intrinsic part of protocol design Collaboration with ACRIN, SWOG, RTOG, ICAS and other cooperative groups A C O S O G

3. Trial Summary Completed Accrual: Z9000 -Phase II imatinib in localized GIST Open: Z9001 -Phase III imatinib versus placebo in localized GIST Z9031 -Phase III surgery versus pre-op XRT plus surgery in retroperitoneal soft tissue sarcoma S0344/Z9041 - Phase II intralesional treatment of chondrosarcoma Developing: ACOSOG/ACRIN – Phase II PET – response assessment A C O S O G

4. Completed Trial Z9000 High-risk GIST Complete Gross Resection Tumor KIT + Ruptured > 10 cm Multifocal = Phase II study of adjuvant Imatinib in patients following completely resected high-risk GIST. Ronald DeMatteo, MD Imatinib x 1 yr A C O S O G

5. Completed Trial Z9000 Rationale Surgery alone – standard of care Imatinib prolongs PFS in Stage IV GIST Primary & Secondary Objectives Overall survival Recurrence Toxicity Correlative Science Mutational analysis (R01 and R21 funded) Accrual Activation: 6/1/2001 Completed: 9/30/2003 Total Accrual: 110 ACOSOG Sites: 31 CTSU Sites: 29 Plans Final toxicity data: 11/2004 Primary endpoint analysis: 2006 A C O S O G

6. Active TrialZ9001 Primary GIST > 3 cm Complete Gross Resection Tumor KIT + Randomize Imatinib x 1 yr Placebo x 1 yr Phase III randomized double-blind study of adjuvant Imatinib versus placebo in patients following resection of primary GIST. Ronald DeMatteo, MD A C O S O G

7. Active Trial Z9001 Rationale Surgery alone – standard of care Imatinib prolongs PFS in Stage IV GIST Need for randomized, placebo- controlled trial Primary & Secondary Objectives Overall survival Recurrence Toxicity Correlative Science (RO1 and R21 funded) Mutational analysis Mechanisms of imatinib resistance Accrual Activation: 6/1/2002 First Registration: 7/31/2002 Total Accrual: 281 Annual Accrual: 2002: 19 2003: 99 2004: estimated 200 Goal: 380, 3.8 years ACOSOG Sites: 51 CTSU Sites: 71 A C O S O G

8. Z9031 Phase III Trial - Background Concept from 2002 Sarcoma State of Science meeting Evolved through RTOG following Intergroup discussion Transitioned to ACOSOG –Feasibility (RTOG S0124 Phase II trial closed for poor accrual) –Primary involvement of surgeons critical for success A C O S O G

9. Active Trial Z9031 Patients with primary STS of the retroperitoneum or pelvis RANDOMIZERANDOMIZE Arm 1: Surgery Arm 2: XRT plus Surgery A randomized trial of preoperative radiation plus surgery versus surgery alone for localized primary retroperitoneal STS. P.W.T. Pisters, MD A C O S O G

10. Active Trial Z9031 Rationale Local recurrence is primary pattern of failure for RP STS Phase III data support use of XRT for extremity STS Primary & Secondary Objectives Progression-free survival Combined modality toxicity Complete resection rate (R0) Overall survival Correlative Science Comparative analysis of proteomic and DNA methylation patterns for treatment effect and prediction of clinical outcomes Accrual Activation: 8/23/04 First Registration: 9/24/04 Goal: 370 patients in 4.5 years Plans International participation Investigator meetings at ASTRO, ACOS A C O S O G

11. Active TrialsS0344/Z9041 Patients with suspected low-grade intracompartmental chondrosarcoma of bone REGISTERREGISTER A Phase II trial of intralesional resection of low-grade intracompartmental chondrosarcoma of bone. R. Lor Randall, MD Intralesional Resection FOLLOWFOLLOW A C O S O G

12. Active Trials S0344/Z9041 Rationale Intralesional resection with margin expansion has excellent local and systemic control rates Primary & Secondary Objectives Local complications Local recurrence Functional status Correlative Science Correlation of telomerase activity with chondrosarcoma tumor grade cDNA microarray hierarchical cluster analysis Accrual Goal: 60 patients in 4 years Plans Develop orthopedic oncology network A C O S O G

13. Biopsy- Confirmed STS Studies in Development Phase II evaluation of PET imaging as a predictor of response to neoadjuvant treatment for STS. Edward Cheng, MD (collaborative effort with ACRIN) Neoadjuvant Rx Repeat FDG-PET Wide local excision, histologic assessment of necrosis FDG-PET scan, routine staging studies (MRI and CT) A C O S O G