1. Current Protocols of the Radiation Therapy Oncology Group Montreal, Quebec Nov. 12, 2004

2. Phase II Trial (RTOG S-0132): Study Design Resectable GIST (candidate for neoadjuvant therapy) Neoadjuvant imatinib mesylate (600 mg/d, 8 wk) SD/PR PD Follow for PFS Adjuvant imatinib mesylate (600 mg/d, PO 2 y) RESECTIONRESECTION RESECTIONRESECTION Off study

3. Phase II Trial (RTOG S-0132): Eligibility Potentially resectable primary tumors > 5cm Potentially resectable metastatic tumors > 2 cm C-Kitt expression must be documented

4. Phase II Trial (RTOG S-0132): Study Design* (Cont’d) Objectives:Primary:PFS with imatinib mesylate in adjuvant setting Secondary:Response rate in neoadjuvant setting Compare CT and PET responses in neoadjuvant setting Safety in adjuvant setting Treatment:Imatinib mesylate 600 mg/d Inclusion:Present with KIT-positive malignant GIST No extra-abdominal disease Imatinib mesylate – naive No prior therapy 28 days before entry *Trial ongoing.

5. RTOG 0132 Biological Correlates Before and After Gleevec: A.Fixed Tissue – KIT mutational analysis – Glut 4 expression correlation with PET SUV B.Frozen Tissue -Global genomic array to evaluate differential gene expression before and after Gleevec -Evaluation of phosphorylation of intermediate signaling molecules within the KIT activation pathway

6. RTOG 0132: Status of Protocol Protocol opened February 28, 2002 Accrual goal is 65 patients Accrual as of Oct. 26, 2004 is 35 patients

7. A Pilot Phase II Study Of Pre-operative Radiation Therapy And Thalidomide For Low Grade Primary Soft Tissue Sarcoma Or Pre-operative Maid/thalidomide/radiation Therapy For High/intermediate Grade Primary Soft Tissue Sarcoma Of The Extremity Or Body Wall RTOG 0330

8. Rationale for Thalidomide immunomodulatory agent antiangiogenic properties –potential relationship to circulating levels of bFGF and VEGF –these appear to be elevated in patients with STS frequently used in combination therapy well tolerated oral agent

9. RTOG 0330: Eligibility for Cohort A Cohort A : tumor > 8.0 cm in maximal diameter and intermediate to high grade Normal heart function (EF ≥ 50%) Accrual goal is 22 patients

10. RTOG 0330: Cohort A based upon experience with RTOG 9514 additional new questions/endpoints –toxicity issues of 9514 & with Thalidomide –benefit of addition of agent with alternative mechanism of action –biologic endpoints –response (clinical response & necrosis on central pathology review)

11. RTOG 0330: Cohort A Diagnosis & Registration MAID RT MAID RT MAID Surgery Day 80 MAID RT: 22 Gy/course, 44 Gy total RT: 16 Gy for + margins Thalidomide Thalidomide 200 mg/day for 1 year Biopsy & submission to central pathology, Blood draws x 6 Accrual goal 22 patients

12. RTOG 0330: Translational Studies RTOG 0330: Translational Studies (an Abbreviated List) Paraffin Blocks from Biopsy and Resections Microvessel Density Biological /Prognostic Markers –uPA/ tPA/ PAI-1 EGFR, p53, Ki-67,Tunel Studies on Circulating Factors Using WB VEGF and  FGF Circulating endothelial cells (CEC)

13. RTOG 0330: Eligibility Cohort B Low grade STS (Grade 1 or 2) and > 5 cm in diameter in greatest dimension. Accrual goal is 22 patients.

14. RTOG 0330: Cohort B RT 50 Gy in 5 weeks Thalidomide 200mg/day Surgery Thalidomide 200mg/day for 6 months 22 patients

15. RTOG 0330: Translational Studies RTOG 0330: Translational Studies (an Abbreviated List) Paraffin Blocks from Biopsy and Resections Microvessel Density Biological /Prognostic Markers –uPA/ tPA/ PAI-1 EGFR, p53, Ki-67,Tunel Studies on Circulating Factors Using WB VEGF and  FGF Circulating endothelial cells (CEC)

16. RTOG 0330: Status CTEP Approved and open for 3 months Open at 5 centers No patients accrued