1. SARC011/NO21157 Alberto Pappo, M.D. Texas Children’s Cancer Center Houston, TX

2. 22 SARC011/NO21157 SARC Global Collaboration: A Phase II trial of R1507, a recombinant human monoclonal antibody to the insulin-like growth factor-1 receptor for the treatment of patients with recurrent or refractory Ewing’s sarcoma, osteosarcoma, synovial sarcoma, rhabdomyosarcoma and other sarcomas

3. R1507 shows anti-tumor activity in the clinic- Phase I Patient 7002: 27yo male Ewing’s sarcoma of chest wall with lung metastasis (1997) SD → Partial Response after 25 weeks of R1507 at 1 mg/kg/week. Patient 8012: 28yo female Ewing’s sarcoma of sacrum with lung metastasis (2003) PR after 6 weeks of R1507 at 9 mg/kg/week Restaging Week 25 Dec 29, 2006 Baseline June 19, 2006 Pt. 7002 Restaging Week 6 Jan 25, 2007 Baseline Dec 8, 2006 Pt. 8012

4.  Determine the ORR to R1507 in pts with recurrent or refractory Ewing sarcoma (secondary cohort) osteosarcoma, synovial sarcoma, rhabdomyosarcoma, and other sarcomas: ASPS, CCS, EMS, DSRCT, MLS  Determine PFS at 18 wks for patients treated with R1507 with progressive, recurrent or refractory ESFT (primary cohort) SARC011/NO21157 Primary Objectives

5. SARC 011 Secondary Objectives  Determine duration of response, PFS at 18 wks and overall PFS for pts with recurrent or refractory osteosarcoma, synovial sarcoma, rhabdomyosarcoma, and other sarcomas-ASPS, CCS, EMS,DSRCT, MLS.  Determine ORR, response duration, overall PFS in patients with Ewing sarcoma  PK,Tolerability and AE profile of R 1507

6.  PET scan changes  Serum Biomarkers SARC011/NO21157 Exploratory Objectives

7. Protocol Amendment v3 8-1-08  Reduced the age from ≥ 12 to ≥ 2 years  Expanded “others” cohort to 10 patients for each subtype, then if 1PR an additional 10 patients  Alveolar Soft Part Sarcoma  Clear Cell Sarcoma  Extraskeletal Myxoid Chondrosarcoma  Desmoplastic Round Cell Tumor  Myxoid Liposarcoma

8. SARC011/NO21157 Statistical Considerations  Ewing’s Primary cohort  Relapse ≤ 24 months AND at least 2 previous chemo regimen, surgically unresectable  65 patients  Two stage design  Ewing’s Secondary cohort (all other Ewing’s patients)  Relapse > 24 months (or ≤ 24 months 1 chemo regimen)  35 patients  Two stage design

9. SARC011/NO21157 Statistical Considerations  Osteosarcoma, Rhabdomyosarcoma, Synovial Sarcoma  35 patients  Two stage design  Other Sarcomas  20 patients for each of 5 other subtypes  Two stage design within each of the 5 subtypes

10. WHO Criteria Bi-dimensional measurements  Complete response (CR)  Disappearance of all known disease  Partial response (PR)  ≥ 50% decrease  Stable disease (SD)  No 50% decrease & no 25% increase  Progressive disease (PD)  ≥ 25% increase

11. Interim Analysis  Open to Recruitment:  Ewing’s 1  Ewing’s 2  Rhabdomyosarcoma  Other Sarcomas  Closed  Osteosarcoma  Undergoing interim analysis Synovial Sarcoma

12. SARC011/NO21157 Patient Enrollment  28 centers are activated and open to enroll patients  n = 189 (177 eligible)  Age:  12-86 yrs  Gender: (n=190*)  118 Male  72 Female * includes patient in screening data from Nov 1 st, 2008

13. Patient Enrollment-All Cohorts 189 enrolled 177 patients are eligible- data from Nov 1 st, 2008

14. Patient Enrollment-Ewing’s 68 eligible Ewing’s patients- data from Nov 1 st, 2008

15. Patient Enrollment by week All Patients Ewing’s Patients

16. Patient Enrollment by month

17. Ewing’s – Only 15% of Enrolled Patients < 18 data from Nov 1 st, 2008

18. SARC011/NO21157 Protocol Violations  Patients must have measurable disease  Index lesions must not be in prior site of radiation  Index lesions must be ≥ 10mm by spiral CT or ≥ 20mm by conventional techniques  Central pathology confirmation required within 6 weeks  Dose of R1507 must not be adjusted unless there is a 10% change in weight

19. Where do we need your help?  Ensuring patients are eligible  Enrolling pediatric patients  Enrolling Ewing’s 1 patients  Enrolling patients to the CBP  Sending samples for central path review  Sending pre study, baseline and efficacy scans to Bioimaging  Entering data answering queries

20. SARC011/NO21157 Enrollment by Cohort Cohorts enrolled patients (n=189) No of patients per cohort Ewing’s 135 Ewing’s 2 33 Osteosarcoma 41 Synovial Sarcoma19 Rhabdomyosarcoma 28 Other Sarcomas 21 Nov 1, 2008

21. SARC011/NO21157 Enrollment by Others Cohort Cohorts enrolled patients (n=189) No of patients per cohort Other Sarcomas21 Desmoplastic round cell tumor 8 Extraskeletal Myxoid chondrosarcoma 4 Myxoid liposarcoma4 Alveolar Soft Part Sacroma 3 2 Clear Cell Sarcoma Nov 1, 2008

22. SARC011/NO21157 Histologic Diagnosis (n=189) EMC: extraskeletal myxoid chondrosarcoma DSRCT: desmoplastic small round cell tumor CCS: clear cell sarcoma ASPS: alveolar soft part sarcoma RMS: rhabdomyosarcoma SS: synovial sarcoma OGS: osteosarcoma EWS-1: Ewing’s sarcoma primary EWS-2: Ewing’s sarcoma secondary MLS: myxoid liposarcoma Nov 1, 2008

23. SARC011/NO21157 SAEs SAE’s (n=51)No of events* Pain8 Infection7 Thrombocytopenia*4 Shortness of Breath, Hypoxemia2 Anemia2 Adrenal Hemorrhage*1 Pulmonary Embolism*1 Dehydration1 DVT1 Pleural effusion1 Acute respiratory failure1 Inflammation of L knee and stump1 Laryngeal Obstruction1 Nausea and Vomiting1 Nausea and Diarrhea1 Acute Febrile Illness1 * 1 event of Thrombocytopenia, Adrenal Hemorrhage and Pulmonary embolism attributed to drug Nov 1, 2008

24. SARC011/NO21157 SAEs SAE’s (n=51) continuedNo of events* Hyperglycemia1 Acute Renal Failure1 L Spontaneous Pneumothorax1 L Frontal Hematoma1 Fatigue1 Hypercalcemia1 Pyelonephritis1 Pneumonia1 Urinary Urgency1 GU Hemorrhage1 Postural Hypotension1 Stomach Outlet Obstruction1 Spinal Cord compression1 Fluid collection around L Femoral Prosthesis1 Increasing Dyspnea1 Respiratory Distress1 Bleeding of the metastases of the pleura1 Nov 1, 2008

25. Thank you

26. Background slides

27. 27 SARC011/NO21157 Background n=605 Pappo et al. JCO, 17, 3487, 1999 Rhabdomyosarcoma Med age 8y [0-20y] The outcome for patients with recurrent sarcomas is uniformly poor

28. 28 The outcome for patients with recurrent sarcomas is uniformly poor 1 Ewing Sarcoma Jürgens ASCO 2007 Asbtract 10012 SARC011/NO21157 Background

29. 29 2 Osteosarcoma n=575 Median age at Diagnosis 15.5 y [2.2 -68.2y] Kempf-Bielack et al. JCO, 23, 559, 2005 SARC011/NO21157 Background The outcome for patients with recurrent sarcomas is uniformly poor

30. 30

31. SARC 011 Background  R 1507 is a IGF-1 MoAb of the IgG1 subclass that binds the extracellular domain of IGF-1R and inhibits receptor activation  Main adverse events in about 40% of patients included GI, and fatigue but NO DLT  4/59 HAHA (3 preexisting)  9 mg/kg weekly. Half life 7 days  Responses:  2/7 PR EWS  5/19 SD