SARC011/NO21157

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

2. 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 2 2

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

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 011Secondary 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/NO21157Statistical 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/NO21157Patient 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 1st, 2008

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

14. Patient Enrollment-Ewing’s 68 eligible Ewing’s patients- data from Nov 1st, 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 1st, 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/NO21157Enrollment by Cohort Nov 1, 2008

21. SARC011/NO21157Enrollment by Others Cohort Nov 1, 2008 Clear Cell Sarcoma

22. SARC011/NO21157Histologic Diagnosis (n=189) Nov 1, 2008 SS: synovial sarcoma OGS: osteosarcoma EWS-1: Ewing’s sarcoma primary EWS-2: Ewing’s sarcoma secondary MLS: myxoid liposarcoma EMC: extraskeletal myxoid chondrosarcoma DSRCT: desmoplastic small round cell tumor CCS: clear cell sarcoma ASPS: alveolar soft part sarcoma RMS: rhabdomyosarcoma

23. SARC011/NO21157 SAEs Nov 1, 2008 *1 event of Thrombocytopenia, Adrenal Hemorrhage and Pulmonary embolism attributed to drug

24. SARC011/NO21157 SAEs Nov 1, 2008

25. Thank you

26. Background slides

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

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

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

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31. SARC 011Background • 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