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SCH 717454 in Subjects with Relapsed Osteosarcoma or Ewing’s Sarcoma Protocol P04720

SCH 717454 in Subjects with Relapsed Osteosarcoma or Ewing’s Sarcoma Protocol P04720. CTOS Nov 2008. Disclosure. Neither I , nor my colleagues have any stock nor have we been paid consultants of Schering-Plough Investigators have received research funds for this study (P04720). .

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SCH 717454 in Subjects with Relapsed Osteosarcoma or Ewing’s Sarcoma Protocol P04720

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  1. SCH 717454 in Subjects with Relapsed Osteosarcoma or Ewing’s SarcomaProtocol P04720 CTOS Nov 2008

  2. Disclosure • Neither I , nor my colleagues have any stock nor have we been paid consultants of Schering-Plough • Investigators have received research funds for this study (P04720).

  3. Insulin Growth Factor Pathway P P P IGF-II/IGF-I IGF-1R AKT ERK1/2

  4. SCH 717454: A Potent & Specific anti-IGF-1R Monoclonal Antibody X X High Affinity Fully Human IgG1 clone 19D12 Does Not Recognize Insulin Receptor Insulin Receptor (IR) IGF-1R IGF-1R/ IR dimer Properties and Activities That May Contribute To Antitumor Effects: • Inhibits IGF ligand binding and IGF-1R signaling • Downregulation of IGF-1R protein level • Antibody-dependent cellular cytotoxicity • Enhances other agents in pre-clinical studies

  5. SCH717454 & OsteosarcomaXenografts 4.0 Control Treatment 3.0 Vehicle Control Relative Tumor Volume 2000 0.02 mg SCH 717454 2.0 1750 0.1 mg SCH 717454 0.5 mg SCH 717454 1500 1.0 1250 Tumor Size (mm3) 1000 0.0 0 1 2 3 4 5 6 750 Time (weeks) 500 250 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Days (post dosing) SCH 717454 Inhibits SJSA-1 Growth in vivo SCH 717454 Causes Regression of OS-1 in vivo (PPTP / NCI) Staged model, starting tumor volume: 250 mm3, 0.5 mg SCH 717454, 2 x weekly Staged model, 2 x weekly • Inhibits osteosarcoma, Ewing’s sarcoma & neuroblastoma xenografts • Pediatric preclinical testing program: complete responses in 2 out of 6 osteosarcoma (OS1, OS9) & 1 Ewing’s sarcoma cell line (EW5). Improved Event Free survival in 4/6 osteosarcoma and 2/5 Ewing’s models. • Kolb, Gorlick et al. 2008

  6. Refractory Osteosarcoma or Ewing’s Sarcoma Cohorts Recurrent/refractory Osteosarcoma or Ewing’s Sarcoma (N25-50 each) SCH 717454 10 mg/kg Q 2 weeks Endpoints • Primary: Response • Secondary: TTP, Safety, PK, PD

  7. Key Inclusion/Exclusion Criteria • Key Inclusions • ≥11 years of age • Osteosarcoma or Ewing’s sarcoma • Key Exclusions • Diabetics: hemoglobin A1C >7.5% • Heart disease, hepatitis or active infection • Prior anti-IGF-1R drug

  8. Serum IGF-1 Concentrations During Treatment 700 600 500 IGF-1 blood level (ng/ml) 400 300 200 100 0 Baseline 2 wks after Single Dose (Trough Level) Subsequent Doses (at Trough)

  9. IGF-1R Occupancy On Peripheral Blood Mononuclear Cells 60 50 40 % of IGF-1R un-occupied 30 20 10 0 Baseline Two Weeks Post-Dose (Obtained at Trough) Flow cytometry assay measuring the percent of cells that bind labeled SCH 717454 at baseline (blue) versus 2 weeks post single dose of SCH 717454 (purple)

  10. Preliminary Response Data • Osteosarcoma: stable disease in >5* (1 stable to >6 months; another ongoing response with both lung and bone metastases) • Ewings: 3 PRs; some of subjects with mixed responses *Initial data on subject at 8 weeks on study

  11. Preliminary Ewing’s Response 11 year old female with recurrent/refractory Ewing’s Sarcoma s/p 3 prior therapies Before After Single Dose

  12. Responding Ewing’s Sarcoma 29 year old male with recurrent/refractory Ewing’s Sarcoma s/p 3 prior therapies Before After (8 weeks)

  13. Near Complete Response in Ewing’s 28 year old male with recurrent/refractory Ewing’s Sarcoma s/p 2 prior therapies Before at 8 week assessment

  14. Most Common Adverse Events

  15. Safety/Tolerability Summary • Well tolerated • Most AEs mild or moderate • Hyperglycemia • Generally mild if present • Only 1 moderate/severe event in an adult diabetic • No severe or life-threatening drug-related AEs

  16. P04720: Group 1 SCH 717454 Dose Level 1 SCH 717454 Dose Level 1 Recurrence Resectable Disease Prior Surgery Surgery Recurrence SCH 717454 Dose Level 2 SCH 717454 Dose Level 2 Tumor Proliferation Tumor Proliferation TTP TTP • Primary Endpoint: tumor proliferation • Secondary Endpoint: TTP/Time to relapse

  17. Summary • Potent in preclinical models • Clinically well-tolerated • Hyperglycemia uncommon, mostly mild • Clinically active in Ewing’s sarcoma • Stable disease in Osteosarcoma • Enrollment continuing- North America, Europe, and South America

  18. Acknowledgements • Contributing Investigators • Drs. Anderson, Skubitz, Miller, Meyer, Arico, Mita, Chawla, Katzenstein, O’Day, Desai, Villarroel, Lopez, Van de Graaf, Mas, Sandoval, Marec-Berard, Jean-Gentet, Bielack, and Klingelbiel • Schering Plough Personnel • Drs. Lu, and Wang; Ms. Whitman • All the patients and their families • ? Questions?

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