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NDA 21-877

NDA 21-877. Nelarabine. Proposed Indication.

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NDA 21-877

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  1. NDA 21-877 Nelarabine

  2. Proposed Indication Nelarabine is indicated for the treatment of patients with T-cell acute lymphoblastic leukemia (ALL) and T-cell lymphoblastic lymphoma (LBL) whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens.

  3. Submitted Phase 2 Studies

  4. Pediatric: Nelarabine 650 mg/m2/day administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days. Adult: Nelarabine 1,500 mg/m2 administered intravenously over 2 hours on days 1, 3 and 5 repeated every 21 days. Nelarabine Dose and Schedule

  5. Response Definitions • CR: - no circulating blasts or extramedullary disease; - an M1 bone marrow (< 5% blasts); and ANC >1.5 × 103/mcL - platelets >100 × 103/mcL and Hgb >10 or 11 g/dL. • CR*: - Patients who have met all criteria for CR except for recovery of peripheral blood counts or marrow cellularity . Independent review of marrow aspirates and/or biopsies for responders whose slides were available

  6. Study Objectives • Primary Objective - CR plus CR* rate • Secondary Objectives - Remission duration - Overall survival ( OS) - Safety

  7. Pediatric Study

  8. Inclusion criteria Age < 21 Refractory or recurrent T-ALL or T-LBL First or subsequent relapse Performance status >50 Adequate organ status Patients with >grade 2 neurotoxicity were excluded.

  9. Study participants 78 Sites: United States and Canada 109 Investigators Independent pathology review

  10. COG Study Groups

  11. AML - Demographics and KPS

  12. COG - Disease Characteristics

  13. Group 2 Prior Therapies

  14. COG Best Response

  15. Response by Disease Type

  16. T-ALL/LBL - Patients Transplanted

  17. Non-Transplant

  18. Adult Study

  19. CALGB - Demographics and KPS

  20. CALGB - Disease Characteristics

  21. CALGB Best Response

  22. Response by Disease Type

  23. CALGB - Patients Transplanted

  24. CALGB Non-Transplant

  25. Supportive Phase 1 Trials

  26. Grade 3/4 Non-Neurologic AE’s; Pediatric N=84

  27. Pediatric Neurologic AE’s N=84 (%)

  28. Grade 3/4 Non-Neurologic AE’s; Adult N=103

  29. Adult Neurologic AE’s N=103 (%)

  30. Efficacy Conclusions>2 Prior Induction Regimens

  31. Efficacy Conclusions1 Prior Induction Regimen

  32. Efficacy Conclusions>2 Prior Induction Regimens

  33. Safety Conclusions • Principal toxicities in pediatric patients were laboratory abnormalities • Principal toxicities in adult patients were hematologic, gastrointestinal, fever, fatigue and respiratory. • Neurologic toxicity was dose limiting. Most neurologic toxicity resolved over time.

  34. Nelarabine Efficacy Considerations Traditional endpoints: - CR rate and duration, OS Study confounding factor: - Transplantation

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