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Zarnestra NDA 21824

Zarnestra NDA 21824. Qin Ryan MD, PhD DODP/CDER/FDA. Outline. Regulatory Background Clinical Overview and Proposed Indication CTEP-20 Design CTEP-20 Efficacy CTEP-20 Safety Summary. Regulatory Background. Regulatory Background.

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Zarnestra NDA 21824

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  1. ZarnestraNDA 21824 Qin Ryan MD, PhD DODP/CDER/FDA

  2. Outline • Regulatory Background • Clinical Overview and Proposed Indication • CTEP-20 Design • CTEP-20 Efficacy • CTEP-20 Safety • Summary

  3. Regulatory Background

  4. Regulatory Background • In oncology, clinical benefit (CB) has been defined as a longer life, a better life or an effect on an established surrogate for either • In acute leukemias, durable complete remission (CR) has been considered evidence of benefit • In some cases where leukemia CR’s were of uncertain duration, CR was considered a surrogate reasonably likely to predict CB

  5. Drug Approvals for AML

  6. Clinical Overview

  7. Induction Therapy for AML • Untreated AML progresses rapidly to death • Standard Rx in Adults < 60: • 60-75% CR • < 20% treatment related death • DFS 20-50% • 30-40% survive > 3 years • Factors affecting outcome: PS, organ function, co-morbidity, age, karyotype

  8. Induction Chemotherapy for Elderly Patients with AML Menzin et al., Arch Intern Med 2002, 162: 1597.

  9. Survival in Elderly Patients with AML Menzin et al., Arch Intern Med 2002, 162: 1597.

  10. Higher mortality and morbidity seen in elderly patients with poor-risk AML receiving standard chemotherapy Elderly Patients with Poor-Risk AML

  11. Clinical Program

  12. Zarnestra • Farnesyl transferase inhibitor • 100 mg Tablets • 600 mg twice daily PO for 21 days, followed by a rest period of 7 - 42 days

  13. Proposed Indication • Treatment of elderly patients with newly diagnosed poor-risk acute myeloid leukemia.

  14. Zarnestra NDA: AML Trials * Conducted by NCI, CTEP as part of a Cooperative Research and Development Agreement with J&J

  15. CTEP-20 Design

  16. CTEP-20 Design • Open-label, single-arm, multicenter • Population • Original: untreated poor-risk hematological malignancies • 6th amendment (after 110 enrollments): untreated elderly poor-risk AML • Age > 75 • Age 65-74 AML with prior MDS

  17. CTEP-20 Design • Primary objective • Original: RR (CR+PR) • 6th amendment: complete response (CR) rate in untreated elderly poor-risk AML • Secondary objectives: • Progression-free survival (PFS) • Overall survival (OS) • Duration of response • Safety

  18. CTEP-20 Major Eligibility After amendment #6 • Inclusion: • Untreated newly diagnosed AML • > 75 • 65-74 with prior MDS • Confirmation with > 20% BM or PB blasts • PS 0 or 1, adequate renal and liver function. • Exclusion: circulating blasts > 30,000/uL, APL (M3), CNS leukemia, DIC

  19. CTEP-20 Efficacy Assessment • Medical history and physical examination, BM aspirate and biopsy, hematological and chemistry labs at baseline and the end of each cycle • CR determined by NCI sponsored AML criteria (Cheson et al., J Clin Oncol 8: 813-819, 1990) • Subsequent treatment and follow up

  20. CTEP-20 Efficacy

  21. CTEP-20 Study Population *One elderly patient with AML did not receive treatment by the time of clinical cut off.

  22. CTEP-20 Elderly Poor-Risk AML Population: Demographics a Some subjects had more than 1 reason for ineligibility for chemotherapy.

  23. CTEP-20 Elderly Poor-Risk AML Population: Risk Factors

  24. CTEP-20 Primary Endpoint: CR Rate

  25. CTEP-20 CR Rate Analysis by FDA

  26. CTEP-20 CR Rate Subgroup Analysis by FDA

  27. CTEP-20 CR Duration

  28. CTEP-20 Safety

  29. CTEP-20 Safety – Exposure

  30. CTEP-20 Safety – Dose Intensity

  31. CTEP-20 Safety – Common AEs

  32. CTEP-20 SafetyFrequent AEs Leading to Treatment Change

  33. CTEP-20 Safety – Grade 3/4 AEs

  34. CTEP-20 Safety - Death

  35. CTEP-20 – Hospitalization on Study

  36. SummaryZarnestra in Elderly Poor-Risk AML • Durable CR : an endpoint supportive of clinical benefit in AML • Consider in the context of : • 11.1% CRR with 275 days median duration • Poor risk patient population • 12% one-month death rate • 60% hospitalization

  37. Question Does the risk benefit analysis support regular approval of Zarnestra for the first-line treatment of AML patients age 65 or older with prior MDS or age 75 and older?

  38. Additional Slides

  39. Standard Treatment Risk & Benefit in general and in elderly poor-risk AML patients: Summary

  40. Zarnestra Risk & Benefit in elderly poor-risk AML patients compare to and Standard Treatment in elderly AML patients: Summary

  41. Approvals for APL, MDS

  42. Unfavorable Karyotype • Per the sponsor, the karyotypes described as unfavorable included: • del 5, del 5q, • del 7, del 7q, • trisomy 8, • 11q23, • complex (> 3 abnormalities).

  43. Summary of Patients with or without Prior MDS

  44. Sponsor’s RR by Risk Factors

  45. CTEP-20: Complete Remission Criteria • Bone marrow < 5% myeloblasts with normal maturation of all cell lines, an ANC > 1000/uL, a platelet > 100, 000/uL, absence of blasts in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. • CR must be confirmed 4-6 weeks after initial documentation. At least one bone marrow biopsy should be performed to confirm CR. NCI-Sponsored Workshop on Definitions of Diagnosis and Response in Acute Myeloid Leukemia, 1990.

  46. CTEP-20 Safety – Overall AEs

  47. CTEP-20 Safety – Common Non Hem. AEs

  48. CTEP-20 Safety – Common Hem & Met AEs

  49. CTEP-20 SafetyAEs Leading to Treatment Termination

  50. CTEP-20 Safety – AEs Leading to Dose Reduction (> 2%)

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