Vincristine Sulfate Liposome Injection (Marqibo ® ) Inex Pharmaceuticals Corporation New Drug Application (021600)

1. Vincristine Sulfate Liposome Injection (Marqibo®)Inex Pharmaceuticals CorporationNew Drug Application (021600) Oncology Drug Advisory Committee Dec 1, 2004 Maitreyee Hazarika, M.D. Division of Oncology Drug Products Center for Drug Evaluation and Research

2. Indication Treatment of patients with aggressive Non-Hodgkin’s Lymphoma (NHL) previously treated with at least two combination chemotherapy regimens

3. Outline • Regulatory Issues • Study CA99002 • Efficacy • Safety • Study DM97-162 • Summary • Issues for ODAC

4. Regulatory Issues • Accelerated Approval • Available Therapy • Endpoints • Adequate and well controlled trials • Confirmatory Trial

5. Accelerated Approval • If a drug appears to provide a benefit over available therapy and • the benefit is determined by the drug’s effect on a surrogate endpoint deemed reasonably likely to predict clinical benefit

6. Available Therapy • AA requires an advantage over available therapy • Available therapy should be interpreted as therapy that is reflected in the approved labeling of regulated products

7. Available TherapyExceptions • “…only in exceptional cases will a treatment that is not FDA-regulated (e.g., surgery) or that is not labeled for use but is supported by compelling literature evidence  (e.g., certain established oncologic treatments) be considered available therapy.”  • The ODAC members will need to use their expertise on what constitutes available therapy for aggressive NHL

8. Methotrexate Cyclophosphamide Vincristine Vinblastine Bleomycin Carmustine Adriamycin Approved Therapies for NHL1957-1988

9. Approved Therapies for Follicular NHL • Rituximab (Rituxan®) • Ibritumomab tiuxetan (Zevalin®) • I-131 tositumomab (Bexxar®) • Interferon alfa-2b (Intron®)

10. Combinations Reported for Relapsed Aggressive NHL

11. Single Agents Reported for Relapsed Aggressive NHL

12. Endpoint Issues • Previous recommendation has been CR • Should FDA consider PR to be “reasonably likely” to predict for clinical benefit in relapsed, aggressive NHL ? • If so, would responses of the magnitude and duration seen in this study predict clinical benefit?

13. Adequate and Well ControlledCFR 21CFR 314.126 (b) • The study uses a design that permits a valid comparison with a control to provide a quantitative assessment of drug effect… • The method of selection of subjects provides adequate assurance that they have the disease or condition being studied… • The methods of assessment of subjects’ response are well-defined and reliable…

14. Regulatory History of VSLI Pre-IND (June, 1999) • Response duration • FDA advised sponsor for the need for a confirmatory trial EOP 2 (April, 2000) • FDA emphasized the endpoint of durable CR

15. Confirmatory Studies • March 2003 ODAC • The FDA expects that confirmatory studies to demonstrate that treatment with the drug is associated with clinical benefit will usually be underway at the time of accelerated approval, though that is not a specific requirement.

16. Study CA99002 • Multi-center, open-label, single-arm Phase 2 study • Primary endpoint: Response Rate (CR, CRu, PR) • Enrolled 119 patients • VSLI 2.0 mg/m2 IV over 1 hour every 2 weeks

17. Eligibility • Relapsed, aggressive NHL • Received 2 or more prior combination chemotherapies, including 1 prior anthracycline-based therapy

18. Histologies Aggressive de novo and transformed lymphomas • Diffuse large B-cell • Intravascular large B-cell • Immunoblastic B-cell • Anaplastic large B-cell • Peripheral T-cell • Anaplastic large null-/T-cell

19. Central Pathology Review Final Histologic Diagnosis

20. Reasons For Exclusion from FDA Efficacy Analysis

21. Study Conduct

22. FDA Analysis Efficacy 72 (61%) patients met critical eligibility criteria • had relapsed, aggressive NHL • received 2 or more prior combination chemotherapies, including 1 prior anthracycline-based therapy • had required baseline scans and bone marrow biopsies

23. International Workshop Response Criteria • 4 categories: CR, CRu, PR, Relapse/Progression • Normal lymph node size based on abnormal nodes at diagnosis • > 1 cm lymph node compatible with involvement by NHL • Do not require response confirmation

24. Sponsor Modifications • Normal lymph node size and nodal mass size defined as 1.5 cm • Indicator lesions to have a minimum size of 2 cm in at least one dimension • FDA analysis used the sponsor modifications

25. Response Assessment • Amendment (Version 3.0, Dec 1999): “Response must be confirmed by repeat assessment (including CT scans) 8 weeks after the first documentation of response” • Amendment (Version 9.0, Aug, 2001): “Response should be confirmed by repeat assessment (including CT scans) 4 weeks following the first documentation of response”

26. Response Rate • Sponsor’s Analysis Response Rate Tumor size reduction documented on at least 1 occasion • FDA Analysis Response Rate Confirmed Response Rate Tumor size reduction confirmed at least 4 weeks later

27. Response Rate(documented on 1 occasion)

28. Confirmed Response Rate

29. Duration of Response (days)

30. Duration of Response • Reasons for treatment cessation in censored patients included: - Neuropathy (7) - Unknown reason (1) - Relapse (3) - Withdrew consent (1) - Went to BMT (2) - Thrombocytopenia (1) - Completed study (5) • 13/30 (43%) responders did not have repeat scans/PE or progressed before a repeat scan • 9 (30%) patients discontinued within 30 days of initial response

31. Safety • Median completed therapy: 4 cycles • Dose intensity: 96.4% planned • 70% dose delays: neuropathy and hematologic toxicity • Dose reduction: neuropathy • Dose reduced by 0.24 mg/m2 (13%)

32. Safety

33. Study DM97-162 • Submitted as supportive evidence • Single-center, open-label, single-arm study in patients with relapsed lymphoma and acute lymphoblastic leukemia • Primary endpoint: response rate • Enrolled 132 patients • Patients with NHL 116, 97 with aggressive lymphoma

34. Study DM97-162 • No independent review of Pathology or Radiology • CTs reviewed retrospectively • Incomplete documentation of bidimensional measurements • Case Report Forms were not used prospectively • Standardized response criteria for NHL not used • Use of this study for support is questionable

35. Study DM97-162 • Response rate in the aggressive NHL population reported as 29% (95% CI [22.2, 42]) • No duration of response assessed

36. Summary • Multicenter, single-arm Phase 2 trial in relapsed, aggressive NHL for AA based on response rate • FDA found 72 (61%) patients evaluable based on: -histologically eligible by Central Pathology Review -no major protocol violations -had complete baseline data to be eligible for assessment of response rate

37. Summary of FDA Analysis • Response Rate (documented on at least 1 occasion) (CR + CRu + PR) ORR 20. 8% CR 1.4% • Confirmed Response Rate ORR 15.3% CR 0 %

38. Summary • Study conduct raises doubts regarding method of assessment of response • Duration was short and not adequately evaluated • Supportive study questionable for support • No confirmatory trial underway

39. Issues for ODAC • Available therapies for relapsed, aggressive NHL? • Relevant primary endpoint for aggressive NHL? • PR and duration of response as predictor of clinical benefit? • Advantage of VSLI over available therapy as required for AA?

40. Medical Maitreyee Hazarika, MD Mary Andrich, MD Ann Farrell, MD Biopharm Gene Williams, PhD Brian Booth, PhD Pharm/Tox Doo Lee Ham, PhD David Morse, PhD Statistics Shenghui Tang, PhD Rajeshwari Sridhara, PhD CMC Xiao Chen, PhD Nallaperum Chidambaram, PhD PM Sheila Ryan NDA 21600 Review Team