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

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

3. OutlineOutline Regulatory Issues Study CA99002 Efficacy Safety Study DM97-162 Summary Issues for ODAC 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 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 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 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 Therapy Exceptions “…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 “…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. Approved Therapies for NHL 1957-1988 Methotrexate Cyclophosphamide Vincristine Vinblastine Methotrexate Cyclophosphamide Vincristine Vinblastine Bleomycin Carmustine Adriamycin

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

10. Combinations Reported for Relapsed Aggressive NHL CombinationORR (%)CR (%) Ifosfamide, carboplatin, etoposide (ICE)5918 Rituxan + ICE7753 EPOCH8727 Rituxan + EPOCH6828 Dexamethasone + cytarabine + cisplatin (DHAP) 6723 Cytarabine + Etoposide6633 ESHAP5320

11. Single Agents Reported for Relapsed Aggressive NHL Single AgentsEvaluable patients ORR (%)CR (%) Etoposide206913 Gemcitabine306633 Methotrexate255221 Rituxan573726

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? 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 Controlled CFR 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… 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 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. 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/m 2 IV over 1 hour every 2 weeks Multi-center, open-label, single-arm Phase 2 study Primary endpoint: Response Rate (CR, CRu, PR) Enrolled 119 patients VSLI 2.0 mg/m 2 IV over 1 hour every 2 weeks

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

18. HistologiesHistologies 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 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 HistologyN=119% Definite Eligible8974.8 Probable Eligible75.8 Ineligible2117.6 Missing21.7

20. Reasons For Exclusion from FDA Efficacy Analysis Inclusion or Exclusion CriteriaPatients N=119 (%) Not definitely eligible by Central Pathology Review30 (25) No measurable disease8 (7) Less than 2 or more prior courses of combination chemotherapy since transformation 5 (4) Radiotherapy, chemotherapy, immunotherapy or steroids within the past 4 weeks 2 (2) Incomplete baseline staging Missing CT scans or Bone Marrow biopsy or marrows done > 8 weeks prior 12 (10) Total Ineligible47 (40)

21. Study Conduct IssuesPatients N=119 (%) Bone marrow biopsy done 3- 8 weeks prior to entry 14 (12) Full set of chest, abdominal and pelvic scans not performed at 1 or more visits 12 (10) CT scans not performed during study to track disease or later than 8 weeks as per the protocol 5 (4) Baseline neurological examination13 (11)

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 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 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 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” 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 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) IRP ResponseSponsor’s Analysis (ITT) N=119 (%) FDA Analysis (evaluable) N=72 (%) Complete Response (CR)4 (3.4)1 (1.4) Complete Response unconfirmed (CRu) 4 (3.4)3 (4.2) Partial Response (PR)22 (18.5)11 (15.3) Response Rate (ORR) 95% CI 30 (25.2) [17.7, 34] 15 (20.8) [12.2, 32]

28. Confirmed Response Rate IRP ResponseFDA Analysis (evaluable) N=72 (%) 95% CI Complete response (CR) 0 (0)[0,5] Complete Response unconfirmed (CRu) 2 (2.8)[0.3, 9.7] Partial Response (PR)9 (12.5)[5.9, 22.4] Response Rate (ORR)11 (15.3)[7.9, 25.7]

29. Duration of Response (days) Sponsor IRP Review N=30 (%) FDA Review (confirmed) N=11 (%) Patients relapsed/progressed 10 (33.3)7 (63.7) Patients censored20 (66.7)4 (36.3) Median duration response (days) (K-M estimate) >8585 95% CI[72.0,-][57.0,-]

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 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. SafetySafety 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/m 2 (13%) 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/m 2 (13%)

32. SafetySafety Adverse EventGrade 3/4 Toxicity N=119 (%) Peripheral Neuropathy71 (60) Neutropenia26 (22) Anemia15 (13) Thrombocytopenia12 (10) Fatigue8 (7) Constipation6 (5)

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 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 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 Response rate in the aggressive NHL population reported as 29% (95% CI [22.2, 42]) No duration of response assessed

36. SummarySummary 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 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 % 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. SummarySummary 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 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 1.Available therapies for relapsed, aggressive NHL? 2.Relevant primary endpoint for aggressive NHL? 3.PR and duration of response as predictor of clinical benefit? 4.Advantage of VSLI over available therapy as required for AA? 1.Available therapies for relapsed, aggressive NHL? 2.Relevant primary endpoint for aggressive NHL? 3.PR and duration of response as predictor of clinical benefit? 4.Advantage of VSLI over available therapy as required for AA?

40. NDA 21600 Review Team 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 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