Vincristine Sulfate Liposome Injection (Marqibo

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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
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Indication

• Treatment of patients with aggressive
• Non-Hodgkins Lymphoma (NHL)
• previously treated with at least two
• combination chemotherapy regimens

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Outline

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

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Regulatory Issues

• Accelerated Approval
• Available Therapy
• Endpoints
• Adequate and well controlled trials
• Confirmatory Trial

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Accelerated Approval

• If a drug appears to provide a benefit over
  available therapy
• and
• the benefit is determined by the drugs effect on
  a surrogate endpoint deemed reasonably likely to
  predict clinical benefit

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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

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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

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Approved Therapies for NHL1957-1988

• Methotrexate
• Cyclophosphamide
• Vincristine
• Vinblastine

• Bleomycin
• Carmustine
• Adriamycin

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Approved Therapies for Follicular NHL

• Rituximab (Rituxan)
• Ibritumomab tiuxetan (Zevalin)
• I-131 tositumomab (Bexxar)
• Interferon alfa-2b (Intron)

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Combinations Reported for Relapsed Aggressive NHL
Combination ORR () CR ()
Ifosfamide, carboplatin, etoposide (ICE) 59 18
Rituxan ICE 77 53
EPOCH 87 27
Rituxan EPOCH 68 28
Dexamethasone cytarabine cisplatin (DHAP) 67 23
Cytarabine Etoposide 66 33
ESHAP 53 20
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Single Agents Reported for Relapsed Aggressive NHL
Single Agents Evaluable patients ORR () CR ()
Etoposide 20 69 13
Gemcitabine 30 66 33
Methotrexate 25 52 21
Rituxan 57 37 26
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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?

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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

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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

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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.

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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

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Eligibility

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

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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

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Central Pathology Review Final Histologic
Diagnosis
Histology N119
Definite Eligible 89 74.8
Probable Eligible 7 5.8
Ineligible 21 17.6
Missing 2 1.7
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Reasons For Exclusion from FDA Efficacy Analysis
Inclusion or Exclusion Criteria Patients N119 ()
Not definitely eligible by Central Pathology Review 30 (25)
No measurable disease 8 (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 gt 8 weeks prior 12 (10)
Total Ineligible 47 (40)
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Study Conduct
Issues Patients N119 ()
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 examination 13 (11)
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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

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International Workshop Response Criteria

• 4 categories CR, CRu, PR, Relapse/Progression
• Normal lymph node size based on abnormal nodes at
  diagnosis
• gt 1 cm lymph node compatible with involvement by
  NHL
• Do not require response confirmation

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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

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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

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Response Rate

• Sponsors 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

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Response Rate(documented on 1 occasion)
IRP Response Sponsors Analysis (ITT) N119 () FDA Analysis (evaluable) N72 ()
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
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Confirmed Response Rate
IRP Response FDA Analysis (evaluable) N72 () 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
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Duration of Response (days)
Sponsor IRP Review N30 () FDA Review (confirmed) N11 ()
Patients relapsed/progressed 10 (33.3) 7 (63.7)
Patients censored 20 (66.7) 4 (36.3)
Median duration response (days) (K-M estimate) gt85 85
95 CI 72.0,- 57.0,-
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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

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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)

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Safety
Adverse Event Grade 3/4 Toxicity N119 ()
Peripheral Neuropathy 71 (60)
Neutropenia 26 (22)
Anemia 15 (13)
Thrombocytopenia 12 (10)
Fatigue 8 (7)
Constipation 6 (5)
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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

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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

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Study DM97-162

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

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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

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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

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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

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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?

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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

• Statistics
• Shenghui Tang, PhD
• Rajeshwari Sridhara, PhD
• CMC
• Xiao Chen, PhD
• Nallaperum Chidambaram, PhD
• PM
• Sheila Ryan