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  • 1. NDA 21-600 Marqibo  (Vincristine Sulfate Liposomes Injection) Treatment of patients with aggressive non-Hodgkin’s lymphoma previously treated with at least two combination chemotherapy regimens
  • 2. External Consultants Fernando Cabanillas, MD Clinician and Clinical Professor of Medicine Presenter MD Anderson Cancer Center Medical Director Auxilio Mutuo Cancer Center Jane Winter, MD Clinician Professor of Medicine 2 nd largest site Department of Hematology/Oncology Northwestern University
  • 3. External Consultants (Continued) Randy Gascoyne, MD Lymphoma Pathologist and Clinical Professor Pathologist British Columbia Cancer Agency Scott Gazelle, MD, MPH, Ph.D Radiologist, Associate Professor Independent Review Massachusetts General Hospital Panel Sandra Chica, MD Radiologist Medical Director - Radiologist Perceptive Informatics, Inc. (Parexel)
  • 4. External Consultants (Continued) Shayne Gad, Ph.D, DABT, AST Toxicologist Gad Consulting Services Jean-Marie Houle, Ph.D Pharmacokineticist Houlemiron BC Enterprises Inc. Louis Gura, MS Statistician Three Flags Consulting
  • 5. Unmet Medical Need in Aggressive NHL Fernando Cabanillas, MD Clinical Professor of Medicine MD Anderson Cancer Center Medical Director Auxilio Mutuo Cancer Center
  • 6. Overview of NHL
    • NHLs broadly classified as aggressive vs. indolent
    • Aggressive NHL
      • 35-40% of NHL
      • Diffuse large B-cell lymphoma, peripheral T-cell lymphoma
        • DLBCL frequently presents with divergent histologies
          • Treatment is driven by the most aggressive histology
          • Response is measured the same way
      • At relapse, life expectancy measured in months
    • Indolent NHL
      • At relapse, life expectancy measured in years
    • No new agents approved for aggressive NHL in last 17 years
  • 7. Overview of Aggressive NHL
    • First-line therapy
      • R-CHOP therapy cures  50% of aggressive B-cell NHL
    • Second-line therapy
      • If <65 years, 20% cured with high dose chemo and ASCT ( only if response to salvage therapy )
      • If  65 years or if ASCT not feasible,  10% curable
        • Median survival 6 months
    • Response rates and duration drop with each relapse
  • 8. Overview of Aggressive NHL (Continued)
    • Third-line or later therapy (indicated population)
      • 10,000 – 15,000 patient prevalence in 2001
      • No standard therapy
      • Bone marrow frequently compromised, thus fewer options
      • Reduction in tumor burden associated with symptom improvement
      • Results are dismal, complete responses are rarely achieved and survival is short
  • 9. Survival After MIME as 3rd Line or Later Therapy for Aggressive NHL Survival Time (mos.) 0 5 10 15 20 25 30 35 40 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative Proportion Surviving By 12 months, 75% are dead By 2 years, 96% are dead n =72 Median = 6 months
  • 10. FDA Single Agent Papers Not Adequate for Comparison to VSLI
  • 11. FDA Papers for Comparison to VSLI
  • 12. Single Agent Rituximab in Aggressive NHL
  • 13. Combination Regimens as 3 rd Line or Later Therapy
  • 14. Unmet Clinical Needs
    • Patients who don’t qualify for aggressive combination regimens or who have relapsed after ASCT
      • Poor marrow function
      • Age >65
      • Poor performance status
      • No response to pre-transplant salvage therapy
      • Co-morbidities
    • Patients with compromised marrow function
      • Rituximab no longer a viable alternative
    • No compelling literature evidence for “available therapy” after 2 nd relapse
    • Need an agent that can provide clinically meaningful benefit without excessive toxicity
  • 15. Pharmacology Presentation Tom Madden, Ph.D Senior Director, Technology Development and Licensing Inex Pharmaceuticals Corporation
  • 16. Vincristine Sulfate Liposomes Injection (VSLI)
    • Active agent: vincristine sulfate
    • Liposome composition: sphingomyelin/cholesterol
    • Liposome size: 115 nm, contains approximately 10,000 drug molecules/vesicle
    Aqueous core with vincristine Liposomal bilayer
  • 17. VSLI: Product Rationale
    • VSLI Increases Tumor Exposure to Vincristine
    • Higher vincristine tumor levels due to preferential delivery
    • Longer duration of exposure due to slow vincristine release
  • 18. VSLI Accumulates in Tumor Tissue by Extravasation Across Tumor Vasculature Tumor tissue demonstrating accumulation of VSLI in interstitial space Normal tissue showing VSLI in blood vessels with no evidence of extravasation
  • 19. Vincristine Activity is Dependent on Duration of Exposure Reproduced from Jackson and Bender, Cancer Res. 39: 4346-9, 1979. Duration of Exposure (hr) Viable Cells
  • 20. Vincristine is Slowly Released from VSLI in Vivo (Rat Plasma) VSLI provides prolonged exposure to vincristine
  • 21. Antitumor Activity of VSLI Is Significantly Greater Than VCR in the Namalwa Lymphoma Xenograft Model
  • 22. P- Plasma Vincristine Concentration-time Profiles for VSLI and VCR in Patients
  • 23. VSLI Nonclinical Summary
    • Compared to conventional vincristine
      • VSLI provides increased tumor exposure
      • VSLI provides increased antitumor activity in nonclinical studies
      • VSLI elicits the same toxicities
  • 24. Clinical Efficacy and Safety Alexandra Mancini, MSc. Senior Vice President, Clinical and Regulatory Affairs Inex Pharmaceuticals Corporation
  • 25. Efficacy Trials in Relapsed Aggressive NHL
    • Supportive Phase IIa Study (DM97-162)
      • NHL or ALL
      • Investigator-sponsored at MD Anderson Cancer Center
      • 92 patients with relapsed aggressive NHL
    • Primary Phase IIb Study (CA99002)
      • International multicenter: 42 sites enrolled
      • 119 patients enrolled
    • Two largest trials in multiply relapsed aggressive NHL
    • Similar study designs and response criteria
    • Consistent results in 211 patients
  • 26. Randomized Controlled Trial
    • Post-approval commitment to confirm clinical benefit
      • 3 meetings and SPA comments from FDA
      • Revised protocol to be resubmitted shortly
      • Study to start in first half 2005
  • 27. Study Conduct Issues Raised by FDA
  • 28. Study Conduct Issues Raised by FDA
    • Low Number of Eligible Patients
    • Numerous protocol amendments and exemptions
    • Low histologic eligibility rate
    • Incomplete staging in 19% of patients
    • Conduct of Independent Review Panel (IRP)
    • Wording of response criteria
    • Operations of core imaging lab
    • Amendments to IRP Charter
  • 29. Protocol Amendments
  • 30. Protocol Version 5.0
    • Key Inclusion Criteria
    • Patients with a CR or CRu to 1 st line chemotherapy
    • Patients with at least a PR to most recent therapy
    A poorer prognosis population  7.0  at least a minor response  deleted
  • 31. Other Amendments
    • Version 7.0  8.0
    • Peripheral T-cell lymphoma (1 pt)
    • Anaplastic large null-/T-cell lymphoma (2 pts)
    • Transformed NHL (11 pts)
    • No further changes in eligibility criteria
    • With each amendment FDA agreed that trial population suitable for accelerated approval
    A poorer prognosis population
  • 32. Protocol Amendments
    • Version 8.0 to 9.0
    • Additional CT scans scheduled 4 weeks after first response instead of the original 8 weeks
    • A clarification changed wording that these confirmatory CT scans “should” instead of “must” be obtained
  • 33. Enrollment Exemptions
    • Careful to not allow exemptions that would have enhanced apparent VSLI response rate
    A poorer prognosis population
  • 34. Histologic Eligibility
    • 19% ineligible by retrospective Central Review
      • Mostly indolent lymphomas
    • FDA excluded additional 7 patients described as ‘probably eligible’ by Central Review
    • Not protocol violations or due to amendments
      • Site pathology defined them as eligible for enrollment
  • 35. Histologic Eligibility by Central Pathology Review (ITT)
  • 36. Other FDA Eligibility Exclusions
    • Stage of disease was not an eligibility criterion
     0  0  0  1
  • 37. Response Criteria Wording
    • In some situations the criteria are ambiguous or silent
    • These clarifications were undertaken to uphold the rigor of the criteria
    • To ensure consistent interpretation in this multicenter study
  • 38. Response Criteria Wording
    • April 3, 2000 Meeting with FDA
    • Protocol Version 5.0 with clarified response criteria wording
    • FDA agreed with the protocol wording
    • No changes to response criteria since that meeting
  • 39. Operations of Core Imaging Lab
    • FDA review noted that procedures manual was dated 1 year after review of images began
    • Earlier version in place before reviews began
    • No changes to core lab procedures for entire IRP process
  • 40. Amendments to IRP Charter
    • No changes to conduct of IRP radiology and oncology reviews
    • Amendments in place before reviews began
    • A few clarifications for situations not previously anticipated requested by Dr. Scott Gazelle
      • Amendments documented what was done
    • All images read in chronologic sequence and locked
  • 41. Conclusions Regarding Study Conduct Issues
    • Protocol amendments and exemptions defined a population with a poorer prognosis
    • Histologic eligibility comparable to literature rates
    • Only 9 patients (8%) ineligible for efficacy evaluation due to protocol violations
    • IRP process was well conducted
    • Well defined and reliable assessment of objective response in the indicated population
    • Adequate and well-controlled trial
  • 42. Pivotal Study Presentation
  • 43. Key Eligibility Criteria
    • Aggressive de novo or transformed NHL
    • At least 2 prior combination regimens including an anthracycline
    • At least a minor response to 1 st line therapy
  • 44. Key Eligibility Criteria (Continued)
    • No maximum number of prior regimens
    • No requirement of response to prior salvage therapies
    • No upper limit on age
    • ECOG PS 0-3 accepted
    • Grade 1-2 neuropathy permitted
    • Granulocytes   0.5 x 10 9 /L
    • Platelets  50 x 10 9 /L
  • 45. VSLI Monotherapy Regimen
    • 2 mg/m 2 without dose capping , 1hr IV infusion
    • Repeat every 2 weeks
    • 12 cycles maximum, 2 cycles after CR
    •  At least 2x dose intensity of vincristine
    • 2 mg/m 2 without dose capping, 1hr IV infusion
    • Repeat every 2 weeks
    • 12 cycles maximum, 2 cycles after CR
  • 46. Efficacy Endpoints and Populations
    • Efficacy Endpoints
    • Primary
      • Objective response rate (CR + CRu + PR)
    • Secondary
      • Duration of response
      • Time to progression
      • Overall survival
    • Efficacy Populations
    • Intent-to-Treat Population (ITT) (n=119)
    • Per-Protocol Population (PP) (n=77)
  • 47. Efficacy Evaluations
    • International Workshop Criteria (Cheson et al 1999)
      • CTs of chest, abdomen, pelvis
      • 6 indicator lesions
      • Response does not require confirmation
    • Independent Review Panel (IRP)
      • Primary efficacy assessment
      • Blinded to site opinion of response
      • Independent selection of indicator lesions
  • 48. Patient Population
  • 49. Extent of Prior Therapy (ITT)
    • Mean: 3.8; Median: 3
    • 33% had prior ASCT
    • Predominantly at 4 th -5 th line
  • 50. Response to Prior Therapy
    • 75% received a combination regimen as last therapy
  • 51. Sensitivity to Last Qualifying Therapy (ITT)
  • 52. Efficacy Data (ITT)
  • 53. Objective Response Rate (ITT) by IRP
  • 54. Objective Response Rate Comparisons
  • 55. Is Objective Response Likely to Predict Clinical Benefit?
  • 56.
    • 8 patients with CR or CRu
      • 3 patients asymptomatic
      • Remaining 5 patients either had resolution of symptoms or improved ECOG PS
    • 22 patients with PR
      • 15 had improvements in symptoms or ECOG PS
    Symptom Improvement in Responders
  • 57. Time-to-Event Endpoints
  • 58. Duration of Response
  • 59. Time to Progression (ITT) by IRP
  • 60. Survival (ITT) 119 68 47 41 35 26 15 5 0 Patients at Risk    Censored Observations Median 6.7 months 25% alive at 2 years
  • 61. Subgroup Analyses
  • 62. ORR by Number of Prior Regimens and Sensitivity to Last Qualifying Regimen
  • 63. Consistent Results in Both Studies (n=211)
  • 64. Univariate Analyses Objective Response Rate
  • 65. VSLI Efficacy Compared to Single-Agent Rituximab
  • 66. Objective Tumor Response by IRP Single-Agent Rituximab as Last Therapy
  • 67. Safety Data
  • 68. Extent of Treatment with VSLI (ITT)
  • 69. Safety – Major Endpoints
    • 14% of patients withdrawn due to associated AEs, mostly neuropathy
    • No treatment-associated deaths
  • 70. Neuropathy
  • 71. Prior Neurotoxic Therapies (ITT)
  • 72. Worst Neuropathy on Study by Grade at Study Entry (Pain, Paresthesia, Numbness, Weakness, Constipation)
  • 73. Mean Change from Baseline for Cycles 1 to 6 for Hand Numbness
  • 74. Dose to Grade 3 or 4 Neuropathy (Pain, Paresthesia, Numbness, Weakness, Constipation)
    • Equivalent to 15 doses of conventional vincristine
  • 75. Comparison of Neuropathy in Responders vs. Nonresponders (Numbness)
  • 76. Timing of Antitumor Effect vs. Neuropathy
    • Antitumor activity evident early in patients who responded, usually within 2 weeks (1 st dose)
      • Symptomatic improvements
      • Reduced palpable adenopathy
      • Decreased LDH
    • Development of neuropathy is gradual and predictable
    • Informed treatment decisions can be made before significant neuropathy develops
  • 77. Hematologic Abnormalities
  • 78. Hematologic Abnormalities at Study Entry
  • 79. Hematology CTC Grade Changes from Baseline to Worst Grade
  • 80. Hematologic Toxicity
    • Neutropenia
    • 8% Grade 4 neutropenia (<0.5 ANC)
    • 3% febrile neutropenia
    • 2% prophylactic filgrastim usage
    • Thrombocytopenia
    • 1% Grade 4 thrombocytopenia (<10x10 9 /L)
    • 6% platelet transfusions
  • 81. Patients with Net Clinical Benefit Fernando Cabanillas, MD Clinical Professor of Medicine MD Anderson Cancer Center Medical Director Auxilio Mutuo Cancer Center
  • 82. Patient Benefit Summaries
    • FDA requested patient benefit summaries to facilitate review for clinical benefit
    • 38 patients considered to be responders by either IRP or Investigator
    • 5 patients with SD (minor response) had evidence of clinical benefit
    • Total of 43 individual patient benefit-risk assessments
  • 83. 41 Patients Had Evidence of Net Clinical Benefit
    • Improvement in symptoms or ECOG PS
    • Tumor response to VSLI that permitted stem cell transplant
    • Durable complete response
    • Durable PR or prolonged SD
    • Better response than with prior regimen
    • Improvement in laboratory parameters
    In case studies
  • 84. Clinical Benefit: Symptomatic and ECOG PS Improvements
  • 85. Clinical Benefit: Stem Cell Transplant
    • 6 patients were able to receive transplants after VSLI study, 5 allogeneic, 1 autologous
    • Responsiveness to VSLI therapy and maintenance of good performance status enabled consideration for transplant
    • 5 patients alive (1 died at 29 months)
      • 1 with disease (survival of 28 + months)
      • 4 with no evidence of disease (27 + , 29 + , 31 + , 39 + months)
  • 86. Case Studies of Selected Patients with Clinical Benefit
  • 87. Patient 35-01
    • 56 y/o F, Stage IV-B, IPI=1
    • Primary mediastinal DLCL, weight loss, fever, night sweats, anemia
    • Prior Rx: 1) CHOP  PR for 3 months; 2) ESHAP  PD; 3) RICE  PD
    • 20 cycles VSLI/38 weeks  CRu of ~ 1 yr
    • Transient Grade 4 neutropenia at Cycle 5
    • Attained CRu after being refractory to all prior Rx; resolution of B symptoms and anemia
  • 88. Patient 40-01
    • 76 y/o F, DLCL-B, IPI=3
    • Multiple pulmonary metastases
    • Low platelets (72k)
    • Prior Rx: 1) CHOP  CR; 2) CTX-VP16-DTIC-Rituxan-Pred  CR
    • 8 cycles VSLI/14 weeks  PR 8 + mos, platelets normalized
    • No Grade 3-4 toxicities
    • Residual pulmonary nodules not changed @ 2.5 years (fibrotic tissue?)
    • Chemo-free interval of 27 + mos, a longer remission than with any prior therapies
  • 89. Patient 33-06
    • 47 y/o M, Stage IV-B, DLCL-B, IPI=1
    • Mediastinal mass and marrow involvement
    • Prior Rx: 1) CHOP  MR; 2) RICE  PD
    • 8 cycles VSLI/14 weeks  PR 9 + mos (IRP); CR 14 + mos (INV)
    • No Grade 3-4 toxicities
    • Alive with no evidence of disease at 30 + mos, with no subsequent therapies
    • Attained CR after being refractory to all prior Rx; resolution of B symptoms and anemia
  • 90. Benefit-Risk Conclusions
  • 91. Summary of Patient Population
    • Median 3 prior regimens  4 th -5 th line therapy
    • 33% had prior ASCT
    • 33% with low blood counts
    • 50% refractory to last therapy
    • 24% >70 years
    • 66% with elevated LDH
  • 92. Summary of VSLI Benefits
    • 25% ORR in heavily pretreated patients with highly resistant disease and compromised marrow
      • 46% ORR in those treated on 2 nd relapse
    • Clinically important ORR for this population
    • 22% of patients with symptomatic or ECOG PS improvement
    • Median duration of response of  3 months,  4 months for time to progression for a population with a median survival of  7 months
  • 93. Summary of Risks
    • Neuropathy is dose-limiting toxicity
      • Gradual cumulative development
      • Only 13% withdrew for neuropathy
    • Well tolerated compared to other agents
      • Low incidence of severe myelotoxicity and hospitalizations
      • Low incidence of severe nausea and vomiting or alopecia
  • 94. Favorable Benefit-Risk Profile
    • Symptomatic improvement and antitumor activity evident early, allowing informed treatment decisions before significant neuropathy develops
    • Favorable benefit-risk profile for this population with no standard treatment options
  • 95. Why Do We Need VSLI?
    • Effective and well-tolerated agent for
      • Patients at 3 rd line or later
      • Patients who don’t qualify for aggressive combination regimens or who have relapsed after ASCT
      • Patients with compromised marrow function
    • Benefits 1 in 4 patients with minimal toxicity