NDA 21-600

643 views

Published on

  • Be the first to comment

  • Be the first to like this

NDA 21-600

  1. 1. P-1 NDA 21-600NDA 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. 2. P-2 External ConsultantsExternal 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 2nd largest site Department of Hematology/Oncology Northwestern University
  3. 3. P-3 External ConsultantsExternal Consultants (Continued)(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. 4. P-4 External ConsultantsExternal Consultants (Continued)(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. 5. P-5 Unmet Medical Need in Aggressive NHLUnmet Medical Need in Aggressive NHL Fernando Cabanillas, MD Clinical Professor of Medicine MD Anderson Cancer Center Medical Director Auxilio Mutuo Cancer Center
  6. 6. P-6 Overview of NHLOverview 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. 7. P-7 Overview of Aggressive NHLOverview 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. 8. P-8 Overview of Aggressive NHLOverview of Aggressive NHL (Continued)(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. 9. P-9 Survival After MIME as 3rd LineSurvival After MIME as 3rd Line or Later Therapy for Aggressive NHLor 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 CumulativeProportionSurviving By 12 months, 75% are dead By 2 years, 96% are dead n =72 Median = 6 months
  10. 10. P-10 FDA Single Agent PapersFDA Single Agent Papers Not Adequate for Comparison to VSLINot Adequate for Comparison to VSLI Regimen/Authors ORR Histologically Relevant n ≤10 Pts No ORR for Aggressive NHL a # Prior Therapies Not Comparable b II-2 (Lauria, n=2) 50% 2 X X Gemcitabine (Bernell, n=3) 66% 3 X Oxaliplatin (Germann, n=22) 40% 3 X Oral Etoposide (Shaklai, n=20) 69% 6 X Bortezomib (Goy, n=45) 20% 9 X X Oxaliplatin (Younes, n=25) 24% 13 X Cytarabine c (Peters, n=59) 64% 22 X Methotrexate (Canellos, n=25) 52% 25 X Idarubicin (Case, n=31) 43% 31 X a ORR includes ineligible histologies, e.g., indolent and mantle cell. b Median number of priors <2 or ORR not analyzed for patients with ≥2 regimens. c All patients treated with combination therapy.
  11. 11. P-11 FDA Papers for Comparison to VSLIFDA Papers for Comparison to VSLI Histologically Eligible Patients ≤10 No ORR for Aggressive NHLa Prior Therapies Not Comparableb Total Comparable Papers Single agent papers (11) 5 1 5 2 Combination therapy papers (35) 2 9 27 5 a ORR includes ineligible histologies, e.g., indolent and mantle cell. b Median number of priors <2 or ORR not analyzed for patients with ≥2 regimens.
  12. 12. P-12 Single Agent Rituximab in Aggressive NHLSingle Agent Rituximab in Aggressive NHL Parameter Rothe (n=21) Tobinai Histologic Subgroup (n=50) Coiffier Histologic Subgroup (n=30) Median prior regimens 2 (38% 1st relapse) 2 a (32% 1st relapse) 2 a (17% untreated, 31% 1st relapse) CR+PR (%) 38 34 37 CR (%) 5 — — TTP (mos) 3.8 2.0 a >3.5 a a Median for entire study, not for subgroup.
  13. 13. P-13 Combination Regimens as 3Combination Regimens as 3rdrd LineLine or Later Therapyor Later Therapy Publication Median # of Priors ORR CR IIVP-16 (Engert, n=38) 2 47 21 FLUDAP (Child, n=33) 2 39 15 CEPP(B) (Chao, n=20) 2 45 15 DHAP (Press, n=26) 3 65 — Ifosfamide, hydroxyurea and etoposide (Gasser, n=19) 3 53 5
  14. 14. P-14 Unmet Clinical NeedsUnmet 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 2nd relapse  Need an agent that can provide clinically meaningful benefit without excessive toxicity
  15. 15. P-15 Pharmacology PresentationPharmacology Presentation Tom Madden, Ph.D Senior Director, Technology Development and Licensing Inex Pharmaceuticals Corporation
  16. 16. P-16 Vincristine Sulfate Liposomes InjectionVincristine Sulfate Liposomes Injection (VSLI)(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. 17. P-17 VSLI: Product RationaleVSLI: 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. 18. P-18 VSLI Accumulates in Tumor Tissue byVSLI Accumulates in Tumor Tissue by Extravasation Across Tumor VasculatureExtravasation 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. 19. P-19 Vincristine Activity is Dependent onVincristine Activity is Dependent on Duration of ExposureDuration of Exposure Duration of Exposure (hr) ViableCells Reproduced from Jackson and Bender, Cancer Res. 39: 4346-9, 1979.
  20. 20. P-20 Vincristine is Slowly Released from VSLIVincristine is Slowly Released from VSLI in Vivo (Rat Plasma)in Vivo (Rat Plasma) 0 20 40 60 80 100 0 20 40 60 80 Time (h) ReleasedVincristine(%) VSLI provides prolonged exposure to vincristine
  21. 21. P-21 Antitumor Activity of VSLI Is SignificantlyAntitumor Activity of VSLI Is Significantly Greater Than VCR in the Namalwa LymphomaGreater Than VCR in the Namalwa Lymphoma Xenograft ModelXenograft Model Day Post-Implantation 0 10 20 30 40 50 MeanTumorVolume(mm3) 0 500 1000 1500 VSLI (4.5 mg/m2) VCR (4.5 mg/m2) PBS Control
  22. 22. P-22 Plasma Vincristine Concentration-timePlasma Vincristine Concentration-time Profiles for VSLI and VCR in PatientsProfiles for VSLI and VCR in Patients 0.1 1 10 100 1000 10000 0 10 20 30 40 50 Time (h) TotalVincristineConcentration(ng/mL) VSLI (2.0 mg/m2, n=26) VCR (1.2 mg/m2, n=4, Nelson 1982)
  23. 23. P-23 VSLI Nonclinical SummaryVSLI 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. 24. P-24 Clinical Efficacy and SafetyClinical Efficacy and Safety Alexandra Mancini, MSc. Senior Vice President, Clinical and Regulatory Affairs Inex Pharmaceuticals Corporation
  25. 25. P-25 Efficacy Trials in RelapsedEfficacy Trials in Relapsed Aggressive NHLAggressive 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. 26. P-26 Randomized Controlled TrialRandomized 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. 27. P-27 Study Conduct Issues Raised by FDA
  28. 28. P-28 Study Conduct Issues Raised by FDAStudy 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. 29. P-29 Protocol AmendmentsProtocol Amendments Protocol Version Number of Patients Enrolled 5.0 7 6.0 8 7.0 9 8.0 54 9.0 41
  30. 30. P-30 Protocol Version 5.0Protocol Version 5.0 Key Inclusion Criteria Patients with a CR or CRu to 1st line chemotherapy Patients with at least a PR to most recent therapy A poorer prognosis population →→ 7.07.0 → at least a minor response → deleted
  31. 31. P-31 Other AmendmentsOther 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. 32. P-32 Protocol AmendmentsProtocol 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. 33. P-33 Enrollment ExemptionsEnrollment Exemptions Careful to not allow exemptions that would have enhanced apparent VSLI response rate A poorer prognosis population
  34. 34. P-34 Histologic EligibilityHistologic 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. 35. P-35 Histologic Eligibility by CentralHistologic Eligibility by Central Pathology Review (ITT)Pathology Review (ITT) Histologic Eligibility SWOG 8516 (n=1128) a 79% SWOG 9240 (n=112) a 81% Coiffier (2002) (n=399) a 86% SWOG 9125 (n=100) a 90% VSLI Phase IIb (n=119) 81% a Newly diagnosed patients
  36. 36. P-36 Other FDA Eligibility ExclusionsOther FDA Eligibility Exclusions Number of Patients CTs incomplete at study entry 3 Bone marrow biopsies >8 weeks before study or not done 9 Missing LDH at study entry 1 Missing neuro exams at study entry 13 Stage of disease was not an eligibility criterion → 0 → 0 → 0 → 1
  37. 37. P-37 Response Criteria WordingResponse 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. 38. P-38 Response Criteria WordingResponse 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. 39. P-39 Operations of Core Imaging LabOperations 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. 40. P-40 Amendments to IRP CharterAmendments 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. 41. P-41 Conclusions RegardingConclusions Regarding Study Conduct IssuesStudy 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. 42. P-42 Pivotal Study Presentation
  43. 43. P-43 Key Eligibility CriteriaKey Eligibility Criteria Aggressive de novo or transformed NHL At least 2 prior combination regimens including an anthracycline At least a minor response to 1st line therapy
  44. 44. P-44 Key Eligibility CriteriaKey Eligibility Criteria (Continued)(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 109 /L Platelets ≥50 x 109 /L
  45. 45. P-45 2 mg/m2 without dose capping, 1hr IV infusion Repeat every 2 weeks 12 cycles maximum, 2 cycles after CR VSLI Monotherapy RegimenVSLI Monotherapy Regimen 2 mg/m2 without dose capping, 1hr IV infusion Repeat every 2 weeks 12 cycles maximum, 2 cycles after CR → At least 2x dose intensity of vincristine
  46. 46. P-46 Efficacy Endpoints and PopulationsEfficacy 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. 47. P-47 Efficacy EvaluationsEfficacy 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. 48. P-48 Patient Population
  49. 49. P-49 Extent of Prior Therapy (ITT)Extent of Prior Therapy (ITT) 25% 23% 33% 19% 1% 0 5 10 15 20 25 30 35 1 2 3 4 5-10 # of Regimens %ofPatients(n=119) • Mean: 3.8; Median: 3 • 33% had prior ASCT • Predominantly at 4th -5th line
  50. 50. P-50 Response to Prior TherapyResponse to Prior Therapy CR+PR (%) CR (%) Response Duration (mos) First line 92 50 8 Second line 41 20 5 Last line 35 13 5  75% received a combination regimen as last therapy
  51. 51. P-51 Sensitivity to Last Qualifying Therapy (ITT)Sensitivity to Last Qualifying Therapy (ITT) % of Patients (n=119) Resistant 67 • Refractory (no response) 50 • Early relapse (response duration <3 months) 17 Sensitive (response duration ≥3 months) 33
  52. 52. P-52 Efficacy Data (ITT)
  53. 53. P-53 Objective Response Rate (ITT)Objective Response Rate (ITT) by IRPby IRP Best Tumor Response Number (%) of Patients (n=119) Responders (ORR) 30 (25) CR, CRu 8 (7) PR 22 (18) Nonresponders SD 31 (26) PD 32 (27) UE 26 (22)
  54. 54. P-54 Objective Response RateObjective Response Rate ComparisonsComparisons % of Patients Best Response ITT (n=119) Per Protocol (n=77) FDA Eligible (n=65) ORR 25 27 22 [95% CI] [18, 34] [18, 39] [12, 34] CR 3 1 2 CRu 3 4 2 PR 18 22 18 SD 26 29 —
  55. 55. P-55 Is Objective Response Likely to Predict Clinical Benefit?
  56. 56. P-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 RespondersSymptom Improvement in Responders
  57. 57. P-57 Time-to-Event Endpoints
  58. 58. P-58 Duration of ResponseDuration of Response Kaplan-Meier Analysis IRP Review (n=30) FDA Analysis (n=30) Median duration of response (days) >85 a 72 95% CI [72, —] b [37, —] b a Probability of ongoing response 52% at last event of PD. b Upper limit cannot be calculated.
  59. 59. P-59 Time to Progression (ITT)Time to Progression (ITT) by IRPby IRP Kaplan-Meier Analysis ITT (n=119) Responders (n=30) Median TTP (days) 89 >127 a 95% CI [64, 217] [113, —] b a Progression-free probability 45% at last event of PD. b Upper limit cannot be calculated.
  60. 60. P-60 Survival (ITT)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. 61. P-61 Subgroup Analyses
  62. 62. P-62 ORR by Number of Prior Regimens andORR by Number of Prior Regimens and Sensitivity to Last Qualifying RegimenSensitivity to Last Qualifying Regimen ORR (% of Patients) 2 Regimens a (n=24) 46 Sensitive a (n=11) 64 Resistant (n=13) 31 >2 Regimens (n=95) 20 Sensitive (n=28) 32 Resistant (n=67) 15 a Includes one patient (sensitive) who had only one prior regimen and responded to VSLI.
  63. 63. P-63 Consistent Results in Both Studies (n=211)Consistent Results in Both Studies (n=211) ORR (% of Patients) Combined Studies Phase IIb Phase IIa Combined 2 Regimens (n=49) 46 52 49 Sensitive (n=28) 64 65 64 Resistant (n=21) 31 25 29 >2 Regimens (n=161) 20 24 22 Sensitive (n=43) 32 47 37 Resistant (n=118) 15 18 16
  64. 64. P-64 Univariate AnalysesUnivariate Analyses Objective Response RateObjective Response Rate Subgroup ORR (% of Patients) 95% CI Prior ASCT Yes (n=39) 26 [13, 42] No (n=80) 25 [16, 36] Age ≤60 years (n=60) 25 [15, 38] >60 years (n=59) 25 [15, 38] >70 years (n=28) 36 [19, 56]
  65. 65. P-65 VSLI Efficacy Compared toVSLI Efficacy Compared to Single-Agent RituximabSingle-Agent Rituximab Parameter Rothe (n=21) Tobinai Subgroup (n=50) Coiffier Subgroup (n=30) Phase IIb Subgroup (n=24) Phase IIb (n=119) Median prior regimens 2 (38% 1st relapse) 2 a (32% 1st relapse) 2 a (17% untreated, 31% 1st relapse) 2 b 3 CR+PR (%) 38 34 37 46 25 CR (%) 5 — — 0 7 Duration of response (mos) — — — 2.0 3.0 TTP (mos) 3.8 2.0 a >3.5 a 3.0 3.0 a Median for entire study, not for subgroup. b 1 patient had only 1 prior regimen.
  66. 66. P-66 Objective Tumor Response by IRPObjective Tumor Response by IRP Single-Agent Rituximab as Last TherapySingle-Agent Rituximab as Last Therapy Number (%) of Patients (n=20) Best Tumor Response Rituximab VSLI ORR 5 (25) 8 (40) CR 0 (0) 2 (10) CRu 0 (0) 1 (5) PR 5 (25) 5 (25) MR+SD 4 (20) 4 (20) PD+UE 11 (55) 8 (40)
  67. 67. P-67 Safety Data
  68. 68. P-68 Extent of Treatment with VSLI (ITT)Extent of Treatment with VSLI (ITT) (n=119) Number of Cycles Received Mean 4.6 Median (range) 4.0 (1-20) Dose Intensity (mg/m 2 /wk) Median 0.98
  69. 69. P-69 Safety – Major EndpointsSafety – Major Endpoints 14% of patients withdrawn due to associated AEs, mostly neuropathy No treatment-associated deaths
  70. 70. P-70 Neuropathy
  71. 71. P-71 Prior Neurotoxic Therapies (ITT)Prior Neurotoxic Therapies (ITT) % of Patients (n=119) Number of Prior Regimens Containing Neurotoxic Agents 1 14 2 56 3-5 30 Neurologic Abnormality at Baseline 85
  72. 72. P-72 Worst Neuropathy on Study by Grade at Study EntryWorst Neuropathy on Study by Grade at Study Entry (Pain, Paresthesia, Numbness,(Pain, Paresthesia, Numbness, Weakness, Constipation)Weakness, Constipation) % of Patients Worst Grade on StudyStudy Entry Grade Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Grade 0 (n=39) 8 26 33 26 0 Grade 1 (n=46) 0 24 41 26 4 Grade 2 (n=21) 0 5 38 52 5
  73. 73. P-73 Mean Change from Baseline for Cycles 1 to 6Mean Change from Baseline for Cycles 1 to 6 for Hand Numbnessfor Hand Numbness Hand Numbness n=94 n=81 n=70 n=50 n=33 n=23 0.0 1.0 2.0 C1 C2 C3 C4 C5 C6 Cycle ChangefromBaseline(+/- SEM) *Significant change from baseline * * * * * *
  74. 74. P-74 Dose to Grade 3 or 4 NeuropathyDose to Grade 3 or 4 Neuropathy (Pain, Paresthesia, Numbness,(Pain, Paresthesia, Numbness, Weakness, Constipation)Weakness, Constipation) Kaplan-Meier Analysis (n=115) Number (%) of patients with Grade 3 or 4 neuropathy 37 (32) Grade 3 neuropathy 34 (30) Grade 4 neuropathy 3 (3) Estimated median cumulative dose 21.2 mg/m2 (~11 doses) • Equivalent to 15 doses of conventional vincristine
  75. 75. P-75 Comparison of Neuropathy in RespondersComparison of Neuropathy in Responders vs. Nonresponders (Numbness)vs. Nonresponders (Numbness) % of Patients Grade Changes From Baseline to Worst Value Parameter No Change 1 Grade 2 Grades 3 Grades 4 Grades Responders, CR+CRu+PR (n=29) 14 41 24 21 0 Nonresponders, SD+PD+UE (n=74) 55 24 16 4 0 PD or UE only (n=48) 69 19 10 1 0
  76. 76. P-76 Timing of Antitumor EffectTiming of Antitumor Effect vs. Neuropathyvs. Neuropathy Antitumor activity evident early in patients who responded, usually within 2 weeks (1st 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. 77. P-77 Hematologic Abnormalities
  78. 78. P-78 Hematologic Abnormalities at Study EntryHematologic Abnormalities at Study Entry % of Patients (n=119) Hematologic Abnormality At Study Entry Anemia 78 Neutropenia 15 Thrombocytopenia 40 ANC <1.5 or Platelets <100K 33
  79. 79. P-79 Hematology CTC Grade Changes fromHematology CTC Grade Changes from Baseline to Worst GradeBaseline to Worst Grade % of Patients Grade Change Parameter No Change 1 Grade 2 Grades 3 Grades 4 Grades Hemoglobin (n=118) 47 40 9 1 0 Neutrophils (n=117) 52 15 11 15 5 Platelet count (n=118) 56 32 6 1 0
  80. 80. P-80 Hematologic ToxicityHematologic Toxicity Neutropenia • 8% Grade 4 neutropenia (<0.5 ANC) • 3% febrile neutropenia • 2% prophylactic filgrastim usage Thrombocytopenia • 1% Grade 4 thrombocytopenia (<10x109 /L) • 6% platelet transfusions
  81. 81. P-81 Patients with Net Clinical BenefitPatients with Net Clinical Benefit Fernando Cabanillas, MD Clinical Professor of Medicine MD Anderson Cancer Center Medical Director Auxilio Mutuo Cancer Center
  82. 82. P-82 Patient Benefit SummariesPatient 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. 83. P-83 41 Patients Had Evidence of41 Patients Had Evidence of Net Clinical BenefitNet 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. 84. P-84 Clinical Benefit: Symptomatic andClinical Benefit: Symptomatic and ECOG PS ImprovementsECOG PS Improvements Category of Improvement Number (%) of Patients (n=43) Symptomatic improvement (B symptoms or other symptoms) 20 (47) ECOG PS improved 13 (30) Symptomatic or ECOG PS improvement 26 (60)
  85. 85. P-85 Clinical Benefit: Stem Cell TransplantClinical 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. 86. P-86 Case Studies of Selected Patients with Clinical Benefit
  87. 87. P-87 Patient 35-01Patient 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. 88. P-88 Patient 40-01Patient 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. 89. P-89 Patient 33-06Patient 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. 90. P-90 Benefit-Risk Conclusions
  91. 91. P-91 Summary of Patient PopulationSummary of Patient Population Median 3 prior regimens → 4th -5th line therapy 33% had prior ASCT 33% with low blood counts 50% refractory to last therapy 24% >70 years 66% with elevated LDH
  92. 92. P-92 Summary of VSLI BenefitsSummary of VSLI Benefits 25% ORR in heavily pretreated patients with highly resistant disease and compromised marrow – 46% ORR in those treated on 2nd 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. 93. P-93 Summary of RisksSummary 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. 94. P-94 Favorable Benefit-Risk ProfileFavorable 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. 95. P-95 Why Do We Need VSLI?Why Do We Need VSLI? Effective and well-tolerated agent for – Patients at 3rd 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

×