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BLA #125019 ZEVALIN™ Kit

BLA #125019 ZEVALIN™ Kit. Philippe Bishop, MD FDA/CBER September 11, 2001. Presentation Outline. Regulatory History Study Results Efficacy Safety Dosimetry & Biodistribution Summary Committee Questions. BLA #125019 Regulatory History. ZEVALIN ™ BLA Contents.

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BLA #125019 ZEVALIN™ Kit

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  1. BLA #125019ZEVALIN™ Kit Philippe Bishop, MD FDA/CBER September 11, 2001

  2. Presentation Outline • Regulatory History • Study Results • Efficacy • Safety • Dosimetry & Biodistribution • Summary • Committee Questions

  3. BLA #125019 Regulatory History

  4. ZEVALIN™ BLA Contents Results of 5 clinical studies were submitted in support of the proposed biologic license application

  5. Proposed Indication Treatment of patients with relapsed or refractory low-grade, follicular or CD20+ transformed B-cell NHL, and for the treatment of patients with RITUXAN®-refractory follicular NHL.

  6. Regulatory History Date 11-24-92 IND Submission 6-13-96 106-03 2-24-98 106-04 5-20-98 106-05 7-7-98 106-06 12-9-99 106-98

  7. Regulatory History

  8. Efficacy

  9. ZEVALIN™ Therapy Development 1 major controlled efficacy study AND 1 supportive trial in the refractory setting

  10. Efficacy StudyTrial 106-04 Active control: rituximab Stratification by histology (IWF A/Follicular/Transformed) 1o efficacy endpoint: superior ORR (LEXCOR)

  11. 106-04 Primary Efficacy Analysis #Protocol Defined Response Criteria/LEXCOR Evaluation *Cochran-Mantel-Haenszel test stratified by histology type

  12. 106-04 Subgroup AnalysisORR

  13. 106-04 Duration of Response (DR) *K-M estimated medians (months)

  14. 106-04 Subgroup AnalysisDuration of Response

  15. Supportive StudyTrial 106-06 Non-randomized trial in rituximab-refractory follicular B-cell NHL 1o efficacy endpoint: ORR (LEXCOR)

  16. Trial 106-06 In this patient population an ORR ≥ 35% and a DR comparable to prior rituximab was considered acceptable evidence of activity

  17. 106-06 Primary Efficacy Analysis *Protocol Defined Response Criteria/LEXCOR Evaluation

  18. 106-06 Duration of Response* * Protocol defined analysis # K-M estimated medians (months)

  19. ZEVALIN vs. Prior Rituximab Therapy Analysis DR for ZEVALIN™ therapy compared to the prior rituximab therapy Each subject used as their own control • Favors ZEVALIN™ if duration of response to ZEVALIN™ is at least 1 month longer • Favors rituximab if duration of response to rituximab is at least 1 month longer

  20. 106-06Duration of Response DR for ZEVALIN™ therapy compared to the prior rituximab therapy Each subject used as their own control N % Favors ZEVALIN™ 29 54 Favors Rituximab 5 9 Neither 20 37

  21. EfficacyFDA Assessment • ZEVALIN™ therapy has demonstrable and durable anti-tumor activity (ORR) in follicular subjects. • Limited data in IWF A and transformed subjects preclude definitive conclusions.

  22. Safety

  23. Hematologic ToxicityWithin First 90 Days (N=392)

  24. Grade 3-4 ANCN=214/392 (55%)

  25. Immunologic Effects • All subjects had B-cell depletion • Median time to baseline recovery = 6 months • Transient IgM decline • IgG and IgA remained normal

  26. Infections 114/358 (32%) had a total of 183 events 28/358 (8%) had Grade 3-4 events

  27. Grade 3-4 PLTN=224/392 (57%)

  28. Study 106-05: Grades 3-4 PLTN=26/30 (87%)

  29. Incidence of Bleeding • 62 (18%) subjects had at least 1 bleeding event • 7 subjects had a total of 12 Grade 3-5 events • 2 intracranial bleed  Death • 1 vaginal bleed • 1 ecchymosis • 4 GI bleed • 1 hematemesis • 3 melena 5 subjects

  30. Exploratory Analyses Cytopenias Risk Factors • Baseline BM involvement • Number of prior regimens • Prior fludarabine therapy • Baseline platelet level

  31. Non Cytopenic AEsPer Patient Incidence (N=358)

  32. Common Non-Heme AEsStudy 106-04

  33. Notable AEs (All Grades)Study 106-04

  34. Secondary Malignanciesn=349 • 3 AML • 2 MDS • 1 meningioma Onset 8 to 34 months post ZEVALIN™ therapy and 4 to 13 years following NHL diagnosis

  35. HAMA/HACA Response(N=211) 5 subjects had positive HAMA titers • 2 had positive baseline HAMA titers • 3 developed titers post-treatment 3 subjects had positive HACA titers • 2 had positive baseline HACA titers • 1 developed titers post-treatment

  36. Deaths 70 of 349 (20%) subjects died • 58  PD • 12  other causes • 2 intracranial hemorrhage • 5 MDS/AML • 3 pulmonary complications • 1 cardiac arrest • 1 pneumonia

  37. Safety FDA Assessment ZEVALIN™ therapy is characterized by a high incidence of cytopenias Gr. 3-4 ANC 55% Gr. 3-4 PLT 57% median duration 3-4 weeks

  38. Safety FDA Assessment Most serious AEs included • Hemorrhage  2 deaths • Myeloid malig.  5 deaths • Infections • Allergic reactions

  39. Dosimetry & Biodistribution

  40. Whole Body Biodistribution Imaging • 179 subjects assessed • Five imaging time points • Diagnostic quality imaging for multiple organs • Diagnostic quality imaging for known tumor sites

  41. Normal Organ Dosimetry • MIRDOSE 3.1 Software • Regions of Interest for Multiple Organs with Localization of Radiolabeled Antibody: Heart, Lung, Liver, Small Intestine, Spleen, Testes, Kidneys, Bone Marrow (Sacrum)

  42. Radiation Absorbed DoseNotable Organs Organ Median dose (cGy) for 32 mCi Range Spleen 1350 781-2368 Red marrow (Sacral ROI) 90 70-106 Liver 547 349-880 Testes 950 38-1184 Upper large bowel 211 122-288 Lower large bowel 368 256-467

  43. GI Toxicity (All Grades)

  44. “Worst Case” Scenarios • Adjacent normal tissues • Alteration in the biodistribution • Obstruction of clearance route - renal obstruction

  45. Dosimetry-BiodistributionFDA Assessment Normal organ dosimetry supports the use of fixed-dose of 90Y-labeled ZEVALIN™. Biodistribution is necessary for assessment of normal organ and tumor site localization

  46. Dosimetry-BiodistributionFDA Assessment • There are inadequate data to assess the safety of additive localized radiation effects from external beam radiation therapy and ZEVALIN™ therapy.

  47. Conclusions

  48. Summary Durable anti-tumor activity (ORR) was documented in both efficacy studies ZEVALIN™ therapy is associated with significant hematologic toxicity in a majority of subjects and serious morbidity in a minority of subjects.

  49. Summary • As compared to RITUXAN®, ZEVALIN™ was associated with superior ORR, similar DR and TTP. • ZEVALIN™ showed 58% ORR in RITUXAN® refractory subjects.

  50. Summary • Data are limited in non-follicular subgroups. • Data in these subgroups is limited to subjects who have not received prior RITUXAN®.

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