BLA

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BLA 125019ZEVALIN Kit

• Philippe Bishop, MD FDA/CBER
• September 11, 2001

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Presentation Outline

• Regulatory History
• Study Results
• Efficacy
• Safety
• Dosimetry Biodistribution
• Summary
• Committee Questions

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BLA 125019 Regulatory History
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ZEVALIN BLA Contents

• Results of 5 clinical studies were submitted in
  support of the proposed biologic license
  application

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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.

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

• 1 major controlled efficacy study
• AND
• 1 supportive trial in the refractory setting

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Efficacy StudyTrial 106-04

• Active control rituximab
• Stratification by histology
• (IWF A/Follicular/Transformed)
• 1o efficacy endpoint superior ORR (LEXCOR)

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106-04 Primary Efficacy Analysis
Protocol Defined Response Criteria/LEXCOR
Evaluation Cochran-Mantel-Haenszel test
stratified by histology type
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106-04 Subgroup AnalysisORR
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106-04 Duration of Response (DR)
K-M estimated medians (months)
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106-04 Subgroup AnalysisDuration of Response
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Supportive StudyTrial 106-06

• Non-randomized trial in rituximab-refractory
  follicular B-cell NHL
• 1o efficacy endpoint ORR (LEXCOR)

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Trial 106-06

• In this patient population an ORR 35 and a DR
  comparable to prior rituximab was considered
  acceptable evidence of activity

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106-06 Primary Efficacy Analysis
Protocol Defined Response Criteria/LEXCOR
Evaluation
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106-06 Duration of Response
Protocol defined analysis K-M estimated
medians (months)
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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

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106-06Duration of Response
DR for ZEVALIN therapy compared to the prior
rituximab therapy Each subject used as their own
control

N
54
29
Favors ZEVALIN
9
5
Favors Rituximab
37
20
Neither
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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.

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Safety
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Hematologic ToxicityWithin First 90 Days (N392)
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Grade 3-4 ANCN214/392 (55)
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Immunologic Effects

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

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Infections
114/358 (32) had a total of 183 events 28/358
(8) had Grade 3-4 events
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Grade 3-4 PLTN224/392 (57)
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Study 106-05 Grades 3-4 PLTN26/30 (87)
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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
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Exploratory Analyses Cytopenias Risk Factors

• Baseline BM involvement
• Number of prior regimens
• Prior fludarabine therapy
• Baseline platelet level

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Non Cytopenic AEsPer Patient Incidence (N358)
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Common Non-Heme AEsStudy 106-04
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Notable AEs (All Grades)Study 106-04
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Secondary Malignanciesn349

• 3 AML
• 2 MDS
• 1 meningioma
• Onset 8 to 34 months post ZEVALIN therapy and 4
  to 13 years following NHL diagnosis

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HAMA/HACA Response(N211)

• 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

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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

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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

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Safety FDA Assessment

• Most serious AEs included
• Hemorrhage ? 2 deaths
• Myeloid malig. ? 5 deaths
• Infections
• Allergic reactions

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Dosimetry Biodistribution
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Whole Body Biodistribution Imaging

• 179 subjects assessed
• Five imaging time points
• Diagnostic quality imaging for multiple organs
• Diagnostic quality imaging for known tumor sites

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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)

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

• Adjacent normal tissues
• Alteration in the biodistribution
• Obstruction of clearance route - renal obstruction

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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

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Dosimetry-BiodistributionFDA Assessment

• There are inadequate data to assess the safety of
  additive localized radiation effects from
  external beam radiation therapy and ZEVALIN
  therapy.

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Conclusions
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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.

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Summary

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

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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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Questions to the Committee