CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`125388Orig1s000
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`MEDICAL REVIEW(S)
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`

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`CLINICAL REVIEW
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`Application Type
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`Application Number(s)
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`Priorityor Standard
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`BLA
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`STN 125388/0
`Priority
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`Submit Date
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`. Received Date
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`PDUFA Goal Date
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`Division / Office
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`’ Reviewer Name
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`Clinical Team Leader
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`Review Completion Date
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`2/25/2011'
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`‘ 2/28/2011
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`8/30/201 1
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`DHP / OODP
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`
`
`R. Angelo de Claro; M.D. ’ g]. m
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`
`
`Virginia Kwitkowski, MS, RN,
`ACNP-BC WW' PM"
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`
`8/1/2011
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`Established Name
`. Trade Name
`Therapeutic Class
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`Applicant
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`Brentuximab vedotin-
`AdcetrisTM
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`Antibody—drug conjugate
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`Seattle Genetics, Inc.
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`Formulation
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`Dosing Regimen
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`.Proposed Indication
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`Intended Population(s)
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`Template Version: March 6, 2009 .
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`.
`50 mg single use Vial
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`1.8 mg/kg intravenously every
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`3 weeks
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`Treatment of patients with
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`Hodgkin lymphoma who have
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`relapsed after autologous stem
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`cell transplant
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`Adults >18 years of age
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`

`
`Clinical Review
`
`
`
`
`R. Angelo de Claro, MD
`
`BLA 125388
`
`
`Adcetris (brentuximab vedotin)
`
`
`
`
`
`Table of Contents
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`1
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`RECOMMENDATIONS/RISK BENEFIT ASSESSMENT .............................................. 8
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`Recommendation on Regulatory Action .......................................................................... 8
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`Risk Benefit Assessment .................................................................................................. 8
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`Recommendations .for Postmarket Risk Evaluation and Mitigation Strategies ................ 9
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`Recommendations for Postmarket Requirements and Commitments .............................. 9
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`INTRODUCTION AND REGULATORY BACKGROUND ............................................ 9
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`1.1
`1.2
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`1.3
`1.4
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`2.1
`Product Information ............. . .......................................................................................... 11
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`2.2
`Tables of Currently Available Treatments for Proposed Indications ............................. 11
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`2.3 Availability of Proposed Active Ingredient in the United States ................................... 12
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`Important Safety Issues With Consideration to Related Drugs ...................................... 12
`2.4
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`Summary of Presubmission Regulatory Activity Related to Submission ...................... 13
`2.5
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`2.6 Other Relevant Background Information ....................................................................... 13
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`ETHICS AND GOOD CLINICAL PRACTICES ............................................................ 14
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`Submission Quality and Integrity......._ ............................................................................ 14
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`Compliance with Good Clinical Practices ...................................................................... 14
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`Financial Disclosures ...................................................................................................... 16
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`3.1
`3.2
`3 .3
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`SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
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`DISCIPLINES ...................................................................................................................... 17
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`4.1
`Chemistry Manufacturing and Controls ......................................................................... 17
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`4.2
`Clinical Microbiology..................................................................................................... 18
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`4.3
`Preclinical Pharmacology/Toxicology ............................................................................ 18
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`4.4
`Clinical Pharmacology ................................................................................................... 20
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`4.4.1 Mechanism of Action .............................................................................................. 20
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`Pharrnacodynamics .................................................................................................. 20
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`Pharmacokinetics............................ ......................................................................... 20
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`4.4.2
`4.4.3
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`5.1
`5.2
`5.3
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`SOURCES OF CLINICAL DATA ................ ..................................................................... 21
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`Tables of Studies/Clinical Trials ............................_........................................................ 21
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`Review Strategy .............................................................................................................. 23
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`Discussion of Individual Studies/Clinical Trials ............................................................ 23
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`REVIEW OF EFFICACY .................................................................................................. 34
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`Efficacy Summary .......................................,............................................................................. 34
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`Indication ........................................................................................................................ 34
`6. l
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`6.1.1 Methods ................................................................................................................... 36
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`6.1.2 Demographics ........................................................................................................... 36
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`Subject Disposition.................................................................................................. 41
`6.1.3
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`' Analysis of Primary Endpoint(s) ............................................................................. 44
`6.1.4
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`Analysis of Secondary Endpoints(s) ....................................................................... '46
`6.1.5
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`2
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`

`

`
`Clinical Review
`
`
`
`
`R. Angelo de Claro, MD
`
`BLA 125388
`
`
`
`Adcetris (brentuximab vedotin)
`
`
`
`6.1.6 Other Endpoints ....................................................................................................... 48
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`Subpopulations ........................................................................................................ 50
`6.1.7
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`Analysis of Clinical Information Relevant to Dosing Recommendations .............. 51
`6.1.8
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`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects ............................. 51
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`6.1.10 Additional Efficacy Issues/Analyses ....................................................................... 52
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`7 REVIEW OF SAFETY ....................................................................................................... 55
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`Safety Summary ........................................................................................................................ 55
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`7.1 Methods ...................................................................................._...................................... 56
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`7.1.1
`Studies/Clinical Trials Used to Evaluate Safety...................................................... 56
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`Categorization of Adverse Events ........................................................................... 57
`7.1.2
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`Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence
`7.1.3
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`................................................................................................................................. 58
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`7.2 Adequacy of Safety Assessments ................................................................................... 59
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`Overall Exposure at Appropriate Doses/Durations and Demographics of Target
`7.2.1
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`Populations ...................................... . ....................................................................... 59
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`7.2.2
`Explorations for Dose Response ............................................................................. 62
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`7.2.3
`Special Animal and/or In Vitro Testing .................................................................. 62
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`7.2.4
`Routine Clinical Testing .......................................................................................... 63
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`7.2.5 Metabolic, Clearance, and Interaction Workup ..............I......................................... 63
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`7.2.6
`Evaluation for Potential Adverse Events for Similar Drugs in Drug Class ............ 63'
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`7.3 Major Safety Results ...................................................................................................... 63
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`7.3.1
`Deaths ..............'........................................................................................................ 63
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`7.3.2 Nonfatal Serious Adverse Events ............................................................................ 64
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`7.3.3
`Dropouts and/or Discontinuations ........................................................................... 67
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`7.3.4
`Significant Adverse Events ..................................................................................... 68
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`7.3.5
`Submission Specific Primary Safety Concerns ....................................................... 76
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`7.4
`Supportive Safety Results ............................................................................................... 77
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`7.4.1
`Common Adverse Events ........................................................................................ 77
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`7.4.2
`Laboratory Findings ................................................................................................ 78
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`7.4.3
`Vital Slgns ........................................................................................... 80
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`7.4.4
`Electrocardiograms (ECGs) .................................................................................... 81
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`7.4.5
`Special Safety Studles/Clinical Trials ..................................................................... 81
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`7.4.6
`Immuno gen1c1ty ....................................................................................................... 8 1
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`7.5
`Other Safety Explorations .............................................................................................. 82
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`7.5.1
`Dose Dependency for Adverse Events .................................................................... 82
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`Time Dependency for Adverse Events .......'............................................................. 82
`7.5.2
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`Drug-Demographic Interactions ...............................'............................................... 82
`7.5.3
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`7.5.4 Drug-Disease Interactions ........ 82
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`7.5.5
`Drug-Drug Interactions .................................._......................................................... 83
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`7.6 Additional Safety Evaluations ........................................................................................ 83
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`7.6.1
`Human Carcinogenicity ........................................................................................... 83
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`Human Reproduction and Pregnancy Data ............................................................. 83
`7.6.2
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`Pediatrics and Assessment of Effects on Growth .................................................... 83
`7.6.3
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`

`

`
`Clinical Review
`
`
`
`
`R. Angelo de Claro, MD
`BLA 125 3 8 8
`
`Adcetris (brentuximab vedotin)
`
`
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`7.6.4
`Overdose, Drug Abuse Potential, Withdrawal and Rebound .................................. 83
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`7.7 Additional Submissions / Safety Issues .......................................................................... 84
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`POSTMARKET EXPERIENCE......, ................................................................................. 84
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`8
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`9 APPENDICES ...................................................................................................................... 85
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`Literature Review/References ........................................................................................ 85
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`Labeling Recommendations ........................................................................................... 86
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`Advisory Committee Meeting ........................................................................................ 87
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`9.1
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`9.2
`9.3
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`

`

`
`Clinical Review
`
`
`
`
`R. Angelo de Claro, MD
`BLA 125388
`
`
`
`
`Adcetris (brentuximab vedotin)
`
`Table of Tables
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`Table 1 FDA Approved Drugs for Hodgkin Lymphoma............................................................. 11
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`Table 2 Therapy for Relapsed Hodgkin Lymphoma Post-ASCT Based on Literature Review .. 12
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`Table 3 Approvals for New Molecular Entities (NMEs) based on Single Arm Clinical Trials,
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`2001 to 2011 (Malignant Hematology Indications) ..................................................... 13
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`Table 4 SG035-0003 Sites Selected for Scientific Investigation ................................................. 15
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`Table 5 Clinical Trials Included in BLA 125388 ........................................................................ 22
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`Table 6 Revised Response Criteria for Malignant Lymphoma (2007 Cheson Criteria) .............. 25
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`Table 7 Recommended Dose Modifications for Treatment-associated Toxicity ........................ 27
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`Table 8 SGO35-0003 Landmarks and Protocol Amendments ..................................................... 28
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`Table 9 SG035-0003 Schedule of Assessments ........................................................................... 30
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`Table 10 Comparison of Response Rates and Brentuximab Doses between SG035-0001, SG035-
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`0002, and SG035-0003 ................................................................................................ 35
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`Table 11 Demographics of ITT Population in SG035-0003 ........................................................ 37
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`Table 12 Countries and Sites of Enrollment in SG035-0003 ...................................................... 38
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`Table 13 Baseline Disease Characteristics in SG035-0003 ......................................................... 39
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`Table 14 Chemotherapy Exposure of Patients Prior to Enrollment to SG035—0003 ................... 41
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`Table 15 FDA Adjudication of Treatment Discontinuations for SG035-0003 ............................ 42
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`Table 16 Applicant's Primary Endpoint Results (ITT population) .............................................. 44
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`Table 17 FDA Primary Endpoint Results (ITT population) ........................................................ 44
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`Table 18 FDA Adjudication of Best Response in SG035-0003 .................................................. 45
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`Table 19 FDA Analysis of Duration of Response ....................................................................... 46
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`Table 20 Follow-up Assessments per Period in SG035-0003 ..................................................... 49
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`Table 21 FDA Exploratory Analysis of SG035-0003 Using 1999 Response Criteria ................ 50
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`Table 22 Protocol Violations in SG035-0003 .............................................................................. 54
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`Table 23 Incidence of Most Common (>10%) Treatment Emergent Adverse Events in ISS
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`(Integrated Summary of Safety) Database ................................................................... 58
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`Table 24 Number of Patients Who Received Brentuximab Vedotin per Dose Level per
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`Chemotherapy Cycle in SG035-0003 (N=102) ........................................................... 60
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`Table 25 Dose Reductions and Delays per Chemotherapy Cycle in SG035-0003 (N=102) ........ 60
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`Table 26 Demographics of Safety Population in SG035-0003 .................................................... 62
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`Table 27 SG035—0003 Deaths ...................................................................................................... 63
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`Table 28 Treatment-Emergent Serious Adverse Events 2 2% of Patients .................................. 65
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`Table 29 Treatment-Emergent Grade 3-4 Adverse Events in Z 2% of Patients .......................... 66
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`Table 30 Adverse Events Leading to Treatment Discontinuation .........................I...................... 67
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`Table 31 Adverse Events Leading to Dose Reductions in SG035-0003 ..................................... 68
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`Table 32 Treatment-emergent peripheral neuropathy (SMQ) adverse events ............................. 69
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`Table 33 Adverse events of infilsion reaction in Z 2 patients ...................................................... 75
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`Table 34 Treatment-Emergent Adverse Events in >10% in SG035-0003 ................................... 77
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`Table 35 Maximum Post-Baseline Laboratory Toxicity by CTCAE Grade in SG035-0003 ...... 78
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`Table 36 Discrepancy between Laboratory-Related AE Reporting and Treatment-Emergent
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`Laboratory Toxicity in SG035-0003 ........................................................................... 79
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`Table 37 SG035-0003 Vital Sign Outlier Analysis ..................................................................... 80
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`5
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`

`

`
`Clinical Review
`
`
`
`
`R. Angelo de Claro, MD
`BLA 125388
`
`
`
`Adcetris (brentuximab vedotin)
`
`
`
`
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`Table 38 SG035—0003 Patient Weight Analysis .......................................................................... 80-
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`Table 39 Effect of positive neutralizing antibody on selected efficacy and safety parameters 82
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`

`

`
`Clinical Review
`
`
`
`
`R. Angelo de Claro, MD
`
`BLA 125388
`
`
`
`Adcetris (brentuximab vedotin)
`
`
`
`Table of Figures
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`Figure 1 Age-Specific Incidence Rate of Hodgkin Lymphoma in the US, SEER Database, 2004
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`to 2008 ......................................................................................................................... 10
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`Figure 2 Total Number of Lines of Systemic Chemotherapy in SG035-0003 ............................ 40
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`Figure 3 Subgroup Analysis for Overall Response Rate ............................................................. 50
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`Figure 4 Subgroup Analysis for Complete Remission Rate ............................'............................ 51
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`Figure 5 Patient Disposition per Treatment Cycle in SG035-0003 ............................................. 61
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`Figure 6 Subgroup Analysis for Peripheral Neuropathy.............................................................. 70
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`Figure 7. Treatment-Emergent Peripheral Neuropathy per Treatment Cycle............................... 71
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`Figure 8 Peripheral Neuropathy per Treatment Cycle ................................................................. 72
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`Figure 9 Clinical Course of Peripheral Neuropathy .................................................................... 73
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`Figure 10 Incidence of Neutropenia or Thrombocytopenia per Treatment Cycle ....................... 74
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`

`

`'
`
`
`Clinical Review
`
`
`
`
`R. Angelo de Claro, MD
`BLA 125388
`
`
`
`
`Adcetris (brentuximab vedotin)
`
`
`
`
`1 Recommendations/Risk Benefit Assessment
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`1.1 Recommendation on Regulatory Action
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`The clinical reviewer recommends accelerated approval of biologic license application (BLA)
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`125388 for the use of brentuximab vedotin injection for the treatment of patients with Hodgkin
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`lymphoma who have relapsed after autologous stem cell transplant.
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`1.2 Risk Benefit Assessment
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`The recommendation for accelerated approval is based on the single, Phase 2, single arm, clinical
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`trial SG035-0003 in which brentuximab vedotin showed a 32% complete remission rate with a
`median duration of response of 20.5 months.
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`SG035-0003 enrolled 102 patients with Hodgkin lymphoma who relapsed after autologous stem
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`cell transplant. The historical median overall survival for these patients is approximately 2 years
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`from time of relapse post-transplant.
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`The trial population in SG035-0003 was mostly young adults. The mean age was 34 years.
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`Seventy-five percent of the patients were between the ages of 18 to 39. The median number of
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`prior lines of systemic chemotherapy was 5. Nearly all of the patients had received drugs or drug
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`classes approved for the treatment of Hodgkin lymphoma.
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`This reviewer recommends that the complete remission rate and prolonged duration of remission
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`in patients achieving CR, 'be used as regulatory efficacy endpoint for approval. Although the
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`overall response rate was 73% (N=74) with a median duration of response of 6.7 months, this
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`included 40 patients with a best response of partial remission with a median duration of response
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`of 3.5 months. This reviewer questions the value of combining the CR and PR populations due
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`to marked differences in the duration of response between these two populations.
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`The complete remission rate of 32% with a median duration of 20.5 months can be considered as
`
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`a “clinical endpoint other than survival or irreversible morbidity” as per 21 CFR 601.41
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`(Accelerated Approval regulations).
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`The main safety issues identified by the applicant include peripheral neuropathy,
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`myelosuppression, and infusion reactions. These risks are acceptable for a population with a
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`life-threatening illness for which there is limited available therapy, wherein the agent is showing
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`a high level of activity.
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`The efficacy and safety evaluation are limited by the small size (N=102) and the single arm
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`design. Time-to—event endpoints such as progression free survival and overall survival cannot be
`
`8
`
`

`

`
`Clinical Review
`
`
`
`
`R. Angelo de Claro, MD
`
`BLA 125388
`Adcetris (brentuximab vedotin)
`
`
`
`
`
`
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`
`adequately interpreted in a single arm trial. Patient reported outcomes were non—evaluable due to
`
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`lack of a validated instrument, and the open-label nature of a single arm trial. For safety,
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`attribution of adverse events is not possible in the absence of a control arm. Finally, initial
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`applications, such as this application, cannot rely upon prior experience for both efficacy and
`safety.
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`The applicant requested regular approval for this application. Due to the limitations of the small
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`trial size and single arm design, this application was presented at the Oncologic Drugs Advisory
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`Committee on July 14, 2011 to discuss the appropriate approval mechanism. The Committee
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`voted unanimously for accelerated approval for this application.
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`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
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`At the time of this review submission, final recommendations for postmarketing REMS have not
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`been made. Refer to the action letter for final recommendations.
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`1.4 Recommendations for Postmarket Requirements and Commitments
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`At the time of this review submission, final recommendations for postmarketing requirements
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`and commitments have not been made. Refer to the action letter for final recommendations.
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`2 Introduction and Regulatory Background
`
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`Hodgkin lymphoma (HL), previously called Hodgkin’s disease, is a hematologic cancer
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`characterized by the presence of Reed-Sternberg cells. Symptoms include painless enlargement
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`of lymph nodes, spleen or other immune tissue. Other symptoms include fever, weight loss,
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`fatigue, and night sweats.
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`The National Cancer Institute estimates that 9,490 men and women (4,670 men and 3,820
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`women) will be diagnosed with and 1,320 men and women will die of Hodgkin lymphoma in
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`2010. The prevalence of Hodgkin lymphoma in the US (as of January 1, 2008) includes
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`approximately 166,776 men and women alive who had a history of Hodgkin lymphoma— 86,21 8
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`men and 80, 558 women
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`The median age of diagnosis of Hodgkin lymphoma in the US is 38 years. Figure 1 shows the
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`bimodal age-specific incidence pattern, in which incidence is highest between the ages of 15 and
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`34 years, declines between ages 35 and 54 years and increases again after 55 years.
`
`

`

`
`Clinical Review
`
`
`
`
`R. Angelo de Claro, MD
`
`BLA 125388
`
`
`
`Adcetris (brentuximab vedotin)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 1 Age-Specific Incidence Rate of Hodgkin Lymphoma in the US, SEER Database,
`
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`2004 to 2008
`I
`
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`IncidenceRate
`Age-SpecificSEER
`
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`
`I'
`l
`I
`I
`I
`l
`I
`|
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`32/
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`
`*
`
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`I||||||II||||II|I||I
`
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`" ”
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`
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`
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`
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`I||||||||||| ||||||||||IIIIIII
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`"
`
`<1
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`1-4 5-9 10-
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`14
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`50— 55- 60- 65- 70- 75- 80- 85+
`15- 20- 25- 30- 35- 40- 45-
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`19
`29
`34
`39
`44
`49
`54
`59
`64
`69
`74
`79
`24
`84
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`Age Group
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`‘13- Surveillance Epidemiology and End Results (SEER) Database, 2004-2008
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`Staging for Hodgkin lymphoma is based on the Ann Arbor Staging System. Stage I or II disease
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`are considered limited or early stages, whereas Stage 3 or 4 are advanced stages. Each stage is
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`subdivided into A and B categories. “A” indicates no systemic symptoms are present, and “B” is
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`assigned to patients with unexplained fevers, drenching night sweats, or unexplained weight loss
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`of more than 10% of the body weight.
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`Initial treatment for Hodgkin lymphoma depends on the stage of the disease, but would typically
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`include chemotherapy and/or radiation therapy.
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`Patients with progressive Hodgkin lymphoma (those who relapse or do not respond to first-line
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`therapy) are typically evaluated for high-dose chemotherapy and autologous stem cell transplant
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`(ASCT). Unfortunately, up to 40% of patients receiving autologous stem cell transplant
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`eventually relapse. The historical median survival is 2 years from time of relapse post-ASCT.
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`
`
`10
`
`

`

`
`Clinical Review
`
`
`
`
`R. Angelo de Claro, MD
`
`BLA 125388
`
`
`
`Adcetris (brentuximab vedotin)
`
`2.1 Product Information
`
`
`
`Established Name:
`
`
`Proprietary Name:
`
`Adcetris
`
`
`brentuximab vedotin
`
`Applicant:
`
`
`
`Seattle Genetics, Inc.
`
`
`
`21830 30th Drive Southeast
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`Bothell, WA 98021
`
`
`Drug Class:
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`Antineoplastic antibody-drug conjugate
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`Applicant’s Proposed Indication: ADCETRIS is a CD30-directed antibody-drug conjugate
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`indicated for the treatment of patients with relapsed or refractory Hodgkin lymphoma.
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`Applicant’s Proposed Dosage and Administration: The recommended dose is 1.8 mg/kg
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`administered as an intravenous infusion over 30 minutes every 3 weeks continued until disease
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`progression or unacceptable toxicity.
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`2.2 Tables of Currently Available Treatments for Proposed Indications
`
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`There are several FDA approved drugs for the treatment of Hodgkin lymphoma (refer to Table
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`1). Systemic therapy for Hodgkin lymphoma typically involves the combination of several
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`chemotherapy drugs. One example is the ABVD regimen. Initially described in the mid 1970s,
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`ABVD is widely used as initial chemotherapy for newly diagnosed Hodgkin Lymphoma. ABVD
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`is the combination of doxorubicin, Bleomycin, Vinblastine, and dacarbazine.
`
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`
`Table 1 FDA Approved Drugs for Hodgkin Lymphoma
`Class Drug
`Year of Approval
`J
`
`
`
`
`Alkylating agents
`
`
`
`Carmustine (BCNU)
`
`Lomustine (CCNU)
`Dacarbazine
`Procarbazine
`
`Cyclophosphamide
`Chlorambucil
`
`Mechlorethamine
`
`I
`
`1977
`1976
`1975
`1969
`
`1959
`1957
`
`1949
`
`
`
`
`
`
`
`Antitumor antibiotics
`1973
`Bleomycin
`
`1965
`Vinblastine
`Antimicrotubule agents
`
`Vincristine 1 963 ‘
`
`‘ Doxorubicin
`
`. 1974
`
`
`
`11
`
`

`

`
`Clinical Review
`
`
`
`
`R. Angelo de Claro, MD
`BLA 125388
`
`
`
`Adcetris (brentuximab vedotin)
`
`
`
`
`
`
`
`
`
`
`
`
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`
`There are no FDA approved drugs for relapsed Hodgkin lymphoma post-transplant. A summary
`
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`
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`of off-label or unapproved therapies based on literature review is presented in Table 2. All
`except the panobinostat clinical trial enrolled fewer than 35 patients. The number of patients
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`achieving complete remissions is small (at most 5 patients) in any of these single arm trials.
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`
`Table 2 Therapy for Relapsed Hodgkin Lymphoma Post-ASCT Based on Literature
`Review
`
`
`
`NS
`11 (46%)
`
`27
`Gemcitabine 20"“
`18 6 (22%)
`
`
`
`2007
`
`
`Vinorelbine + Gemcitabine
`NS
`
`8
`
`
` 4 (50%)
`6 (75%)
`
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`
`
`22
`
`Rituximab 2008
`
`
`5 (23%)
`1 (5%)
`
`
`2008
`
`
`
`16 (48%)
`5 (15%)
`
`
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`
`Bortezomib 2006
`1 (7%)
`0
`
`
`
`
`30
`Bortezomib 20‘”
`0
`19
`0
`
`Bortezomib 2007
`‘
`NS
`0
`0
`_i
`
`
`
`
`
`2 (12%)
`3 (13%)
`
`
`0
`
`
`
`l
`
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`
`Agent (year reported)
`
`Vinblastine ‘998
`
`
`Number
`treated
`
`
`17
`17
`
`
`10 (59%)
`
`0
`Prior
`'
`0
`
`CR+PR (A)
`ASCT
`CR (A1)
`
`
`
`33
`
`
`Vinorelbine ‘994
`
`
`24
`
`Rituximab + Gemcitabine
`
`
`
`
`
`129
`
`
`
`
`35 (27%)
`5 (4%)
`129
`Panobinostat2010
`
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`
`Disclaimer: Data in Table 2 was not independently verified by the FDA.
`
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`2.3 Availability of Proposed Active Ingredient in the United States
`
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`Adcetris is not presently marketed in the US.
`
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`
`
`2.4 Important Safety Issues With Consideration to Related Drugs
`
`
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`
`Brentuximab vedotin is an antibody drug conjugate (ADC) consisting of 3 components:
`
`
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`
`
`
`1) the antibody cAClO specific for human CD30,
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`2) the antimicrotubule agent monomethyl auristatin E (MMAE), and
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`3) a protease-cleavable linker that covalently attaches MMAE to cAClO.
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`Class effects with the monoclonal antibodies include infusion reactions and myelosuppression.
`
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`Class effects with antimicrotubule agents include neuropathy and myelosuppression.
`
`'12
`
`

`

`
`Clinical Review
`
`
`
`
`R. Angelo de Claro, MD
`
`BLA 125388
`
`
`Adcetris (brentuximab vedotin)
`
`
`
`
`
`
`
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
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`Pre-IND meetings were held on 15 March 2005 and 30 June 2005. Seattle Genetics, Inc. opened
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`
`IND 71634 on 27 June 2006. FDA granted orphan drug designation to brentuximab vedotin for
`
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`
`
`
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`
`
`
`the Hodgkin l