`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`761104Orig1s000
`
`MULTI-DISCIPLINE REVIEW
`Summary Review
`Office Director
`Cross Discipline Team Leader Review
`Clinical Review
`Non-Clinical Review
`Statistical Review
`Clinical Pharmacology Review
`
`

`

`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
`
`
`NDA/BLA Multi-disciplinary Review and Evaluation
`
`Application Type BLA
`Application Number(s) 761104
`Priority or Standard Priority
`Submit Date(s) November 30, 2017 and January 29, 2018
`Received Date(s) November 30, 2017 and January 29, 2018
`PDUFA Goal Date September 29, 2018
`Division/Office Division of Hematology Products/Office of Hematology and
`Oncology Products
`Review Completion Date September 12, 2018
`Established Name Moxetumomab pasudotox
`(Proposed) Trade Name Lumoxiti
`Pharmacologic Class CD22-directed cytotoxin
`Code name CAT-8015
`Applicant AstraZeneca AB
`Formulation(s) Lyophilized powder
`Dosing Regimen 0.04 mg/kg administered as a 30-minute intravenous infusion on
`Days 1, 3, and 5 of each 28-day cycle
`Treatment of adult patients with relapsed or refractory hairy cell
`leukemia who received at least two prior systemic therapies,
`including with a purine nucleoside analog
`Approval
`
`Applicant Proposed
`Indication(s)/Population(s)
`
`Recommendation on
`Regulatory Action
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`
`Treatment of patients with relapsed or refractory hairy cell
`leukemia who received at least two prior systemic therapies,
`including a purine nucleoside analog
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4319411
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`

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`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
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`Table of Contents
`Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 9
`Additional Reviewers of Application ............................................................................................... 9
`Glossary ......................................................................................................................................... 11
`1
`Executive Summary ............................................................................................................... 13
` Product Introduction ...................................................................................................... 13
` Conclusions on the Substantial Evidence of Effectiveness ............................................ 13
` Benefit-Risk Assessment ................................................................................................ 15
` Patient Experience Data ................................................................................................. 18
`Therapeutic Context .............................................................................................................. 20
` Analysis of Condition ...................................................................................................... 20
` Analysis of Current Treatment Options ......................................................................... 20
`Regulatory Background ......................................................................................................... 24
` U.S. Regulatory Actions and Marketing History ............................................................. 24
`Summary of Presubmission/Submission Regulatory Activity ........................................ 24
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety ................................................................................................................. 25
` Office of Scientific Investigations (OSI) .......................................................................... 25
` Product Quality .............................................................................................................. 25
` Clinical Microbiology ...................................................................................................... 26
` Devices and Companion Diagnostic Issues .................................................................... 26
`5 Nonclinical Pharmacology/Toxicology................................................................................... 27
` Executive Summary ........................................................................................................ 27
` Referenced NDAs, BLAs, DMFs ....................................................................................... 29
` Pharmacology ................................................................................................................. 29
` ADME/PK ........................................................................................................................ 32
` Toxicology ....................................................................................................................... 32
` General Toxicology .................................................................................................. 32
` Genetic Toxicology .................................................................................................. 41
` Carcinogenicity ........................................................................................................ 41
` Reproductive and Developmental Toxicology ........................................................ 41
` Other Toxicology Studies ........................................................................................ 42
`Clinical Pharmacology ............................................................................................................ 43
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4319411
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`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
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` Executive Summary ........................................................................................................ 43
`Summary of Clinical Pharmacology Assessment ............................................................ 44
`
` Pharmacology and Clinical Pharmacokinetics ........................................................ 44
` General Dosing and Therapeutic Individualization ................................................. 45
` Comprehensive Clinical Pharmacology Review ............................................................. 46
` General Pharmacology and Pharmacokinetic Characteristics ................................ 46
` Clinical Pharmacology Questions ............................................................................ 47
`Sources of Clinical Data and Review Strategy ....................................................................... 53
` Table of Clinical Studies .................................................................................................. 53
` Review Strategy .............................................................................................................. 55
`Statistical and Clinical and Evaluation ................................................................................... 57
` Review of Relevant Individual Trials Used to Support Efficacy ...................................... 57
` Study CD-ON-CAT-8015-1053 ................................................................................. 57
` Study Results ........................................................................................................... 63
` Assessment of Efficacy Across Trials ....................................................................... 78
`Study CAT-8015-1053 is the only trial supporting the efficacy of moxetumomab
`pasudotox in patients with R/R HCL. ................................................................................ 78
` Integrated Assessment of Effectiveness ................................................................. 78
` Safety Review Approach ......................................................................................... 80
` Review of the Safety Database ............................................................................... 81
` Adequacy of Applicant’s Clinical Safety Assessments ............................................ 84
` Safety Results .......................................................................................................... 85
` Analysis of Submission-Specific Safety Issues ......................................................... 94
`Capillary Leak Syndrome ................................................................................. 94
`
`Hemolytic Uremic Syndrome (HUS) ................................................................ 97
`
`Infusion-related reactions ............................................................................. 100
`
`Hepatic function abnormality ........................................................................ 102
`
`Nephrotoxicity ............................................................................................... 105
`
`Electrolyte abnormalities .............................................................................. 107
`
`Ocular Toxicity ............................................................................................... 109
`
`Fluid Retention .............................................................................................. 110
`
`Severe Infections (Including Opportunistic Infections) ................................. 111
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4319411
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`

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`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
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`Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability
`
`
`112
`Safety Analyses by Demographic Subgroups ................................................ 112
`
`Specific Safety Studies/Clinical Trials ............................................................ 116
`
`Additional Safety Explorations ...................................................................... 116
`
`Safety in the Postmarket Setting ................................................................... 117
`
`Integrated Assessment of Safety ................................................................... 117
`
`Statistical Issues ........................................................................................................... 118
`
` Conclusions and Recommendations ............................................................................ 119
`9 Advisory Committee Meeting and Other External Consultations ....................................... 121
`10 Pediatrics ............................................................................................................................. 122
`11 Labeling Recommendations ................................................................................................ 123
`Prescription Drug Labeling ....................................................................................... 123
`
`12 Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 124
`13 Postmarketing Requirements and Commitment ................................................................ 125
`14 Division Director (DHOT) ..................................................................................................... 126
`15 Division Director (OCP) ........................................................................................................ 127
`16 Division Director (OB) .......................................................................................................... 128
`17 Division Director (Clinical) ................................................................................................... 129
`18 Office Director (or designated signatory authority) ............................................................ 131
`19 Appendices .......................................................................................................................... 132
`References ................................................................................................................ 132
`
`Financial Disclosure .................................................................................................. 133
`
`OCP Appendices (Technical documents supporting OCP recommendations) ......... 134
`
`Bioanalytical Method Validation and Performance ...................................... 134
`
`Clinical Pharmacokinetics and Pharmacodynamics ...................................... 139
`
`Immunogenicity ............................................................................................. 145
`
`Pharmacometrics ........................................................................................... 147
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`Additional Clinical Outcome Assessment Analyses .................................................. 154
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4319411
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`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
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`
`Table of Tables
`
`
`Table 1 Treatment Options for Patients with Relapsed HCL ........................................................ 21
`Table 2 Key Regulatory Interactions related to BLA 761104 ........................................................ 24
`Table 3 OSI Inspection Sites .......................................................................................................... 25
`Table 4 Non-reproductive Microscopic Findings in the Monkey at the End of Dosing (Study
`Report 20009858) ......................................................................................................................... 36
`Table 5 Non-reproductive Microscopic Findings in the Monkey at the End of Recovery (Study
`Report 20009858) ......................................................................................................................... 39
`Table 6 Reproductive Microscopic Findings in the Monkey (Study Report 20009858) ............... 40
`Table 7. Subgroup Analysis of Safety Parameters–Immunogenicity (Study 1053) ...................... 50
`Table 8 Clinical Trials Relevant to this BLA ................................................................................... 53
`Table 9 Study Calendar for Cycle 1 and Subsequent Cycles ......................................................... 59
`Table 10 Study Calendar for End of Treatment and Follow -up ................................................... 60
`Table 11 Study 1053-Patient Disposition ...................................................................................... 64
`Table 12 Important Protocol Violations/Deviations ..................................................................... 65
`Table 13 Demographic Characteristics- ITT Population ................................................................ 66
`Table 14 Baseline Disease Characteristics-ITT Population ........................................................... 67
`Table 15 Study 1053-Prior HCL Therapy ....................................................................................... 67
`Table 16 Concordance of Durable CR between BICR and investigator’s assessment .................. 69
`Table 17 Complete Response, Time to Complete Response and Duration of Complete Response
`by BICR and Investigator’s Assessment – ITT Population .............................................................. 72
`Table 18 Objective Response per BICR and Investigator Assessment – ITT population .............. 72
`Table 19 Disease Response Assessed by BICR and investigator assessment – ITT Population .... 73
`Table 20 Best Overall Response Comparison – Investigator’s Assessment vs BICR – ITT
`Population ..................................................................................................................................... 73
`Table 21 Hematologic Remission from Onset of Hematologic Remission – ITT Population ......... 74
`Table 22 Hematologic Remission for Subjects with Complete Response per BICR and
`Investigator’s Assessment – ITT Population ................................................................................. 74
`Table 23 Safety Population ........................................................................................................... 81
`Table 24 Overall Exposure-Safety Population .............................................................................. 81
`Table 25 Demographics-Safety Population................................................................................... 82
`Table 26 Deaths- HCL Population ................................................................................................. 85
`Table 28 Summary of TEAEs Leading to Discontinuations and Treatment Modifications ........... 88
`Table 29 TEAEs Leading to Treatment Discontinuation ............................................................... 88
`Table 30 Safety Analysis-Common TEAEs (>10% in the Pivotal HCL Population) ......................... 89
`Table 31 FDA criteria for Identifying Cases of Possible CLS .......................................................... 96
`Table 32 HUS or HUS- like AEs-HCL population ............................................................................ 98
`Table 33 IRR related TEAEs -HCL Population .............................................................................. 100
`Table 34 AESI of Hepatic Function Abnormality-HCL Population ............................................... 102
`Table 35 TEAEs of AST/ALT Elevations-HCL population .............................................................. 103
`Table 36 Adverse Events Related to Renal Toxicity-Safety Population ...................................... 106
`Table 37 TEAEs of Electrolyte abnormalities-HCL population .................................................... 108
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4319411
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`

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`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
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`Table 38 Changes in Electrolyte laboratory values ..................................................................... 108
`Table 39 TEAEs of Fluid Retention -HCL Population ................................................................... 111
`Table 40 Overall Safety by Age- Primary HCL population ........................................................... 112
`Table 41 TEAEs by Age Subgroups -Primary HCL Population ..................................................... 113
`Table 42 Outcomes-Moderate Renal Impairment ...................................................................... 115
`Table 43. Bioanalytical Methods for Moxetumomab Pasudotox Concentration Determinations in
`Plasma ......................................................................................................................................... 135
`Table 44. Summary of Validation ADA Assay Parameters .......................................................... 136
`Table 45. Summary of Validation nAb Assay Parameters........................................................... 137
`Table 46. PK Parameters Following Multiple IV Administration of 40 µg/kg Moxetumomab
`Pasudotox in Patients with HCL (Study 1053)............................................................................. 141
`Table 47. Summary of Cycle 1 PK Parameters of Moxetumomab Pasudotox in Patients with HCL
`(Trial 1001) .................................................................................................................................. 144
`Table 48. Summary of studies included in the analysis .............................................................. 148
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4319411
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`

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`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
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`Table of Figures
`
`
`Figure 1 The Internalization of Moxetumomab Pasudotox on CD22-expressing Cells ................ 29
`Figure 2 ADP-ribosylation of Eukaryotic Elongation Factor 2 by Moxetumomab Pasudotox ...... 30
`Figure 3 Dose-response Curve of the Apoptosis Bioassay for Moxetumomab Pasudotox .......... 30
`Figure 4 Moxetumomab Pasudotox Inhibits Growth of JD38 Tumors in a Xenograft Model ...... 31
`Figure 5. Median Baseline Normalized CD19+ B Cell Counts Over Time (Study 1053) ................ 47
`Figure 6. Relationships between PK exposure (AUC on Day 1 Cycle 2) and durable CR, CR or ORR
`(Study 1053) .................................................................................................................................. 48
`Figure 7. Correlation between PK exposure (AUC on Day 1 Cycle 1) and adverse events (Study
`1053 and 1001) ............................................................................................................................. 49
`Figure 8. Relationship between ADA Titer and Efficacy Endpoints in Study 1053 ....................... 50
`Figure 9. Comparison of AUC by Renal Function (Study 1053, population PK analysis) .............. 51
`Figure 10 Study 1053 Flow Diagram ............................................................................................. 57
`Figure 11 Forest Plot of Durable CR Assessed by BICR – ITT population ...................................... 76
`Figure 12 Forest Plot of Durable CR Assessed by BICR, prior cancer therapy – ITT population... 77
`Figure 13 Mean Change and Standard Deviation from Baseline in Hemoglobin ...................... 91
`Figure 14 Mean Change and Standard Deviation from Baseline in Absolute Neutrophil Count . 91
`Figure 15 Mean Change and Standard Deviation from Baseline in Platelets ............................... 92
`Figure 16 Serum AST levels -Pivotal HCL population .................................................................. 104
`Figure 17 Serum ALT Levels (U/L) -Pivotal HCL Population ........................................................ 105
`Figure 18 Creatinine values (mg/dL), Pivotal HCL population .................................................... 107
`Figure 19. Mean Concentration-time Profiles of Moxetumomab Pasudotox Following IV
`Administration in the First Two Cycles of Treatment – PK Population ...................................... 140
`Figure 20. Mean Peak Concentration Levels of Moxetumomab Pasudotox in HCL Subjects after
`Each Cycle ................................................................................................................................... 141
`Figure 21. Relationship Between PK and Baseline CD19+ B cells in Subjects after First (Left) and
`Third Dose (Right) of Cycle 1 (Trial 1053) ................................................................................... 142
`Figure 22. Moxetumomab Pasudotox Exposure Comparison between CD19 Low and CD19 High
`Group at Baseline ........................................................................................................................ 143
`Figure 23. Mean Concentration-time Profiles of Moxetumomab Pasudotox in Patients with HCL
`Following the First and Third Dose of Cycle 1 (Study 1001) ....................................................... 144
`Figure 24. Median Baseline Normalized CD19+ B Cell Counts Over Time Stratified by Clinical
`Response Category (Trial 1053) .................................................................................................. 145
`Figure 25. ADA Titers in HCL Subjects with Positive Neutralizing ADA Results (Trial 1053)...... 146
`Figure 26. Effect of Post-Baseline ADA Status by Cycle on PK Exposure in Subjects with HCL (Trial
`1053) ........................................................................................................................................... 147
`Figure 27. Pharmacokinetics Model ........................................................................................... 149
`Figure 24. Exposure-Response Relationships Between Cmax or AUC and ORR (Trial 1053) ..... 150
`Figure 25. Exposure-Response Relationships Between AUC in Cycle 2 and Durable CR, CR, and
`ORR (Trial 1053) .......................................................................................................................... 151
`Figure 26. Distribution of AUC in Cycle 1, 2, and 5 Among Subjects with Various Responses (Trial
`1053) ........................................................................................................................................... 151
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4319411
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`

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`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
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`Figure 27. Exposure-Response Relationships by ADA Titer (Trial 1053) .................................... 152
`Figure 28. Exposure-Response Relationships for Safety Endpoints (Trial 1053 and Trial 1001) 154
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4319411
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`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
`
`Reviewers of Multi-Disciplinary Review and Evaluation
`
`Nonclinical Reviewer
`Nonclinical Team Leader
`Clinical Pharmacology Reviewer
`Pharmacometrics Reviewer
`Pharmacometrics Team Leader
`Clinical Pharmacology Team Leader
`Clinical Reviewer
`Clinical Team Leader
`Statistical Reviewer
`Statistical Team Leader
`Cross-Disciplinary Team Leader
`Division Director (DHOT)
`Deputy Division Director (OCP)
`Deputy Division Director (OB)
`Acting Deputy Division Director (DHP)
`Office Director (or designated signatory authority)
`
`Additional Reviewers of Application
`
`Matthew Thompson, PhD
`Christopher Sheth, PhD
`Guoxiang Shen, PhD
`Jee Eun Lee, PhD
`Lian Ma, PhD
`Olanrewaju Okusanya, PharmD, MS,
`Bindu Kanapuru, MD
`Nicole Gormley, MD
`Jiaxi Zhou, MS
`Yuan Li Shen, DrPH
`Nicole Gormley, MD
`John Leighton, PhD
`Brian Booth, PhD
`Thomas Gwise, PhD
`Nicole Gormley, MD
`Richard Pazdur, MD
`
`RPM
`Associate Director of Labeling
`DHP DDS
`OPQ
`Microbiology
`OPDP
`PLT
`OSI
`OSE/DEPI
`OSE/DMEPA
`
`OSE/DRISK
`
`QT
`CDRH
`DTOP
`
`Wanda Nguyen, PharmD
`Virginia Kwitkowski, MS, RN, ACNP-BC
`Barry Miller, MS, CRNP
`Chana Fuchs, PhD/Sang Bong Lee PhD
`Maria Jose Lopez-Barragan, PhD/ Virginia Carroll, PhD
`Nisha Patel, PharmD
`Morgan Walker, PharmD, MBA, CPH
`Anthony Orencia, MD, FACP
`Peter Waldron, MD/Afrouz Nayernama, PharmD
`Casmir Ogbonna, PharmD, MBA, BCPS, BCGP/Hina
`Mehta, PharmD
`Ingrid Chapman, PharmD, BCPS/Elizabeth Everhart,
`MSN, RN, ACNP
`Lars Johannesen, PhD/Christine E. Garnett, PharmD
`Janaki Veeraraghavan, PhD
`Wiley Chambers, MD
`
`OPQ=Office of Pharmaceutical Quality
`OPDP=Office of Prescription Drug Promotion
`OSI=Office of Scientific Investigations
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4319411
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`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
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`OSE= Office of Surveillance and Epidemiology
`DEPI= Division of Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DRISK=Division of Risk Management
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4319411
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`

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`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
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`Glossary
`
`anti-drug antibodies
`
`ADA
`absorption, distribution, metabolism, excretion
`ADME
`adverse event
`AE
`
`adverse event of special interest
`AESI
`
`ALT alanine aminotransferase
`AST aspartate aminotransferase
`BICR blinded independent central review
`BLA
`
`biologics license application
`CDRH
`
`Center for Devices and Radiological Health
`CFR
`
`Code of Federal Regulations
`CI confidence interval
`CLS capillary leak syndrome
`CMC
`
`chemistry, manufacturing, and controls
`CR complete response
`CSR
`
`clinical study report
`DHOT
`Division of Hematology Oncology Toxicology
`ECG
`
`electrocardiogram
`ECL
`
`electrochemiluminescent (assay)
`EOT
`
`end of treatment
`FDA
`
`Food and Drug Administration
`GCP
`
`good clinical practice
`HCL
`
`hairy cell leukemia
`HUS Hemolytic uremic syndrome
`ICH
`
`International Conference on Harmonization
`IND
`
`Investigational New Drug
`IRR
`
`infusion-related reactions
`ITT
`
`intent to treat
`IV
`
`intravenous
`LDH Lactate dehydrogenase
`MAED
`MedDRA Adverse Events Diagnostic
`MedDRA
`Medical Dictionary for Regulatory Activities
`MRD
`
`minimal residual disease
`NCI CTCAE
`National Cancer Institute-Common Terminology Criteria for Adverse Event
`NDA
`
`new drug application
`NHL
`
`non-Hodgkin lymphoma
`NME
`
`new molecular entity
`OPQ
`
`Office of Pharmaceutical Quality
`OR
`
`objective response
`ORR
`
`objective response rate
`OSE
`
`Office of Surveillance and Epidemiology
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4319411
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`

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`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
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`
`OSI
`
`PD
`
`PK
`
`PNA
`
`PR
`
`PT
`REMS
`SAE
`
`SOC
`
`TEAE
`
`
`
`Office of Scientific Investigation
`progressive disease
`pharmacokinetics
`purine nucleoside analogue
`partial response
`preferred term
`risk evaluation and mitigation strategy
`serious adverse event
`system organ class
`treatment emergent adverse event
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4319411
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`

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`NDA/BLA Multi-Disciplinary Review and Evaluation
`BLA 761104, Lumoxiti, Moxetumomab pasudotox
`
`1 Executive Summary
`
`
`
`Product Introduction
`
`Established Names:
`Trade Name:
`Applicant:
`Drug Class:
`Applicant’s Proposed
`Indication:
`
`Applicant’s Proposed
`Dosage:
`
`
`Moxetumomab pasudotox, CAT-8015
`Lumoxiti
`AstraZeneca
`Recombinant cytotoxin targeting CD22
`For the treatment of adult patients with relapsed or refractory
`hairy cell leukemia (HCL) who received at least two prior systemic
`therapies, including treatment with a purine nucleoside analog (PNA).
`40 μg/kg administered intravenously over 30 minutes on Days 1, 3, and
`5 of a 28-day cycle for a maximum of 6 cycles.
`
`
`
`Conclusions on the Substantial Evidence of Effectiveness
`
`The review team recommends regular approval of moxetumomab pasudotox for the following
`indication: “treatment of patients with relapsed or refractory hairy cell leukemia (HCL) who
`have received two prior therapies including
` treatment with a purine nucleoside
`analog”. This recommendation is based on the finding of high rates of durable complete
`response (CR) in the pivotal Phase 3 study CD-ON-CAT-8015-1053 (Study 1053). The
`recommended dose is 0.04 mg/kg administered as a 30-minute intravenous (IV) infusion on
`Days 1, 3, and 5 of each 28-day cycle.
`
`Study 1053 was an open-label single-arm multicenter clinical trial of moxetumomab pasudotox
`which enrolled adults with relapsed or refractory HCL. The median age was 60 years (range: 34-
`84) and the median number of prior therapies was 3 (range: 2-11). The primary endpoint was
`rate of durable CR based on CR as determined by blinded independent central review (BICR).
`Durable CR was defined as the overall response that meets blood, bone marrow, and imaging
`criteria for CR per BICR, followed by hematologic remission with duration of > 180 days, with
`hematologic remission defined as the blood counts needed for CR. No statistical hypothesis
`tests were performed but the 95% confidence interval (CI) for the durable CR rate was
`constructed using the Clopper-Pearson exact method. The protocol indicated that a lower
`bound of the 95% CI above 13% was considered clinically meaningful (the estimated durable CR
`rate to best alternative therapy rituximab). FDA’s analysis of the primary endpoint includes 80
`subjects with relapsed HCL; the durable CR rate for Study 1053 was 30.3% (95% CI: 20.3%,
`41.3%)
`
`The Agency has previously granted regular approval of new therapies for treatment of patients
`with HCL based on single arm trials. For example, the initial regular approval of cladribine for
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`Version date: February 1, 2016 for initial rollout (NME/original BL