`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`210259Orig1s000
`
`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 {NDA 210259}
`{CALQUENCE, acalabrutinib}
`
`NDA/BLA Multi-disciplinary Review and Evaluation
`Application Type NDA, 505(b)(1)
`Application Number(s) 210259
`Priority or Standard Priority
`Submit Date(s)
`June 13, 2017
`Received Date(s)
`June 13, 2017
`PDUFA Goal Date February 13, 2018 (expedited date of October 31, 2017)
`Division/Office CDER/OHOP/DHP
`Review Completion Date October 26, 2017
`Established Name Acalabrutinib
`(Proposed) Trade Name CALQUENCE
`Pharmacologic Class Kinase inhibitor
`Code name ACP-196
`Applicant Acerta Pharma B.V.
`Formulation(s) hard shell capsule
`Dosing Regimen 100 mg orally approximately every 12 hours
`Applicant Proposed
`Treatment of patients with mantle cell lymphoma (MCL) who
`Indication(s)/Population(s)
`have received at least one prior therapy
`Recommendation on
`Accelerated Approval
`Regulatory Action
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`
`Treatment of adult patients with mantle cell lymphoma (MCL)
`who have received at least one prior therapy.
`
`1
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4173186
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {NDA 210259}
`{CALQUENCE, acalabrutinib}
`
`Table of Contents
`
`Reviewers of Multi-Disciplinary Review and Evaluation...............................................................10
`
`Additional Reviewers of Application ............................................................................................10
`
`Glossary ........................................................................................................................................11
`
`1
`
`2
`
`3
`
`4
`
`5
`
`Executive Summary...............................................................................................................14
`1.1.
`Product Introduction......................................................................................................14
`1.2.
`Conclusions on the Substantial Evidence of Effectiveness.............................................14
`1.3.
`Benefit-Risk Assessment ................................................................................................16
`
`Therapeutic Context..............................................................................................................21
`2.1. Analysis of Condition......................................................................................................21
`2.2. Analysis of Current Treatment Options .........................................................................21
`
`Regulatory Background .........................................................................................................23
`3.1. U.S. Regulatory Actions and Marketing History.............................................................23
`3.2.
`Summary of Presubmission/Submission Regulatory Activity ........................................23
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety ................................................................................................................24
`4.1. Office of Scientific Investigations (OSI) ..........................................................................24
`4.2.
`Product Quality ..............................................................................................................24
`4.1.
`Clinical Microbiology......................................................................................................24
`4.2. Devices and Companion Diagnostic Issues ....................................................................24
`
`Nonclinical Pharmacology/Toxicology ..................................................................................25
`5.1.
`Executive Summary........................................................................................................25
`5.2.
`Referenced NDAs, BLAs, DMFs ......................................................................................28
`5.3.
`Pharmacology ................................................................................................................29
`5.4. ADME/PK........................................................................................................................36
`5.5.
`Toxicology ......................................................................................................................40
`5.5.1. General Toxicology .................................................................................................40
`5.5.2. Genetic Toxicology..................................................................................................48
`5.5.3. Carcinogenicity .......................................................................................................49
`5.5.4. Reproductive and Developmental Toxicology ........................................................49
`
`2
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4173186
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {NDA 210259}
`{CALQUENCE, acalabrutinib}
`
`6
`
`7
`
`8
`
`5.5.5. Other Toxicology Studies ........................................................................................53
`
`6.3.
`
`Clinical Pharmacology ...........................................................................................................57
`6.1.
`Executive Summary........................................................................................................57
`6.2.
`Summary of Clinical Pharmacology Assessment............................................................58
`6.2.1. Pharmacology and Clinical Pharmacokinetics.........................................................58
`6.2.2. General Dosing and Therapeutic Individualization.................................................58
`Comprehensive Clinical Pharmacology Review..............................................................59
`6.3.1. General Pharmacology and Pharmacokinetic Characteristics ................................59
`6.3.2. Clinical Pharmacology Questions............................................................................61
`6.3.3. Physiologically-Based Pharmacokinetic Modeling Review .....................................72
`6.3.4. Results ....................................................................................................................76
`6.3.5. Population Pharmacokinetics and Exposure-Response Analyses...........................82
`6.3.6. Recommendations..................................................................................................83
`6.3.7. Results of Sponsor’s Analysis..................................................................................83
`6.3.8. Reviewer’s Analysis.................................................................................................91
`6.3.9. Results ....................................................................................................................91
`
`Sources of Clinical Data and Review Strategy .......................................................................99
`7.1.
`Table of Clinical Studies .................................................................................................99
`7.2.
`Review Strategy ...........................................................................................................101
`
`Statistical and Clinical and Evaluation.................................................................................102
`8.1.
`Review of Relevant Individual Trials Used to Support Efficacy ....................................102
`
`8.1.1.Study ACE-LY-004: An Open Label, Phase 2 Study of ACP-196 in Subjects with
`Mantle Cell Lymphoma .................................................................................................102
`
`8.2.
`
`8.1.2. Study Results ACE-LY-004 .....................................................................................108
`8.1.3. Assessment of Efficacy Across Trials.....................................................................119
`8.1.4. Integrated Assessment of Effectiveness...............................................................120
`Review of Safety...........................................................................................................120
`8.2.1. Safety Review Approach .......................................................................................120
`8.2.2. Review of the Safety Database .............................................................................121
`8.2.3. Adequacy of Applicant’s Clinical Safety Assessments...........................................123
`8.2.4. Safety Results........................................................................................................124
`8.2.5. Analysis of Submission-Specific Safety Issues.......................................................148
`3
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4173186
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {NDA 210259}
`{CALQUENCE, acalabrutinib}
`
`8.2.6. Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ......148
`8.2.7. Safety Analyses by Demographic Subgroups........................................................149
`8.2.8. Specific Safety Studies/Clinical Trials....................................................................150
`8.2.9. Additional Safety Explorations..............................................................................150
`8.2.10.
`Safety in the Postmarket Setting...................................................................151
`8.2.11.
`Integrated Assessment of Safety...................................................................151
`
`SUMMARY AND CONCLUSIONS..................................................................................................153
`8.3.
`Statistical Issues ...........................................................................................................153
`8.4.
`Conclusions and Recommendations ............................................................................153
`
`9
`
`Advisory Committee Meeting and Other External Consultations .......................................155
`
`10 Pediatrics.............................................................................................................................156
`
`11 Labeling Recommendations ................................................................................................156
`11.1.
`Prescribing Information............................................................................................156
`11.2.
`Patient Labeling........................................................................................................156
`
`12 Risk Evaluation and Mitigation Strategies (REMS) ..............................................................158
`
`13 Postmarketing Requirements and Commitments...............................................................159
`
`14 Appendices..........................................................................................................................160
`14.1.
`References................................................................................................................160
`14.2.
`Financial Disclosure ..................................................................................................160
`14.3.
`Nonclinical Pharmacology/Toxicology......................................................................162
`14.4.
`OCP Appendices (Technical documents supporting OCP recommendations)..........162
`14.4.1.
`Summary of Bioanalytical Method Validation and Performance ..................162
`14.4.2.
`Relative Bioavailability of Acalabrutinib Formulations..................................164
`14.4.3.
`Supplemental Tables and Figures..................................................................164
`
`15 Division Director (DHOT) .....................................................................................................169
`
`16 Division Director (OCP)........................................................................................................170
`
`17 Division Director (OB)..........................................................................................................171
`
`18 Division Director (Clinical) ...................................................................................................172
`
`4
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4173186
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {NDA 210259}
`{CALQUENCE, acalabrutinib}
`
`19 Office Director (or designated signatory authority)............................................................174
`
`5
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4173186
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {NDA 210259}
`{CALQUENCE, acalabrutinib}
`
`Table of Tables
`
`Table 1: FDA Approved Drugs for the Treatment of MCL............................................................22
`Table 2: Summary of Regulatory Activity for acalabrutinib.........................................................23
`Table 3 Variation in half-maximal inhibitory concentrations (IC50) of acalabrutinib and ACP-5862
`in BTK IMAP ATP competition assay.............................................................................................29
`Table 4 Kd Values of kinases with >65% inhibition at 1 µM for Acalabrutinib and ACP-5862......30
`Table 5 Potency of Acalabrutinib and ACP-5862 on 3F-Cys Kinases.............................................30
`Table 6 Return of Function Profile of CD86 and CD69 Expression in Response to Ex Vivo BCR
`Stimulation in mouse splenocyte B cells ......................................................................................31
`Table 7 Summary of Effects of Acalabrutinib and Ibrutinib on T Cells and NK cells .....................31
`Table 8 ADME/PK..........................................................................................................................36
`Table 9 Observations and Results: changes from control ............................................................41
`Table 10 Histopathology Changes in Surviving Animals in 26-week Toxicology Study in Rats.....43
`Table 11 Observations and Results: changes from control ..........................................................45
`Table 12 Histopathology Changes in 3-month (91-day) Toxicology Study in Dogs.......................46
`Table 13 Observations and Results...............................................................................................50
`Table 14 Observations and Results...............................................................................................52
`Table 15 Results of Genetic Toxicology Studies Conducted with Impurities present in
`Acalabrutinib ................................................................................................................................54
`Table 16 Impurity Qualification with Doses Based on BSA (mg/m2) for Drug Substance.............55
`Table 17 Impurity Qualification with Doses Based on BSA (mg/m2) for Drug Product.................55
`Table 18 General Pharmacology and Pharmacokinetic Characteristics .......................................59
`Table 19 Summary of Clinical Studies and Data Used for Exposure-Response Analyses .............63
`Table 20 Summary of acalabrutinib PK parameters and LSM analysis in hepatic impairment
`study.............................................................................................................................................66
`Table 21 Summary of acalabrutinib PK parameters and LSM analysis in juice-effect parts of
`Study ACE-HV-112 ........................................................................................................................67
`Table 22 Summary of acalabrutinib PK parameters and LSM analysis in food-effect part of Study
`ACE-HV-001 ..................................................................................................................................68
`Table 23 Summary of acalabrutinib PK parameters and LSM analysis in gastric acid reducing
`agent parts of Study ACE-HV-004.................................................................................................68
`Table 24 Summary of acalabrutinib PK parameters and LSM analysis in rifampin DDI part of
`Study ACE-HV-004 ........................................................................................................................69
`Table 25 Summary of acalabrutinib PK parameters and LSM analysis in itraconazole DDI part of
`Study ACE-HV-001 ........................................................................................................................69
`Table 26 Predicted effect of moderate CYP3A inhibitors on acalabrutinib exposure ..................70
`Table 27 Trial designs for key PBPK simulations used in the PK and DDI simulations..................75
`Table 28 Observed and simulated PK of acalabrutinib and ACP-5862 after a single oral dosing of
`400 mg acalabrutinib in healthy subjects.....................................................................................77
`Table 29 Observed and simulated PK of acalabrutinib and ACP-5862 following repeat dosing of
`itraconazole 200mg bid ................................................................................................................78
`
`6
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4173186
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {NDA 210259}
`{CALQUENCE, acalabrutinib}
`
`Table 30 Observed and simulated PK of acalabrutinib and ACP-5862 following repeat dosing of
`rifampicin 600mg qd.....................................................................................................................78
`Table 31 Simulated geometric mean AUC values of acalabrutinib and ACP-5862 in the absence
`and presence of different CYP3A4 inhibitors/inducers ................................................................79
`Table 32 Predicted effect of moderate CYP3A inhibitors on acalabrutinib exposure ..................80
`Table 33 Simulated effects of acalabrutinib on PK of midazolam ................................................80
`Table 34 Simulated effects of acalabrutinib on PK of rosiglitazone .............................................81
`Table 35: Summary of AUC24h,ss and Cmax,ss from 100 mg BID regimen by categorical covariate
`category........................................................................................................................................86
`Table 36: Studies included in exposure-response analyses..........................................................87
`Table 37: Summary of AUC0-24 by efficacy response as assessed by IRC per Lugano classification
`(ACE-LY-004; n=45) .......................................................................................................................89
`Table 38: Pop-PK model comparison by removing certain covariate on clearance .....................92
`Table 39: Parameter comparison between sponsor’s final Pop-PK model and FDA’s final Pop-PK
`model............................................................................................................................................94
`Table 40: Overall response rate based on investigator and IRC assessment ...............................95
`Table 41: Estimated Parameters in logistic regression for ER relationship for efficacy ...............96
`Table 42: Incident rate of neutropenia prediction by logistic regression.....................................97
`Table 43: Parameters estimated for ER-Safety logistic regression...............................................98
`Table 44 Listing of Analyses Codes and Output Files....................................................................98
`Table 45: Listing of Clinical Studies Relevant to this NDA ............................................................99
`Table 46: Summary of Major Protocol Changes to Pivotal Study ACE-LY-004...........................106
`Table 47: Summary of Patient Disposition on Study ACE-LY-004 (All Treated)(N=124) .............109
`Table 48: Important Protocol Deviations in Study ACE-LY-004 .................................................110
`Table 49: Baseline Demographic Characteristics of Patients Enrolled on ACE-LY-004 ..............111
`Table 50: Additional Disease - Related Baseline Characteristics of Patients on ACE-LY-004.....111
`Table 51: Select Prior Therapy Regimens for Patients on ACE-LY-004 ......................................113
`Table 52: Overall response rate and best overall response by investigator assessment and
`Independent Review Committee according to Lugano classification (all treated subjects).......114
`Table 53: Secondary Endpoints Results (Progression based on Investigator assessment)........115
`Table 54: Secondary endpoint result - IRC-assessed .................................................................115
`Table 55: Concordance between investigator and IRC-assessed responses according to 2014
`Lugano classification (all treated subjects).................................................................................115
`Table 56 Best Response for Patients with Dose Interruption of > 7 days...................................118
`Table 57: Response rates(percentage) in Patients with Extranodal Disease.............................119
`Table 58: Duration of Exposure in the Primary Safety Population ............................................121
`Table 59: Demographics of the Safety Population ....................................................................122
`Table 60: Summary of Deaths....................................................................................................124
`Table 61: Selected Summaries of Deaths within 30 days of study drug, death due to an AE or
`death due to “other” or “unknown” in Ace-LY-004....................................................................125
`Table 62: Serious Adverse Events by System Organ Class and Preferred Term .........................129
`Table 63: SAEs by Preferred Term Occurring in > 2% patients in study ACE-LY-004 .................131
`
`7
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4173186
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {NDA 210259}
`{CALQUENCE, acalabrutinib}
`
`Table 64: Summary of AEs leading to Acalabrutinib Discontinuation in ACE-LY-004, ISS-100 and
`ISS-ALL populations ....................................................................................................................131
`Table 65: Treatment Emergent Adverse Events Resulting in Acalabrutinib Treatment Delay
`Occurring in > 2 patients ............................................................................................................132
`Table 66: Grade >3 AEs in > 2% of any analysis safety population............................................133
`Table 67: Events of Clinical Interests in patients in ACE-LY-004................................................134
`Table 68: SPMs occurring in patients in Study ACE-LY-004 .......................................................137
`Table 69: Treatment Emergent Adverse Events reported in greater than 10% of the safety
`population ..................................................................................................................................138
`Table 70: Summary of Hematology Laboratory Abnormalities .................................................139
`Table 71 Hematologic Adverse Reactions (NCI-CTACAE and laboratory measurements)..........139
`Table 72: Summary of > Grade 3 Chemistry Laboratory Abnormalities occurring in > 5% of
`patients.......................................................................................................................................141
`Table 73: Summary of Selected All Grades Chemistry Laboratory Abnormalities occurring in >
`20% of patients...........................................................................................................................142
`Table 74: Percentage Shift increase in AST, ALT and Bilirubin from baseline in Study ACE-LY-004
`(N = 124) .....................................................................................................................................143
`Table 75: Lymphocytosis in patients receiving acalabrutinib therapy.......................................144
`Table 76: Lymphocytosis related AEs on study ACE-LY-004 ......................................................145
`Table 77 Hypertension in Study ACE-LY-004 ..............................................................................147
`Table 78 Validated bioanalytical methods for acalabrutinib and ACP-5862 in human biological
`samples.......................................................................................................................................162
`Table 79 Validation accuracy, precision, stability data for bioanalytical methods for
`acalabrutinib in human biological samples ................................................................................163
`Table 80 Validation accuracy, precision, stability data for bioanalytical methods for
`acalabrutinib and ACP-5862 in human biological samples.........................................................163
`
`8
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4173186
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {NDA 210259}
`{CALQUENCE, acalabrutinib}
`
`Table of Figures
`
`Figure 1 Effects of Acalabrutinib on Tumor Growth in the Jeko-1 Model of Mantle Cell
`Lymphoma....................................................................................................................................32
`Figure 2 Convulxin-induced aggregation of platelets harvested from patients with CLL.............33
`Figure 3 Effect of ibrutinib vs. acalabrutinib on human platelet thrombus formation ................34
`Figure 4 Pharmacodynamic properties of acalabrutinib and ibrutinib.........................................34
`Figure 5 Response rates from Study ACE-CL-001 .........................................................................62
`Figure 6 BTK occupancy from Study ACE-CL-001..........................................................................62
`Figure 7 Exposure-response for efficacy by logistic regression....................................................64
`Figure 8 Exposure-response relationship for AUC0-24h versus incident rate of neutropenia by
`logistic regression.........................................................................................................................65
`Figure 9 Workflow of development, verification and application of final acalabrutinib PBPK
`model............................................................................................................................................74
`Figure 10 Observed and simulated PK of acalabrutinib and ACP-5862 after a single oral dosing of
`100 mg acalabrutinib in healthy subjects.....................................................................................76
`Figure 11: Boxplots of random Effects of CL/F(top row) and Vc/F (bottom row) vs Categorical
`Covariates (columns) ....................................................................................................................85
`Figure 12: Box plot of acalabrutinib AUC0-24 by overall response rate as assessed by...............88
`Figure 13: Box plot of acalabrutinib AUC0-24 by AEs in patients with B-cell malignancies (==292)
`......................................................................................................................................................90
`Figure 14: Boxplots of random Effects of CL/F vs Categorical Covariates ....................................93
`Figure 15: Exposure response for efficacy by logistic regression .................................................96
`Figure 16: Exposure response relationship for AUC(0-24hr) versus incident rate of neutropenia
`by logistic regression ....................................................................................................................97
`Figure 17: Waterfall plot or tumor shrinkage and response to treatment for individual patients
`on ACE-LY-004 ............................................................................................................................116
`Figure 18: Best response and baseline tumor volume ..............................................................117
`Figure 20: Mean (+/-) SEM of ANC (109/L).................................................................................140
`Figure 21
`Mean (+/-) SEM of Hemoglobin g/L......................................................................140
`Figure 22 Mean (+/-) SEM Platelets (109/L)................................................................................141
`Figure 23: Mean plot of absolute lymphocyte counts over time – all treated subjects on ACE-LY-
`004..............................................................................................................................................145
`Figure 24: Mean plot of EORTC QLQ-C30 over time, global health status/quality of life (all
`treated subjects).........................................................................................................................149
`Figure 25 Comparison of AUC and CMAX by formulation in various clinical studies....................164
`
`9
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4173186
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {NDA 210259}
`{CALQUENCE, acalabrutinib}
`
`Reviewers of Multi-Disciplinary Review and Evaluation
`
`Regulatory Project Manager
`Nonclinical Reviewer
`Nonclinical Team Leader
`Office of Clinical Pharmacology Reviewer(s)
`Office of Clinical Pharmacology Team Leader(s)
`Clinical Reviewer
`Clinical Team Leader
`Statistical Reviewer
`Statistical Team Leader
`Cross-Disciplinary Team Leader
`Division Director (DHOT)
`Division Director (OCP)
`Division Director (OB)
`Division Director (OHOP)
`Office Director (or designated signatory authority)
`
`Ashley Lucci Vaughn
`Brenda Gehrke
`Christopher Sheth
`Vicky Hsu
`Gene Williams
`Margret Merino
`Tanya Wroblewski
`Jingjing Ye
`Lei Nie
`Tanya Wroblewski
`John Leighton
`Nam Atiqur Rahman
`Rajeshwari Sridhara
`Albert Deisseroth
`Richard Pazdur
`
`Additional Reviewers of Application
`
`Sherita McLamore
`Not Applicable
`Nisha Patel
`Anthony Orencia
`Not Applicable
`Leeza Rahimi
`Ingrid Chapman
`Sharon Mills
`
`OPQ
`Microbiology
`OPDP
`OSI
`OSE/DEPI
`OSE/DMEPA
`OSE/DRISK
`DMPP
`OPQ=Office of Pharmaceutical Quality
`OPDP=Office of Prescription Drug Promotion
`OSI=Office of Scientific Investigations
`OSE= Office of Surveillance and Epidemiology
`DEPI= Division of Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DRISK=Division of Risk Management
`
`10
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4173186
`
`

`

`NDA/BLA Multi-disciplinary Review and Evaluation {NDA 210259}
`{CALQUENCE, acalabrutinib}
`
`Glossary
`
`AC
`ADME
`AE
`ALT
`ANC
`AST
`BCR
`BLA
`BPCA
`BRF
`BTK
`CBER
`CDER
`CDRH
`CDTL
`CFR
`CLL
`CMC
`CNS
`COSTART
`CR
`CRF
`CRO
`CRT
`CSR
`CSS
`CSR
`CT
`DHOT
`DMC
`ECG
`eCTD
`EORTC
`ETASU
`FDA
`FDAAA
`FDASIA
`GALT
`GCP
`
`advisory committee
`absorption, distribution, metabolism, excretion
`adverse event
`alanine aminotransferase
`Absolute neutrophil count
`aspartate aminotransferase
`B-cell antigen receptor
`biologics license application
`Best Pharmaceuticals for Children Act
`Benefit Risk Framework
`Bruton tyrosine kinase
`Center for Biologics Evaluation and Research
`Center for Drug Evaluation and Research
`Center for Devices and Radiological Health
`Cross-Discipline Team Leader
`Code of Federal Regulations
`Chronic lymphocytic leukemia
`chemistry, manufacturing, and controls
`central nervous system
`Coding Symbols for Thesaurus of Adverse Reaction Terms
`Complete Response
`case report form
`contract research organization
`clinical review template
`clinical study report
`Controlled Substance Staff
`Clinical Study Report
`Computed tomography
`Division of Hematology Oncology Toxicology
`data monitoring committee
`electrocardiogram
`electronic common technical document
`European Organization for Research and Treatment of Cancer
`element