`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205552Orig2s000
`
`MEDICAL REVIEW(S)
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`

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`CLINICAL REVIEW
`
`Application Type NDA
`Application Number 205552 Original-2
`Priority or Standard Priority
`
`Submit Date 28 June 2013
`Received Date 28 June 2013
`PDUFA Goal Date 28 February 2014
`Division / Office DHP/OHOP
`
`Reviewer Name Nicole Verdun, MD
`Review Completion Date 10 February 2014
`
`Established Name Ibrutinib
`Trade Name Imbruvica
`Therapeutic Class Kinase Inhibitor
`Applicant Pharmacyclics, Inc.
`
`Formulation(s) Tablet, 140 mg
`Dosing Regimen 420 mg once daily
`Indication(s) Patients with CLL who have
`received at least one prior
`therapy.
`Intended Population(s) ≥ 18 years of age
`
`Template Version: March 6, 2009
`
`Reference ID: 3452364
`
`

`

`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT......................................... 9
`1.1 Recommendation on Regulatory Action ............................................................. 9
`1.2 Risk Benefit Assessment.................................................................................... 9
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 12
`1.4 Recommendations for Postmarket Requirements and Commitments .............. 12
`INTRODUCTION AND REGULATORY BACKGROUND ...................................... 15
`2.1 Product Information .......................................................................................... 16
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 16
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 17
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 18
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 18
`2.6 Other Relevant Background Information .......................................................... 18
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 19
`3.1 Submission Quality and Integrity ...................................................................... 19
`3.2 Compliance with Good Clinical Practices ......................................................... 19
`Protocol Violations (N=48)......................................................................................... 20
`3.3 Financial Disclosures........................................................................................ 20
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 21
`4.1 Chemistry Manufacturing and Controls ............................................................ 21
`Source: Module 3.2.S.1.3 ......................................................................................... 22
`4.2 Clinical Microbiology......................................................................................... 23
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 23
`4.4 Clinical Pharmacology...................................................................................... 23
`4.4.1 Mechanism of Action.................................................................................. 23
`4.4.2 Pharmacodynamics.................................................................................... 24
`4.4.3 Pharmacokinetics....................................................................................... 24
`5 SOURCES OF CLINICAL DATA............................................................................ 25
`5.1 Tables of Studies/Clinical Trials ....................................................................... 25
`5.2 Review Strategy ............................................................................................... 27
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 27
`6 REVIEW OF EFFICACY......................................................................................... 37
`Efficacy Summary...................................................................................................... 37
`6.1
`Indication .......................................................................................................... 38
`6.1.1 Methods ..................................................................................................... 38
`6.1.2 Demographics............................................................................................ 38
`6.1.3 Subject Disposition .................................................................................... 40
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`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 40
`6.1.5 Analysis of Secondary Endpoints(s)........................................................... 41
`6.1.6 Other Endpoints ......................................................................................... 41
`Other secondary endpoints of the study not outlined above included the following:
`................................................................................................................... 42
`6.1.7 Subpopulations .......................................................................................... 42
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 42
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 42
`6.1.10 Additional Efficacy Issues/Analyses........................................................... 42
`7 REVIEW OF SAFETY............................................................................................. 44
`Safety Summary ........................................................................................................ 44
`7.1 Methods............................................................................................................ 45
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 45
`7.1.2 Categorization of Adverse Events.............................................................. 46
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 46
`7.2 Adequacy of Safety Assessments .................................................................... 47
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 47
`7.2.2 Explorations for Dose Response................................................................ 50
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 50
`7.2.4 Routine Clinical Testing ............................................................................. 50
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 51
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 51
`7.3 Major Safety Results ........................................................................................ 51
`7.3.1 Deaths........................................................................................................ 51
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 51
`7.3.3 Dropouts and/or Discontinuations .............................................................. 52
`7.3.4 Significant Adverse Events ........................................................................ 53
`7.3.4.1 Hemorrhage ............................................................................................... 53
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 58
`7.4 Supportive Safety Results ................................................................................ 58
`7.4.1 Common Adverse Events .......................................................................... 58
`7.4.2
`Laboratory Findings ................................................................................... 59
`7.4.3 Vital Signs .................................................................................................. 61
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 61
`7.4.5 Special Safety Studies/Clinical Trials......................................................... 61
`7.4.6
`Immunogenicity.......................................................................................... 62
`7.5 Other Safety Explorations................................................................................. 62
`7.5.1 Dose Dependency for Adverse Events ...................................................... 62
`7.5.2 Time Dependency for Adverse Events....................................................... 62
`7.5.3 Drug-Demographic Interactions ................................................................. 62
`7.5.4 Drug-Disease Interactions.......................................................................... 62
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`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`7.5.5 Drug-Drug Interactions............................................................................... 63
`7.6 Additional Safety Evaluations ........................................................................... 63
`7.6.1 Human Carcinogenicity.............................................................................. 63
`7.6.2 Human Reproduction and Pregnancy Data................................................ 63
`See the non-clinical review for further details......................................................... 63
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 64
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 64
`7.7 Additional Submissions / Safety Issues............................................................ 64
`8 POSTMARKET EXPERIENCE............................................................................... 64
`9 APPENDICES ........................................................................................................ 65
`9.1
`Literature Review/References .......................................................................... 65
`9.2
`Labeling Recommendations ............................................................................. 69
`9.3 Advisory Committee Meeting............................................................................ 69
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`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`Table of Tables
`
`Table 1 Benefit-Risk Assessment ................................................................................. 10
`Table 2 FDA-Approved Drugs for CLL .......................................................................... 17
`Table 3 Summary of Presubmission Regulatory Activites ............................................. 18
`Table 4 Solubility of Drug Substance at Room Temperature ........................................ 22
`Table 5 Table of Clinical Trials ...................................................................................... 25
`Table 6 Drug Discontinuation Actions for Subjects on Ibrutinib..................................... 31
`Table 8 Schedule of Assessments (All Treatment Groups)........................................... 33
`Table 7 Protocol Amendments and Trial Milestones ..................................................... 35
`Table 9 Demographics of Efficacy Population............................................................... 39
`Table 10 Disease Characteristics of Patients in Efficacy Population............................. 39
`Table 11 Study 1102-CA Disposition (Data Cutoff 18 December 2012)........................ 40
`Table 12 FDA Adjudication for Overall Response ......................................................... 41
`Table 13 FDA Adjudication for Duration of Response................................................... 41
`Table 14 2008 IWCLL Response Assessment Criteria ................................................. 43
`Table 15 Baseline Patient Characteristics at Study Entry ............................................. 47
`Table 16 Baseline Disease Characteristics ................................................................... 48
`Table 17 Prior Treatment History .................................................................................. 49
`Table 18 Safety Summary for Study 1102-CA .............................................................. 51
`Table 19 Deaths within 30 days of Ibrutinib Treatment in Study 1102-CA .................... 51
`Table 20 Non-Fatal Serious Adverse Events in Study 1102-CA ................................... 51
`Table 21 Adverse Events Leading to Discontinuation ................................................... 52
`Table 22 Bleeding Events ............................................................................................. 53
`Table 23 Serious Adverse Events of Infection............................................................... 55
`Table 24 Treatment-Emergent Decrease of Platelets, Neutrophils, or Hemoglobin in
`Patients with CLL (N=48) .............................................................................................. 56
`Table 25 Secondary Malignancies in Study 1102-CA (N=48) ....................................... 56
`Table 26 Treatment-Emergent Adverse Events in ≥ 10% of Patients in Study 1102-CA
`...................................................................................................................................... 58
`Table 27 Treatment-Emergent Non-Hematology Laboratory Abnormalities.................. 60
`Table 28 Treatment-Emergent Decrease of Hematology Laboratory Parameters in
`Patients with CLL (N=48) .............................................................................................. 60
`Table 29 Increase in Blood Pressure Study 1102-CA .................................................. 61
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`

`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`Figure 1 Structure of ibrutinib ....................................................................................... 21
`
`Table of Figures
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`Reference ID: 3452364
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`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`LIST OF ABBREVIATIONS
`
`AE
`ALC
`ALT
`ANC
`AST
`AUC
`AUClast
`
`B cells
`BCR
`BCS
`BR
`BTK
`CFAR
`CI
`CLL
`Cmax
`CR
`CSR
`CV
`CXC
`CYP
`Cys
`del 17p
`ECG
`ECOG
`EU
`FA
`FC
`FCR
`FDA
`IC50
`ICH
`Ig
`IRC
`ISE
`ISS
`IWCLL
`
`adverse event
`absolute lymphocyte counts
`alanine aminotransferase
`absolute neutrophil count
`aspartate aminotransferase
`area under the plasma concentration versus time curve
`area under the plasma concentration-time curve to the last
`quantifiable concentration
`B lymphocytes
`B-cell antigen receptor
`Biopharmaceutics Classification System
`bendamustine and rituximab
`Bruton’s tyrosine kinase
`cyclophosphamide + fludarabine + alemtuzumab + rituximab
`confidence interval
`chronic lymphocytic leukemia
`maximum observed plasma concentration
`complete response
`clinical study report
`coefficient of variation
`chemokine receptors
`cytochrome P450
`cysteine residue
`deletion of the short arm of chromosome 17
`electrocardiogram
`Eastern Cooperative Oncology Group
`European Union
`fludarabine + alemtuzumab
`fludarabine + cyclophosphamide
`fludarbarine + cyclophosphamide + rituximab
`Food and Drug Administration
`half maximal inhibitory concentration
`International Conference on Harmonisation
`immunoglobulin
`Independent Review Committee
`Integrated Summary of Efficacy
`Integrated Summary of Safety
`International Workshop on Chronic Lymphocytic Leukemia
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`Reference ID: 3452364
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`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`lactate dehydrogenase
`LDH
`mantle cell lymphoma
`MCL
`MedDRA Medical Dictionary for Regulatory Activities
`MIPI
`mantle cell lymphoma international prognostic index
`MTD
`maximum tolerated dose
`NCCN
`National Comprehensive Cancer Network
`NDA
`New Drug Application
`NE
`not estimable
`NHL
`non-Hodgkin lymphoma
`NOAEL
`no-observed-adverse-effect level
`NR
`not reported
`ORR
`overall response rate
`PBMC
`peripheral blood mononuclear cells
`PFS
`progression-free survival
`P-gp
`p-glycoprotein
`PR
`partial response
`SAE
`serious adverse event(s)
`SCE
`summary of clinical efficacy
`SCS
`summary of clinical safety
`SCT
`stem cell transplantation
`SLL
`small lymphocytic lymphoma
`Syk
`spleen tyrosine kinase
`TEAE
`treatment-emergent adverse event
`Tmax
`time of maximum concentration
`ULN
`upper limit of normal
`US
`United States
`WHO
`World Health Organization
`
`Reference ID: 3452364
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`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`I recommend accelerated approval for Imbruvica for the treatment of adult patients with
`chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.
`
`1.2 Risk Benefit Assessment
`
`The basis for accelerated approval is a single Phase 1b/2 clinical trial. Study 1102-CA
`was a single-arm, fixed-dose clinical trial where the efficacy and safety of ibrutinib was
`demonstrated in cohorts of patients with CLL. The efficacy and safety population
`consists of 48 patients with relapsed or refractory CLL who received ibrutinib 420 mg
`daily.
`
`Risk. The primary endpoint of Study 1102-CA was frequency, severity, and relatedness
`of adverse events. A summary of the key safety findings are listed below:
`
` The ibrutinib dose was 420 mg once daily. The median exposure duration was
`15.6 months.
`
` All treated subjects experienced at least 1 treatment-emergent adverse event.
`
` Sixty-three percent of patients (n=28) had at least one bleeding event,
`characterized as bruising (54%), epistaxis (6%), eye related hemorrhage (6%),
`rectal hemorrhage (4%), or subdural hematoma (4%). Seventeen percent of
`patients experienced petechiae during the clinical trial.
`
` The most common non-hematological adverse events (occurring in ≥ 20% of
`patients) were diarrhea (63%), bruising (54%), upper respiratory tract infection
`(48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%),
`peripheral edema (23%), arthralgia (23%), constipation (23%), stomatitis (21%),
`sinusitis (21%), nausea (21%), and dizziness (21%).
`
` The most common Grade 3 or 4 adverse events (occurring in ≥ 5% of patients)
`were neutropenia, pneumonia, thrombocytopenia, hypertension, dehydration,
`and sinusitis, atrial fibrillation, skin infection, and musculoskeletal pain.
`
` Forty-two percent (n=20) of patients required a dose modification or interruption
`due to an adverse event. The most common adverse events leading to a
`modification or interruption were infections (19%).
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`Reference ID: 3452364
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`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`Clinical Benefit. The efficacy of ibrutinib at the proposed dose was evaluated in 48
`patients with relapsed or refractory CLL enrolled in study 1102-CA in 4 of the 6 study
`cohorts. Participation in a specific cohort was according to age at the time of enrollment,
`treatment history, and disease severity. A summary of the key efficacy endpoints and
`findings based on the data cut-off date of 18 December 2012 are listed below:
`
` To assess for efficacy, the overall response rate by Independent Review
`Committee (IRC) assessment was accepted.
`
` Overall response (ORR) and duration of response (DOR) were assessed using a
`modified version of the International Working Group CLL Criteria by an
`Independent Review Committee. The ORR was 58.3% (95% CI: 43.2%, 72.4%),
`all partial responses. None of the patients achieved a complete response.
`
` The DOR ranged from 5.6 to 24.2+ months. The median DOR was not reached.
`
` During the review, the Applicant notified the Agency regarding early stopping of
`the RESONATE trial (PCYC-1112-CA), a Phase 3, randomized controlled trial of
`ibrutinib or ofatumumab in patients with previously treated CLL due to significant
`improvements in progression-free survival and overall survival in the ibrutinib
`arm.
`
`Table 1 Benefit-Risk Assessment
`Decision Factor
`Evidence and Uncertainties
`Analysis of
`The condition is an orphan
`Condition:
`indication that is considered serious
`Relapsed or
`and life threatening. Current
`Refractory CLL
`treatments are limited by
`subsequent relapse, development
`of resistance, and toxicities.
`Current FDA approved therapies for
`CLL include chlorambucil,
`cyclophosphamide, fludarabine,
`alemtuzumab, bendamustine,
`ofatumumab, the combination of
`rituximab with fludarabine and
`cyclophosphamide and
`obinutuzumab
`
`Unmet Medical
`Need
`
`Clinical Benefit
`
`Efficacy results from one Phase
`1b/2 single arm trial demonstrated
`
`Conclusions and Reasons
`Relapsed or refractory CLL is
`a serious and life threatening
`condition for which ibrutinib
`demonstrated clinical activity.
`
`There remains an unmet
`medical need for therapies
`that improve disease control,
`delay disease progression,
`and have a better toxicity
`profile. Relapse is a
`significant problem in the
`treatment of CLL, and effective
`treatments in the relapsed or
`refractory setting are limited.
`The applicant’s results were
`verified on analysis of the raw
`
`Reference ID: 3452364
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`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`Decision Factor
`
`Evidence and Uncertainties
`an ORR of 58.3% with a median
`duration of treatment of 15.6
`months.
`
`Risks
`
`The safety profile is notable for the
`development of serious adverse
`events in 52% of patients treated.
`Bleeding events occurred in 63% of
`patients. At least 35% of patients
`treated had infections of Grade 3 or
`higher during the trial. Ten percent
`of patients developed a secondary
`malignancy during the course of the
`clinical trial, with one death due to a
`secondary malignancy, and one
`death due to infection.
`
`Risk
`Management
`
`The applicant has not proposed a
`REMS assessment plan, but has
`proposed a pharmacovigilance plan
`to monitor bleeding events,
`infections, secondary malignancies,
`renal toxicity, and leukostasis.
`
`Conclusions and Reasons
`data. OSI inspections of the
`clinical site data concluded
`that the data were reliable.
`The evidence for clinical
`benefit is acceptable and
`supports accelerated approval.
`Randomized confirmatory
`trials are needed to further
`characterize the safety profile
`and are ongoing. The
`Applicant also has
`pharmacovigilance plans to
`capture more data regarding
`bleeding events, infections,
`and secondary malignancies.
`In addition, post marketing
`requirements are
`recommended to attempt to
`characterize further the
`pathophysiology of bleeding
`events.
`A REMS assessment plan is
`not recommended.
`
`1.2.1 Recommendation for Accelerated Approval versus Regular Approval
`
`Section 21 CFR 314.510 addresses approval based on a clinical endpoint other than
`survival or irreversible morbidity. Accelerated approval is subject to the requirement that
`the applicant study the drug further, to verify and describe its clinical benefit, where
`there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of
`the observed clinical benefit to ultimate outcome. The recommendation for accelerated
`approval for ibrutinib rather than regular approval is based upon the following
`considerations:
` Uncertainty in the relation of overall response rate and duration of response to
`overall survival.
` The median duration of response is based upon a small number of events with
`limited follow up.
`
`Reference ID: 3452364
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`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
` Limited number of patients treated at the proposed dose (N=48) in a single arm
`trial. Further study with randomized trials is needed.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`At the time of completion of this review, the clinical team determined that a Risk
`Evaluation and Mitigation Strategy (REMS) would not be required for this approval. The
`Applicant did not submit a REMS proposal with the application.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`At the time of completion of this review, the clinical team determined the need for the
`following post-marketing requirements:
`
`Subpart H
`
` PMR-2122-1: Submit the results of the completed randomized, open-label
`Phase 3 clinical trial (PCYC-1112-CA) of ibrutinib versus ofatumumab in
`patients with relapsed or refractory chronic lymphocytic leukemia or
`relapsed or refractory small lymphocytic lymphoma. Enrollment of 391
`patients was completed. The primary endpoint is progression-free survival
`as assessed by an Independent Review Committee.
`
`Final Protocol Submission: Completed (01/2014)
`Trial Completion:
`Completed (01/2014)
`Final Report Submission: 06/2014
`
` PMR -2122-2: Complete and submit the results of the ongoing
`randomized, double-blind, placebo-controlled Phase 3 clinical trial (PCI-
`32765CLL3001) of ibrutinib in combination with bendamustine and
`rituximab in patients with relapsed or refractory chronic lymphocytic
`leukemia or relapsed or refractory small lymphocytic lymphoma.
`Enrollment of 578 patients was completed. The primary endpoint is
`progression-free survival as assessed by an Independent Review
`Committee.
`
`Final Protocol Submission: Completed (09/2013)
`Trial Completion:
`07/2016
`Final Report Submission: 11/2016
`
`Reference ID: 3452364
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`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`Successful completion of either PMR 2122-1 or PMR 2122-2 could verify clinical
`benefit and fulfill accelerated approval requirements for the Chronic Lymphocytic
`Leukemia (CLL) indication.
`
`Postmarketing Requirements PMR 2060-3; PMR 2060-4; PMR 2060-5; PMR
`2060-6; PMR 2060-7 and Postmarketing Commitment PMC 2060-8 listed in the
`approval letter dated November 13, 2013, for NDA 205552-Original #1, for the
`treatment of mantle cell lymphoma will also apply to this NDA 20552-Original-2.
`They are as follows:
`
` PMR 2060-3 Determine the effect of a broad range of concentrations of
`ibrutinib on the potential to inhibit platelet function by conducting in vitro
`studies. Assessment methods should include evaluation of effects on
`platelet aggregation, including GPIb-mediated aggregation. Evaluation
`should include samples from subjects with and without concomitant
`conditions associated with platelet dysfunction (e.g., severe renal
`dysfunction, use of a concomitant anticoagulant, and use of aspirin).
`
`Draft Protocol Submission: 06/2014
`Final Protocol Submission: 12/2014
`Study Completion:
` 06/2016
`Final Report Submission: 12/2016
`
` PMR 2060-4 Conduct an assessment and an analysis of data from
`clinical trials and all post-marketing sources in order to characterize the
`risk of serious bleeding in patients treated with Imbruvica®, (ibrutinib)
`Capsules. The risks of special interest are major hemorrhagic events and
`their potential association with concomitant use of anti-platelet and/or
`anticoagulant drugs. Major hemorrhagic events are defined as any one of
`the following:
`
`Symptomatic bleeding in a critical area or organ, such as
`I.
`intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or
`pericardial, or intramuscular with compartment syndrome,
`II.
`Bleeding causing a fall in hemoglobin level of 20 g/L or more, or
`leading to transfusion of two or more units of whole blood or red cells,
`III.
`Bleeding resulting in a serious adverse drug experience [as per 21
`CFR 314.80(a)]
`
`This enhanced pharmacovigilance study will include:
`
`Targeted and expedited surveillance with a guided collection form
`1.
`(as referenced in Pharmacyclics’ Pharmacovigilance Plan dated August
`
`Reference ID: 3452364
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`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`23, 2013) to obtain additional salient clinical and diagnostic information
`related to major hemorrhagic events.
`
`Submission of Post-marketing 15-day Alert Reports for all initial and
`2.
`follow-up reports of serious hemorrhagic adverse events from clinical trials
`and all post-marketing sources, including consumer reports, solicited
`reports, and foreign reports, utilizing the Standardized Medical Dictionary
`for Regulatory Activities (MedDRA) Query (SMQ) – Haemorrhages.
`
`Submission of interval and cumulative analyses, as well as line
`3.
`listing for all major hemorrhagic events (utilizing the SMQ Haemorrhages)
`from clinical trials and all post-marketing sources, including consumer
`reports, solicited reports, and foreign reports.
`
`The interval and cumulative analyses should assess potential risk
`4.
`factors for cumulative major hemorrhagic events identified from both
`clinical trials and all postmarketing sources, and an overall assessment
`about these events in patients treated with Imbruvica® (ibrutinib)
`Capsules. In the overall assessment, discuss whether the data warrants
`further detailed assessment, labeling changes and/or other
`communication about these adverse events.
`
`Continue the study for a period of four years from the date of final protocol
`submission as noted below. Prior to starting the study, submit for FDA
`review, a protocol describing how you will conduct the study and report
`results, according to the timeline below.
`
`Draft Protocol Submission:
`Final Protocol Submission:
`#1 Interim Report Submission
`#2 Interim Report Submission
`#3 Interim Report Submission
`#4 Interim Report Submission
`#5 Interim Report Submission
`#6 Interim Report Submission
`#7 Interim Report Submission
`Study Completion:
`Final Report Submission:
`
`03/2014
`06/2014
`12/2014
`06/2015
`12/2015
`06/2016
`12/2016
`06/2017
`12/2017
`06/2018
`11/2018
`
` PMR 2060-5 Evaluate the effect of hepatic impairment on ibrutinib
`pharmacokinetics. Submit the final report for trial PCI-32765CLL1006
`entitled, “An Open-Label, Multicenter, Pharmacokinetic Study of PCI-
`32765 in Subjects with Varying Degrees of Hepatic Impairment”.
`
`Reference ID: 3452364
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`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`Final Protocol Submission:
`Trial Completion:
`Final Report Submission:
`
`Completed 11/2012
`06/2014
`12/2014
`
` PMR 2060-6 Determine effect of a strong CYP3A Inducer on ibrutinib
`pharmacokinetics. Submit the final report for trial PCI-32765CLL1010
`entitled, “An Open-Label, Sequential Design Study to Assess the Effect of
`Rifampin on the Pharmacokinetics of PCI-32765 in Healthy Subjects”.
`
`Final Protocol Submission:
`Trial Completion:
`Final Report Submission:
`
`Completed 01/2013
`Completed 01/2013
`04/2014
`
` PMR 2060-7 Determine the effect of ibrutinib on the QT/QTc interval in
`healthy subjects on one or more therapeutic dose levels. Conduct and
`submit results of a thorough QT trial to evaluate the effects of ibrutinib on
`the QT /QTc interval.
`
`Draft Protocol Submission:
`Final Protocol Submission:
`Trial Completion:
`Final Report Submission:
`
`03/2014
`06/2014
`06/2015
`12/2015
`
` PMC 2060-8 Collect additional dissolution profile data (n=12 at release
`and n=12 on stability) using USP Apparatus Type 2 (Paddle) at 75 rpm in
`3.0% w/v polysorbate 20 (Tween® 20) in 50 mM phosphate buffer pH 6.8
`at 37.0°C from at least ten drug product release batches and from the
`drug product stability-registration/ primary batches through 12 months of
`storage at the long-term condition. Use the overall dissolution data that
`were collected from the drug product’s release and stability batches to set
`the final dissolution acceptance criteria.
`
`11/2014
`Study Completion:
`Final Report Submission: 02/2015
`
`2 Introduction and Regulatory Background
`
`Chronic lymphocytic leukemia (CLL) is the most common form of adulthood leukemia.
`CLL is a myeloproliferative neoplasm characterized by an accumulation of monoclonal
`
`Reference ID: 3452364
`
`15
`
`

`

`Clinical Review
`Nicole Verdun, MD
`NDA 205552 Original-2
`Ibrutinib
`
`mature B-cells (CD5+CD23+) in the blood, bone marrow, and secondary lymphatic
`organs.
`
`The National Cancer Institute estimates that 15,680 men and women (9,720 men and
`5,960 women) will be diagnosed with CLL in 2013. It is estimated that 4,580 men and
`women will die of CLL in 2013. One in 192 men and women will be diagnosed with CLL
`in thei