Clinical trial NCT01776840
Conditions: Mantle Cell Lymphoma
Keywords: Mantle cell lymphoma Ibrutinib Bruton's tyrosine kinase inhibitor Bendamustine hydrochloride Rituximab
Sponsor: Janssen Research & Development, LLC
Start date: 2013-05-16; Completion date: 2024-06-24
Enrollment: 523 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of ibrutinib given in combination with bendamustine and rituximab in patients 65 years of age or older with newly diagnosed mantle cell lymphoma.

Detailed description:
This is a randomized (individuals assigned to study treatment by chance), double blind (neither physician nor participant knows the treatment that the participant receives), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial)-controlled study to compare the efficacy and safety of ibrutinib given in combination with bendamustine and rituximab (BR) with BR alone in participants newly diagnosed with mantle cell lymphoma (MCL) who are 65 years of age or older. Approximately 520 participants will be randomly assigned in a 1:1 ratio and stratified by simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) score (low risk \[0-3\] versus intermediate risk \[4-5\] versus high risk \[6-11\]). The treatment phase will extend from randomization until discontinuation of all study treatment or the clinical cutoff for the end of study. A cycle is defined as 28 days. All participants will receive open-label (identity of assigned study drug will be known) BR background therapy for a maximum of 6 cycles; participants with a complete response or partial response will continue to receive open-label background therapy with rituximab maintenance every second cycle for a maximum of 12 additional doses. In addition to the background therapy, all participants will receive blinded study drug (ibrutinib or placebo). Participants randomized to treatment Arm A will receive placebo capsules and participants randomized to treatment Arm B will receive ibrutinib capsules. Study drug will be administered daily and continuously until disease progression, unacceptable toxicity, or study end. Participants with stable disease after initial chemoimmunotherapy (BR+ibrutinib/placebo) should continue treatment with ibrutinib/placebo until disease progression, unacceptable toxicity, or study end. Participants with progressive disease must discontinue all study treatment. For participants who discontinue background therapy and do not have progressive disease, treatment with study drug will continue until disease progression or unacceptable toxicity or the clinical cutoff for the final analysis of progression-free survival (PFS). Participants receiving BR, rituximab, or ibrutinib at the clinical cutoff for the final analysis of PFS will continue open-label treatment until disease progression or unacceptable toxicity. Placebo will be stopped when the study is unblinded for the clinical cutoff for the final analysis of PFS. The posttreatment follow-up phase will begin once a participant discontinues bendamustine and rituximab and study drug. Participants who discontinue for reasons other than disease progression must continue to have disease evaluations as outlined in the protocol. Participants who discontinue due to disease progression will be followed for survival and subsequent anti-MCL therapy. The posttreatment follow-up phase will continue until death, lost to follow up, consent withdrawal, or study end, whichever occurs first. Four clinical cutoffs are planned. The first 3 clinical cutoffs will occur when approximately 134, 180, and 265 PFS events have been observed, respectively. The interim analyses and the final analysis of PFS will take place at these 3 clinical cutoffs, respectively; participant treatment assignment will be unblinded and placebo treatment will be stopped at the clinical cutoff for the final analysis of PFS. Treatment unblinding and stopping of placebo treatment could occur before the planned final analysis of PFS if recommended by the independent Data Monitoring Committee (DMC) after an interim analysis. The last cutoff will occur at the end of study, when 60% of the randomized participants have died or the Sponsor terminates the study, whichever comes first. Efficacy assessments will be conducted in accordance with the Revised Response Criteria for Malignant Lymphoma. Safety will be monitored throughout the study and summarized. Blood samples will be drawn for assessment of pharmacokinetic parameters. Blood and bone marrow will be collected for assessment of minimal residual disease and biomarker studies.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Bendamustine intervention 2: Rituximab intervention 3: Ibrutinib intervention 4: Placebo
Intervention descriptions: intervention 1: 90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6 intervention 2: 375 mg/m2 administered intravenously on Day 1, Cycles 1-6; if complete response or partial response is achieved, 375 mg/m2 is administered on Day 1 of every second cycle for a maximum of 12 additional doses intervention 3: 560 mg (4 x 140 mg capsules) administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end intervention 4: 4 capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or the final analysis of progression-free survival

Protocol documents:
Prot_000.pdf: 
1
Approved, Date: 19 December 2019
Janssen Research & Development *
Clinical Protocol
A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine 
Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination with Bendamustine and 
Rituximab (BR) in Subjects With Newly Diagnosed Mantle Cell Lymphoma
Protocol PCI-32765MCL3002; Phase 3
Amendment INT-7
JNJ-54179060 (ibrutinib)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc.; Janssen
Infectious Diseases BVBA; Janssen Sciences Ireland UC; or Janssen Research & Development, LLC. The
term “sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
This compound is being investigated in Phase 1, 2, and 3 clinical studies.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2012-004056-11
Universal Trial Number: U1111-1137-0389
Status:
Approved
Date:
19 December 2019
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-50002361, 8.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT01776840


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 25
ABBREVIATIONS ...................................................................................................................................... 34
1.
INTRODUCTION................................................................................................................................ 36
1.1.
Mantle Cell Lymphoma .................................................................................................................. 36
1.2.
First-line Treatment for Mantle Cell Lymphoma............................................................................. 36
1.3.
Investigational Product Name and Description.............................................................................. 37
1.4.
Summary of Relevant Non-clinical and Clinical Pharmacology Data ............................................ 38
1.4.1.
Non-clinical Data......................................................................................................................... 38
1.4.2.
Clinical Pharmacokinetic Data.................................................................................................... 38
1.5.
Clinical Efficacy of Ibrutinib in Mantle Cell Lymphoma .................................................................. 38
1.5.1.
Study PCYC-04753 .................................................................................................................... 38
1.5.2.
Study PCYC-1104-CA ................................................................................................................ 39
1.5.3.
Study of Bendamustine and Rituximab with Ibrutinib in Patients with 
Relapsed/Refractory NHL........................................................................................................... 39
1.6.
Lymphocytosis and Leukostasis .................................................................................................... 40
1.7.
Clinical Safety of Ibrutinib............................................................................................................... 40
1.8.
Study Drugs Used as Background Therapy................................................................................... 43
1.9.
Rationale for the Study................................................................................................................... 43
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 44
2.1.
Objectives ...................................................................................................................................... 44
2.2.
Hypothesis ..................................................................................................................................... 44
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 45
3.1.
Overview of Study Design.............................................................................................................. 45
3.2.
Study Design Rationale.................................................................................................................. 48
3.2.1.
Study Population and Study Treatment...................................................................................... 48
3.2.2.
Study Design and Endpoints ...................................................................................................... 49
3.2.3.
Ibrutinib Route of Administration and Dosing Schedule............................................................. 50
4.
SUBJECT SELECTION..................................................................................................................... 50
4.1.
Inclusion Criteria ............................................................................................................................ 50
4.2.
Exclusion Criteria ........................................................................................................................... 52
4.3.
Prohibitions and Restrictions ......................................................................................................... 53
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 53
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 54
6.1.
Study Treatment............................................................................................................................. 55
6.2.
Bendamustine and Rituximab Administration ................................................................................ 56
6.3.
Ibrutinib or Placebo Administration ................................................................................................ 56
6.4.
Dose Modification........................................................................................................................... 56
6.4.1.
Bendamustine Hydrochloride ..................................................................................................... 56
6.4.2.
Rituximab.................................................................................................................................... 57
6.4.3.
Ibrutinib or Placebo..................................................................................................................... 57
6.4.3.1.
Dose Modification for Subjects With Chronic Hepatic Impairment.......................................... 58


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7.
TREATMENT COMPLIANCE............................................................................................................ 59
7.1.
Ibrutinib or Placebo Compliance.................................................................................................... 59
7.2.
Bendamustine and Rituximab Compliance.................................................................................... 59
8.
CONCOMITANT THERAPY.............................................................................................................. 60
8.1.
Permitted Medications.................................................................................................................... 60
8.2.
Prohibited Medications................................................................................................................... 61
8.3.
Precautions with Concomitant Medications ................................................................................... 61
8.4.
Subsequent Therapies................................................................................................................... 62
9.
STUDY EVALUATIONS .................................................................................................................... 63
9.1.
Study Procedures........................................................................................................................... 63
9.1.1.
Overview..................................................................................................................................... 63
9.1.2.
Screening Phase ........................................................................................................................ 63
9.1.3.
Treatment Phase ........................................................................................................................ 64
9.1.4.
Posttreatment Follow-Up Phase................................................................................................. 65
9.1.5.
Clinical Cutoffs............................................................................................................................ 66
9.2.
Efficacy........................................................................................................................................... 66
9.2.1.
Evaluations ................................................................................................................................. 66
9.2.1.1.
Radiographic Image Assessments (CT/MRI).......................................................................... 67
9.2.1.2.
Positron Emission Tomography (PET Scan)........................................................................... 67
9.2.1.3.
Bone Marrow Assessment....................................................................................................... 68
9.2.1.4.
Endoscopy............................................................................................................................... 68
9.2.1.5.
Biopsies of Other Sites ............................................................................................................ 68
9.2.1.6.
Physical Examination .............................................................................................................. 68
9.2.1.7.
Patient-Reported Outcomes.................................................................................................... 68
9.2.2.
Efficacy Criteria........................................................................................................................... 69
9.2.2.1.
Assessment of Disease Response and Progressive Disease ................................................ 69
9.2.2.2.
Definition of Measurable and Assessable Disease ................................................................. 70
9.2.2.3.
Response Categories .............................................................................................................. 70
9.2.3.
Endpoints.................................................................................................................................... 72
9.3.
Pharmacokinetics........................................................................................................................... 73
9.3.1.
Evaluations ................................................................................................................................. 73
9.3.2.
Analytical Procedures................................................................................................................. 74
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 74
9.4.
Biomarkers ..................................................................................................................................... 74
9.4.1.
Biomarker and Minimal Residual Disease Assessments ........................................................... 75
9.4.2.
Formalin-Fixed Paraffin-Embedded Tumor Tissue and Lymph Node Biopsies ......................... 75
9.5.
Safety Evaluations ......................................................................................................................... 76
9.6.
Sample Collection and Handling.................................................................................................... 78
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 79
10.1.
Completion ..................................................................................................................................... 79
10.2.
Discontinuation of Study Treatment............................................................................................... 79
10.3.
Withdrawal From the Study............................................................................................................ 79
11.
STATISTICAL METHODS................................................................................................................. 80
11.1.
Subject Information ........................................................................................................................ 80
11.2.
Sample Size Determination ........................................................................................................... 80
11.3.
Efficacy Analyses ........................................................................................................................... 81
11.3.1.
Primary Endpoint ........................................................................................................................ 81
11.3.2.
Secondary Endpoints.................................................................................................................. 82
11.3.3.
Exploratory Endpoints................................................................................................................. 82
11.3.4.
Baseline Assessments................................................................................................................ 82
11.4.
Patient-reported Outcomes............................................................................................................ 82
11.5.
Pharmacokinetic Analyses............................................................................................................. 82
11.6.
Biomarker Analyses ....................................................................................................................... 83
11.7.
Safety Analyses ............................................................................................................................. 83


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11.8.
Interim Analyses............................................................................................................................. 84
11.9.
Independent Data Monitoring Committee ...................................................................................... 85
12.
ADVERSE EVENT REPORTING ...................................................................................................... 85
12.1.
Definitions ...................................................................................................................................... 85
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 85
12.1.2.
Attribution Definitions.................................................................................................................. 87
12.1.3.
Severity Criteria .......................................................................................................................... 87
12.2.
Special Reporting Situations.......................................................................................................... 87
12.3.
Procedures..................................................................................................................................... 88
12.3.1.
All Adverse Events...................................................................................................................... 88
12.3.2.
Serious Adverse Events ............................................................................................................. 89
12.3.3.
Adverse Events of Interest.......................................................................................................... 90
12.3.3.1.
Major Hemorrhage................................................................................................................... 90
12.3.4.
Other Malignancies..................................................................................................................... 90
12.3.5.
Pregnancy................................................................................................................................... 91
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 91
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 91
13.1.
Procedures..................................................................................................................................... 91
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 91
14.
STUDY DRUG AND BACKGROUND DRUG INFORMATION......................................................... 92
14.1.
Study Drug - Ibrutinib or Placebo................................................................................................... 92
14.1.1.
Physical Description ................................................................................................................... 92
14.1.2.
Packaging ................................................................................................................................... 92
14.1.3.
Labeling ...................................................................................................................................... 92
14.1.4.
Preparation, Handling, and Storage ........................................................................................... 92
14.2.
Background Therapy – Bendamustine and Rituximab .................................................................. 92
14.3.
Drug Accountability ........................................................................................................................ 93
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 93
16.
ETHICAL ASPECTS ......................................................................................................................... 94
16.1.
Study-Specific Design Considerations........................................................................................... 94
16.2.
Regulatory Ethics Compliance....................................................................................................... 94
16.2.1.
Investigator Responsibilities ....................................................................................................... 94
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 95
16.2.3.
Informed Consent ....................................................................................................................... 96
16.2.4.
Privacy of Personal Data ............................................................................................................ 97
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 98
16.2.6.
Country Selection ....................................................................................................................... 98
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 98
17.1.
Protocol Amendments.................................................................................................................... 98
17.2.
Regulatory Documentation ............................................................................................................ 98
17.2.1.
Regulatory Approval/Notification ................................................................................................ 98
17.2.2.
Required Prestudy Documentation............................................................................................. 99
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 99
17.4.
Source Documentation................................................................................................................. 100
17.5.
Case Report Form Completion .................................................................................................... 100
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 101
17.7.
Record Retention ......................................................................................................................... 101
17.8.
Monitoring .................................................................................................................................... 101
17.9.
Study Completion/Termination..................................................................................................... 102
17.9.1.
Study Completion ..................................................................................................................... 102
17.9.2.
Study Termination..................................................................................................................... 102
17.10.
On-Site Audits .............................................................................................................................. 102
17.11.
Use of Information and Publication.............................................................................................. 103


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REFERENCES.......................................................................................................................................... 105
INVESTIGATOR AGREEMENT ............................................................................................................... 120
LIST OF ATTACHMENTS
Attachment 1:
Ann Arbor Classification and the Cotswold Modifications........................................ 108
Attachment 2:
Eastern Cooperative Oncology Group Performance Status Scale .......................... 109
Attachment 3:
Calculating the Simplified MIPI for MCL................................................................... 110
Attachment 4:
Inhibitors and Inducers of CYP3A ............................................................................ 111
Attachment 5:
Blood Volumes for Laboratory Samples................................................................... 112
Attachment 6:
Sample FACT-Lym (Version 4) ................................................................................ 113
Attachment 7:
Sample Health Questionnaire EQ–5D–5L................................................................ 116
Attachment 8:
Child-Pugh Score for Subjects With Liver Impairment............................................. 119
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Time and Events Schedule....................................................................................................... 29
Table 2:
Study Treatment Scheme ......................................................................................................... 33
Table 3:
Ibrutinib/Placebo Dose Modifications........................................................................................ 58
FIGURES
Figure 1:
Study Diagram .......................................................................................................................... 47


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PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
20 December 2012
Amendment INT-1
26 December 2013
Amendment INT-2
15 December 2014
Amendment INT-3
20 August 2015
Amendment INT-4
29 April 2016
Amendment INT-5
12 July 2017
Amendment INT-6
16 August 2019
Amendment INT-7
19 December 2019
Amendments are listed beginning with the most recent amendment.
Amendment INT-7 (19 December 2019)
The overall reasons for the amendment: To update safety information to align with the ibrutinib Investigator’s 
Brochure (IB) to include information regarding cerebrovascular accidents as a new safety observation identified 
from the post-marketing setting, and to clarify that assessment of pulse/heart rate and blood pressure is expected at 
every protocol-specified visit until end of treatment.
Applicable Section(s)
Description of Change(s)
Rationale: To update the safety for ibrutinib, including information on cerebrovascular accidents.
1.6 Lymphocytosis 
and Leukostasis; 
1.7. Clinical Safety of 
Ibrutinib
Safety information on ibrutinib updated to align with the current IB.
Rationale: To clarify that regular monitoring of pulse/heart rate and blood pressure is expected during the 
Treatment Phase.
Table 1, Time and 
Events Schedule (row 
“Vital signs and 
height”; footnote “j” 
added); 
9.5 Safety 
Evaluations
Additional pulse/heart rate and blood pressure assessments added. 
Footnote j added to clarify that vital sign assessments should be recorded in source 
documents but will not be routinely collected in the eCRF.
Rationale: To clarify that after the clinical cutoff for the final analysis of PFS, new malignancies should continue 
to be reported for all subjects, including subjects who are no longer receiving treatment.
9.1.5 Clinical Cutoffs
Added reports of new malignancies to the data that will be collected for all subjects after 
the clinical cutoff for the final analysis of PFS.
Rationale: To update external links for examples of CYP3A inhibitors and inducers.
8.3 Precautions with 
Concomitant 
Medications;
Attachment 4 
(Inhibitors and 
Inducers of CYP3A); 
References
Updated external links for classification of CYP3A inhibitors and inducers; deleted 
outdated link/references.


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Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Applicable Section(s)
Description of Change(s)
Rationale: Minor editorial changes implemented as needed to correct typographical errors, clarify text, or 
address inconsistencies.
1.5.1 Study 
PCYC-04753
Corrected typo for definition of follicular lymphoma.
Edits for improved grammar implemented.
Throughout protocol
Abbreviations spelled out.
Amendment INT-6 (16 August 2019)
The overall reason for the amendment: To halt the collection of the complete response (CR) minimal residual 
disease (MRD) samples, except in subjects whose first assessment of CR is after the issue date of this amendment. 
Stopping the collection of MRD samples from current CR subjects will have no impact on the MRD-negative rate 
secondary endpoint, as all current CR subjects who are still on study and providing samples already have an 
MRD-negative sample.  
Applicable Section(s)
Description of Change(s)
Rationale: To halt the collection of the CR MRD samples, except in subjects whose first assessment of CR is 
after the issue date of this amendment. Stopping the collection of MRD samples from current CR subjects will 
have no impact on the MRD-negative rate secondary endpoint, as all current CR subjects who are still on study 
and providing samples already have an MRD-negative sample.
Table 1, Time and 
Events Schedule (row 
“Blood samples for 
minimal residual 
disease [MRD]”);
Section 9.4.1,
Biomarker and 
Minimal Residual 
Disease Assessments;
Attachment 5, Blood 
Volumes for 
Laboratory Samples
Clarification that blood samples for the assessment of CR MRD will no longer be 
collected except in subjects whose first assessment of CR is after the issue date of this 
amendment. Samples for the comparative MRD assessment will continue to be collected
in all subjects participating in this assessment.  
Rationale: Throughout the protocol, minor formatting changes were made where required.  


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Approved, Date: 19 December 2019
Amendment INT-5 (12 July 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To clarify that independent Data Monitoring Committee (DMC) 
recommendations, including treatment unblinding and stopping placebo treatment, may be implemented following 
an interim analysis. This amendment also updates the protocol to align with the most recent Investigator’s Brochure 
for ibrutinib: specifically, changes associated with dose modification for subjects with chronic hepatic impairment, 
and antimicrobial prophylaxis as a permitted medication in subjects who are at increased risk for opportunistic 
infections.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify that independent DMC recommendations, including treatment unblinding and stopping 
placebo treatment, may be implemented following an interim analysis.
Synopsis (Overview 
of Study Design, 
Statistical Methods);
3.1 Overview of 
Study Design;
9.1.5 Clinical 
Cutoffs;
11.8 Interim
Analyses;
11.9 Independent 
Data Monitoring 
Committee
Treatment unblinding and stopping of placebo treatment may occur before the planned 
final analysis of PFS if recommended by the independent DMC after an interim
analysis.
Rationale: To update the protocol to align with the most recent Investigator’s Brochure for ibrutinib: 
specifically, changes associated with dose modification for subjects with chronic hepatic impairment, and 
antimicrobial prophylaxis as a permitted medication in subjects who are at increased risk for opportunistic 
infections.
1.7 Clinical Safety of 
Ibrutinib
Infection:
Added instructions to consider prophylaxis according to standard of care in subjects 
who are at increased risk for opportunistic infections.
6.4.3.1 Dose 
Modification for 
Subjects With 
Chronic Hepatic 
Impairment (new 
subheading)
Added instructions for dose modification of ibrutinib/placebo in subjects with chronic 
hepatic impairment based on Child-Pugh class A, B, or C.
8.1 Permitted 
Medications
Use of antimicrobial prophylaxis in accordance with standard practice (eg, American 
Society of Clinical Oncology [ASCO] guidelines) is permitted, and should be 
considered in subjects who are at increased risk for opportunistic infections.
References
Added a reference citation (Flowers 2013) for ASCO guidelines on use of antimicrobial 
prophylaxis and outpatient management of fever and neutropenia in adults treated for 
malignancy.
Attachment 8
Added the Child-Pugh score for subjects with liver impairment.


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Approved, Date: 19 December 2019
Applicable Section(s)
Description of Change(s)
Rationale: Minor changes were made for consistency, and to conform with the current protocol template.
Title page
The legal entities acting as the sponsor for Janssen Research & Development studies 
was updated.
Throughout the 
protocol
Minor changes were made for consistency.
Amendment INT-4 (29 April 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment:  The knowledge gained on the efficacy of ibrutinib from completed 
randomized clinical studies, which was not available at time of MCL3002 study design, and the lower than expected 
event rate are the key drivers for this amendment. The sponsor has added a second interim analysis to occur at 
approximately 180 PFS events to mitigate for the potential long interval between the planned first interim analysis 
(134 PFS events) and the final analysis (265 PFS events).
Applicable Section(s)
Description of Change(s)
Rationale: The knowledge gained on the efficacy of ibrutinib based on results from completed randomized studies, 
not available at time of study design and the lower than expected event rate in this study are the basis for the 
addition of a second interim analysis before the final analysis.
Synopsis Overview of 
Study Design; Synopsis 
Statistical 
Methods; 3.1 Overview 
of Study Design; 
9.1.5 Clinical Cutoffs; 
11.2 Sample Size 
Determination; 
11.8 Interim Analysis 
Text was revised to add a second interim analysis to occur at 180 (68%) of total PFS 
events.
The study will have at least 77% power.
Rationale: The alpha spend for the interim analyses has changed with the addition of another interim analysis. The 
sponsor will continue to use the Lan-Demets spending function resembling O’Brien and Fleming boundary to 
control overall Type I error rate. 
11.8 Interim Analysis 
Text was revised to add interim analysis to occur at 68% total events.
Text was revised to update the alpha spend for first interim analysis from 0.0015 to 
0.002, and to add text describing 0.007 alpha spend for the second interim analysis. Text 
was added to explain that the cumulative Type II error spend will be 0.088 at the first 
interim, 0.141 at the second interim, and 0.225 at the final analysis. Text was revised to 
update the timing of the first and second interim analyses (ie, after approximately 40 and 
50 months after the first subject has been randomized, respectively).
Rationale: At the time of Protocol Amendment INT-4, the last dose of bendamustine given to any subject was in 
May 2015. The study will continue for the purpose of evaluating long-term efficacy and safety of ibrutinib.
16.2.2 Independent 
Ethics Committee or 
Institutional Review 
Board 
As of Amendment INT-4, reports of adverse events that are serious, unlisted/unexpected, 
and associated with bendamustine will no longer be provided for reporting to IEC/IRB. 
Rationale: Throughout the protocol, minor grammatical, formatting, or spelling changes were made where required, 
or clarifications, if needed.  


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Approved, Date: 19 December 2019
Amendment INT-3 (20 August 2015)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: To update the safety language for diarrhea and other safety topics in the 
Introduction, the background safety information for ibrutinib has been aligned with the recently updated ibrutinib 
Investigator’s Brochure (IB) and other protocols within the clinical development program.
Applicable Section(s)
Description of Change(s)
Rationale: Clinical safety information for ibrutinib has been updated for consistency with both the ibrutinib 
Investigator’s Brochure and other protocols within the ibrutinib clinical development program.
1.6 Lymphocytosis 
and Leukostasis; 
1.7 Clinical Safety of 
Ibrutinib
Clinical safety information for ibrutinib has been updated to show currently available data 
for hematological adverse events (cytopenias, lymphocytosis, and leukostasis) and non-
hematological adverse events (bleeding-related events, atrial fibrillation, diarrhea, 
infections, second primary malignancies, and rash). Additionally, information on tumor 
lysis syndrome has been added to the non-hematological adverse event section.
Rationale: A correction has been made to the criteria used to determine complete response.
9.2.2.3. Response 
Categories
The length of the short axis of previously involved nodes before treatment has been 
corrected from 1.1 cm to 1.0 cm.
Rationale: The name of the co-development company for ibrutinib has changed from Pharmacyclics, Inc to 
Pharmacyclics LLC.
Synopsis;
1. Introduction
“Pharmacyclics, Inc” has been changed to “Pharmacyclics LLC”.
Rationale: To update the Sponsorship statement.
Title Page
In the Sponsorship statement, replaced “Janssen R&D Ireland” with “Janssen Sciences 
Ireland UC”.
Rationale: Typographical errors were noted.
Protocol Amendments 
Section
Typographical errors in the Protocol Amendments section were corrected.


JNJ-54179060  (ibrutinib)
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Approved, Date: 19 December 2019
Amendment INT-2 (15 December 2014)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: to update the protocol with safety-related information for monitoring 
ocular events and atrial fibrillation, updates to potential risks with ibrutinib, and updates to administration of 
ibrutinib with certain concomitant medications. 
Applicable Section(s)
Description of Change(s)
Rationale: Safety data from a Phase 3, randomized comparator-controlled (ibrutinib vs. ofatumumab) study of 
ibrutinib monotherapy in subjects with CLL/SLL (ibrutinib: 195 subjects, ofatumumab: 191) showed that adverse 
events in the System Organ Class of eye disorders (eg, vision blurred, dry eye, lacrimation increased) occurred at a 
higher incidence in the ibrutinib arm (36.4%) compared with the ofatumumab arm (18.8%). All eye disorders were 
reported as Grade 1 or 2 in severity for the ibrutinib arm. Therefore, instructions have been added to monitor for 
ocular events.
Table 1 (footnote “j”); 9.1.3 Treatment Phase; 
9.5 Safety Evaluations
Review of systems should include inquiry of ocular 
symptoms (eg, dry eye, watering eye/abnormal discharge, eye 
pain, blurred vision/double vision, decreased visual acuity, 
photophobia/sensitivity to light, floaters, flashing lights, and 
eye 
irritation). 
Subjects 
should 
be 
referred 
to 
an 
ophthalmologist for a formal examination if any Grade ≥ 2 
symptoms are reported.
Rationale: Potential risks associated with ibrutinib have been updated based on the 2014 IB (version 8.0) and new 
risks (cytopenias, diarrhea) have been added. Important new information is provided below. A complete description 
of each risk is provided in Section 1.7.  
1.7 Clinical Safety of Ibrutinib
Cytopenias
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, 
thrombocytopenia, and anemia) were reported in subjects 
treated with ibrutinib. Monitor complete blood counts 
monthly.
Bleeding-related Events
These include primarily minor hemorrhagic events such as 
contusion, epistaxis, and petechiae; and major hemorrhagic 
events 
including 
gastrointestinal 
bleeding, 
intracranial 
hemorrhage, and hematuria (see also 12.3.3.1).
Cardiac Events
Atrial fibrillation and atrial flutter have been reported in 
subjects treated with ibrutinib, particularly in subjects with 
cardiac risk factors, acute infections, and a previous history of 
atrial fibrillation.
Diarrhea
Approximately one-third of patients treated with ibrutinib 
monotherapy and two-thirds treated with combination therapy 
reported diarrhea.
Infection
Fatal and non-fatal infections have occurred with ibrutinib 
therapy. At least 25% of subjects with MCL and 35% of 
subjects with CLL had Grade 3 or greater infections.
Other malignancies
Other malignancies, most frequently skin cancers, have 
occurred in subjects treated with ibrutinib.
Rash
Rash has been commonly reported in subjects treated with 
either single agent ibrutinib or in combination with 
chemotherapy. Rash occurred at a higher rate in the ibrutinib 
arm than in the ofatumumab arm in Study 1112. Most rashes 
were mild to moderate in severity. Subjects should be closely 
monitored for signs and symptoms suggestive of SJS. 


JNJ-54179060  (ibrutinib)
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Approved, Date: 19 December 2019
Rationale: The previous definition of a major hemorrhagic bleeding event has been broadened in scope to include 
any bleeding event that is Grade 3 or higher, is considered a SAE, or any CNS hemorrhage/hematoma. 
Section 12.3.3.2 is no longer needed with the addition of the fourth bullet under Section 12.3.3.1.
Synopsis; 11.7 Safety Analyses; 12.3.3.1 Major 
Hemorrhage; 12.3.3.2 Intracranial Hemorrhage 
(deleted)
Previous definition: 
Any hemorrhagic event that is Grade 3 or greater in severity 
or that results in 1 of the following: intraocular bleeding 
causing loss of vision, the need for a transfusion of 2 or more 
units of red cells or an equivalent amount of whole blood, 
hospitalization, or prolongation of hospitalization.
New definition:

Any treatment-emergent hemorrhagic adverse event of 
Grade 3 or higher. All hemorrhagic events requiring a 
transfusion of red blood cells should be reported as 
Grade 3 or higher adverse events per NCI CTCAE. 

Any treatment-emergent serious adverse event of 
bleeding of any grade. 

Any 
treatment-emergent 
central 
nervous 
system 
hemorrhage/hematoma of any grade.
Rationale: Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, particularly in 
subjects with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Instructions have been 
added to periodically monitor subjects clinically for atrial fibrillation.
9.5 Safety Evaluations
ECGs should also be performed at the investigator’s 
discretion, particularly in subjects with arrhythmic symptoms 
(eg, palpitations, lightheadedness or new onset dyspnea).
Rationale: The precautions for concomitant use of ibrutinib with the following drugs have been revised: CYP3A 
inhibitors, CYP3A inducers, P-gp substrates, QT prolonging agents and antiplatelet agents and anticoagulants. 
Relevant new information is provided below.

The list of strong and moderate CYP3A inhibitors has been expanded and ibrutinib dose modifications 
instructions for use with strong inhibitors revised. 

The percent decrease in ibrutinib plasma concentrations when ibrutinib is used concomitantly with strong
CYP3A inducers has been added.

Instructions for digoxin administration relative to ibrutinib administration added.

Statement that concomitant use of ibrutinib and anticoagulants or medications that inhibit platelet function 
may increase the risk of bleeding.

Statement added that there is no evidence of QT prolongation associated with ibrutinib.

Clarification to instructions for anticoagulation therapy (eg, atrial fibrillation).


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
8.3 Precautions with Concomitant Medications
Concomitant use of ibrutinib and drugs that strongly or 
moderately inhibit CYP3A can increase ibrutinib exposure 
and should be avoided. If the benefit outweighs the risk and a 
strong CYP3A inhibitor must be used, reduce the ibrutinib 
dose to 140 mg or withhold treatment temporarily (for 7 days 
or less). If the benefit outweighs the risk and a moderate 
CYP3A inhibitor must be used, monitor subject for toxicity 
and follow dose modification guidance as needed. No dose 
adjustment is required in combination with mild inhibitors. 
Monitor patient closely for toxicity and follow dose 
modification guidance as needed.
Administration of ibrutinib with rifampin, a strong CYP3A 
inducer, decreases ibrutinib plasma concentrations by 
approximately 90%.
To avoid a potential interaction in the GI tract, narrow 
therapeutic range P-gp substrates such as digoxin should be 
taken at least 6 hours before or after ibrutinib.
Use of ibrutinib in subjects requiring other anticoagulants or 
medications that inhibit platelet function may increase the risk 
of bleeding.
There is no evidence of QT prolongation with increasing 
plasma concentrations of ibrutinib.
For 
subjects 
requiring 
the 
initiation 
of 
therapeutic 
anticoagulation therapy (eg, atrial fibrillation), consider the 
risks and benefits of continuing ibrutinib treatment. If 
therapeutic anticoagulation is clinically indicated during the 
course of the study, treatment with ibrutinib/placebo should 
be held, and ibrutinib/placebo should not be restarted until the 
subject is clinically stable and has no signs of bleeding.
Rationale: Instructions for the definition of maximal tumor reduction have been clarified.
Synopsis; Table 1 (PET scan); 9.2.1.2 Positron 
Emission Tomography (PET Scan)
Deleted:  At maximal tumor reduction (eg, CR or PR with 
2 consecutive CT scans showing no further tumor reduction), 
and at suspected disease progression, if a new lesion was 
detected on CT.
Replaced with: Maximal tumor reduction defined as time of 
CR or when 2 consecutive CT scans show no further tumor 
reduction, and at suspected disease progression if a new 
lesion was detected on CT.
Rationale: Clarification that the timeframe for collecting serum immunoglobulin and beta2 microglobulin samples 
is the same (within ± 7 days of the scheduled assessment day) as other assessments/procedures.
Table 1 (footnote “a”); 9.1.1 Overview
Assessments/procedures should be completed on the day 
indicated in the Time and Events Schedule; if this is not 
possible (eg, because of a weekend, holiday, emergency), the 
assessment/procedure should be completed within 48 hours of 
the scheduled day; PET, CT/MRI, serum immunoglobulin, 
and beta2 microglobulins should be performed within ± 7 
days of the scheduled assessment day. Laboratory results 
must be reviewed before the start of the cycle. The last 
assessment/procedure or laboratory result obtained prior to 
randomization will be used to determine eligibility.


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Rationale: Collection of minimal residual disease (MRD) samples has been clarified. It is also clarified that the 
fresh lymph node biopsy should be collected at the timepoints outlined within the protocol even if a sample was not 
collected at screening. 
Table 1 (footnote “v); Abbreviations; 9.4.1 
Biomarker 
and 
Minimal 
Residual 
Disease 
Assessments
Original text:
Day 1 of Cycle 1, every 12 weeks in first 12 months 
following CR, and every 16 weeks thereafter. Additional 
blood samples will be collected for comparative MRD testing 
in approximately the first 100 subjects with a CR (excluding 
subjects at sites in China).  
Changed to:
Day 1 Cycle 1 MRD (peripheral blood mononuclear cell 
[PBMC]) sample to be collected on all subjects. At CR and 
after as noted in table, CR MRD samples will be collected. 
Additionally, MRD (PBMC) samples for comparative MRD 
testing in approximately the first 100 subjects with a CR 
(excluding subjects at sites in China) should be collected at 
same time points as CR MRD, but only if Day 1 Cycle 1 
MRD (PBMC) was collected.
Table 1 (footnote “aa”); 9.4.2 Formalin-Fixed 
Paraffin-Embedded Tumor Tissue and Lymph 
Node Biopsies
A fresh lymph node biopsy also should be collected, if 
feasible, for biomarker evaluation (where local regulations 
and shipping logistics permit) during Screening (after 
eligibility is determined) or prior to Cycle 1, and at the time 
of progressive disease (even if screening sample was not 
collected).
Rationale: Clarification to the description of ibrutinib; “white to off-white crystalline solid” was changed to “white 
to off-white solid” and “capsule” has been added to describe the formulation.
1.3 Investigational Product Name and Description
Ibrutinib is a white to off-white solid. It has a single chiral 
center and is the R-enantiomer. The investigational drug 
product, ibrutinib, is an oral capsule formulation containing 
micronized ibrutinib.
Rationale: In the rationale for changes for Amendment 1 it states that inclusion criteria #7 and #8 were modified by 
deleting the specific timeframe (“within 14 days prior to randomization”) for laboratory parameters.  However, in 
error, the timeframe was not removed.  Per this amendment, the timeframe has been deleted.
4.1 Inclusion Criteria (#7 and #8)
Original text:
Hematology values must be within the following limits within 
14 days prior to randomization:  
Biochemical values within the following limits within 
14 days prior to randomization:
Changed to:
Hematology values must be within the following limits:  
Biochemical values within the following limits:
Rationale Instructions specific to ibrutinib administration for a missed dose have been updated for consistency with 
the product label. In the event the drug is not taken at the schedule time it can be taken as soon as possible on the 
same day.
6.3 Ibrutinib or Placebo Administration
If a dose of study drug is not taken at the scheduled time, it 
can be taken as soon as possible on the same day with a return 
to the normal schedule the following day. The subject should 
not take extra capsules to make up the missed dose. 
Rationale: Clarification that concomitant therapies will be recorded on the CRF up to 30 days after the last dose of 
any study treatment or until the start of a subsequent systemic anti-MCL therapy, if earlier.
Table 
1 
(row 
“Concomitant 
Medications”); 
8 Concomitant Therapy; 12.3.1 All Adverse Events
The following concomitant therapies must be recorded in the 
CRF throughout the study, beginning with signing of 
informed consent form (ICF) to 30 days after the last dose of 
any study treatment or until the start of a subsequent systemic 
anti-MCL therapy, if earlier:


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Rationale: Clarification that data collection after the clinical cutoff will include response to treatment as assessed by 
the investigator, and best response and progressive disease on subsequent anti-MCL therapy.
Table 1 (new footnote “l”); 9.1.5 Clinical Cutoffs
The following data will be collected for all subjects, after the 
clinical cutoff for the final analysis of PFS: survival data, 
EQ-5D-5L (up to 3 times), and investigator assessment of 
response to treatment. Best response as well as progressive 
disease on subsequent anti-MCL therapy will also be 
collected.
Rationale: The recommended supportive care for the treatment of leukostasis has been changed from leukapheresis 
to cytoreduction and the guidance was updated accordingly.
1.6 Lymphocytosis and Leukostasis; 8.1 Permitted 
Medications
There were isolated cases of leukostasis reported in subjects 
treated with ibrutinib. A high number of circulating 
lymphocytes (>400000/mm3) may confer increased risk; these 
patients should be closely monitored. Administer supportive 
care including hydration and/or cytoreduction as indicated.
Rationale: The Ibrutinib Investigator’s Brochure (IB) is updated yearly with the most current AEs incidence data 
for ibrutinib monotherapy and combination therapy studies, and AEs leading to treatment discontinuation. 
Therefore, previously reported AE data have been deleted and AEs leading to treatment discontinuation are listed 
without incidence data.
1.7 Clinical Safety of Ibrutinib
Monotherapy and combination therapy AE data have been 
deleted and the following statements added: 
Because ibrutinib is in clinical development, the safety profile 
is not yet fully understood. Further investigation is necessary 
to better understand the safety of ibrutinib. Therefore, 
unanticipated side effects that have not been previously 
observed may occur. A brief overview of the potential risks 
associated with the administration of ibrutinib based on 
sponsor-initiated clinical studies is presented in the ibrutinib 
Investigator’s Brochure and is outlined below.
Rationale: The protocol has been modified to allow rituximab administration split over 2 days for not only TLS but 
for other toxicities as well.
Table 2 (footnote “c”); 6.4.2 Rituximab
For subjects with an increased risk of tumor lysis syndrome 
(TLS) or other toxicities, rituximab can be split over a 2-day 
period in Cycle 1 or throughout Cycles 1 to 6, to comply with 
the study site’s practice. 
Rationale: In the previous amendment it was incorrectly noted that the subject’s name would be removed from the 
wallet card.  
12.3.1 All Adverse Events
The subject’s name has been added to the “wallet (study) 
card" that he/she carries with them for the duration of the 
study.
Rationale: IMBRUVICA is now a registered trademark; therefore, the registered trademark symbol has been 
added. Furthermore, the specific reference to the US approval of IMBRUVICA on 13 Nov 2013 has been deleted 
since it is also approved in countries outside the US.  
Synopsis; 1 Introduction
IMBRUVICA™ has been changed to IMBRUVICA®
Deleted:  On 13 November 2013, the FDA approved ibrutinib 
for the treatment of adult patients with MCL who have 
received at least one prior therapy. This indication is based on 
overall response rate. An improvement in survival or disease-
related symptoms has not been established.


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Rationale: Periodic reviews of the protocol template are conducted to provide corrections and improvements.
10.2 Discontinuation of Study Treatment
Section title has changed from “Discontinuation of 
Treatment” to “Discontinuation of Study Treatment”.
13.1. Procedures
“Investigational staff” changed to “study-site personnel”.
16.2.2 
Independent 
Ethics 
Committee 
or 
Institutional Review Board
Clarification that documents will be submitted “as required by 
local regulations”
Protocol amendments will be provided to IEC/IRB except for 
amendments that are purely administrative with no 
consequences for subjects, data or study conduct.
Rationale: Throughout the protocol, minor grammatical, formatting, or spelling changes were made where required, 
or clarifications, if needed.  


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Amendment INT-1 (26 December 2013)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: To update the protocol with new safety-related information and safety 
instructions; further clarify study treatment dosing instructions and dose modifications; revise operational aspects of 
the study; provide updates based on new information, and perform minor modifications and formatting changes.
Applicable Section(s)
Description of Change(s)
Rationale: Clarification to the mechanism of action of ibrutinib. 
Synopsis; 
1 Introduction
Based on current information, the description of the 
mechanism 
of 
action 
of 
ibrutinib 
as 
a 
potent, 
orally-administered, 
covalently-binding 
small 
molecule 
inhibitor of Bruton’s tyrosine kinase (BTK) has been update 
in the protocol.
Rationale: On November 13, 2013 the FDA approved IMBRUVICA™ (ibrutinib) for the treatment of adult patients 
with MCL who have received at least one prior therapy. This indication is based on overall response rate. An 
improvement in survival or disease-related symptoms has not been established. Therefore, the statement below 
indicating ibrutinib has not been approved has been deleted.
Synopsis;
1 Introduction
The 
following 
has 
been 
deleted: 
“Ibrutinib 
is 
an 
investigational product that has not been approved for 
marketing in any country.”
The trade name and text regarding the US approval have been 
added.
Rationale: Addition of biomarker assessments; Fresh lymph node biopsies at Screening and at the time of 
progressive disease may help to identify expression and mutation patterns of MCL and potentially predict response 
or resistance to ibrutinib. Diagnostic block or slides may be evaluated for minimal residual disease (MRD) and 
biomarkers.
A comparison between blood and bone marrow MRD results will be conducted in approximately the first 
100 subjects with a CR to cross-validate globally accessible flow cytometry-based MRD assessments with highly 
sensitive regionally restricted PCR-based analysis.
The timeframe for obtaining MRD samples has been added.
Synopsis; 
Time 
and 
Events 
Schedule; 
3.1 
Overview 
of 
Study 
Design; 
9.1.1 
Overview; 9.4.1 Biomarker and Minimal Residual 
Disease 
Assessments; 
9.4.2 
Formalin-Fixed 
Paraffin-Embedded Tumor Tissue and Lymph 
Node; 16.1 Study-Specific Design Considerations; 
Attachment 5
A fresh lymph node biopsy sample should be collected if 
feasible, for biomarker evaluation (where local regulations 
and shipping logistics permit) during Screening (after 
eligibility is determined) or prior to Cycle 1, and at the time 
of progressive disease. If a fresh lymph node biopsy was 
performed during Screening to confirm MCL diagnosis, a 
portion of the sample may be used for the biomarker 
evaluation. 
A 
portion 
of 
the 
formalin-fixed 
paraffin-embedded tumor (FFPE) block or slides collected for 
confirmation of diagnosis may be evaluated for biomarker 
assessments.
Additional blood samples will be collected for comparative 
MRD testing in approximately the first 100 subjects with a 
CR (except for subjects in China). The increased number of 
samples 
and 
total 
blood 
volume 
are 
presented 
in 
Attachment 5.
Clarification that blood samples for assessment of MRD will 
be collected from all subjects on Day 1 of Cycle 1.


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Rationale: It may not be possible to perform the PET or CT/MRI assessment, PRO, and survival follow-up on the 
scheduled day due to patient or site conflicts. Therefore, a ±7 day window has been added to these assessments after 
Cycle 6. The timeframe for performing the PET scan if a CR or PR is observed has been added.
Previously, the Time and Event Schedule indicated results of tests obtained prior to signing the informed consent 
conducted as part of the subject’s standard care and CT, MRI, and bone marrow aspirate/biopsy assessment were to 
be available before the first administration of study drug. These test results are now required prior to randomization.
Time and Events Schedule;
9.1.1 Overview; 9.1.2 Screening Phase; 9.2.1.2 
Positron Emission Tomography (PET Scan);
9.2.1.3 Bone Marrow Assessment
For PET and CT/MRI, the test should be completed within 
± 7 days of the scheduled assessment.
Whole body FDG-PET scan (skull base to the proximal 
femur) is optional at Screening but mandatory within 30 days 
of the time of maximal tumor reduction (eg, CR or PR with 
2 consecutive CT scans showing no further tumor reduction), 
and at suspected disease progression, if a new lesion was 
detected on CT.
Results of tests obtained prior to signing the informed consent 
conducted as part of the subject’s standard care may be used 
for this study if performed within 30 days before the first 
administration of study drug randomization. CT, MRI, and 
bone marrow aspirate/biopsy assessments performed up to 
60 days before the first dose of study drug randomization are 
acceptable.
Rationale: Throughout the protocol, references to CYP3A4/5 have been corrected to CYP3A. 
The average increase (ie, 26-fold) in ibrutinib exposure when administered in combination with ketoconazole was 
provided in the protocol.  The protocol has been updated with the actual increase for the Cmax and AUC0-last. A 
cross-reference to Section 8.2 was added for additional guidance on concomitant use of ibrutinib/placebo with 
CYP3A inhibitors or inducers. 
Guidance for the administration of CYP3A inhibitors and inducers during ibrutinib/placebo administration is 
provided. In addition, new text has been added to describe the effect of ibrutinib as a weak inducer of CYP450 
isoenzymes and a mild inhibitor of P-gp substrate.
Furthermore, the pharmacokinetic definitions for Cmax, Cmin, and AUC0-last have been corrected, as plasma is 
evaluated for these parameters.
Abbreviations; 
Synopsis; 
1.4.2 
Clinical 
Pharmacokinetic Data; 4.2 Exclusion Criteria (#7); 
6.3 Ibrutinib or Placebo Administration; 6.4.3 
Ibrutinib or Placebo; 8 Concomitant Therapy; 8.3 
Precautions with Concomitant Medications; 9.2.3 
Endpoints; References; Attachment 4
Ketoconazole, a strong CYP3A inhibitor, increased ibrutinib 
exposure (maximum observed plasma concentration [Cmax] 
and area under the plasma concentration versus time curve 
from time zero to the time corresponding to the last 
quantifiable concentration [AUC0-last]) by 29- and 24-fold, 
respectively.
Avoid co-administration with strong or moderate CYP3A 
inhibitors and consider alternative agents with less CYP3A 
inhibition.
New text has been added to describe the effect of ibrutinib as 
a weak inhibitor/inducer of CYP450 isoenzymes and a mild 
inhibitor of P-gp.
A new reference website for CYP450 enzymes has been 
added.
CYP3A4/5 has been corrected to CYP3A.
Rationale: Clarification made to the frequency of site visits throughout the study.
Time and Events Schedule;
9.1.3 Treatment Phase
The frequency of site visits was clarified: Subjects will be 
seen at the site every 4 weeks during Cycles 1 to 6; then every 
other cycle (ie, approximately every 8weeks) for study 
procedures and assessments.


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Rationale: Hematology and chemistry laboratory assessments to determine subject eligibility for the study must be 
performed within 14 days prior to randomization. This timeframe, previously mentioned in Section 4.1, Inclusion 
Criteria, has been moved to the Time and Events Schedule and Screening Phase (Section 9.1.2) for site convenience 
when referencing study procedures. It has also been clarified that the results of scheduled clinical laboratory samples 
collected during the Treatment Phase must be available before any study treatment is administered. 
Furthermore, more frequent monitoring of hematology parameters will be conducted during the first 12 cycles. 
Hematology assessments will be performed every other week during Cycles 1 to 6, inclusive; and every 4 weeks 
during Cycles 7 to 12, inclusive. Previously these samples were collected every 4 weeks and every 8 weeks, 
respectively.
Time and Events Schedule; 4.1 Inclusion criteria 
(#7 and #8); 9.1.1 Overview; 9.1.2 Screening 
Phase; 16.1. Study-Specific Design Considerations; 
Attachment 5
Hematology and chemistry laboratory assessments must be 
within specified limits to determine subject eligibility. These 
tests must be performed 14 days prior to randomization.
New footnote was added to indicate that during the Treatment 
Phase, clinical laboratory samples can be taken on the day of 
or day prior to dosing, provided the results are available 
before any study treatment is administered.  
Hematology laboratory samples will be collected every other 
week during Cycles 1 to 6, inclusive; and every 4 weeks 
during Cycles 7 to 12, inclusive. As a result, the number of 
hematology samples to be collected per subject in first year 
has been increased from 10 to 20 samples; and the overall 
volume of blood that will be collected increased from 
approximately 250 mL to 350 mL.
Rationale: New data regarding the incidence and duration of ibrutinib treatment-related lymphocytosis and reports 
of leukostasis have been added, and guidance for the treatment of leukostasis. The title of Section 1.6 has been 
revised to reflect the discussion of both lymphocytosis and leukostasis.
1.6 Lymphocytosis and Leukostasis; 8.1 Permitted 
Medications; References
Current knowledge of reversible lymphocytosis and incidence 
of leukostasis observed with ibrutinib is described and a 
supporting reference added (Stevenson et al, 2011).
Rationale: Safety data, since the time the original protocol was finalized, have been updated. These data included 
information from the 2013 Investigator’s Brochure, the PCYC-04753 CSR, and the supporting publication for the 
PCYC-1104-CA CSR (Wang, et al 2013). A cross-reference (Advani et al, 2012) for Study PCYC-04753 BTK 
occupancy results has also been added to Section 3.2.3.
Synopsis; 1.5.1 Study PCYC-04753; 1.5.2 Study 
PCYC-1104-CA; 1.7 Clinical Safety of Ibrutinib;
1.9 Rationale for the Study; 3.2.1 Study Population 
and Study Treatment; 3.2.3 Ibrutinib Route of 
Administration and Dosing Schedule; References
At the time of the original protocol (20 Dec 2012), safety data 
for 312 subjects were available. Safety data as of 06 Apr 2013 
for the 506 subjects treated with ibrutinib monotherapy and 
130 subjects treated with ibrutinib in combination with 
chemotherapy have been added. 
Data regarding hemorrhagic adverse events occurring in 
ibrutinib clinical studies have been updated.  
Results of Study PCYC-1104-CA were revised based on the 
Wang et al, 2013 publication.
The Rummel publication reference, reporting results from the 
study of BR vs. R-CHOP, has been updated (2013).


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Rationale: Additional new safety information (other malignancies, rashes, and infection) based on studies 
conducted with ibrutinib has been added. Other malignancies occurring in subjects treated in this study will be 
reported and collected on the CRF. A description of other malignant diseases observed in subjects treated with 
ibrutinib is also provided.
Synopsis; 1.7 Clinical Safety of Ibrutinib; Figure 1; 
9.1.4 Posttreatment Follow-Up Phase; 9.1.5 
Clinical Cutoffs; 12.3.4 Other Malignancies
In addition to all routine AE reporting, all new malignant 
tumors, including solid tumors, skin malignancies, and 
hematologic malignancies, are to be reported for the duration 
of study treatment and during any protocol-specified 
follow-up periods including post-progression follow-up for 
overall survival.
Mild to moderate rashes have been observed with ibrutinib 
alone or in combination with other drugs; and a single case of 
Stevens-Johnson Syndrome (SJS) was reported 
Infections (including sepsis, bacterial, viral, or fungal
infections) 
were 
observed 
in 
subjects 
with 
MCL 
(≥Grade 3; 25.2%) and CLL/SLL (≥ Grade 3; 37.6%). Some 
of these infections have been associated with hospitalization 
and death.
Rationale: The protocol has been revised to align with the NCCN guidelines and allow for inclusion of atypical 
MCL subjects who may be CD5 negative. This change is supported by the publication by Liu, et al (2002). 
Time and Events Schedule; 1.1 Mantle Cell 
Lymphoma; References
Diagnosis of MCL must include morphology and expression 
of either cyclin D1 in association with other relevant markers 
(eg, CD19, CD20, PAX5, CD5) or evidence of t(11;14) as 
assessed by cytogenetics, FISH, or PCR. 
Rationale: Details to describe personnel who may potentially be unblinded, conditions for unblinding treatment, 
and the continuation of treatment if a subject is unblinded have been added.  
5 Treatment Allocation and Blinding
An explanation of the necessary personnel who will be
unblinded to treatment and the prevailing conditions for 
unblinding was added to the protocol. If a subject’s treatment 
assignment is unblinded he/she may continue the study 
treatment if receiving clinical benefit.
Rationale: Additional details regarding treatment delays for toxicity have been added.
6.1 Study Treatment
The start of a new cycle may be delayed on a weekly basis 
until the subject recovers from the toxicity to a level allowing 
continuation of therapy. The subject should be assessed 
weekly until the toxicity resolves to a level allowing 
continuation of therapy. If the toxicity persists after a 2-week 
cycle delay, and is considered to be related to one specific 
drug (eg, rituximab, ibrutinib, etc.), the offending drug can be 
withheld and the new cycle may be started with the remaining 
drugs.
Rationale: A recommendation to follow rituximab premedication guidelines has been added.
6.2 Bendamustine and Rituximab Administration
It is strongly recommended that premedication guidelines are 
also followed per rituximab package insert.
Rationale: Instructions specific to ibrutinib/placebo administration have been updated. 
6.3 Ibrutinib or Placebo Administration 
Ibrutinib/placebo capsules should be swallowed whole and 
should not be opened, broken, or chewed. If a dose of study 
drug is missed it can be taken as soon as possible on the same 
day with a return to the normal schedule the following day. 
The subject should not take extra capsules to make up the 
missed dose. 


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Rationale: Discontinuation of one component of study treatment will not result in discontinuation of all study 
treatment.
6.4 Dose Modification (through the section)
Within this section it has been clarified that if any one 
component of the study treatment (bendamustine, rituximab, 
ibrutinib/placebo) is discontinued for toxicity, the study 
treatment may continue with the other components.
Rationale: Bendamustine dose holding and discontinuation instructions have been added. Furthermore, it has been 
clarified that dose re-escalation of bendamustine is not permitted.
6.4.1 Bendamustine Hydrochloride
Bendamustine may be held for a maximum of 28 consecutive 
days; a hold >28 days must be reviewed and approved by the 
sponsor. Discontinue bendamustine permanently if it cannot be 
restarted within 28 days due to toxicity.
Dose re-escalation of bendamustine is not permitted
Rationale: Rituximab dose holding and discontinuation instructions have been added. Previously, rituximab 
administration may be split over a 2-day period for subjects at risk of tumor lysis syndrome (TLS) in Cycle 1 only; 
this is now allowed for Cycles 1 through 6, if  necessary, to comply with the study site’s practice.
Study Treatment Scheme;
6.4.2 Rituximab;
8.1 Permitted Medications
Rituximab may be held for a maximum of 28 consecutive days; 
a hold >28 days must be reviewed and approved by the sponsor. 
Discontinue rituximab permanently if it cannot be restarted 
within 28 days due to toxicity.
For subjects with an increased risk of TLS, rituximab can be 
split over a 2-day period in Cycle 1, or throughout Cycles 1 to 6, 
to comply with the study site’s practice.
Rationale: Instructions for ibrutinib/placebo dose modification in the event of Grade 4 neutropenia occurring for 
more than 14 days are now independent of the background therapy. In addition, instructions for Grade 3 or greater 
neutropenia with infection or fever have been added and instructions for any Grade 3 or greater non-hematological 
toxicity.  Specific instructions for nausea, vomiting, and diarrhea have been removed.
6.4.3 Ibrutinib or Placebo
Ibrutinib/placebo dose modifications for Grade 4 neutropenia 
that persists for >14 days will be conducted according to the 
instructions in Table 3. Therefore, the following text for Grade 4 
neutropenia was deleted: “if receiving study drug only, actions 
in the table below should be taken immediately. If receiving 
concurrent BR and study drug, action should be taken if the 
Grade 4 neutropenia persists for >14 days.”
Dose modification instructions were added for Grade 3 or 
greater neutropenia with infection or fever and any Grade 3 or 
greater non-hematological toxicity.  
Rationale: QT prolongation is not expected with ibrutinib; the precaution for concomitant use of ibrutinib and 
medications known to cause QT prolongation has been simplified.
8.3 Precautions with Concomitant Medications
Any medications known to cause QT prolongation should be used 
with caution; periodic monitoring with electrocardiograms (ECG) 
and electrolytes should be considered.
Rationale: Instructions for concomitant use of ibrutinib and antiplatelet agents, anticoagulants, supplements such as 
fish oil and vitamin E preparations have been updated. 
8.3. Precautions with Concomitant Medications
Warfarin or other vitamin K antagonists should not be 
administered concomitantly with ibrutinib. Supplements such as 
fish oil and vitamin E preparations should be avoided. Use 
ibrutinib with caution in subjects requiring other anticoagulants 
or medications that inhibit platelet function. Subjects with 
congenital bleeding diathesis have not been studied. Ibrutinib 
should be withheld at least 3 to 7 days pre- and post-surgery 
depending upon the type of surgery and the risk of bleeding.


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Rationale: To date, the ocular adverse events observed in subjects treated with ibrutinib monotherapy clinical 
studies do not indicate the need for additional monitoring. Therefore, this is no longer a required assessment.
Time and Events Schedule; 9.1.3 Treatment 
Phase; 9.5 Safety Evaluations; 11.7 Safety 
Analysis
The following text has been deleted: Review of systems should 
include inquiry of ocular symptoms (eg, dry eye, watering 
eye/abnormal discharge, eye pain, blurred vision/double vision, 
decreased visual acuity, photophobia/sensitivity to light, 
floaters, flashing lights, and eye irritation). Subjects should be 
referred to an ophthalmologist for a formal examination if any 
Grade ≥ 2 symptoms are reported.
Rationale: Correction to the range of scores for the 6 item subscale on the FACT-G from 0 to 21 to 0 to 24. In 
addition, it has been clarified that the first PRO assessments should be performed prior to the first dose of study 
treatment. Previously, these assessments were required prior to randomization. It has also been clarified that the 
preferred time for conducting the PRO questionnaires is at the beginning of the clinic visits, prior to any procedures, 
laboratory testing, or physician interactions. After Cycle 6, a time window of +/- 7 days for conducting PRO 
assessments is added.
Time and Events Schedule; 9.1.2 Screening 
Phase; 9.1.3 Treatment Phase; 9.2.1.7 Patient-
Reported Outcomes
The FACT-G consists of three 7 item subscales scored 0 to 28 
(physical 
well-being, 
social 
well-being, 
and 
functional 
well-being) plus one 6 item subscale (emotional well-being) 
scored 0 to 24.
The first FACT-Lym and EQ-5D-5L assessment will be 
administered prior to the first dose of study treatment.
Rationale: Additional information for the Screening hepatitis B and C sample collection has been added.  
Instructions for monitoring carriers with hepatitis B infection have been deleted as this will be performed on a case 
by case basis.
Time 
and 
Events 
Schedule;
9.5 
Safety 
Evaluations
Screening for Hepatitis B and C will include the following 
evaluations: Hepatitis B surface antigen, Hepatitis B core 
antibody, and Hepatitis C antibody. Subjects who test positive 
for Hepatitis B core antibody must have Hepatitis B DNA by 
PCR performed and confirmed as 
negative prior to 
randomization. Subjects who test positive for Hepatitis C 
antibody are eligible if previously treated and achieved a 
sustained viral response, defined as a negative viral load for 
Hepatitis C after completion of the treatment for hepatitis.
Previous instructions for HBV monitoring were deleted.
Rationale: A statement has been added to clarify that anti-hormonal therapy may be administered to subjects 
receiving ibrutinib.
8.1 Permitted Medications
Anti-hormonal therapies are permitted, after discussion with the 
sponsor’s medical monitor.
Rationale: Clarification that pregnancy tests are to be conducted only for women of childbearing potential.
Time and Event Schedule; 9.1.1 Overview
Serum or urine pregnancy tests should be performed for women 
of childbearing potential, as determined necessary by the 
investigator or required by local regulation to establish the 
absence of pregnancy at any time during the subject's 
participation in the study.
Rationale: The definition of the baseline assessment has been expanded; baseline is defined as the time prior to 
randomization, unless otherwise specified.
11.3.4 Baseline Assessments
All 
demographic 
and 
baseline 
characteristics 
will 
be 
summarized for the ITT population. The baseline value is 
defined as the value collected at the time closest to, but prior to, 
randomization, unless otherwise specified.


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Rationale: The protocol has been revised to be consistent with the Statistical Analysis Plan. The 3 planned safety
review meetings will be conducted approximately 2 months after enrollment of 40, 200, and 400 subjects, not at 
1 month, as previously stated. The alpha spend for the final analysis of 0.0245 was corrected to 0.025
11.9 Independent Data Monitoring Committee
11.8 Interim Analysis
The independent DMC may recommend stopping the study for 
efficacy or futility if the pre-specified stopping boundary is 
crossed. In addition to the ongoing safety monitoring and 
planned interim analyses for efficacy and futility, 3 safety 
review meetings are planned for approximately 2 months after 
40 subjects, 200 subjects, and 400 subjects have been 
randomized.
The alpha spend for the final analysis is 0.025.
Rationale: Periodic reviews of the protocol template are conducted to provide corrections and improvements. 
Changes to the protocol template include the subject “wallet card”, Product Quality Complaints reporting, and 
conditions for stopping biomarker analyses and the collection of additional FFPE material.
Title page; 9.4 Biomarkers; 12.3.1 All Adverse 
Events; 13.1 Procedures

The EDMS and protocol version number were moved to the 
cover page.

If the study is terminated early or shows poor clinical 
efficacy, completion of biomarker assessments is based on 
justification and intended utility of the data.  Additional 
FFPE collections may be used to investigate mechanisms of 
resistance and identify biomarkers associated with response 
and resistance to ibrutinib therapy from previously collected 
tumor samples during or after study completion for a 
retrospective analysis.

Subject name has been removed from the “wallet card” and 
replaced with subject number and site number. Information 
regarding breaking the blind in emergency situations (if 
applicable) has been added.

Change in the reporting period for Product Quality 
Complaints from “as soon as possible” to “within 24 hours”.
Rationale: The list of study-specific materials provided to the sites has been revised according to company 
operational standards. Some of these items may be provided via other processes, and the Eligibility Notification 
Form is not applicable for this study.
15 Study-Specific Materials
The following materials have been removed from the list:  
ibrutinib and placebo capsules; NCI-CTCAE Version 4.03; 
Eligibility Notification Form.
Rationale: Throughout the protocol references to ‘study drug’ - meaning ibrutinib or placebo - versus ‘study 
treatment’ - meaning ibrutinib or placebo plus bendamustine and rituximab, have been clarified.  Examples or 
characterization of the changes are provided below.
Synopsis; Time and Events Schedule; 3.1 
Overview of Study Design; 6 Dosage and 
Administration; 
7.1 
Ibrutinib 
or 
Placebo 
Compliance; 8 Concomitant Therapy; 9.1.3 
Treatment Phase; 9.1.5 Clinical Cutoffs; 9.2.1.1 
Radiographic Image Assessments (CT/MRI); 9.5 
Safety Evaluations; 10.2 Discontinuation of 
Treatment; 11.7 Safety Analyses; 12.2. Special 
Reporting Situations; 12.3.1 All Adverse Events; 
12.3.2 Serious Adverse Events; 14.3 Drug 
Accountability 
17.2.2 
Required 
Prestudy 
Documentation; 17.4. Source Documentation
For the purposes of this study, ‘study drug’ refers to ibrutinib or 
placebo and ‘study treatment’ refers to ibrutinib/placebo, 
bendamustine, and rituximab.
The Treatment Phase will extend from randomization until 
discontinuation of all study treatment or the clinical cutoff for 
the end of study. 
The timeframe for collection data on concomitant medications 
and adverse events, and study assessment and procedures now 
reference study treatment instead of study drug, where 
applicable.
An End of Treatment Visit will be scheduled within 30 days 
after the last dose of the last study treatment.
The investigator is responsible for ensuring that all study 
treatment received at the site is inventoried and accounted for 
throughout the study and recorded in source documents.


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Rationale: For subjects without progressive disease after the clinical cutoff, efficacy data will continue to be 
collected.  Previously, efficacy assessments were to be conducted according to the schedule outlined in the protocol. 
This has been changed to comply with the standard of care at the site.
Synopsis; 
9.1.5 
Clinical 
Cutoffs;
9.2.1.1 
Radiographic Image Assessments (CT/MRI)
It has been clarified that after the clinical cutoff for the final 
analysis of PFS, all subjects without progressive disease will 
continue disease assessments, according to the standard of care 
until disease progression.
Rationale: Throughout the protocol, minor grammatical, formatting, or spelling changes were made where 
required, or clarifications, if needed.  Examples are provided below.
16.2.5 Long-Term Retention of Samples for 
Additional Future Research
Clarification was made to explain the meaning of ‘differential 
drug responders’. This was changed to ‘differences in response’ 
to drug to the following: Samples collected in this study may be 
stored for up to 15 years (or according to local regulations) for 
additional research. Samples will only be used to understand 
ibrutinib, to understand MCL, to understand differences in 
response to drug and to develop tests/assays related to ibrutinib 
and MCL. The research may begin at any time during the study 
or the post-study storage period.
4.2 Exclusion Criteria #10
Cross-reference added for Section 9.5.
7.1 Ibrutinib or Placebo Compliance
Not all study treatment will be provided by the IWRS.  
Therefore, it has been clarified that the IWRS will be used to 
assign only centrally supplied study treatment kits.
9.1.3 Treatment Phase
Clarified that the 28 days cycle begins with the administration 
of BR.
9.2.1.6 Physical Examination
Text has been corrected to clarify that physical examinations 
will not be conducted during the Posttreatment Follow-up 
phase.  
9.2.2.2 Definition of Measurable and Assessable 
Disease
The distinction that eligible subjects must have at least 1 
measurable site of disease “by radiological assessment” was 
deleted as it is stated elsewhere in this section.
9.5 Safety Evaluations
It has been clarified that INR and/or prothrombin time are
acceptable laboratory evaluations for bleeding times.
17.10 On-Site Audits
Grammar correct to change the reference to the investigator as 
‘they’ to ‘he/she’.
Time and Events Schedule
Instruction added that subject weight must be obtained within 
14 days of randomization.
Study Treatment Scheme
Clarification that study drug is to be administered before the 
bendamustine infusion on the mornings designated for 
pharmacokinetic sampling.


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
SYNOPSIS
A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) 
Inhibitor, PCI-32765 (Ibrutinib), in Combination with Bendamustine and Rituximab (BR) in Subjects 
With Newly Diagnosed Mantle Cell Lymphoma
Ibrutinib (IMBRUVICA®; PCI-32765; JNJ-54179060) is a first-in-class, potent, orally-administered,
covalently-binding small molecule inhibitor of Bruton’s tyrosine kinase (BTK) currently being 
co-developed by Janssen Research & Development, LLC (JRD) and Pharmacyclics LLC for the treatment 
of B-cell malignancies. Ibrutinib and PCI-32765 refer to the same molecule; hereafter, ibrutinib will be 
used.
Despite recent progress, there remains an unmet medical need for patients with newly diagnosed mantle 
cell lymphoma (MCL), particularly for those who are 65 years of age or older. Phase 1 and 2 studies 
demonstrated that ibrutinib has activity in relapsed or refractory MCL with an overall response rate of 
68% and a complete response (CR) rate of 21%. This study will evaluate whether the addition of ibrutinib 
to standard treatment (bendamustine and rituximab [BR] followed by rituximab [R] maintenance) will 
improve the outcomes of subjects with newly diagnosed MCL.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective of this study is to evaluate whether the addition of ibrutinib to bendamustine and 
rituximab will result in prolongation of progression-free survival (PFS) in subjects with newly diagnosed 
MCL who are 65 years of age or older.
Secondary Objectives
Secondary objectives include evaluation of overall survival; CR rate; overall response rate (CR+ partial 
response [PR]); patient-reported lymphoma symptoms and concerns as measured by the lymphoma (Lym)
subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym); minimal residual 
disease (MRD) negative rate; duration of response; time-to-next treatment (TTNT); safety of ibrutinib
when combined with BR; and to characterize the pharmacokinetics of ibrutinib and explore the potential 
relationships between ibrutinib metrics of exposure with relevant clinical, pharmacodynamic, or 
biomarker information.
Exploratory Objectives
Exploratory objectives are to evaluate patient-reported outcomes (PRO) related to well-being and general 
health status utilizing the FACT-Lym and EuroQol (EQ-5D-5L); and to explore biomarkers identified 
from other studies of ibrutinib in samples collected for MRD assessments.
Hypothesis
The primary hypothesis of the study is that ibrutinib in combination with BR compared with BR alone 
will prolong PFS in subjects with newly diagnosed MCL who are 65 years of age or older.
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study to compare the 
efficacy and safety of ibrutinib in combination with BR with BR alone in subjects with newly diagnosed 
MCL who are 65 years of age or older. Approximately 520 subjects will be randomized in a 1:1 ratio and 
stratified by simplified mantle cell lymphoma international prognostic index (MIPI) score (low risk [0-3] 
vs. intermediate risk [4-5] vs. high risk [6-11]).


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Subject eligibility will be determined up to 30 days prior to randomization. The Treatment Phase will 
extend from randomization until discontinuation of all study treatment or the clinical cutoff for the end of
study. A cycle is defined as 28 days. All subjects will receive open-label BR background therapy for a 
maximum of 6 cycles; subjects with a CR or PR will continue to receive open-label background therapy 
with R maintenance every second cycle for a maximum of 12 additional doses (ie, Cycle 8, 10, 12, 14, 16, 
18, 20, 22, 24, 26, 28, and 30). In addition to the background therapy, all subjects will receive blinded 
study drug (ibrutinib or placebo). Subjects randomized to Treatment Arm A will receive placebo capsules 
and subjects randomized to Treatment Arm B will receive ibrutinib capsules. Study drug will be 
administered daily and continuously until disease progression, unacceptable toxicity, or study end.
Subjects with stable disease after initial chemoimmunotherapy (BR+ibrutinib/placebo) should continue
treatment with ibrutinib/placebo until disease progression, unacceptable toxicity, or study end. Subjects 
with progressive disease must discontinue all study treatment. For subjects who discontinue background 
therapy and do not have progressive disease, treatment with study drug will continue until disease
progression or unacceptable toxicity or the clinical cutoff for the final analysis of PFS. Subjects receiving 
BR, R, or ibrutinib at the clinical cutoff for the final analysis of PFS will continue open-label treatment 
until disease progression or unacceptable toxicity. Placebo will be stopped when the study is unblinded 
for the clinical cutoff for the final analysis of PFS.
Four clinical cutoffs are planned. The first 3 clinical cutoffs will occur when approximately 134, 180, and 
265 PFS events have been observed, respectively. The interim analyses and the final analysis of PFS will 
take place at these 3 clinical cutoffs; subject treatment assignment will be unblinded and placebo 
treatment will be stopped at the clinical cutoff for the final analysis of PFS. Treatment unblinding and 
stopping of placebo treatment may occur before the planned final analysis of PFS if recommended by the 
independent Data Monitoring Committee (DMC) after an interim analysis. The last cutoff will occur at 
the end of study, when 60% of the randomized subjects have died or the sponsor terminates the study, 
whichever comes first. Assessment of tumor response and progression will be conducted in accordance 
with the Revised Response Criteria for Malignant Lymphoma.
SUBJECT SELECTION
Key eligibility criteria include the following: subjects who are 65 years of age or older; have confirmed 
MCL diagnosis; and Stage II, III, or IV disease by Ann Arbor Classification. Subjects also must have had 
no prior therapy for MCL; must have at least 1 measurable site of disease; and have Eastern Cooperative 
Oncology Group (ECOG) performance status grade of 0 or 1.
DOSAGE AND ADMINISTRATION
Bendamustine hydrochloride will be administered as a 90 mg/m2 intravenous (IV) infusion on Days 1 and 
2 of Cycles 1 to 6, for a maximum of 6 cycles, unless progression of disease or unacceptable toxicity is 
encountered prior to Cycle 6. Rituximab will be administered as a 375 mg/m2 IV infusion on Day 1 of 
Cycles 1 to 6; subjects with a CR or PR will continue to receive rituximab on Day 1 of every second cycle 
for a maximum of 12 additional doses, unless progression of disease or unacceptable toxicity is 
encountered. Subjects will be randomized in a 1:1 ratio to receive blinded study drug. Starting at Cycle 1, 
Day 1 study drug will be administered orally once daily continuously in either Treatment Arm A 
(placebo) or Treatment Arm B (560 mg of ibrutinib). Ibrutinib or placebo will be self-administered at 
home. The start of a cycle coincides with the administration of BR on Day 1 during Cycles 1 to 6; and the 
administration of R on Day 1 during even Cycles 8 to 30; and the administration of ibrutinib/placebo on 
Day 1 of all other cycles. The sponsor will ensure that subjects benefiting from treatment with ibrutinib
will be able to continue treatment after the end of the study.


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
EFFICACY EVALUATIONS/ENDPOINTS
Radiological assessments (computed tomography [CT]/magnetic resonance imaging [MRI]) will be 
performed at Screening, and every 12 weeks in the first 12 months after the start of study treatment. 
Thereafter, scans will be performed every 16 weeks until disease progression or the clinical cutoff for the 
final analysis of PFS, whichever comes first. Subjects who discontinue treatment prior to disease 
progression (for other reasons such as an adverse event) must continue to have regularly scheduled CT 
scans/efficacy assessments every 12 weeks in the first 12 months then every 16 weeks until disease 
progression. After the clinical cutoff for the final analysis of PFS, all subjects without progressive disease 
will continue disease assessments according to standard of care until disease progression. Positron 
emission tomography (PET) scan is optional at Screening but mandatory at the time of maximal tumor 
reduction, defined as time of CR or when 2 consecutive CT scans show no further tumor reduction, and at
suspected disease progression, if a new lesion was detected on CT.
Response to treatment will be assessed by the investigator at the site and the results will be recorded in 
the case report form (CRF). Radiological and PET scans performed prior to the database lock for the final 
analysis of PFS must be transferred to the independent imaging laboratory for storage; the scans may be
reviewed, if deemed necessary.
PHARMACOKINETIC EVALUATIONS
Venous blood samples will be collected according to a sparse sampling scheme, and will be used for the 
development of a population-based pharmacokinetic model. Model-derived plasma concentrations or 
metrics of exposure parameters (eg, maximum observed plasma concentration [Cmax] or area under the 
plasma concentration versus time curve [AUC]) may be subjected to further analyses to explore 
pharmacokinetic correlation between exposure and relevant clinical or biomarker information.
BIOMARKER EVALUATIONS 
Blood samples for assessments of MRD and biomarker evaluations will be collected at multiple 
timepoints. If feasible, a bone marrow sample for MRD assessment will be collected at suspected CR, if 
taken for clinical evaluations.
Tumor from diagnostic biopsy tissue collected during screening may be evaluated to identify markers 
predictive of response to ibrutinib. A fresh lymph node biopsy sample also should be collected, if 
feasible, for biomarker evaluation (where local regulations and shipping logistics permit) during 
Screening or prior to Cycle 1, and at the time of progressive disease. If a fresh lymph node biopsy was 
performed during Screening to confirm MCL diagnosis, a portion of the sample may be used for the 
biomarker evaluation. A portion of the formalin-fixed paraffin-embedded tumor (FFPE) block or slides 
collected for confirmation of diagnosis may be evaluated for biomarker assessments.
SAFETY EVALUATIONS
The safety will be assessed by physical examinations, ECOG criteria for performance status, laboratory 
tests, monitoring adverse events, and concomitant medication usage. Adverse events that occur between 
the signing of the informed consent through 30 days following the last dose of any study treatment
(ibrutinib or placebo or BR background therapy) will be recorded. The severity of adverse events will be 
assessed using National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.03. Major hemorrhage (treatment-emergent adverse events defined as: Grade 3 or higher; 
serious adverse event of bleeding; or central nervous system hemorrhage/hematoma) has been identified 
as adverse events of special interest and will require enhanced reporting and data collection. Data also 
will be collected on new malignant tumors occurring during study treatment and during any 
protocol-specified follow-up periods, including post-progression follow-up for overall survival.


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
STATISTICAL METHODS
The primary efficacy endpoint of PFS will be determined by investigators. Approximately 520 subjects 
(about 260 subjects to each arm) will be randomized. Assuming a 43% improvement in median PFS of 
the ibrutinib + BR arm over the placebo + BR (hazard ratio of 0.7 for the ibrutinib + BR arm relative to 
placebo + BR arm, under the exponential distribution assumption), the study has at least 77% power 
assuming an overall statistical significance level of 2.5% (1-sided). Three analyses are planned: 2 interim 
analyses for both efficacy and futility using an O’Brien and Fleming boundary after approximately 
134(50%) and 180 (68%) PFS events (progressive disease or death) have occurred, and the final analysis 
after 265 PFS events has occurred. An independent DMC will review safety data periodically and data 
from the interim analyses. The independent DMC may recommend stopping the study or unblinding the 
study/stopping placebo treatment for efficacy or futility if the pre-specified stopping boundary is crossed 
at interim analysis, and the sponsor may implement the recommendations.
EudraCT NUMBER:  2012-004056-11
Universal Trial Number: U1111-1137-0389


JNJ-54179060  (ibrutinib)
Clinical Protocol PCI-32765MCL3002 - Amendment INT-7
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Approved, Date: 19 December 2019
Table 1:
Time and Events Schedule
Study Period
Screening 
Phase
Treatment Phasey, z
(1 cycle = 28 days)
Posttreatment 
Follow-up Phase y, z
BR Treatment Period
Cycles 1 to 6d, g
R Treatment
Every 2 cycles
up to Cycle 30d, f, g
After 
Cycle 30d, g
End of 
Treatment 
Visit
Follow-up 
until 
Progressive 
Disease
Survival 
Follow-
upaa
Study Day
Procedures and Assessmentsa
Day -30 to 
randomizationb
Day 1c
Day 2
Day 1
Day 1
Within 30 
days after 
last dose
Drug Administration (see Table 2)
Rituximab 375 mg/m2 
X
Xe,f
Bendamustine hydrochloride 90 mg/m2
X
Xu
Study drug:
Arm A: placebo (4 capsules)h
Arm B: ibrutinib 560 mg (4 capsules)
<-----------------------------------Continuoush---------------------------------->
Dispense study drug and check drug 
accountability
X
X
X
Ongoing Subject Review
Concomitant medications
<-----------Continuous from informed consent to 30 days after the last dose of study treatment or until the start 
of a subsequent systemic anti-MCL therapy, if earlier-------------->
Adverse events
<-----------Continuous from informed consent to 30 days after the last dose of study treatment-------------->
Procedures
Informed consent
X
Review inclusion/exclusion criteria
X
Medical and disease history
X
MCL diagnosis (see Section 9.1.2)i
X
Vital signsj and height
X
Pulse/heart rate and blood 
pressure are expected in all 
protocol-specified visits.
ECOG
X
X
X
X
X
Body surface area (BSA)
X
X
Weight
Xb
X
X
Electrocardiogram
X
Disease-related symptoms and physical 
examination
X
Xk
Xk
Xk
Xk


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Study Period
Screening 
Phase
Treatment Phasey, z
(1 cycle = 28 days)
Posttreatment 
Follow-up Phase y, z
BR Treatment Period
Cycles 1 to 6d, g
R Treatment
Every 2 cycles
up to Cycle 30d, f, g
After 
Cycle 30d, g
End of 
Treatment 
Visit
Follow-up 
until 
Progressive 
Disease
Survival 
Follow-
upaa
Study Day
Procedures and Assessmentsa
Day -30 to 
randomizationb
Day 1c
Day 2
Day 1
Day 1
Within 30 
days after 
last dose
Disease Evaluations
CT/MRI
X
Every 12 weeks in first 12 months; then, every 16 weeks until disease progression or the clinical cutoff for 
the final analysis of PFS (see Section 9.2.1.1). 
PET scan
Maximal tumor reduction defined as time of CR or when 2 consecutive CT scans show no further tumor 
reduction, and at suspected disease progression if a new lesion was detected on CT.
Endoscopy
To confirm CR for subjects with known gastrointestinal involvement at baseline. 
Bone marrow aspirate and biopsyl
X
To confirm CR for subjects with bone marrow involvement baseline.
Survival status
<-------------------------------------------------------------- Continuous------------------------------------------------------------>
Subsequent anti-MCL therapiesm
X
X
X
PRO questionnairesn
Xo
Every 12 weeks in first 12 months; then, every 
16 weeks
X
X
Xp
Laboratory Assessments
Hematology (see Section 9.5)
Xb
Xc,q
Xq
Xq
X
Serum chemistry (see Section 9.5)
Xb
Xc
X
X
Magnesiumr
Xc,r
Hepatitis B and C s
X
Urine or serum pregnancy testt
X
Coagulation (aPTT and PT/INR) 
X
Pharmacokinetic sample 
Xu
Serum immunoglobulin and beta 2-
microglobulin
Xv
Every 12 weeks in the first 12 months; thereafter, every 16 weeks and at disease progression
Blood samples for minimal residual 
disease (MRD)w
Xw
For subjects with CR, every 12 weeks in the first 12 months; thereafter, every 16 weeks and 
at disease progression or the clinical cutoff for the final analysis of PFS. As of 
Amendment INT-6, CR MRD samples will only be collected for new CRs; the comparative 
MRD samples will continue be collected in all subjects participating in this assessment (see 
Section 9.4.1).
Blood samples for biomarker 
evaluations
Xx
Xx
Xx
Fresh lymph node biopsybb
X
X
X


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a
Assessments/procedures should be completed on the day indicated in the Time and Events Schedule; if this is not possible (eg, because of a weekend, holiday, emergency), the 
assessment/procedure should be completed within 48 hours of the scheduled day; PET, CT/MRI, serum immunoglobulin, and beta2 microglobulins should be performed within 
± 7 days of the scheduled assessment day. Laboratory results must be reviewed before the start of the cycle. The last assessment/procedure or laboratory result obtained prior to 
randomization will be used to determine eligibility.
b
Results of tests obtained prior to signing the informed consent conducted as part of the subject’s standard care may be used for this study if performed within 30 days before 
randomization. CT, MRI, and bone marrow aspirate/biopsy assessments performed up to 60 days before randomization are acceptable. Subjects should start study treatment 
within 72 hours after randomization in the IWRS. Hematology and chemistry laboratory assessments to determine subject eligibility must be performed within 14 days prior to 
randomization. Subject’s body weight also must be obtained within 14 days of randomization. 
c
For Day 1, Cycle 1, clinical laboratory tests do not need to be repeated if the Screening tests were performed within 5 days of the first dose of study treatment.
d
During the Treatment Phase, clinical laboratory samples may be obtained on the day of or day prior to dosing, provided the results are available before study treatment is 
administered.  
e
Subjects with stable disease after initial chemoimmunotherapy (BR+ibrutinib/placebo) should continue treatment with ibrutinib or placebo until disease progression, 
unacceptable toxicity, or study end.
f
Only subjects with a CR or PR are eligible to receive rituximab therapy for a maximum of 12 additional doses.
g
Subjects will be seen at the site every 4 weeks during Cycles 1 to 6; however, more frequent visit may be necessary for collection of hematology samples (see footnote “q” 
below). Thereafter, site visits will be conducted every other cycle (ie, approximately every 8 weeks) for study procedures and assessments.
h
Placebo will be administered until the study is unblinded at the time of the clinical cutoff for the final analysis of PFS.
i
Approval or confirmation of the diagnosis of MCL from the central laboratory must also be obtained within 30 days prior to randomization; however, the slides or tumor block 
used for diagnosis may be either newly obtained or from previous biopsy. FFPE block or slides may be used for biomarker evaluations. 
j
These assessments should be recorded in source documents but will not be routinely collected in the eCRF. Clinically significant abnormalities should be recorded as adverse 
events and reported in the eCRF.
k
Only a limited symptom-directed physical examination is required. Review of systems should include inquiry of ocular symptoms; subjects should be referred to an 
ophthalmologist for a formal examination if any Grade ≥ 2 symptoms are reported (see Section 9.5).
l
A portion of the bone marrow sample collected at CR will be used for MRD assessments.
m
Investigator assessment of response to treatment will be collected. Best response as well as progressive disease on subsequent anti-MCL therapy will also be collected.
n
It is preferred that the PRO questionnaires (FACT-Lym and EQ-5D-5L) are completed prior to any assessments, and before being clinically evaluated by the study nurse or 
physician. 
o
PRO assessments will be performed on Day 1 of the first 6 cycles. The first PRO assessment should be obtained at Cycle 1, Day 1 before the first dose of study treatment. If the 
PRO assessment was conducted but the cycle subsequently delayed, the PRO assessment should be repeated on Day 1 of the cycle when treatment is resumed. After the Cycle 6 
they can be administered +/- 7 days.
p
Following disease progression, sites should attempt to administer the EQ-5D-5L every 16 weeks (up to 3 times) during the survival follow-up period, unless death or study end 
occurs first. Data will be collected in person (preferred) or with the subject via telephone.
q
Hematology laboratory samples will be collected as follows: every other week during Cycle 1 to Cycle 6, inclusive starting with Day 1 of Cycle 1; on Day 1 during Cycles 7 to 
12, inclusive (ie, every 4 weeks); and every 8 weeks after Cycle 12.
r
Day 1 of Cycle 1 and 2, and as clinically indicated.
s
Screening for Hepatitis B and C will include the following evaluations: Hepatitis B surface antigen, Hepatitis B core antibody, and Hepatitis C antibody. Subjects who test 
positive for Hepatitis B core antibody must have Hepatitis B DNA by PCR performed and confirmed as negative prior to randomization. Subjects who test positive for Hepatitis 
C antibody are eligible if previously treated and achieved a sustained viral response, defined as a negative viral load for Hepatitis C after completion of the treatment for 
hepatitis.
t
Pregnancy tests should be performed for women of childbearing potential, as determined necessary by the investigator or required by local regulation to establish the absence of 
pregnancy at any time during the subject's participation in the study.


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u
Predose sample to be obtained on Day 2 in Cycles 1, 2 and 3, and postdose on Day 2 in Cycles 1 and 2, at 1 hour (window 45-75 min), 2 hours (window 1.5-2.5 hour), and 
4 hours (window 3.5-6 hours) following dosing of study drug. The study drug will be administered before the bendamustine infusion. See Section 9.3.1 for study drug dosing 
instructions on pharmacokinetic sampling days.
v
Day 1 of Cycle 1 only.
w
Day 1 Cycle 1 MRD (peripheral blood mononuclear cell [PBMC]) sample to be collected on all subjects. At CR and after as noted in table, CR MRD samples will be collected. 
Additionally, MRD (PBMC) samples for comparative MRD testing in approximately the first 100 subjects with a CR (excluding subjects at sites in China) should be collected 
at same time points as CR MRD, but only if Day 1 Cycle 1 MRD (PBMC) was collected.
x
Day 1 of Cycle 1 and at the time of disease progression, or the End of Treatment Visit, for subjects who discontinue treatment without disease progression.
y
Notification of progressive disease and supportive clinical results must be sent within 24 hours to the sponsor’s medical monitor using a form provided by the sponsor.
z
Refer to Section 9.1.5 for data collection after the clinical cutoff.
aa
Following disease progression, contact will be made to determine survival status and subsequent anti-MCL therapy administered after participation in this study every 16 weeks 
until the clinical cutoff for the study end.
bb
A fresh lymph node biopsy also should be collected, if feasible, for biomarker evaluation (where local regulations and shipping logistics permit) during Screening (after 
eligibility is determined) or prior to Cycle 1, and at the time of progressive disease (even if screening sample was not collected). If a fresh lymph node biopsy was performed 
during Screening to confirm MCL diagnosis, a portion of the sample may be used for the biomarker evaluation. A portion of the formalin-fixed paraffin-embedded tumor 
(FFPE) block or slides collected for confirmation of diagnosis may be evaluated for biomarker assessments.


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Table 2:
Study Treatment Scheme
Duration of 
Treatment Cycle
28-Day Treatment Cycle
Study Phase
Cycles 1 to 6 
Rituximab Maintenance
Up to Cycles 30 a
Every second cycle
Single Agent 
Treatmentb
Cycle No.
1
2
3
4
5
6
8
10
12
14
16
18
20
22
24
26
28
30
After Cycle 
30
Cycle Day
1
2
1
2
1
2
1
2
1
2
1
2
1
1
1
1
1
1
1
1
1
1
1
1
Rituximabc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bendamustine
X
Xd
X
Xd
X
Xd
X
X
X
X
X
X
Ibrutinib or placebo
<-------------------------------------------------------------- 4 capsules daily, continuously------------------------------------------------------------------>
a
Subject with a CR or PR will continue to receive background therapy with rituximab every second cycle for a maximum of 12 additional doses. Rituximab 
maintenance dosing starts at Cycle 8. 
Subjects with stable disease after initial chemoimmunotherapy (BR+ibrutinib/placebo) should continue treatment with ibrutinib or placebo until disease 
progression, unacceptable toxicity, or study end. 
b
Subjects with a response of CR or PR after Cycle 30 will continue treatment with ibrutinib or placebo (see Section 6.1). Treatment with ibrutinib/placebo will 
continue until disease progression, unacceptable toxicity, or study end. Placebo will be stopped when the study is unblinded for the clinical cutoff for the final 
analysis of PFS.
c
For subjects with an increased risk of tumor lysis syndrome or other toxicities, rituximab can be split over a 2-day period in Cycle 1, or throughout Cycles 1 to 6, 
to comply with the study site’s practice.
d
On the morning of study visits designated for pharmacokinetic sampling, the study drug (ibrutinib or placebo) will be administered before the bendamustine 
infusion (see Section 6.3).


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ABBREVIATIONS
ALT
alanine aminotransferase
ANC
absolute neutrophil count 
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
Ara-C
cytarabine
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-last
area under the plasma concentration versus time curve from time zero to the time corresponding to 
the last quantifiable concentration
B
bendamustine
B-cell
B-lymphocyte
-hCG
beta-human chorionic gonadotropin
BR
bendamustine and rituximab
BSA
body surface area
BTK
Bruton’s tyrosine kinase 
CHOP
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CI
confidence interval 
CL/F
apparent total systemic clearance of drug after
extravascular administration
CLL
chronic lymphocytic leukemia
Cmax
maximum observed plasma concentration
Cmin
minimum observed plasma concentration
CR
complete response
CRF
case report form
CT
computed tomography (scan)
CYP
cytochrome
DMC
Data Monitoring Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDC
electronic data capture
EQ-5D
EuroQol
EU
European Union
FACT-G
Functional Assessment of Chronic Illness Therapy General
FACT-Lym
Functional Assessment of Cancer Therapy-Lymphoma
FCR
fludarabine, cyclophosphamide, and rituximab
FDG
[18F]-fluorodeoxyglucose 
FFPE
formalin-fixed paraffin-embedded tumor (tissue) 
FISH
fluorescent in situ hybridization 
FL
follicular lymphoma
GCP
Good Clinical Practice
GEP
gene expression profiling
GI
gastrointestinal
GTD
greatest transverse diameter 
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
Hyper-CVAD
hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating 
with methotrexate and cytarabine
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
Ig
immunoglobulin
IHC
immunohistochemistry 
INR
international normalized ratio


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IRB
Institutional Review Board
ITT
intent-to-treat (population)
IV
intravenous 
IWRS
interactive web response system
JRD
Janssen Research & Development
LDH
lactic acid dehydrogenase 
Lym
lymphoma specific additional concerns subscale
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MIPI
Mantle Cell Lymphoma International Prognostic Index
MRD
minimal residual disease
MRI
magnetic resonance imaging 
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin Lymphoma
NONMEM
nonlinear mixed-effects modeling
ORR
overall response rate
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PET
positron emission tomography
PFS
progression-free survival
PP
per-protocol population
PQC
product quality complaint
PR
partial response
PRO
patient-reported outcome(s)
PT
prothrombin time
R
rituximab
R-CHOP
rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone
R-DHAP
rituximab, dexamethasone, high-dose cytarabine, and cisplatin
REAL
Revised European-American Lymphoma
R-Hyper-
CVAD
hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone
RNA
ribonucleic acid
SCT
stem cell transplant
SPD
sum of the product of the diameters 
TLS
tumor lysis syndrome
TTNT
time-to-next treatment
TTW
Time to worsening
ULN
upper limit of normal
US
United States
USPI
United States Package Insert
Vss/F
volume of distribution at steady state
WBC
white blood cell (count)


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1.
INTRODUCTION
Ibrutinib 
(IMBRUVICA®, 
PCI-32765; 
JNJ-54179060) 
is 
a 
first-in-class 
potent, 
orally-administered, covalently-binding small molecule inhibitor of Bruton’s tyrosine kinase 
(BTK) currently being co-developed by Janssen Research & Development, LLC (JRD) and 
Pharmacyclics LLC. It has demonstrated single-agent activity in several B-cell lymphomas, 
including relapsed/refractory mantle cell lymphoma (MCL), with an acceptable safety profile.
Ibrutinib and PCI-32765 refer to the same molecule; hereafter, ibrutinib will be used.
Relevant clinical and nonclinical information are discussed within this section. For the most 
comprehensive clinical and nonclinical information regarding the efficacy and safety of ibrutinib, 
refer to the latest version of the Investigator's Brochure and Addenda/Supplements for ibrutinib. 
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Mantle Cell Lymphoma
Mantle cell lymphoma is an uncommon clinicopathologic subtype of B-lymphocyte (B-cell)
non-Hodgkin Lymphoma (NHL). It accounts for about 6% of all NHL cases in the Western 
world, and has been recognized as a distinct entity in the Revised European-American 
Lymphoma (REAL) classification since 1994. At the molecular level, MCL is uniquely 
characterized by overexpression of the cell cycle regulator protein cyclin D1. This is due to the 
chromosomal translocation t(11;14)(q13;q32), which puts the cyclin D1 gene (bcl-1), under the 
control of the immunoglobulin (Ig) heavy chain enhancer with subsequent overexpression of 
cyclin D1.20,44,49 By immunohistochemistry (IHC), it is characterized by the coexpression of the 
B-cell marker CD20 and T-cell marker CD5; however, there are atypical forms which do not 
express CD5.29,31 Its treated natural history is also distinct: unlike the other indolent NHLs, it is 
associated with a poor prognosis and a relatively short median overall survival.
1.2.
First-line Treatment for Mantle Cell Lymphoma
There is no single, globally accepted and approved standard treatment regimen for patients with 
first-line MCL. Current initial therapy for the treatment of MCL includes cyclophosphamide,
doxorubicin, vincristine, and prednisone (CHOP) or hyperfractionated cyclophosphamide, 
vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine 
(Hyper-CVAD), often in combination with Rituxan®
(rituximab
[R])
(R-CHOP or 
R-Hyper CVAD). Younger patients with good performance status are frequently considered for 
more intensive induction therapy with combinations such as R-Hyper-CVAD or alternating 
R-CHOP and rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) 
followed by consolidation therapy with autologous stem cell transplant (SCT). The use of 
R-CHOP in previously untreated patients resulted in an overall response rate of 96%, including a 
complete response (CR) of 48%.22 More recently, the use of first-line treatment with CHOP was 
compared with R-CHOP.27 In this study, the addition of rituximab improved the overall response 
rate from 75% to 94% and the CR rate from 7% to 34%, but did not significantly improve 
progression-free survival (PFS) or overall survival. The addition of rituximab to Hyper-CVAD 
resulted in an 87% CR rate with a 7-year failure-free survival rate of 52% and an overall survival 


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of 68%. However, this regimen is associated with significant Grade 4 neutropenia and 
thrombocytopenia; furthermore, there was a trend toward cumulative toxicity for 
thrombocytopenia.39
Due to their age and comorbidities, the intensive therapies described above are not an option for 
the majority of patients with MCL.13,31 For elderly patients, commonly used therapies include 
CHOP alone47 or in combination with rituximab.27 Purine analogues have also been used for the 
treatment of MCL in the older patient population. Single-agent fludarabine demonstrated an 
overall response rate < 40%; and when combined with cyclophosphamide and rituximab, the 
response rate is closer to 60%.11,19
Recently, a randomized controlled study comparing the bendamustine and rituximab
combination (BR) with R-CHOP as first-line treatment in elderly patients with indolent NHL and 
MCL demonstrated that BR significantly prolongs the PFS in these patients and in addition, is
less toxic.38,40 In the subset of patients with MCL, the median PFS of the BR arm was superior to 
the R-CHOP arm (36 months vs. 24 months, respectively).41 Favorable safety data for the BR 
regimen were also reported (see Section 1.8).41 Due to prolonged PFS, high response rates, and 
lower toxicity, the BR regimen has been increasingly used over the last several years for this 
patient population.
The role of rituximab maintenance after initial treatment has already been reported.2,25 Recently, 
a large randomized study compared 2 different induction (R-CHOP vs. fludarabine, 
cyclophosphamide, and rituximab [FCR]) and 2 different maintenance regimens in elderly 
patients with MCL (rituximab vs. interferon-alfa).26 This large randomized study demonstrated, 
for the first time, a benefit in PFS with rituximab maintenance therapy. These results prompted 
the use of rituximab as maintenance treatment to be incorporated into practice guidelines around 
the world.
In summary, there is an unmet medical need for patients with newly diagnosed MCL, 
particularly for those who are 65 years of age or older, as these patients are usually not 
considered for intensified chemotherapy (eg, high-dose Ara-C [cytarabine]) or SCT. Although
there is no globally accepted standard of care, BR followed by rituximab maintenance emerged
as a standard treatment option based on results from large randomized controlled studies. 41,26,31
1.3.
Investigational Product Name and Description
Ibrutinib
is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidin-1-yl]-1-
piperidinyl]-2-propen-1-one and has a molecular weight of 440.50 g/mole (anhydrous basis). 
Ibrutinib is a white to off-white solid. It has a single chiral center and is the R-enantiomer. The 
investigational drug product, ibrutinib, is an oral capsule formulation containing micronized
ibrutinib. 


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1.4.
Summary of Relevant Non-clinical and Clinical Pharmacology Data
1.4.1.
Non-clinical Data
In vitro studies have shown that ibrutinib binds covalently to a cysteine residue (Cys-481) in the 
BTK active site, leading to potent and irreversible inhibition of BTK enzymatic activity.35 In 
cellular signal transduction assays with a B-cell lymphoma cell line, ibrutinib inhibited 
autophosphorylation 
of 
BTK, 
phosphorylation 
of 
BTK’s
physiological 
substrate, 
phospholipase-Cγ (PLCγ), and phosphorylation of a further downstream kinase, extracellular 
signal-regulated kinase. Ibrutinib
also inhibited the growth of a subset of B-cell 
lymphoma-derived cell lines, with 50% growth inhibition (GI50) values ranging from 0.1 to 
5.5 µM. Refer to the ibrutinib Investigator’s Brochure for more information on nonclinical 
pharmacology and toxicology studies.
1.4.2.
Clinical Pharmacokinetic Data
In vitro preclinical data show that ibrutinib is metabolized primarily by CYP3A. Its 
bioavailability is variable and relatively low (data on file). Study PCI-32765CLL1002 was an 
open-label drug-drug interaction study of 18 healthy men, in which ibrutinib was administered 
alone at a 120 mg dose or in combination with ketoconazole at a 40 mg dose. Results 
demonstrated that ketoconazole, a strong CYP3A4 inhibitor, increased ibrutinib exposure 
(maximum observed plasma concentration [Cmax] and area under the plasma concentration versus
time curve from time zero to the time corresponding to the last quantifiable concentration 
[AUC0-last]) by 29- and 24-fold, respectively. Terminal half-life was not increased. Ibrutinib 
single-dose administration was well-tolerated. No drug-related adverse events, Grade 3 or 
4 toxicities, or serious adverse events were reported. Guidance on concomitant use of 
ibrutinib/placebo with CYP3A inhibitors or inducers is provided in Section 8.3.
1.5.
Clinical Efficacy of Ibrutinib in Mantle Cell Lymphoma
Efficacy results from Study PCYC-04753 and Study PCYC-1104-CA demonstrate that ibrutinib
has activity as a single-agent in treatment of subjects with relapsed or refractory MCL.
1.5.1.
Study PCYC-04753
In this Phase 1, multicenter, multicohort, open-label, dose-escalation study, 66 subjects with a 
variety of B-cell malignancies, including chronic lymphocytic leukemia (CLL), Waldenström’s 
macroglobulinemia, follicular lymphoma (FL), and MCL were enrolled across 8 dose cohorts. 
Nine of 66 subjects had a diagnosis of MCL, and they were all evaluable for response; 7 of the 
9 (78%) evaluable subjects achieved an objective response including 3 CRs and 4 PRs; 1 subject 
had stable disease and 1 subject had progressive disease as best response.1 All of the subjects 
responding to treatment achieved a response at the time of the first postbaseline response 
assessment (after 2 cycles of treatment). The responses have been durable, with a median time on 
ibrutinib treatment of 8 months (1.3 to 14.7 months) and median PFS of 11.6 months for the 
9 subjects. At the time of study closure, 6 subjects with MCL continued to receive ibrutinib 
treatment.


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1.5.2.
Study PCYC-1104-CA
This is an ongoing Phase 2 study of single-agent ibrutinib (560 mg daily administered orally) in
subjects with relapsed or refractory MCL. Subjects were assigned to 1 of 2 cohorts based on 
prior exposure to bortezomib. The “bortezomib-naïve” cohort was defined as having exposure to 
fewer than 2 cycles of bortezomib therapy prior to enrollment. The primary endpoint of the study 
is overall response rate and secondary efficacy endpoints include PFS, duration of response, and 
overall survival.
One hundred eleven subjects (63 bortezomib-naïve and 48 bortezomib-exposed) have been 
enrolled in the study. The median age was 68 years (range, 40 to 84 years), median time since 
diagnosis was 42.4 months, and median number of prior treatments was 3 (range, 1 to 
5 treatments), including 35.1% with prior high-intensity therapy, 24.3% with prior lenalidomide, 
and 10.8% with prior SCT. At baseline, 8.1% of subjects had bulky disease (≥10 cm), 48.6% 
had high-risk score by Mantle Cell Lymphoma International Prognostic Index (MIPI), and 45.0% 
had refractory disease.45
The overall response rate for the 111 treated subjects is 68.0% including a CR rate of 21.0%.
Additionally, the rate of response to ibrutinib appears to be independent of prior exposure to 
bortezomib or underlying risk/prognosis, bulky disease, or age. The estimated median duration 
of response was 17.5 months and overall survival was not reached at the time of the clinical 
cutoff. With an estimated median follow-up of 15.3 months, the estimated median PFS was 
13.9 months. Median time to initial response is 1.9 months (range, 1.4 to 13.7 months). The 
estimated rate of overall survival was 58% at 18 months.45
Median duration of ibrutinib treatment was 8.3 months (range, 0.7 to 21.4 months) and 
46 subjects remain on treatment as of the clinical data cutoff and 68% of the subjects who 
responded to ibrutinib treatment have not progressed or died at the clinical data cutoff.
1.5.3.
Study of Bendamustine and Rituximab with Ibrutinib in Patients with 
Relapsed/Refractory NHL
Results from an ongoing Phase 1 study designed to determine the maximum tolerated dose, dose 
limiting toxicity, and preliminary efficacy of BR in combination with ibrutinib in 20 patients 
with relapsed/refractory NHL are available. Patients with at least 1 prior therapy or previously 
untreated but not candidates for autologous SCT were eligible. Bendamustine 90 mg/m2 on 
Days 1 and 2 with rituximab 375 mg/m2 on Day 1 were administered with escalating doses of 
ibrutinib (280 mg or 560 mg) on Days 1 to 28 every 28 days for 6 cycles. Responding patients 
could continue ibrutinib alone after Cycle 6 until disease progression or unacceptable toxicity. 
Nine of the 20 patients had MCL (2 previously untreated; 7 received 1 to 5 prior therapies). The 
overall response rate was 100% (4 CRs and 1 PR) for the 5 patients with MCL who were 
evaluable for response to treatment. No DLTs were reported. Grade 3/4 adverse events (N=20) 
included lymphopenia (15 subjects), neutropenia (5 subjects), rash (3 subjects), and anemia, 
thrombocytopenia, nausea and vomiting (2 subjects each event). The combination of ibrutinib 
with BR was well-tolerated without unexpected toxicity and with preliminary activity in patients 
with previously untreated and relapsed MCL.4


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1.6.
Lymphocytosis and Leukostasis
Similar to other agents targeting B-cell receptor signaling, transient lymphocytosis is a 
pharmacodynamic effect of ibrutinib, in which the inhibition of BTK-mediated cellular homing 
and adhesion results in a mobilization of tumor cells to the peripheral blood.42
Upon initiation of single-agent treatment with ibrutinib, a reversible increase in lymphocyte 
counts (ie, ≥50% increase from baseline and an absolute count >5000/mm3), often associated 
with reduction of lymphadenopathy, has been observed in most subjects (66%) with CLL/small 
lymphocytic lymphoma (SLL). This effect has also been observed in some subjects (35%) with 
MCL treated with ibrutinib. This observed lymphocytosis is a pharmacodynamic effect and 
should not be considered progressive disease in the absence of other clinical findings. In both 
disease types, lymphocytosis typically occurs during the first month of ibrutinib therapy and 
typically resolves within a median of 8.0 weeks in subjects with MCL and 14.0 weeks in subjects 
with CLL/SLL (range, 0.1 to 104 weeks).
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high 
number of circulating lymphocytes (>400000/mm3) may confer increased risk. These subjects
should be
closely monitored.
Administer supportive care including hydration and/or 
cytoreduction as indicated. Ibrutinib may be temporarily held and the medical monitor should be 
contacted.
1.7.
Clinical Safety of Ibrutinib
As of 6 April 2015, safety data from completed studies (primary analysis or final analysis 
completed) are available for 1,214 subjects treated with single-agent ibrutinib (1,071 subjects 
with B-cell malignancies and 143 healthy volunteers) and for 423 subjects with B-cell 
malignancies treated with ibrutinib in combination with immunotherapy and/or chemotherapy. 
Because ibrutinib is in clinical development, the safety profile is not yet fully understood. 
Further investigation is necessary to better understand the safety of ibrutinib. Therefore, 
unanticipated side effects that have not been previously observed may occur. A brief overview of 
the potential risks associated with the administration of ibrutinib based on sponsor-initiated 
clinical studies is presented in the ibrutinib Investigator’s Brochure and is outlined below. Please 
refer to the latest Investigator’s Brochure for the most updated information.
Hematological Adverse Events
Cytopenias
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Monitor complete blood counts monthly.


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Non-Hematological Adverse Events
Bleeding-related Events
There are reports of bleeding events in subjects treated with ibrutinib, both with or without 
thrombocytopenia. These include minor bleeding events such as contusion, epistaxis, and 
petechiae; and major bleeding events, some fatal, including gastrointestinal bleeding, intracranial 
hemorrhage, and hematuria (see also 12.3.3.1). 
In an in vitro platelet function study, inhibitory effects of ibrutinib on collagen-induced platelet 
aggregation were observed. Use of either anticoagulant or antiplatelet agents concomitantly with 
ibrutinib increases the risk of major bleeding. A higher risk for major bleeding was observed 
with anticoagulant than with antiplatelet agents. Consider the risks and benefits of anticoagulant 
or antiplatelet therapy when co-administered with ibrutinib. Subjects in the current study will be 
monitored closely for signs and symptoms of bleeding (see Section 12.3.3). Guidance for 
subjects who require surgical intervention or an invasive procedure while receiving ibrutinib is 
provided in Section 4.3. Guidance on use of antiplatelet agents and anticoagulants is provided in 
Section 8.3.
Cardiac Arrhythmias
Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia including some fatal 
events, have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac 
risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmia. 
Periodically monitor subjects clinically for cardiac arrhythmia. Subjects who develop arrhythmic 
symptoms (eg, palpitations, lightheadedness, syncope, chest discomfort, or new onset of 
dyspnea) should be evaluated clinically and if indicated have an ECG performed. For cardiac 
arrhythmias which persist, consider the risks and benefits of ibrutinib treatment and follow the 
dose modification guidelines (Section 6.4.3).
Cerebrovascular Accidents
Although causality has not been established, cases of cerebrovascular accident, transient 
ischemic attack, and ischemic stroke including fatalities have been reported with the use of 
ibrutinib in the post-marketing setting, with and without concomitant atrial fibrillation and/or 
hypertension. Regular monitoring and appropriate treatment of conditions that can contribute to 
the occurrence of these events is recommended.
Diarrhea
Diarrhea is the most frequently reported nonhematologic adverse event with ibrutinib 
monotherapy and combination therapy. Other frequently reported gastrointestinal events include 
nausea, vomiting, and constipation. These events are rarely severe and are generally managed 
with supportive therapies including antidiarrheals and antiemetics. Subjects should be monitored 
carefully for gastrointestinal adverse events and cautioned to maintain fluid intake to avoid 
dehydration. Medical evaluation should be made to rule out other etiologies such as Clostridium 
difficile or other infectious agents. Should symptoms be severe or prolonged, ibrutinib treatment 
should be modified as directed in Section 6.4.3.


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Infections
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects 
treated with ibrutinib therapy. Some of these infections have been associated with hospitalization 
and death. Consider prophylaxis according to standard of care in subjects who are at increased 
risk for opportunistic infections (see Section 8.1). Although causality has not been established, 
cases of progressive multifocal leukoencephalopathy and Hepatitis B reactivation have occurred 
in subjects treated with ibrutinib. Subjects should be monitored for signs and symptoms (fever, 
chills, weakness, confusion, vomiting, and jaundice) and appropriate therapy should be instituted 
as indicated.
Interstitial Lung Disease 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. 
Monitor subjects for pulmonary symptoms indicative of ILD. If symptoms develop, follow the 
protocol dose modification guidelines (see Section 6.4.3). If symptoms persist, consider the risks 
and benefits of ibrutinib treatment and follow the dose modification guidelines (Section 6.4.3).
Non-Melanoma Skin Cancer
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor subjects 
for the appearance of non-melanoma skin cancer.
Rash
Rash has been commonly reported in subjects treated with either single-agent ibrutinib or in 
combination with chemotherapy. Rash occurred at a higher rate in the ibrutinib arm than in the 
ofatumumab arm in Study 1112. Most rashes were mild to moderate in severity. Isolated cases of 
severe cutaneous adverse reactions (SCARs) including Stevens-Johnson Syndrome (SJS) have 
been reported in subjects treated with ibrutinib. Subjects should be closely monitored for signs 
and symptoms suggestive of SCAR including SJS. Subjects receiving ibrutinib should be 
observed closely for rashes and treated symptomatically, including interruption of the suspected 
agent as appropriate. In addition, hypersensitivity-related events erythema, urticaria, and 
angioedema have been reported.
Hypertension 
Hypertension has occurred in subjects treated with ibrutinib. Regularly monitor blood pressure in 
subjects treated with ibrutinib and initiate or adjust antihypertensive medication throughout 
treatment with ibrutinib as appropriate.
Tumor Lysis Syndrome
Tumor lysis syndrome has been reported with ibrutinib therapy. Subjects at risk of tumor lysis 
syndrome are those with high tumor burden prior to treatment. Monitor subjects closely and take 
appropriate precautions.


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1.8.
Study Drugs Used as Background Therapy 
Bendamustine is an antineoplastic alkylating agent with limited cross-resistance to other 
alkylating agents. It is a mechlorethamine derivative with structural similarities both to 
alkylating agents and to purine analogues.7,9 Bendamustine is indicated for the treatment of 
patients with CLL and indolent B-cell NHL that has progressed during or within 6 months of 
treatment with rituximab or a rituximab-containing regimen.28,43
Rituximab is a CD20-directed cytolytic antibody indicated for the treatment of 
relapsed/refractory and previously untreated CD20-positive FL B-cell NHL and previously 
untreated CD20-positive diffuse large B-cell NHL. It has also been approved as maintenance 
therapy for up to 2 years after initial treatment, for patients with previously untreated FL B-cell 
NHL who have a complete or partial remission
to rituximab in combination with 
chemotherapy.30,37
1.9.
Rationale for the Study
There is no single, globally accepted and approved standard regimen for first-line treatment of
patients with MCL; and despite the recently published improvements in overall survival rates to 
approximately 5 years, there is an unmet medical need for newly diagnosed MCL patients who 
are 65 years of age or older.
Younger patients with good performance status are frequently considered for more intensive 
induction therapy with combinations such as R-Hyper-CVAD or alternating R-CHOP and 
R-DHAP followed by consolidation therapy with autologous SCT. However, as these regimens 
are associated with significant toxicity, they are unsuitable for the elderly and unfit patients who 
are most commonly treated with chemoimmunotherapy regimens such as R-CHOP or BR. Based 
on recent data reported by Rummel et al (2013)41 in which BR provides superior clinical
outcomes over R-CHOP with a better safety profile, BR is emerging as a standard treatment 
regimen in this setting. Furthermore, a recent large randomized study demonstrated improved 
PFS in patients who received rituximab maintenance after initial chemoimmunotherapy.26 Based 
on these data and consistent with National Comprehensive Cancer Network guidelines
(NCCN)31, BR regimen followed by rituximab maintenance is an accepted treatment option for
patients who are 65 years of age or older.
The rationale for use of ibrutinib in the proposed study is based on the results from 
Studies PCYC-04753 and PCYC-1104-CA that demonstrate promising single-agent activity in 
subjects with relapsed or refractory MCL (Section 1.5.1 and Section 1.5.2, respectively). 
Phase 1 combination studies PCYC-1108-CA and PCYC-1109-CA demonstrated that ibrutinib
may be safely combined with chemoimmunotherapy regimens such as BR and monoclonal 
CD-20 antibody, ofatumumab, and even more, the combinations may enhance its clinical activity
in patients with relapsed and refractory CLL. In study PCYC-1108-CA, ibrutinib in combination 
with the BR regimen resulted in an overall response rate of 93% (13% CR). The toxicity profile 
of the combination is similar to that of BR alone.32 In study PCYC-1109-CA, ibrutinib in 


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combination with ofatumumab resulted in an overall response rate of 100% when combining 
these 2 agents, without additional toxicity.23
In addition, preliminary data from an ongoing Phase 1 study evaluating the combination of 
BR+ibrutinib in patients with previously untreated and relapsed MCL (N=9) indicate that the 
combination appears to be well-tolerated and resulted in an overall response rate of 100% (4 CRs 
and 1 PR) for the 5 patients who were evaluable for response.4
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective of this study is to evaluate whether the addition of ibrutinib to
bendamustine and rituximab will result in prolongation of PFS in subjects with newly diagnosed 
MCL who are 65 years of age or older.  
Secondary Objectives
The secondary objectives are:

To evaluate overall survival 

To evaluate the CR rate and overall response rate (CR+PR) 

To evaluate patient-reported lymphoma symptoms and concerns as measured by the Lym 
subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)

To evaluate the minimal residual disease (MRD) negative rate

To evaluate duration of response

To evaluate time-to-next treatment (TTNT)

To evaluate the safety of ibrutinib when combined with BR 

To characterize the pharmacokinetics of ibrutinib and explore the potential relationships 
between ibrutinib metrics of exposure with relevant clinical, pharmacodynamic, or 
biomarker information
Exploratory Objectives
The exploratory objectives are:

To evaluate patient-reported outcomes (PRO) related to well-being and general health status 
utilizing the FACT-Lym and EuroQol (EQ-5D-5L) 

To explore biomarkers identified from other studies of ibrutinib in samples collected for 
MRD assessments
2.2.
Hypothesis
The primary hypothesis of the study is that ibrutinib in combination with BR compared with BR
alone will prolong PFS in subjects with newly diagnosed MCL who are 65 years of age or older.


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3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study to compare 
the efficacy and safety of ibrutinib in combination with BR with BR alone in subjects with newly
diagnosed MCL who are 65 years of age or older. Subject eligibility will be determined up to 
30 days prior to randomization. The Treatment Phase will extend from randomization until 
discontinuation of all study treatment or the clinical cutoff for the end of study.
Approximately 520 subjects will be stratified by simplified MIPI score (low risk [0-3] vs. 
intermediate risk [4-5] vs. high risk [6-11]) and then randomized in a 1:1 ratio. A cycle is defined 
as 28 days. All subjects will receive open-label BR background therapy for a maximum of 
6 cycles; subjects with a CR or PR will continue to receive open-label background therapy with 
R maintenance every second cycle for a maximum of 12 additional doses (ie, Cycle 8, 10, 12, 14,
16, 18, 20, 22, 24, 26, 28, and 30). In addition to the background therapy, all subjects will 
receive blinded study drug (ibrutinib or placebo). Subjects randomized to Treatment Arm A will 
receive placebo capsules and subjects randomized to Treatment Arm B will receive ibrutinib
capsules. Study drug will be administered daily and continuously until disease progression, 
unacceptable toxicity, or study end. Study treatment scheme is provided in Table 2.
Subjects with stable disease after initial chemoimmunotherapy (BR+ibrutinib/placebo) should 
continue treatment with ibrutinib/placebo until disease progression, unacceptable toxicity, or 
study end. Subjects with progressive disease must discontinue all study treatment. For subjects 
who discontinue background therapy and do not have progressive disease, treatment with study 
drug will continue until disease progression or unacceptable toxicity or the clinical cutoff for the 
final analysis of PFS. Subjects receiving BR, R, or ibrutinib at the clinical cutoff for the final
analysis of PFS may continue open-label treatment until disease progression or unacceptable 
toxicity. Placebo will be stopped when the study is unblinded for the clinical cutoff for the final 
analysis of PFS.
The Posttreatment Follow-up Phase will begin once a subject discontinues bendamustine (B) and 
R and study drug. Subjects who discontinue for reasons other than disease progression must 
continue to have disease evaluations according to the Time and Events Schedule (Table 1). 
Subjects who discontinue due to disease progression will be followed for survival and 
subsequent anti-MCL therapy. The Posttreatment Follow-up Phase will continue until death, lost
to follow up, consent withdrawal, or study end, whichever occurs first.
Four clinical cutoffs are planned. The first 3 clinical cutoffs will occur when approximately 134, 
180, and 265 PFS events have been observed, respectively. The interim analyses and the final 
analysis of PFS will take place at these 3 clinical cutoffs, respectively. Treatment assignment 
will be unblinded and placebo treatment will be stopped at the clinical cutoff for the final 
analysis of PFS. Treatment unblinding and stopping of placebo treatment may occur before the 
planned final analysis of PFS if recommended by the independent DMC after an interim analysis 
(see Section 11.9). The last cutoff will occur at the end of study, when 60% of the randomized 
subjects have died or the sponsor terminates the study, whichever comes first. Investigators will 
be informed when the cutoffs will occur. All available data prior to the time of a clinical cutoff 


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will be included in each of the respective analyses. The sponsor will ensure that subjects 
benefiting from treatment with ibrutinib will be able to continue treatment after the end of the 
study. 
Efficacy assessments will be conducted in accordance with the Revised Response Criteria for 
Malignant Lymphoma.8 The investigator will evaluate sites of disease by radiological imaging, 
physical examination, and other procedures as necessary and all results will be recorded in the 
case report form (CRF). Radiological and PET scans performed prior to the database lock for the 
final analysis of PFS must be transferred to the independent imaging laboratory for storage; the 
scans may be reviewed, if deemed necessary. The primary efficacy analysis of PFS will be based 
on investigators assessment. 
At each site visit, subjects will be evaluated for toxicity. Safety evaluations will include adverse 
event monitoring, physical examinations, concomitant medication usage, and clinical laboratory 
parameters. Blood samples will be drawn for assessment of pharmacokinetic parameters
(see Section 9.3). Blood and bone marrow will be collected for MRD and biomarker studies as 
described in Section 9.2.1.3. Fresh lymph node samples will be collected at Screening and at the 
time of progressive disease for biomarker evaluation, if feasible. 
An independent Data Monitoring Committee (DMC) will be formed and constituted according to 
regulatory agency guidelines. The independent DMC will review the safety and efficacy of the 
treatment combination and make recommendations as to the future conduct of the study (see 
Section 11.9). Further details regarding the composition and procedures will be provided in the 
DMC charter.


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A diagram of the study design is provided below in Figure 1.
Figure 1:
Study Diagram
aA cycle is defined as 28 days. 
Treatment Arm Aa
BACKGROUND THERAPY: 
Bendamustine 90 mg/m2 IV on Days 1-2, Cycles 1-6
Rituximab 375 mg/m2 on Day 1, Cycles 1-6;
If CR or PR is achieved;
Rituximab 375 mg/m2 on Day 1 of every second cycle 
for a maximum of 12 doses
STUDY DRUG: 
Placebo orally, once daily, continuously 
starting on Cycle 1, Day 1 until disease progression, 
or unacceptable toxicity, or the final analysis of PFS
Treatment Arm Ba
BACKGROUND THERAPY: 
Bendamustine 90 mg/m2 IV on Days 1-2, Cycles 1-6
Rituximab 375 mg/m2 on Day 1, Cycles 1-6;
If CR or PR is achieved;
Rituximab 375 mg/m2 on Day 1 of every second cycle 
for a maximum of 12 doses
STUDY DRUG: 
Ibrutinib 560 mg orally, once daily, continuously
starting on Cycle 1, Day 1 until disease progression, 
or unacceptable toxicity, or the 
study end
Screening Phase
Within 30 days before randomization
Assess Subject Eligibility
Randomization
Subjects must start study treatment within 72 hours after randomization
Treatment Phase
Treatment Discontinuation
Complete End of Treatment Visit
Posttreatment Follow-up Phase
Prior to Disease Progression: 
Continue disease evaluations
Following disease progression: 
Follow-up for survival status, EQ-5D-5L, and record 
subsequent anti-MCL therapies and new malignancies


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3.2.
Study Design Rationale
3.2.1.
Study Population and Study Treatment
Mantle cell lymphoma is a subtype of NHL. It is often said that it carries the worse features from 
both the indolent and aggressive lymphomas.
Chemoimmunotherapy regimens such as R-CHOP and BR are the most commonly used initial 
treatment regimens for patients with newly diagnosed MCL who are 65 years of age or older, for 
whom intensified chemo regimens are not an option. Based on recent data reported by Rummel 
et al (2013)41 in which BR provides superior clinical outcomes (24 months of PFS for the 
R-CHOP arm vs. 36 months of PFS for the BR arm) with less toxicity, BR has emerged as a 
standard treatment regimen in this setting. Furthermore, a recent large randomized study 
demonstrated improved PFS in patients who received R maintenance after initial induction 
chemoimmunotherapy.26 Based on these data and consistent with NCCN guidelines31, BR 
combination therapy followed by R maintenance therapy is an accepted treatment option for 
patients with newly diagnosed MCL who are 65 years of age or older.
Durability of tumor control achieved with single-agent ibrutinib treatment is suggested in studies 
PCYC-04753 and PCYC-1104-CA. In Study PCYC-04753, 6 of the 9 subjects with MCL were 
progression-free and continued treatment in an extension study at the time of study closure. In 
the ongoing Study PCYC-1104-CA, for all treated subjects, the median time on treatment is
15.3 months (range, 1.9 to 22.3 months) and 46 patients remain on treatment. Estimated median 
duration of response was 17.5 months (range, 0 to 19.6 months) and overall survival has not been 
reached. The median PFS is estimated to be 13.9 months for all subjects and the overall response 
rate is 68.0%.45 Based on these efficacy data, and the modest and acceptable toxicity profile of 
ibrutinib, subjects in Study PCI-32765MCL3002 will be treated with ibrutinib 560 mg until
disease progression, occurrence of unacceptable toxicity, or the end of the study, whichever 
comes first.
The combination of ibrutinib+BR has been tested in Study PCYC-1108-CA in patients with 
relapsed CLL. The regimen consisted of ibrutinib 420 mg (continuous daily dosing), and 
bendamustine (70 mg/m2) plus rituximab (375 mg/m2 Cycle 1: 500 mg/m2, Cycles 2 to 6) for 
6 cycles. The safety profile of the ibrutinib+BR combination regimen appears to be very similar 
to that when bendamustine (70 mg/m2) + rituximab (375 mg/m2 Cycle 1; 500 mg/m2, Cycles 2 to 
6) alone are used.17 Furthermore, the overall response rate for the ibrutinib+BR treatment group 
is 93% (13% CR), whereas, the overall response rate reported by Fischer et al (2011)17 was 59% 
(9% CR). These data suggest that ibrutinib
may be safely combined with a 
chemoimmunotherapy regimen such as BR, and in addition, may enhance clinical activity. In 
Study PCYC-1109-CA, ibrutinib is administered in combination with the monoclonal antibody 
ofatumumab in patients with relapsed and refractory CLL. Again, there is no additional toxicity 
when these 2 agents are combined; furthermore, an overall response rate of 100% was reported.23


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The combination of ibrutinib+BR is being tested in an ongoing Phase 1 study of patients with 
relapsed/refractory NHL. Bendamustine 90 mg/m2 on Days 1 and 2 with rituximab 375 mg/m2
on Day 1 were administered with escalating doses of ibrutinib (280 mg or 560 mg) on Days 1 to 
28 every 28 days for 6 cycles. The combination is well-tolerated without unexpected toxicity 
with evidence of preliminary activity. The overall response rate is 100% (4 CRs and 1 PR) for 
the 5 patients with MCL (n=9) who were evaluable for response to treatment.4
Given that the combination of bendamustine and rituximab has an acceptable safety profile and 
good response rates in indolent NHL and MCL patients,40,41 and that the preliminary results from 
the study conducted by Blum et al (2012) using bendamustine 90 mg/m2 and rituximab 
375 mg/m2 in combination with ibrutinib 560 mg daily look promising4, the same dose and 
schedule are proposed for combination treatment in this study (PCI-32765MCL3002).
3.2.2.
Study Design and Endpoints
The primary endpoint of PFS has served as the basis for regulatory approvals in MCL. The 
secondary endpoint, overall survival, is a gold standard endpoint for the clinical evaluation of 
new treatments. 
Advances in detection technologies have determined that some patients who achieve CR have 
MRD as shown by the continued presence of small numbers of MCL cells. Therefore, the 
absence of MRD is included as a secondary endpoint. In addition to MRD, biomarker analysis 
will be conducted to explore genes identified in previous studies for associations with resistance.
The purpose of the FACT-Lym questionnaire is to provide an assessment of the subject’s own 
functional status, well-being, and lymphoma symptoms over time. The EQ-5D-5L assessment 
will provide estimates of utility to include in future cost effectiveness models.
The assessment of pharmacokinetics in the patient population is important in understanding both 
safety and efficacy. The study includes a sparse pharmacokinetic sampling strategy for 
population pharmacokinetic purposes, which will serve as a means to derive the individual 
subject’s ibrutinib exposure. In addition to the determination of the subject-covariates that 
influence the pharmacokinetics of the drug, this may provide supportive evidence to the efficacy 
and safety analyses, may help in deriving dosing regimens not directly studied in clinical studies, 
and may identify at-risk subjects who require a dose-adaptation. 
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. Blinded treatment will be used to reduce 
potential bias during data collection and evaluation of endpoints. Subjects will be stratified by 
simplified MIPI score, which is a well-established prognostic index for patients with MCL.21


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3.2.3.
Ibrutinib Route of Administration and Dosing Schedule
Data from Study PCYC-04753 showed that although ibrutinib is rapidly eliminated from the 
plasma after oral administration, once daily dosing is adequate to sustain maximal 
pharmacodynamic activity for 24 hours postdose at dose levels ≥ 2.5 mg/kg. In 
Study PCYC-04753, greater than 85% of subjects who received dosages ≥ 2.5 mg/kg/day had 
Day 1 AUC0-24 values ≥ 160 ng∙h/mL. The analysis of pharmacokinetic and pharmacodynamic 
profiles showed that BTK active-site occupancy was saturated or near saturated (> 95%) at area 
under the plasma concentration-time curve (AUC) values of ≥ 160 ng∙h/mL.1
In Study PCYC-1104-CA,
in which ibrutinib
was administered to patients with 
relapsed/refractory MCL as a fixed dosage of 560 mg/day, 96% of the patients retained 
steady-state ibrutinib AUC values greater than 160 ng∙h/mL. This result indicates that the vast 
majority of patients who received a dose of 560 mg/day will achieve exposures yielding full 
BTK active-site occupancy. With the most recent analysis of the data in Study PCYC-1104-CA, 
a high overall response rate (68%)45 was reported with this dose in patients with 
relapsed/refractory MCL with a corresponding acceptable toxicity profile. Based on these data, 
the oral daily 560 mg dose has been selected for this study.
Durability 
of 
tumor 
control 
achieved 
with 
ibrutinib
treatment 
is 
suggested 
in 
Studies PCYC-04753 and PCYC-1104-CA (see Section 1.5.1 and Section 1.5.2, respectively). 
Based on these efficacy data and the modest and acceptable toxicity profile of ibrutinib, subjects 
in Study PCI-32765MCL3002 will be treated with 560 mg ibrutinib until disease progression, 
occurrence of unacceptable toxicity, or the end of the study, whichever comes first.
4.
SUBJECT SELECTION
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor representative before enrolling a subject 
in the study. For a discussion of the statistical considerations of subject selection, refer to 
Section 11.2, Sample Size Determination.
The last assessment/evaluation or laboratory result obtained prior to randomization will be used 
to determine eligibility.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
Subject is 65 years of age or older 
2.
Criterion modified per Amendment INT-1:
2.1 Diagnosis of MCL must include morphology and expression of either cyclin D1 in 
association with other relevant markers (eg, CD19, CD20, PAX5, CD5) or evidence of 
t(11;14) as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or 
polymerase chain reaction (PCR) (see Section 9.1.2). 


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-
A report from the local laboratory is acceptable; however, it must be reviewed and 
approved by the central pathology laboratory to verify the above criteria prior to 
randomization. The formalin-fixed paraffin-embedded tumor tissue (FFPE) block or
slides must be sent to the central laboratory for final confirmation of MCL diagnosis
after randomization.
-
If the report from the local laboratory is not available prior to randomization, the tumor 
block or slides must be sent to the central pathology laboratory for confirmation of 
MCL diagnosis.
3.
Clinical Stage II, III, or IV by Ann Arbor Classification (see Attachment 1)
4.
At least 1 measurable site of disease according to Revised Response Criteria for Malignant 
Lymphoma. The site of disease must be greater than 1.5 cm in the long axis regardless of 
short axis measurement or greater than 1.0 cm in the short axis regardless of long axis 
measurement, and clearly measurable in 2 perpendicular dimensions8
5.
No prior therapies for MCL
6.
Eastern Cooperative Oncology Group
(ECOG) performance status grade 0 or 1 
(Attachment 2)
7.
Criterion modified per Amendment INT-1:
-
7.1 Hematology values must be within the following limits:
a.
Absolute neutrophil count (ANC) 1000/mm3 independent of growth factor 
support
b.
Platelets 100,000/mm3 or 50,000/mm3 if bone marrow involvement independent 
of transfusion support in either situation
8.
Criterion modified per Amendment INT-1:
-
8.1 Biochemical values within the following limits:
a.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x 
upper limit of normal (ULN)
b.
Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin
c.
Serum creatinine ≤ 2 x ULN or estimated Glomerular Filtration Rate
(Cockroft-Gault10) ≥ 40 mL/min/1.73m2
9.
Women of childbearing potential and men who are sexually active must be practicing a 
highly effective method of birth control during and after the study consistent with local 
regulations regarding the use of birth control methods for subjects participating in clinical 
trials. Men must agree to not donate sperm during and after the study. For females, these 
restrictions apply for 6 months after last dose of bendamustine, 12 months after the last dose 
of rituximab, or 1 month after the last dose of study drug, whichever is later. For males, 
these restrictions apply for 6 months after the last dose of bendamustine, 12 months after the 
last dose of rituximab, or 3 months after the last dose of study drug, whichever is later.


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10. Women of childbearing potential must have a negative serum (beta-human chorionic 
gonadotropin [-hCG]) or urine pregnancy test at Screening. Women who are pregnant or 
breastfeeding are ineligible for this study.
11. Sign (or their legally-acceptable representatives must sign) an informed consent document 
indicating that they understand the purpose of and procedures required for the study,
including biomarkers, and are willing to participate in the study.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1.
Major surgery within 4 weeks of randomization.
2.
Known central nervous system lymphoma.
3.
Diagnosed or treated for malignancy other than MCL, except:
a.
Malignancy treated with curative intent and with no known active disease present for 
≥3 years before randomization 
b.
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease.
c.
Adequately treated cervical carcinoma in situ without evidence of disease.
4.
Subjects for whom the goal of therapy is tumor debulking prior to stem cell transplant.
5.
History of stroke or intracranial hemorrhage within 6 months prior to randomization.
6.
Requires 
anticoagulation 
with 
warfarin 
or 
equivalent 
vitamin 
K 
antagonists 
(eg, phenprocoumon).
7.
Criterion modified per Amendment INT-1:
-
7.1 Requires treatment with strong CYP3A inhibitors.  
8.
Clinically significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the 
New York Heart Association Functional Classification.
9.
Vaccinated with live, attenuated vaccines within 4 weeks of randomization.
10. Criterion modified per Amendment INT-1
-
10.1 Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus 
or active Hepatitis B Virus infection or any uncontrolled active systemic infection 
requiring intravenous (IV) antibiotics (see Section 9.5).  
11. Any life-threatening illness, medical condition, or organ system dysfunction which, in the 
investigator’s opinion, could compromise the subject’s safety, interfere with the absorption 
or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.


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4.3.
Prohibitions and Restrictions
The following guidance should be applied during the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib:

For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib
should be held at least 7 days prior to the intervention and should be held at least 7 days 
after the procedure, and restarted at the discretion of the investigator when the surgical site 
is reasonably healed without serosanguineous drainage or the need for drainage tubes. 

For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis) ibrutinib should be held for at least 3 days prior to the procedure and should 
not be restarted for at least 3 days after the procedure. For bone marrow biopsies that are
performed while the subject is on ibrutinib, it is not necessary to hold ibrutinib for these 
procedures.

For emergency procedures, ibrutinib should be held after the procedure until the surgical site 
is reasonably healed, for at least 7 days after the urgent surgical procedure.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups based on a computer-generated randomization schedule prepared before 
the study by or under the supervision of the sponsor. The randomization will be balanced by 
using randomly permuted blocks and will be stratified by the simplified MIPI score (low risk 
[0-3] vs. intermediate risk [4-5] vs. high risk [6-11]) (see Attachment 3). The interactive web 
response system (IWRS) will assign a unique treatment code, which will dictate the treatment 
assignment and matching study drug kit for the subject. The requestor must use his or her own 
user identification and personal identification number when contacting the IWRS, and will then 
give the relevant subject details to uniquely identify the subject.
Blinding
This is a double-blind study; therefore, subjects, investigators, and the sponsor’s study team 
members will remain blinded to treatment assignment until the database has been locked for the 
Clinical Study Report. Examples of personnel who may be unblinded during the study are: 

The independent DMC, and the independent biostatistician and statistical programmers 
from an independent Statistical Support Group who are responsible for preparing interim 
tables, listings, and graphs for DMC review. Unblinding procedures and the control of the 
unblinded data are described in the DMC charter.

Sponsor’s representative responsible for pharmacokinetics testing and analysis.

Sponsor safety representative to fulfill regulatory reporting requirements for suspected 
unexpected serious adverse events.


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
In case of an urgent safety concern, site personnel and the sponsor maybe unblinded if 
treatment assignment information is needed to determine further actions to address the 
urgent safety concern (eg, life-threatening event, medication error, such as an accidental 
overdose).
The investigator will not be provided with randomization codes. The codes will be maintained
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (ie, study drug plasma
concentrations) will be handled with special care to ensure that the integrity of the blind is 
maintained and the potential for bias is minimized. This may include making special provisions, 
such as segregating the data in question from view by the investigators, clinical team, or others 
as appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until the database is locked for the 
final analysis of PFS. Otherwise, the blind should be broken only if specific emergency 
treatment/course of action would be dictated by knowing the treatment status of the subject. In 
such cases, the investigator may in an emergency determine the identity of the treatment by 
contacting the IWRS. It is recommended that the investigator contact the sponsor or its designee,
if possible, to discuss the particular situation before breaking the blind. Telephone contact with 
the sponsor or its designee will be available 24 hours per day, 7 days per week. In the event the 
blind is broken, the sponsor must be informed as soon as possible. The date, time, and reason for 
the unblinding must be documented by the IWRS in the appropriate section of the CRF and in 
the source document. The documentation received from the IWRS indicating the code break 
must be retained with the subject's source documents in a secure manner. A subject whose 
treatment assignment has been unblinded may continue the study treatment if receiving clinical 
benefit, and the subject should continue to return for scheduled study evaluations. The 
single-blind (ie, subject remains blinded to treatment assignment) should be maintained provided
the subject’s safety is not compromised.
At the time of these interim analyses, the randomization codes and, if required, the translation of 
randomization codes into treatment and control groups will be disclosed to those authorized and 
only for those subjects included in the interim analyses. 
6.
DOSAGE AND ADMINISTRATION
For the purposes of this study, ‘study drug’ refers to ibrutinib or placebo; and ‘study treatment’ 
refers to ibrutinib/placebo, bendamustine, and rituximab. The dosages for the treatment
combination are described below. All dosing information must be recorded in the Dosage 
Administration page of the CRF. A treatment scheme is provided in Table 2.


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6.1.
Study Treatment
All subjects will receive a maximum of 6 cycles of BR background therapy. Subjects with a CR 
or PR will continue to receive background therapy with R maintenance every second cycle for a 
maximum of 12 additional doses. A cycle will be defined as 28 days. Total number of 
background treatment cycles on the study is 18 (6 cycles of BR followed by 12 doses of 
R maintenance given every second cycle), as shown in Table 2. Subjects with a CR or PR after 
Cycle 30 will continue to receive blinded study drug (ibrutinib/placebo) until disease 
progression, unacceptable toxicity, or study end. Subjects with stable disease after initial 
chemoimmunotherapy (BR+ibrutinib/placebo) should continue treatment with ibrutinib or 
placebo until disease progression, unacceptable toxicity, or study end. Subjects with progressive 
disease must discontinue all study treatment.
The start of a cycle coincides with the administration of BR on Day 1 during Cycles 1 to 6; and 
the administration of R on Day 1 during even Cycles 8 to 30; and the administration of 
ibrutinib/placebo on Day 1 of all other cycles.

Bendamustine hydrochloride 90 mg/m2 IV on Days 1 and 2 of Cycles 1 to 6, for a maximum 
of 6 cycles, unless progression of disease or unacceptable toxicity is encountered prior to 
Cycle 6.

Rituximab 375 mg/m2 IV on Day 1 of Cycles 1 to 6; subjects with CR or PR will continue to 
receive rituximab on Day 1 of every second cycle for a maximum of 12 additional doses 
unless progression of disease or unacceptable toxicity is encountered. Rituximab 
maintenance therapy will start at Cycle 8.
The start of a new cycle may be delayed on a weekly basis until the subject recovers from the 
toxicity to a level allowing continuation of therapy. The subject should be assessed weekly until 
the toxicity resolves to a level allowing continuation of therapy. If the toxicity persists after a 
2-week cycle delay, and is considered to be related to one specific drug (ie, rituximab or 
bendamustine), the offending drug can be withheld and the new cycle may be started with the 
remaining drugs.
Subjects will be randomized on 1:1 ratio to receive study drug on either Treatment Arm A or B. 
Treatment with blinded study drug will continue until disease progression, or unacceptable 
toxicity, or study end, whichever occurs first. Ibrutinib or placebo will be self-administered at
home. 
Treatment Arm A: 
Placebo (4 capsules) will be administered orally, once daily, continuously.
Treatment Arm B: 
560 mg (4 x 140 mg capsules) of ibrutinib will be administered orally, once daily, continuously.


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6.2.
Bendamustine and Rituximab Administration
Investigators should refer to the package inserts for the storage and handling, and detailed 
instructions on the administration of bendamustine hydrochloride and rituximab.28,30,37,43 It is 
strongly recommended that premedication guidelines are also followed per rituximab package 
insert. Both drugs are administered IV, per institutional standards, at the dosages described above 
in Section 6.1. Refer also to the study Investigational Product Procedures Manual.
6.3.
Ibrutinib or Placebo Administration
Subjects will be instructed to take 4 capsules of ibrutinib (for a dose of 560 mg) or placebo orally 
once daily, starting at Cycle 1, Day 1. The capsules are to be taken around the same time each 
day with approximately 240 mL of water (ie, 8 ounces). The capsules should be swallowed 
whole and should not be opened, broken, or chewed. Each dose of study drug should be taken at 
least 30 minutes before eating or at least 2 hours after a meal. Ibrutinib/placebo will be 
administered before the bendamustine infusion on Day 2 of Cycles 1, 2, and 3 when the 
pharmacokinetic samples are collected.
Subjects should avoid consuming food and beverages containing grapefruit or Seville oranges for 
the duration of the study due to cytochrome (CYP) 3A inhibition. Subjects should refrain from 
taking the study drug on the morning of study visits designated for pharmacokinetic sampling 
until seen at the site (see Section 9.3.1).
If a dose of study drug is not taken at the scheduled time, it can be taken as soon as possible on
the same day with a return to the normal schedule the following day. The subject should not take 
extra capsules to make up the missed dose. 
Sufficient study drug required for treatment until the next visit will be dispensed. Unused study 
drug dispensed during previous visits must be returned and drug accountability records will be 
updated. Returned capsules must be discarded and may not be re-used in this study or outside the 
study. Study staff will instruct subjects on how to store study drug for at-home use as indicated 
for this protocol. Storage instructions are provided in the Site Investigational Product Procedures 
Manual.
6.4.
Dose Modification
Below are recommendations for the management of toxicities with bendamustine and rituximab. 
However, dose modifications should be done in accordance with the respective product labels
and clinical practice.
6.4.1.
Bendamustine Hydrochloride
Bendamustine 
hydrochloride 
administration 
should 
be 
delayed
in 
the 
event 
of 
bendamustine-related Grade 4 hematologic toxicity or clinically significant Grade 2 
non-hematologic toxicity. Once non-hematologic toxicity has recovered to Grade 1, 
bendamustine hydrochloride may be reinitiated at the discretion of the investigator. For 
bendamustine-related hematologic events, bendamustine hydrochloride may be reinitiated after 


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blood counts have improved (ANC 1 x 109/L [1,000/mm3]; platelets 75 x 109/L 
[75,000/mm3]), at the discretion of the investigator.
In addition, dose reduction may be warranted as follows:

Dose modifications for Grade 4 hematologic toxicity: reduce the dose to 70 mg/m2 on Day 1 
and Day 2 of each cycle. If Grade 4 toxicity recurs, the dose may be reduced to 45 mg/m2 on 
Day 1 and Day 2 of each cycle.

Dose modifications for Grade 3 non-hematologic toxicity: reduce the dose to 70 mg/m2 on 
Day 1 and Day 2 of each cycle. If Grade 3 or greater toxicity recurs, the dose should be 
reduced to 45 mg/m2 on Day 1 and Day 2 of each cycle.
Bendamustine may be held for a maximum of 28 consecutive days; a hold >28 days must be
reviewed and approved by the sponsor. Discontinue bendamustine permanently if it cannot be 
restarted within 28 days due to toxicity. If bendamustine is discontinued for toxicity, treatment 
with rituximab and/or ibrutinib or placebo may be continued. Dose re-escalation of 
bendamustine hydrochloride is not permitted.
6.4.2.
Rituximab
There will be no dose reductions for rituximab. Particular attention should be paid to the 
Warnings and Precautions sections of the product label. Rituximab administration and dose 
modifications for infusion reactions must follow the product label. Rituximab may be held for a 
maximum of 28 consecutive days; a hold >28 days must be reviewed and approved by the 
sponsor. Discontinue rituximab permanently if it cannot be restarted within 28 days due to 
toxicity. If rituximab is discontinued for toxicity, treatment with bendamustine hydrochloride 
and/or ibrutinib or placebo may be continued.
For subjects with an increased risk of tumor lysis syndrome (TLS) or other toxicities, rituximab 
can be split over a 2-day period in Cycle 1 or throughout Cycles 1 to 6, to comply with the study 
site’s practice. See Section 8.1 for further details about TLS.
6.4.3.
Ibrutinib or Placebo
At each site visit, the subject will be evaluated for possible drug toxicities. All previously 
established or new toxicities observed at any time are to be managed as described below. The 
investigator is encouraged to contact the sponsor with any questions regarding ibrutinib/placebo
dose reduction. 
Treatment with ibrutinib /placebo should be held as outlined below. Ibrutinib/placebo may be 
held for a maximum of 28 consecutive days, unless reviewed and approved by the sponsor. 
Discontinue ibrutinib/placebo permanently if ibrutinib cannot be restarted within 28 days due to 
toxicity. No dose escalation of ibrutinib/placebo (more than 4 capsules/day [ie, above 
560 mg/day]) is allowed in this study. Once the ibrutinib dose is reduced for toxicity it cannot be 
re-escalated.


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The actions in Table 3 below should be taken for the following drug-related toxicities. Changes 
must be recorded in the Dosage Administration page of the CRF: 

Grade 3 or greater neutropenia with infection or fever

Grade 4 neutropenia (ANC < 0.5 x 109/L [< 500/mm3]) > 14 days.

Grade 3 thrombocytopenia (platelets < 50 x 109/L [< 50,000/mm3]) in the presence of 
significant bleeding. 

Grade 4 thrombocytopenia (platelets < 25 x 109/L [< 25,000/mm3]). 

Grade 3 or greater non-hematological toxicity
Table 3:
Ibrutinib/Placebo Dose Modifications
Occurrence
Action
First
Hold study drug until recovery to Grade ≤ 1 or baseline; may restart at original dose 
level
Second
Hold study drug until recovery to Grade ≤ 1 or baseline; restart at 1 dose level lower 
(3 capsules [ie, 420 mg daily])
Third
Hold study drug until recovery to Grade ≤ 1 or baseline; restart at 1 dose level lower 
(2 capsules [ie, 280 mg daily])
Fourth
Discontinue study drug
If ibrutinib/placebo is discontinued for toxicity, treatment with rituximab and/or bendamustine 
hydrochloride may be continued.
Refer to Section 8.3 for subjects requiring the initiation of anticoagulants while receiving study 
drug and for instructions on dose modifications or temporary hold during concomitant
administration of CYP3A inhibitors or inducers. Refer to Section 4.3 for guidance on dose delays 
during the perioperative period for subjects who require surgical intervention or an invasive 
procedure while receiving study drug.
6.4.3.1.
Dose Modification for Subjects With Chronic Hepatic Impairment
Ibrutinib is metabolized in the liver, and therefore, subjects with chronic hepatic impairment 
(Child-Pugh class A, B, or C) should have the dose of ibrutinib/placebo modified as indicated 
below. Refer to Attachment 8 for Child-Pugh classification.

For subjects who develop mild hepatic impairment while on study (Child-Pugh class A), the 
recommended dose of ibrutinib/placebo is 280 mg daily (2 capsules) unless lower doses
have already been implemented

For subjects who develop moderate hepatic impairment while on study (Child-Pugh 
class B), the recommended dose of ibrutinib/placebo is 140 mg daily (1 capsule)

For subjects who develop severe hepatic impairment (Child-Pugh class C), ibrutinib/placebo 
must be withheld until resolved to moderate impairment (Child-Pugh class B) or better


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Subjects who develop acute hepatic toxicity with liver enzymes Grade 3 or higher while on study 
should be managed per standard dose modification guidelines in Section 6.4.3.
7.
TREATMENT COMPLIANCE
Upon termination of the study, or at the request of the sponsor or its designee, the pharmacist 
must return the study drug to the sponsor or its designee, after all drug supplies have been 
accounted for, unless it is destroyed at the site as agreed upon by both the sponsor and the site.  
Instructions regarding accountability for study drug are provided in the Site Investigational 
Product Procedures Manual. 
7.1.
Ibrutinib or Placebo Compliance
The study drug (ibrutinib/placebo) is to be prescribed only by the principal investigator or a 
qualified physician listed as a sub-investigator on required forms. Records should be kept on the 
study drug accountability form provided by the sponsor or its designee. Dispensing of the study 
drug (ibrutinib/placebo) must be recorded in the subject’s source documents. The 
ibrutinib/placebo may not be used for any purpose other than that outlined in this protocol, 
including other human studies, animal investigations, or in vitro testing.  
The IWRS will be used to assign centrally supplied study treatment kits for each subject
randomized to ibrutinib/placebo treatment. The investigator or the site pharmacist will maintain a 
log of all ibrutinib/placebo dispensed and returned. Drug supplies for each subject will be 
inventoried and accounted for throughout the study. Subjects will be provided with a diary card 
to record intake at home. Site personnel are to instruct the subject to bring the diary card and any 
unused ibrutinib/placebo to the site at the beginning of each treatment cycle to check 
ibrutinib/placebo dosing compliance.
Instructions for proper self-administration and ibrutinib/placebo storage conditions will be 
provided. Precautions associated with the use of ibrutinib/placebo and prohibited concomitant 
medications will be reviewed. Site staff will provide additional instruction to reeducate any 
subject who is not compliant with the ibrutinib/placebo schedule.
7.2.
Bendamustine and Rituximab Compliance
Background therapy with BR for up to 6 cycles and R maintenance for up to 12 additional doses 
will be administered as an IV infusion by qualified study-site personnel and the details of each 
administration will be recorded in the CRF; date, start and stop time of the BR infusions, dose, 
volume infused. The site pharmacist will maintain a log of all bendamustine and rituximab vials 
prepared for infusion and administration. Drug supplies for each subject will be inventoried and 
accounted for throughout the study. The infusion will be administered according to the approved 
United States package insert (USPI) or approved institutional guidelines.


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8.
CONCOMITANT THERAPY
The following concomitant therapies must be recorded in the CRF throughout the study, 
beginning with signing of informed consent form (ICF) to 30 days after the last dose of any
study treatment or until the start of a subsequent systemic anti-MCL therapy, if earlier:
antiemetics, antidiarrheals, anticoagulants, antiplatelet agents, growth factors, transfusions, 
anti-infectives (antibacterials, antivirals, and antimycotics), cardiac supportive therapy, and 
CYP3A inducers. In addition, any per protocol prohibited medication (eg, CYP3A inhibitors, 
vitamin K antagonists, and systemic corticosteroids) must also be recorded. In addition, 
concomitant therapies administered at the time of, and used in the treatment of a serious adverse 
event, should be recorded.
8.1.
Permitted Medications
Standard supportive care therapies (eg, antiemetics, loperamide) needed for the management of 
symptoms are permitted, as clinically indicated. Hematopoietic growth factors may be 
administered according to the institution’s guidelines. Anti-hormonal therapies are permitted, 
after discussion with the sponsor’s medical monitor. Use of antimicrobial prophylaxis in 
accordance with standard practice (eg, American Society of Clinical Oncology [ASCO]
guidelines [Flowers 2013]18) is permitted, and should be considered in subjects who are at 
increased risk for opportunistic infections.
Subjects with more than 1 of the factors listed below are considered to be at increased risk of 
TLS and should be considered for hydration and treatment with a uric acid-lowering agent as 
well as for frequent monitoring of tumor lysis associated signs and symptoms. Uric-acid 
lowering agents may include xanthine oxidase inhibitor allopurinol or Uloric® [febuxostat] with 
or without rasburicase per the drug product package inserts (note: it is recommended that 
allopurinol is not administered on the same day as bendamustine). For subjects with an increased 
risk of TLS, rituximab can be split over a 2-day period in Cycle 1, or throughout Cycles 1 to 6, to 
comply with the study site’s practice.

Serum creatinine ≥ 1.5 x ULN or calculated creatinine clearance < 60 mL/min

White blood cell (WBC) ≥ 50,000/µL

Uric acid ≥ 450 µmol/L or 7.5 mg/dL

Bulky disease (eg, lymph node > 10 cm or massive splenomegaly)

Elevated lactic acid dehydrogenase (LDH) > 2 x ULN
Subjects at risk of leukostasis (>400000/mm3 circulating lymphocytes) should be closely 
monitored and supportive care such as hydration and/or cytoreduction administered as indicated.
Ibrutinib may be temporarily held and the medical monitor should be contacted (Section 1.6).


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8.2.
Prohibited Medications
The following medications are prohibited during the study: any chemotherapy (other than 
bendamustine and rituximab), anticancer immunotherapy, experimental therapy, and
radiotherapy. Systemic use of corticosteroids in excess of prednisone 20 mg/day or its equivalent 
for more than 10 days is prohibited unless reviewed and approved by the sponsor’s medical 
monitor. Corticosteroids used as premedication for administration of rituximab or for the 
management of hypersensitivity as per institutional policy are permitted. The sponsor must be 
notified in advance (or as soon as possible, thereafter) of any instances in which prohibited 
therapies are administered.
8.3.
Precautions with Concomitant Medications
Concomitant Use of Ibrutinib/Placebo and CYP3A Inhibitor or Inducer
Ibrutinib is metabolized primarily by CYP3A. Concomitant use of ibrutinib and drugs that 
strongly or moderately inhibit CYP3A can increase ibrutinib exposure and should be avoided.
Co-administration of ketoconazole, a strong CYP3A inhibitor, in 18 healthy subjects increased 
dose normalized exposure, Cmax and AUC0-last, of ibrutinib by 29- and 24-fold, respectively. The 
maximal observed ibrutinib exposure (AUC) was ≤ 2-fold in 37 patients treated with mild and/or 
moderate CYP3A inhibitors when compared with the ibrutinib exposure in 76 patients not 
treated concomitantly with CYP3A inhibitors. Clinical safety data in 66 patients treated with 
moderate (n=47) or strong CYP3A inhibitors (n=19) did not reveal meaningful increases in 
toxicities. Strong inhibitors of CYP3A (eg, ketoconazole, indinavir, nelfinavir, ritonavir, 
saquinavir, clarithromycin, telithromycin, itraconazole, nefazadone, and cobicistat) and moderate 
inhibitors (eg, voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, 
crizotinib, darunavir/ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, 
should be avoided. If the benefit outweighs the risk and a strong CYP3A inhibitor must be used, 
reduce the ibrutinib dose to 140 mg or withhold treatment temporarily (for 7 days or less). If the 
benefit outweighs the risk and a moderate CYP3A inhibitor must be used, monitor subject for 
toxicity and follow dose modification guidance as needed. No dose adjustment is required in 
combination with mild inhibitors. Monitor patient closely for toxicity and follow dose 
modification guidance as needed. Avoid grapefruit and Seville oranges during ibrutinib 
treatment, as these contain moderate inhibitors of CYP3A (see Section 6.4.3).
Administration of ibrutinib with rifampin, a strong CYP3A inducer, decreases ibrutinib plasma 
concentrations by approximately 90%. Avoid concomitant use of strong CYP3A inducers 
(eg, carbamazepine, rifampin, phenytoin, and St. John’s Wort). Consider alternative agents with 
less CYP3A induction.
Examples of inhibitors, inducers, and substrates can be found in Attachment 4 and at 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers14
and http://medicine.iupui.edu/clinpharm/ddis/main-
table/.12


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Drugs That may Have Their Plasma Concentrations Altered by Ibrutinib
In vitro studies indicated that ibrutinib is a weak inhibitor toward CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, and CYP3A4/5. The dihydrodiol metabolite of ibrutinib is a weak inhibitor 
toward CYP2B6, CYP2C8, CYP2C9, and CYP2D6. Both ibrutinib and the dihydrodiol 
metabolite are at most weak inducers of CYP450 isoenzymes in vitro. Therefore, it is unlikely 
that ibrutinib has any clinically relevant drug-drug interactions with drugs that may be 
metabolized by the CYP450 enzymes. 
In vitro studies indicated that ibrutinib is not a substrate of P-gp, but is a mild inhibitor. Ibrutinib 
is not expected to have systemic drug-drug interactions with P-gp substrates. However, it cannot 
be excluded that ibrutinib could inhibit intestinal P-gp after a therapeutic dose. There are no 
clinical data available. To avoid a potential interaction in the GI tract, narrow therapeutic range 
P-gp substrates such as digoxin should be taken at least 6 hours before or after ibrutinib.
Concomitant Use of Ibrutinib/Placebo and QT Prolonging Agents
There is no evidence of QT prolongation with increasing plasma concentrations of ibrutinib. Any 
medications known to cause QT prolongation should be used with caution; periodic monitoring
with electrocardiograms (ECG) and electrolytes should be considered and, if needed, the medical 
monitor may be contacted.
Concomitant Use of Ibrutinib/Placebo and Antiplatelet Agents and Anticoagulants
Warfarin or other vitamin K antagonists should not be administered concomitantly with 
ibrutinib. Supplements, such as fish oil and vitamin E preparation should be avoided. Use of 
ibrutinib in subjects requiring other anticoagulants or medications that inhibit platelet function
may increase the risk of bleeding. Subjects with congenital bleeding diathesis have not been 
studied. Ibrutinib should be held at least 3 to 7 days pre- and post-surgery depending upon the 
type of surgery and the risk of bleeding (see Section 4.3).
For subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), 
consider the risks and benefits of continuing ibrutinib treatment. If therapeutic anticoagulation is 
clinically indicated during the course of the study, treatment with ibrutinib/placebo should be
held, and ibrutinib/placebo should not be restarted until the subject is clinically stable and has no 
signs of bleeding. Subjects should be observed closely for signs and symptoms of bleeding. No 
dose reduction is required when study drug is restarted.
8.4.
Subsequent Therapies
Administration of subsequent anti-MCL therapy should not be initiated until progressive disease 
(or relapse after CR) is established according to the criteria described in Section 9.2.2.3. The 
start and end date and best response should be documented in the CRF.


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9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The study is divided into 3 phases: a Screening Phase, a Treatment Phase, and a Posttreatment 
Follow-up Phase. The frequency and timing of assessments and procedures to be performed 
during the study are outlined in the Time and Events Schedule (Table 1) and further discussed 
within this section. Assessments/procedures should be completed on the day indicated; if this is 
not possible because of a weekend, holiday, or emergency, the assessment/procedure should be 
completed within 48 hours of the scheduled day. During treatment, the clinical laboratory 
samples can be taken on the day of or day prior to dosing, provided the results are available 
before any study treatment is administered. For PET, CT/MRI, serum immunoglobulin, and 
beta 2-microglobulins, the test should be completed within ± 7 days of the scheduled assessment.
The amount of blood drawn from each subject in this study will be approximately 350 mL in the 
first year. Approximately 140 mL will be collected every year after the first year, and 20 mL at 
the End of Treatment Visit (see Attachment 5). Blood volumes for the additional MRD samples 
are provided in Attachment 5. Repeat or unscheduled samples may be taken for safety reasons. 
Serum or urine pregnancy tests should be performed for women of childbearing potential, as 
determined necessary by the investigator or required by local regulation to establish the absence 
of pregnancy at any time during the subject's participation in the study. It should be noted that
the volume of blood is an estimate; the actual amount may vary depending on local laboratory
standard procedures.
9.1.2.
Screening Phase
All subjects must sign an ICF prior to the conduct of any study-related procedures. Screening 
procedures will be performed up to 30 days before randomization. Approval or confirmation of 
the diagnosis of MCL from the central laboratory must also be obtained within 30 days prior to 
randomization; however, the slides or tumor block may be either newly obtained or from 
previous biopsy. The computed tomography [CT], magnetic resonance imaging [MRI], and bone 
marrow biopsy and aspirate may be done up to 60 days before randomization.
Eligibility criteria will be reviewed and a complete clinical evaluation will be performed. 
Laboratory tests noted in the inclusion criteria must be performed within 14 days prior to 
randomization and the results within the limits specified in the inclusion criteria.
Testing may be repeated for this purpose. The last result obtained prior to randomization will be 
used to determine eligibility. Assessments performed as part of the subject’s routine clinical 
evaluation and not specifically for this study need not be repeated after signed informed consent 
has been obtained provided the assessments fulfill the study requirements and are performed 
within the specified timeframe prior randomization.


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Diagnosis of MCL must include morphology and expression of either cyclin D1 in association 
with other relevant markers (eg, CD19, CD20, PAX5, CD5) or evidence of t(11;14) as assessed
by cytogenetics, FISH, or PCR. A report from the local laboratory is acceptable; however, it 
must be reviewed and approved by the central pathology laboratory to verify the above criteria
prior to randomization. The FFPE tumor tissue block or slides must be sent to the central 
laboratory for final confirmation of MCL diagnosis. If the report from the local laboratory is not 
available prior to randomization, the tumor block or slides must be sent to the central pathology 
laboratory for confirmation of MCL diagnosis. The slides or tumor block may be either newly 
obtained or from previous biopsy. The concordance between the local and central laboratory 
diagnosis of MCL will be reviewed by the sponsor on a regular basis.
The first FACT-Lym and EQ-5D-5L assessment will be administered prior to the first dose of 
study treatment. Subjects should be provided a private, quiet area to complete the questionnaires. 
The study site staff should instruct the subject to carefully read the instructions and questions of 
the PRO instrument(s) prior to marking responses, that there are no right or wrong answers, and 
that their responses to the questionnaire will not be used to determined their study eligibility.
9.1.3.
Treatment Phase
The Treatment Phase will begin at randomization and will continue until B and R and study drug
discontinuation. Subjects should start study treatment within 72 hours after randomization in the 
IWRS. Laboratory values at randomization should be consistent with the values in the inclusion 
and exclusion criteria in order for the subject to receive treatment. 
It is preferred that the FACT-Lym and EQ-5D-5L are administered before any tests, procedures, 
or other consultations. After the PRO questionnaires have been administered, a 
symptom-directed physical exam including lymphoma B symptoms and ocular changes will be 
conducted (see Section 9.5). Laboratory test results must be reviewed prior to administering 
study treatment. Adverse events and changes to concomitant medications will be recorded 
(see Section 8.1). Subjects will be evaluated throughout this phase for possible toxicities. Dose 
modifications will be made as according to criteria described in Section 6.4. The investigator will 
assess subject response to therapy using the efficacy measurements and disease response criteria 
according to the schedule described in Section 9.2.2.
A cycle will be defined as 28 days; the cycle begins with the administration of BR. All subjects 
will receive a maximum of 6 cycles of BR of background therapy. Subjects who achieve CR or 
PR will continue to receive background therapy with R maintenance every second cycle for a 
maximum of 12 additional doses. The total number of BR plus R treatment cycles is 18 (6 cycles 
of BR + 12 cycles of R) (see Table 2). Subjects will be seen at the site approximately every 
4 weeks during the first 6 cycles; however, more frequent visit may be necessary for collection 
of hematology samples (see Table 1). Thereafter, site visits will be conducted every other cycle 
(ie, approximately every 8 weeks) up to Cycle 30 for study procedures and assessments. After 
Cycle 30, subjects with CR or PR will continue to receive ibrutinib or placebo alone until disease 
progression, unacceptable toxicity, or study end. They will return to the site on Day 1 of every 


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second cycle (ie, approximately every 8 weeks) for dispensing of study drug and study 
evaluations.
Subjects with stable disease after initial chemoimmunotherapy (BR+ibrutinib/placebo) should 
continue treatment with ibrutinib or placebo until disease progression, unacceptable toxicity, or 
study end. Subjects with progressive disease must discontinue all study treatment. For subjects 
who discontinue background therapy and do not have progressive disease, treatment with study 
drug will continue until disease progression or unacceptable toxicity or the clinical cutoff for the 
final analysis of PFS.
Clinical evaluations and laboratory studies may be repeated more frequently, if clinically 
indicated. Sufficient study drug will be dispensed for self-administration. The subject should 
refrain from taking the study drug on the morning of study visits designated for pharmacokinetic 
sampling until seen at the site (see Section 9.3.1). If progressive disease is diagnosed, or the 
subject discontinues study treatment for other reasons, then the subject will complete the End of 
Treatment Visit within 30 days after the last dose of study treatment, and enter the Posttreatment 
Follow-up Phase.
End of Treatment
An End of Treatment Visit will be scheduled within 30 days after the last dose of the last study 
treatment for all subjects, including those discontinuing treatment for any reason, except for lost 
to follow-up, death, or withdrawal of consent for study participation. Subjects who discontinued 
from treatment due to disease progression, adverse event, or other reasons and enter the 
Posttreatment Follow-up Phase should have the End of Treatment Visit completed before starting 
any subsequent anti-MCL treatment. If a subject is unable to return to the site for the End of 
Treatment Visit, the subject should be contacted to collect adverse events that occur within 
30 days after the last dose of the last study treatment. Additional information on reporting 
adverse events may be found in Section 12.
9.1.4.
Posttreatment Follow-Up Phase
The Posttreatment Follow-up Phase is the time between the End of Treatment Visit and the end 
of study participation or end of study. 
Progression-free survival is the primary endpoint for this study. Therefore, it is imperative that 
the regularly scheduled disease assessments are performed throughout the Posttreatment 
Follow-up Phase for subjects who discontinue treatment prior to disease progression, as outlined
in Section 9.2.1. Disease progression must be evaluated in accordance with the Revised 
Response Criteria for Malignant Lymphoma8 and documented at the time at which it is first 
detected.
Following disease progression, contact will be made to determine survival status, and subsequent 
anti-MCL therapy every 16 weeks until the study end (see Section 16.2.3). If the information on 
survival status and subsequent therapy is obtained via telephone contact, then written 
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the subject has died, then the date and cause of death will be collected and documented on the 
CRF. Where allowed by local law, public records may be used to document death for the purpose 
of obtaining survival status. Any new malignancy reported during the Posttreatment Follow-up 
Phase will be recorded in the CRF (Section 12.3.4).
During the Posttreatment Phase, the FACT-Lym will be performed until disease progression or 
the clinical cutoff for the final analysis of PFS, whichever comes first. The EQ-5D-5L will be 
performed until death or study end (see Section 9.2.1.7). Following disease progression, sites
should attempt to administer the EQ-5D-5L every 16 weeks (up to 3 times), unless death or study
end occurs first. Subjects who visit the site for the follow-up assessments should complete the 
EQ-5D-5L questionnaire at that time. If the EQ-5D-5L is conducted via a telephone call with the 
subject, then the subject’s questionnaire responses will be read over the telephone to the site staff
who will record the data in the EQ-5D-5L. If the subject is unable to complete the EQ-5D-5L 
during the Posttreatment Follow-up Phase, the reason for not completing the questionnaire will 
be documented (ie, too ill, subject refused).
9.1.5.
Clinical Cutoffs
Four clinical cutoffs are planned. The first 3 clinical cutoffs will occur when approximately 134, 
180, and 265 PFS events have been observed, respectively. The interim analyses and the final 
analysis of PFS will take place at these 3 clinical cutoffs, respectively; subject treatment 
assignment will be unblinded and placebo treatment will be stopped at the final analysis of PFS. 
Treatment unblinding and stopping of placebo treatment may occur before the planned final 
analysis of PFS if recommended by the independent DMC after an interim analysis (see 
Section 11.9). The last cutoff will occur at the end of study, when 60% of the randomized 
subjects have died or the sponsor terminates the study, whichever comes first. Investigators will 
be informed when the clinical cutoffs are to occur. 
The following data will be collected for all subjects, after the clinical cutoff for the final analysis 
of PFS: survival data, EQ-5D-5L (up to 3 times), investigator assessment of response to 
treatment, and reports of new malignancies. Best response as well as progressive disease on
subsequent anti-MCL therapy will also be collected. In addition, subjects without progressive 
disease will continue to have disease assessments according to standard of care, until disease 
progression. For subjects still receiving study treatment after the clinical cutoff for the final 
analysis of PFS, the following data will be collected: study treatment administration, adverse 
events during treatment or within 30 days after last dose, including reports of new malignancies, 
concomitant medications associated with a serious adverse event, and laboratory studies 
indicative of the onset and recovery from an adverse event. 
9.2.
Efficacy
9.2.1.
Evaluations 
Eligible subjects must have at least 1 measurable site of disease by radiological assessment.8
Efficacy evaluations will be conducted as specified in the Time and Events Schedule and will 
include the following: CT scans, MRI, positron emission tomography (PET) using 


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[18F]-fluorodeoxyglucose (FDG), bone marrow aspirate and biopsy, endoscopy, physical 
examination including lymphoma B symptoms, and other procedures as necessary. These 
assessments should be performed throughout the study at each time point using the same method 
of assessment used to assess disease at baseline. Patient-reported symptoms, functional status, 
and well-being will be measured by the FACT-Lym and EQ-5D-5L. 
Response to treatment will be assessed by the investigator at the site and the results will be 
recorded in the CRF. Radiological and PET scans performed prior to the database lock for the 
final analysis of PFS must be transferred to the independent imaging laboratory for storage; the 
scans may be reviewed, if deemed necessary.
9.2.1.1.
Radiographic Image Assessments (CT/MRI)
Efficacy assessments with CT scans of the neck, chest, abdomen, and pelvis and any other 
location where disease is present must be performed at Screening and at the scheduled timepoints
(see Table 1). A separate CT scan and PET scan are preferred but, if the only available modality 
is combined/dual PET/CT scanner, then the CT portion of a PET/CT may be submitted in lieu of 
a dedicated CT. The CT scanning must be done according to the imaging requirements provided 
in the radiology manual to ensure that an optimized examination is done. 
Magnetic resonance imaging may be used to evaluate sites of disease that cannot be adequately 
imaged using CT, or if preferred by local health care regulations. In cases where MRI is 
desirable, the MRI must be obtained at baseline and at all subsequent response evaluations. For 
all other sites of disease, MRI studies do not replace the required CT scans. Brain MRI and 
lumbar puncture are required only if clinically indicated.
Radiological assessments will be performed at Screening, then every 12 weeks in the first 
12 months after the start of study treatment. Thereafter, scans will be performed every 16 weeks 
until disease progression or the clinical cutoff for the final analysis of PFS, whichever comes 
first. Subjects who discontinue treatment prior to disease progression (for other reasons such as 
an adverse event) must continue to have regularly scheduled CT scans/efficacy assessments 
every 12 weeks in the first 12 months then every 16 weeks until disease progression. 
After the clinical cutoff for the final analysis of PFS, all subjects without progressive disease will 
continue disease assessments according to standard of care until disease progression.
9.2.1.2.
Positron Emission Tomography (PET Scan)
Whole body FDG-PET scan (skull base to the proximal femur) is optional at Screening but 
mandatory within 30 days of the time of maximal tumor reduction (defined as time of CR or 
when 2 consecutive CT scans show no further tumor reduction, and at suspected disease 
progression, if a new lesion was detected on CT).
Assessment of PET results should be based on published criteria.24 Visual assessment is 
considered adequate for determining whether a PET scan is positive, and use of the standardized 
uptake value is not necessary. A positive scan is defined as focal or diffuse FDG uptake above
background in a location incompatible with normal anatomy or physiology, without a specific 


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standardized uptake value cutoff. Other causes of false-positive scans should be ruled out. 
Exceptions include mild and diffusely increased FDG uptake at the site of moderate- or 
large-sized masses with an intensity that is lower than or equal to the mediastinal blood pool, 
hepatic or splenic nodules 1.5 cm with FDG uptake lower than the surrounding liver/spleen 
uptake, and diffusely increased bone marrow uptake within weeks after treatment.
9.2.1.3.
Bone Marrow Assessment
Bone marrow aspirate and biopsy must be obtained during screening or up to 60 days before 
randomization. Subjects with bone marrow involvement before the start of treatment must have a 
repeat bone marrow evaluation at the time of CR, preferably within 30 days of the initial 
documentation of CR. A portion of the bone marrow aspirate obtained to confirm CR will be 
used for assessments of MRD (see Section 9.4.1). If bone marrow involvement is confirmed with
morphology, IHC does not need to be performed.
9.2.1.4.
Endoscopy
Endoscopy is optional at baseline but is required to confirm CR (preferably within 30 days of the 
initial documentation of CR) in subjects with known GI involvement at baseline.
9.2.1.5.
Biopsies of Other Sites
For fluid collection such as ascites, pleural, or pericardial effusions, biopsy must be performed 
and cytology confirmation for presence of lymphoma must be obtained before disease 
progression is claimed for a subject. 
9.2.1.6.
Physical Examination 
During the Screening and Treatment Phases, subjects should have physical examination to
evaluate possible presence of palpable lymph nodes, tumor masses or enlargement of spleen and 
liver (see Table 1). Symptom-directed questions will be asked to evaluate for presence of 
B-symptoms. 
9.2.1.7.
Patient-Reported Outcomes
Two PRO instruments, the FACT-Lym and EQ-5D-5L, will be administered in this study. The 
FACT-Lym was originally developed to assess functional status and well-being of patients with 
NHL.15 Reliability and validity have been assessed in NHL46 and more recently construct 
validity has been supported in subjects with relapsed/refractory MCL.5
The FACT-Lym consists of the Functional Assessment of Chronic Illness Therapy - General 
(FACT-G) and a lymphoma specific additional concerns subscale (Lym) (Attachment 6). 
Responses to all items are rated on a 5-point scale ranging from 0 “not at all” to 4 “very much”. 
The FACT-G consists of three 7 item subscales scored 0 to 28 (physical well-being, social 
well-being, and functional well-being) plus one 6 item subscale (emotional well-being) scored 0 
to 24. The recall period is the past 7 days. The lymphoma scale includes 15 items and scores 
range from 0 to 60. Two summary scores may also be calculated: the FACT-Lym total score 
(FACT-G plus Lym) and the FACT-Lym trial outcome index (TOI) score (physical 


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well-being+functional well-being+lymphoma). Higher scores represent better functional status 
and well-being for all subscales and summary scales. 
The subscale of most interest in this study will be the Lym subscale. Carter et al (2008)5 and 
Cella et al (2005)6 reported a minimal important change score for the Lym subscale in a 
relapsed/refractory MCL population range from approximately 2.9 to 5.4. Therefore, a 5-point 
change in the Lym subscale was selected as a conservative estimate of clinically meaningful 
deterioration in lymphoma symptoms. Time to complete the FACT-Lym is approximately 7 to 
12 minutes. All translations not currently available will be completed according to best practice 
guidelines for translating PRO instruments to the local language(s).48
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome 
(Attachment 7).16 The EQ-5D-5L is a revised version of the traditional EQ-5D-3L. Mapping 
algorithms are available to crosswalk scores between the 2 versions.36 For purposes of this study, 
the EQ-5D-5L will be used to generate utility scores for use in cost effective analyses. The 
EQ-5D-5L is a 5-item questionnaire and a visual analogue scale ranging from 0 (worst 
imaginable health state) to 100 (best imaginable health state). In addition, the scores for the 
5 dimensions are used to compute a single utility score ranging from zero (0.0) to 1 (1.0) 
representing the general health status of the individual.
The FACT-Lym and EQ-5D-5L will be collected at the beginning of the clinic visits prior to any 
procedures or physician interactions to prevent influencing subject perceptions. The 
questionnaires will be administered on Day 1 of the first 6 cycles, then every 12 weeks in the 
first 12 months. Thereafter PROs will be performed every 16 weeks. During the first 6 cycles, if 
the PRO assessment was conducted but the cycle subsequently delayed, the PRO assessment 
should be repeated on Day 1 of the cycle when treatment is resumed.
The FACT-Lym will be performed until disease progression or the clinical cutoff for the final 
analysis of PFS, whichever comes first. The EQ-5D-5L will be performed until death or study 
end. Following disease progression, sites should attempt to administer the EQ-5D-5L every
16 weeks (up to 3 times) during the survival follow-up period, unless death or study end occurs
first. 
9.2.2.
Efficacy Criteria
9.2.2.1.
Assessment of Disease Response and Progressive Disease
Efficacy assessments for the purpose of the study result analyses will be performed by the 
investigators according to the Revised Response Criteria for Malignant Lymphoma. All efficacy 
assessments must continue until disease progression (even if subsequent therapy is started), 
withdrawal of consent from study participation, or clinical cutoff for primary analysis of PFS.
For all subjects with disease progression, a “progressive disease notification” form accompanied 
with documentation of disease progression should be sent to the sponsor medical monitor 
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9.2.2.2.
Definition of Measurable and Assessable Disease
Eligible subjects must have at least 1 measurable site of disease. Measurable sites of disease are 
defined as lymph nodes, lymph node masses, or extranodal sites of lymphoma. Each measurable 
site of disease must be greater than 1.5 cm in the long axis regardless of short axis measurement 
or greater than 1.0 cm in the short axis regardless of long axis measurement, and clearly 
measurable in 2 perpendicular dimensions. Measurement must be determined by imaging 
evaluation. All other sites of disease are considered assessable, but not measurable. 
Up to 6 measurable sites of disease, clearly measurable in 2 perpendicular dimensions, will be 
followed for each subject. Measurable sites of disease should be chosen such that they are 
representative of the subject’s disease (this includes splenic and extranodal disease). If there are 
lymph nodes or lymph node masses in the mediastinum or retroperitoneum larger than 1.5 cm in 
2 perpendicular dimensions, at least 1 lymph node mass from each region should always be 
included. In addition, selection of measurable lesions should be from as disparate regions of the 
body as possible.
All other sites of disease will be considered assessable. Assessable disease includes objective 
evidence of disease that is identified by radiological imaging, physical examination, or other 
procedures as necessary, but is not measurable as defined above. Examples of assessable disease 
include bone lesions; mucosal lesions in the GI tract; effusions; pleural, peritoneal, or bowel wall 
thickening; disease limited to bone marrow; and groups of lymph nodes that are not measurable 
but are thought to represent lymphoma. In addition, if more than 6 sites of disease are 
measurable, these other sites of measurable disease may be included as assessable disease.
9.2.2.3.
Response Categories
The response categories being used to assess efficacy are based on the Revised Response Criteria 
for Malignant Lymphoma.8
Complete Response
For CR determination, all the following criteria must be met:

Complete disappearance of all detectable evidence of disease and disease-related symptoms, 
including GI involvement, if present before therapy.

All lymph nodes and nodal masses must have regressed on CT to normal size (equal to or 
smaller than 1.5 cm in the greatest transverse diameter [GTD] for nodes greater than 1.5 cm 
before therapy, regardless of the short axis). Previously involved nodes that were between 
1.1 cm and 1.5 cm in the long axis and more than 1.0 cm in the short axis before treatment 
must have decreased to or be equal to 1 cm in the short axis after treatment. All splenic and 
hepatic nodules and other extranodal disease must have disappeared.

PET scan must be negative (for the combined CT+PET assessment of CR). A posttreatment 
residual mass of any size is permitted as long as it is PET-negative.

The spleen or liver, if enlarged before therapy on the basis of physical examination or CT 
scan, should not be palpable on physical examination and should be considered normal size 
by imaging studies.


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
If bone marrow was involved before treatment, the infiltrate must have cleared on repeated 
bone marrow biopsy. If a sample is indeterminate by morphology, it should be negative by 
IHC (if bone marrow was involved before therapy and a radiological CR was achieved, but 
with no bone marrow assessment after treatment, the response should be classified as a PR.)

No new sites of disease are detected during assessment.
Partial Response
For PR determination, all the following criteria must be met:

A ≥ 50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the largest 
dominant nodes or nodal masses.

No increase should be observed in the size of other nodes, liver, or spleen, meeting the 
criteria for progressive disease.

Splenic and hepatic nodules must regress by ≥ 50% in the SPD or, for single nodules, in the 
GTD.

With the exception of splenic and hepatic nodules, other organs should not have any 
measurable disease.

Bone marrow assessment is not required for PR determination.

No new sites of disease should be observed.

At least 1 PET-positive site of disease (required for the CT+PET assessment of PR).
Stable Disease
Stable disease is defined as:

A subject is considered to have stable disease when he or she fails to attain the criteria 
needed for a CR or PR, but does not fulfill those for progressive disease.

The PET should be positive at, at least, 1 previously involved site of disease, with no new 
areas of lymphoma involvement on the posttreatment CT or PET (for the combined 
CT+PET assessment of stable disease).
Progressive Disease or Relapsed Disease 
Progressive disease or relapsed disease (after CR) is defined as:
Lymph nodes should be considered abnormal if the long axis is ≥ 1.6 cm, regardless of the short 
axis length. If a lymph node has a long axis from 1.1 cm to 1.5 cm, it should be considered 
abnormal only if its short axis is > 1.0 cm. Lymph nodes ≤ 1.0 cm x ≤ 1.0 cm will not be 
considered abnormal for the assessment of progressive disease/relapsed disease.

Appearance of any new nodal lesion ≥ 1.6 cm in GTD or ≥ 1.1 cm in short axis during or 
after the end of therapy even if other lesions are decreasing in size.

Appearance of any new unequivocal extra-nodal lesion measuring > 1.0 cm in GTD, not 
thought to be benign by the reviewer, even if other lesions are decreasing in size.


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
At least a 50% increase from the nadir in the SPD of any previously involved nodes, or in a 
single involved node, or in the size of other lesions (eg, splenic or hepatic nodules). To be 
considered progressive disease, a lymph node with a diameter of the short axis of less than 
1 cm must increase by ≥ 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long 
axis.

At least a 50% increase from the nadir in the longest diameter of any single previously 
identified node more than 1 cm in its short axis. 
For the combined CT+PET assessment of progressive disease, lesions should be 
PET-positive or the lesion was PET-positive before therapy unless the lesion was too small 
to be detected with current PET systems (smaller or equal to 1.5 cm in the long axis by CT). 
Any previously involved FDG-positive site that became negative and subsequently became 
positive will be considered progressive disease. Increased FDG uptake in a previously 
unaffected site should only be considered progressive disease after confirmation with other 
modalities. 
Cytology confirmation of MCL is required when there is an appearance on CT of a new 
lesion ≥ 1.5 cm in its long axis and is PET-negative.
For fluid collection (ascites, pleural, or pericardial effusions) cytology confirmation for 
presence of lymphoma is required.
9.2.3.
Endpoints 
Primary Endpoint
The primary endpoint is PFS, as assessed by the treating physician, which is defined as duration 
from the date of randomization to the date of disease progression or relapse from CR or death, 
whichever is first reported.
Subjects who withdraw from study, are lost to follow-up, or receive subsequent anti-MCL 
therapy are subjects with a (potential) censoring event. For subjects who have a censoring event 
before observation of PFS event (progressive disease or death if progressive disease is not 
observed before death), PFS will be censored at the time of the last adequate disease assessment 
on or before the earliest date when such a censoring event occurred. For subjects who have a 
censoring event but without observation of PFS event, PFS will be censored at the time of the 
last adequate disease assessment on or before the earliest date when such a censoring event 
occurred. For subjects who do not have a censoring event and who do not have disease 
progression and are alive, as well as for subjects with unknown disease progression or unknown 
survival status as of the data cutoff date, PFS will be censored at the date of the last adequate
disease assessment. If there is no postbaseline tumor assessment and no death is observed for a 
subject, PFS will be censored on the date of randomization. The adequate disease assessment is 
defined as having sufficient evidence to correctly indicate that progression has or has not 
occurred.


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Secondary Endpoints
The secondary endpoints are defined as follows:

Overall survival is measured from the date of randomization to the date of the subject’s 
death. If the subject is alive or the vital status is unknown, the subject will be censored at the 
date the subject was last known to be alive.

CR rate is defined as the proportion of subjects who achieve CR.

Overall response rate is defined as the proportion of subjects who achieve CR or PR.

Minimal residual disease negative rate is defined as the proportion of subjects who are 
MRD-negative (ie, less than the lower limit of detection for the MRD assay). All 
randomized subjects with a valid MRD result (negative or positive) will be included in this 
analysis.

Time to worsening (TTW) in the Lym subscale of the FACT-Lym as measured from the 
date of randomization to the start date of worsening. Worsening is defined by a 5-point 
decrease from baseline, death, or a missing assessment due to being “too ill”, whichever 
occurs first. The censoring rules for TTW are the same as PFS with progressive disease 
replaced by worsening.

Duration of response (CR or PR) is defined as duration in days from the date of initial 
documentation of a response to the date of first documented evidence of progressive disease 
(or relapse for subjects who experience CR during the study) or death. The censoring is 
similar to PFS.

Time-to-next treatment is measured from the date of randomization to the start date of any 
anti-MCL treatment subsequent to the study treatment. Subjects without subsequent 
treatment will be censored at the date of the last site visit.

Safety parameters of ibrutinib when combined with BR.

Pharmacokinetic parameters (eg, oral plasma clearance [CL/F], oral volume of distribution 
at steady state [Vss/F]) or metrics of systemic exposure (eg, AUC, minimum observed 
plasma concentration [Cmin]) of ibrutinib after oral daily dosing. Parameters describing the
potential relationships between ibrutinib metrics of exposure with relevant clinical or
biomarker information.
Exploratory Endpoints

The mean change from baseline in EQ-5D-5L score for each post baseline assessment.

Frequency of biomarkers associated with resistance to ibrutinib in subjects who develop
resistance compared to those who respond.
9.3.
Pharmacokinetics 
9.3.1.
Evaluations 
In both treatment arms, venous blood samples (2 mL) will be collected for determination of 
plasma concentrations of ibrutinib and the PCI-45227 metabolite (if possible and judged
relevant) predose on Day 2 in Cycles 1, 2 and 3, and postdose on Day 2 in Cycles 1 and 2, at


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1 hour (window 45-75 minutes), 2 hours (window 1.5-2.5 hours), and 4 hours (window 
3.5-6 hours) following dosing of study drug (see Table 1). These sparse samples will be used for 
the development of a population-based pharmacokinetic model.
The subject should refrain from taking the study drug on the morning of study visits designated 
for pharmacokinetic sampling. The subject should be instructed to fast from midnight prior (or at 
a minimum, 2 hours prior) to dosing and continue fasting until approximately 30 minutes after 
capsule intake. The time of the last meal prior to the dosing is to be recorded on the laboratory 
requisition form. The investigator or designee will supervise administration of the study drug and 
record the exact time of study drug administration.
9.3.2.
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of ibrutinib and the metabolite 
PCI-45227 using a validated, specific, and sensitive liquid chromatography/tandem mass 
spectrometry (LC-MS/MS) method by or under the supervision of the sponsor.
9.3.3.
Pharmacokinetic Parameters 
Population pharmacokinetic analysis of plasma concentration-time data of ibrutinib will be 
performed using nonlinear mixed-effects modeling (NONMEM), with the aim of providing 
estimates of pharmacokinetic parameters (eg, oral clearance) or metrics of systemic exposure 
(eg, AUC within the dosing interval). Model-derived plasma concentrations or metrics of
exposure parameters (eg, Cmax or AUC) may be subjected to further analyses to explore 
pharmacokinetic correlation between exposure and relevant clinical or biomarker information.
9.4.
Biomarkers 
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the 
end of the study, it becomes clear that the analysis will not have sufficient scientific value for 
biomarker evaluation, or if there are not enough samples or responders to allow for adequate 
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy, 
completion of biomarker assessments is based on justification and intended utility of the data.
Additional Collections
If it is determined at any time before study completion that additional material is needed from a 
formalin-fixed, paraffin-embedded (FFPE) tumor sample for the successful completion of the 
protocol-specified analyses, the sponsor may request that additional material be retrieved from 
existing samples. Also, based on emerging scientific evidence, the sponsor may request 
additional material from previously collected tumor samples during or after study completion for 
a retrospective analysis. These additional collections will be used to investigate mechanisms of 
resistance and identify biomarkers associated with response and resistance to ibrutinib therapy.


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9.4.1.
Biomarker and Minimal Residual Disease Assessments 
Blood samples for biomarker evaluations will be collected from all subjects on Day 1 of Cycle 1
and at the time of disease progression, or the End of Treatment Visit, for subjects who 
discontinue treatment without disease progression. These samples will be collected only at sites 
where local regulations and shipping logistics permit. 
Blood samples for assessment of MRD (peripheral blood mononuclear cell [PBMC]) will be
collected from all subjects on Day 1 of Cycle 1. For subjects who have a CR, blood samples will 
be collected every 12 weeks in the first 12 months; thereafter, every 16 weeks until disease 
progression or the clinical cutoff for the final analysis of PFS, whichever comes first. A portion 
of the bone marrow sample collected to confirm CR may be assessed for MRD. For comparative 
MRD (PBMC) testing, additional blood samples will be collected in approximately the first 
100 subjects with a CR (excluding subjects at sites in China) at same time points as CR MRD, 
but only if Day 1 Cycle 1 MRD (PBMC) was collected. Sites will be notified to discontinue 
collection of the additional blood samples when the requirement is fulfilled. (Note: As of 
Amendment INT-6, blood samples for the CR MRD assessment will no longer be collected,
except in subjects whose first assessment of CR is after the issue date of Amendment INT-6. The 
samples for the comparative MRD assessment will continue to be collected in all subjects 
participating in this assessment).
Current technologies will be used to assess MRD. Malignant B-lymphocytes may be isolated 
from blood and bone marrow taken for MRD assessments (if sufficient malignant cells are 
present) and characterized by technologies such as quantitative real-time polymerase chain 
reaction (qRT-PCR), gene expression profiling (GEP), micro-ribonucleic acid (miRNA), 
methylation, mutational and RNA sequencing (RNASeq) analyses or other similar technologies 
utilized for analysis of RNA expression or for somatic deoxyribonucleic acid (DNA) analysis. 
Genes identified in previous studies with ibrutinib may be explored in isolated malignant B-cells 
and analyses will be restricted to identification or confirmation of genes associated with 
resistance to the drugs given in this study.
9.4.2.
Formalin-Fixed Paraffin-Embedded Tumor Tissue and Lymph Node 
Biopsies
A fresh lymph node biopsy sample also should be collected if feasible, for biomarker evaluation 
(where local regulations and shipping logistics permit) during Screening (after eligibility is 
determined) or prior to Cycle 1, and at the time of progressive disease (even if screening sample 
was not collected). If a fresh lymph node biopsy was performed during Screening to confirm 
MCL diagnosis, a portion of the sample may be used for the biomarker evaluation. A portion of 
the FFPE block or slides collected for confirmation of diagnosis may be evaluated for biomarker
assessments.
Expression and mutation patterns may be investigated within the FFPE tissue to determine 
whether characterization of the FFPE sample taken from MCL diagnosis could predict response 
or resistance to ibrutinib. FFPE tissue and lymph node biopsies may be subjected to IHC, 
qRT-PCR, GEP, miRNA, methylation, mutational and RNASeq analyses or other similar 


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technologies utilized for analysis of protein or RNA expression or for somatic DNA analysis to 
identify genes and pathways associated with resistance or response in subjects. Subjects may 
have differential response to treatment following inhibition of BTK tyrosine phosphorylation by 
ibrutinib based on differences in active signaling pathways and tumor microenvironment 
composition. Molecular characterization of the lymph nodes may identify altered signaling 
patterns that associate with response or resistance to ibrutinib treatment. This data will be used to 
inform development of ibrutinib in earlier MCL disease stages or other B-cell malignancies if 
significant associations are found with clinical endpoints.
9.5.
Safety Evaluations
All subjects who receive treatment will be considered evaluable for toxicity. Any clinically 
relevant changes occurring during the study must be recorded on the Adverse Event section of 
the CRF. Any clinically significant abnormalities persisting at the end of the study/early 
withdrawal will be followed by the investigator until resolution or until a clinically stable 
endpoint is reached. The study will be monitored by an independent DMC. Details are provided 
in Section 11.9.
The study will include the following evaluations of safety and tolerability according to the 
timepoints provided in the Time and Events Schedule (Table 1).  
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally-acceptable representative) for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 12, Adverse Event Reporting and
graded according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), Version 4.03. 
Clinical Laboratory Tests 
All laboratory tests should be performed at the laboratory facilities associated with the 
investigational site. Laboratory certificates or accreditation and normal ranges of the laboratory 
facility at the site must be submitted to the sponsor before the enrollment of any subject at the 
site. If the subject has the laboratory assessments conducted at a laboratory facility other than the 
one associated with the investigational site, the investigator must submit to the sponsor 
laboratory certificates or accreditation and normal ranges for that facility as well. The laboratory 
reports must be filed with the source documents.
Blood samples to assess the safety of study treatment will be collected. Required laboratory tests 
must be performed within 48 hours of the scheduled visit. For Day 1, Cycle 1 only, clinical 
laboratory tests do not need to be repeated if the Screening tests were performed within 5 days of 
the first dose of study agent. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the adverse event section of the CRF. 
For example, laboratory abnormalities leading to an action regarding any study treatment


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(dose reduction, temporary stop, delay of the start of a cycle or permanent stop) or the start of 
concomitant therapy should be reported. For each laboratory abnormality reported as an adverse 
event, the following laboratory values should be reported in the laboratory section of the CRF: 
the value indicative of the onset of each toxicity grade; the most abnormal value observed during 
the adverse event, and the value supporting recovery to Grade ≤ 1 or to baseline values.
The following tests will be performed by the local laboratory at the timepoints shown in Table 1:

Hematology
-hemoglobin
-ANC
-WBC count
-absolute lymphocyte count
-platelet count

Coagulation Studies 

aPTT (activate partial thromboplastin time)

international normalized ratio (INR) and/or prothrombin time (PT)

Serum Chemistry Panel 
-sodium
-AST
-potassium
-ALT
-creatinine
-uric acid
-LDH
-total bilirubin
-alkaline phosphatase
-albumin
-calcium
-magnesium*
-phosphate
* To be evaluated on Day 1 of Cycle 1 and Cycle 2, and as clinically indicated.

Screening for Hepatitis B and C will include the following evaluations: Hepatitis B surface 
antigen, Hepatitis B core antibody, and Hepatitis C antibody. Subjects who test positive for 
Hepatitis B core antibody must have Hepatitis B DNA by PCR performed and confirmed as 
negative prior to randomization. Subjects who test positive for Hepatitis C antibody are 
eligible if previously treated and achieved a sustained viral response, defined as a negative 
viral load for Hepatitis C after completion of the treatment for hepatitis. 

Pregnancy test (serum β-hCG or urine): for women of childbearing potential only

Beta2-microglobulin and serum Ig levels (IgG, IgM, IgA)
Vital Signs 
Temperature, pulse/heart rate, and blood pressure will be recorded at Screening. Assessment of 
pulse/heart rate and blood pressure is expected at every protocol-specified visit until end of 
treatment. Blood pressure and pulse/heart rate measurements should be preceded by at least 
5 minutes of rest in a quiet setting without distractions (eg, television, cell phones). If an 
abnormal heart rhythm is suspected, further investigation (ECG and/or Holter monitor) is 


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required per investigator’s discretion. Vital signs that are considered to be clinically relevant by 
the investigator are to be documented as adverse events.
Body Surface Area
Calculation of body surface area (BSA) at Cycle 1, Day 1 is required for bendamustine 
hydrochloride and rituximab dosing. The BSA should be recalculated if a subject experiences a 
> 10% change in weight from the weight used in the most recent BSA calculation. Weight will 
be collected as specified in the Table 1.
Physical Examination 
The Screening physical examination will include, at a minimum, subject’s height, general
appearance, examination of the skin, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal 
system, 
lymphatic 
system, 
and 
nervous 
system. 
Only 
a 
limited 
symptom-directed physical examination and weight assessment is required on Day 1 of all cycles 
after Cycle 1. An assessment of lymphoma B-symptoms (fever, night sweats and weight loss) 
should also be conducted. Review of systems should include inquiry of ocular symptoms (eg, dry 
eye, watering eye/abnormal discharge, eye pain, blurred vision/double vision, decreased visual 
acuity, photophobia/sensitivity to light, floaters, flashing lights, and eye irritation). Subjects 
should be referred to an ophthalmologist for a formal examination if any Grade ≥ 2 symptoms 
are reported. 
ECGs should also be performed at the investigator’s discretion, particularly in subjects with 
arrhythmic symptoms (eg, palpitations, lightheadedness or new onset dyspnea).
Electrocardiograms
Electrocardiogram will be performed for all subjects during Screening. Abnormalities noted at 
screening should be included in the medical history.
During the collection of ECGs, subjects should be in a quiet setting without distractions 
(eg, television, cell phones). Subjects should rest in a supine position for at least 5 minutes 
before ECG collection and should refrain from talking or moving arms or legs. 
ECOG Performance Status
The ECOG performance status scale will be used to grade changes in the subject’s daily living 
activities.34 ECOG performance status scale is provided in Attachment 2. The frequency of 
ECOG performance status assessment is provided in Table 1.
9.6.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. Refer to the Time and Events Schedule for the timing and frequency of all 
sample collections (Table 1). Instructions for the collection, handling, and shipment of samples 
are found in the laboratory manual that will be provided for sample collection and handling.


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10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost to follow up, or has not withdrawn consent before the end of study.
10.2.
Discontinuation of Study Treatment 
Investigators are encouraged to keep a subject experiencing clinical benefit (as defined in see 
Section 9.2.2.3) in the study unless significant toxicity puts the subject at risk or routine 
noncompliance puts the study outcomes at risk. If a subject's study treatment must be 
discontinued, this will not result in automatic withdrawal of the subject from the study. 
A subject's study treatment should be discontinued if:

The subject experiences overt disease progression or relapse

Unacceptable toxicity

The subject becomes pregnant

The subject refuses further treatment 

A serious protocol violation has occurred, as determined by the principal investigator or the 
sponsor
If a subject discontinues study treatment before the onset of disease progression, end of treatment 
and posttreatment assessments should be obtained and follow-up of scheduled assessments 
should be continued. Refer to Section 9.2.1 for instructions regarding the posttreatment efficacy 
assessments and Section 9.2.2.1 for instructions on the progressive disease form. The reason(s) a 
subject discontinues treatment will be recorded on the CRF.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Withdrawal of consent

The sponsor discontinues the study (see Section 17.9.2)
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented. When a subject withdraws before completing the study, 
the reason for withdrawal is to be documented in the CRF and in the source document. Study 
drug assigned to the withdrawn subject may not be assigned to another subject. Subjects who 
withdraw will not be replaced.


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Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the ICF.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
11.1.
Subject Information
The analysis populations are defined as:
1.
Intent-to-Treat (ITT) population: defined as all randomized subjects. Subjects in this 
population will be analyzed according to the treatment to which they are randomized.
2.
Per-protocol (PP) population: defined as all randomized subjects who undergo at least 
1 adequate postbaseline disease assessment and do not have major protocol violations
including, but not limited to, the following:
a.
did not meet all inclusion and exclusion criteria
b.
did not receive the treatment to which they were randomized
c.
had less than 75% (the cutoff values are subject to change) of study drug compliance
3.
Pharmacokinetic-evaluable population: defined as all randomized subjects who received at 
least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained 
posttreatment.
4.
Biomarker population: All randomized subjects with sufficient malignant cells collected 
from at least 1 timepoint during the study. 
5.
Safety population: All randomized subjects who received at least 1 dose of study drug.
Safety data will be analyzed according to the actual treatment received.
The ITT population will be used to summarize the study population and characteristics, efficacy, 
and PRO data; and the safety population will be used to summarize the safety data, unless 
otherwise specified.
11.2.
Sample Size Determination
This study is designed to evaluate the effect of treatment on PFS and is powered for this 
endpoint. The sample size for the study is calculated based on the following considerations:
a.
1:1 randomization ratio between 2 treatment arms
b.
Target hazard ratio of 0.7. Assuming the median PFS for the control arm (BR+placebo) is 
42 months from randomization (this is based on the scientific advisor’s best estimates), a 
target hazard ratio of 0.7 corresponds to an 18 months increase in median PFS for the 


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treatment arm (ibrutinib+BR) relative to the control (ie, 60 months vs. 42 months, 
respectively)
c.
Minimum 77% power 
d.
1-sided overall significance level of 0.025
e.
Two interim analyses for both efficacy and futility at approximately 50% and 68% of the 
planned PFS events
Using the above assumptions and based on a uniform accrual rate of approximately 35 subjects 
per month, the study will enroll approximately 520 subjects (about 260 subjects to each arm) to 
observe 265 events. As of Amendment INT4, based on actual enrollment, the current projections 
are to reach 265 events at 72 months.
The data cutoffs based on the interim and final analysis of PFS will be when about 50%, 68%, 
and 100% of total 265 PFS events, respectively, have occurred. Assuming 43% improvement in 
median PFS of the ibrutinib arm over the placebo arm (a hazard ratio of 0.70 for the ibrutinib
relative to placebo group, under the exponential distribution assumption, or for example, an 
improvement in median PFS from 42 months to 60 months), the study has at least 77% power 
assuming a statistical significance level of 2.5% (1-sided). Note that based on the strong efficacy 
of ibrutinib observed in other recently completed studies, the expected study power will exceed 
80% (corresponding to a target hazard ratio of 0.69). 
11.3.
Efficacy Analyses 
Descriptive statistics will be used to summarize the data. For continuous variables, number of 
observations, means, standard deviations, medians, and ranges will be used.  For discrete 
variables, frequency will be summarized. For time-to-event variables, Kaplan-Meier estimates 
will be provided. 
The comparisons between the 2 treatment groups will be performed as follows: for the 
continuous variable representing change from baseline to a particular postbaseline timepoint, 
analysis of variance (ANOVA) will be used. For discrete variables, Cochran-Mantel-Haenszel 
chi-square test will be used. For time-to-event variables, stratified log-rank test will be used. All 
tests will be conducted at a 2-sided alpha level of 0.05, and 95% confidence intervals (CI) will be 
provided, unless stated otherwise. 
11.3.1.
Primary Endpoint
The stratified log-rank test will be used to compare survival curves between the 2 treatment 
groups for the primary endpoint, PFS. The stratification factor to be used in the analysis is 
simplified MIPI score (low risk [0-3] vs. intermediate risk [4-5] vs. high risk [6-11])
(Attachment 3). Additionally, the Kaplan-Meier method will be used to estimate the distribution 
of PFS for each treatment group. The median PFS will be provided for each treatment group and 
the hazard ratio for ibrutinib relative to placebo and its associated 95% CI will be calculated 
based on the Cox proportional hazards model stratified by the stratification factor. The sensitivity 
analyses for PFS using different censoring mechanisms based on the ITT population, as well as 


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analyses based on the PP population, will be performed similarly. Other exploratory analyses, 
such as sensitivity analysis to address the potential effect of an unequal number of subject visits 
that could result in unscheduled tumor assessments because of the different treatment schedules 
in the 2 groups, will be performed as appropriate.
11.3.2.
Secondary Endpoints
Analyses for the secondary endpoints will be performed using an appropriate model. Multiplicity 
adjustment will be made to control the overall Type 1 error. Details will be specified in the 
Statistical Analysis Plan.
11.3.3.
Exploratory Endpoints
Analyses for the exploratory efficacy endpoints will be performed using the methods specified in 
Section 11.3.
11.3.4.
Baseline Assessments
All demographic and baseline characteristics will be summarized for the ITT population. The 
baseline value is defined as the value collected at the time closest to, but prior to, randomization, 
unless otherwise specified.
11.4.
Patient-reported Outcomes
PRO measures listed in Section 9.2.3 will be analyzed using the methods specified in 
Section 11.3. For individual items and sub-scale scores within the PRO measures, descriptive 
statistics (mean, standard deviation, median, and range) will be calculated for each time point, 
for changes from baseline at each time point, as well as for changes from baseline to the last 
value. In addition, time to worsening in the Lym subscale of the FACT-Lym will be evaluated.
Other exploratory analyses will be performed as appropriate.
11.5.
Pharmacokinetic Analyses 
Population pharmacokinetic analysis of ibrutinib plasma concentration-time data will be 
performed using NONMEM. Data may be combined with data from other studies to support a 
relevant structural population-based pharmacokinetic model. Available subject characteristics 
(demographics, laboratory variables, genotypes, etc.) will be tested as potential covariates 
affecting pharmacokinetic parameters. Ibrutinib data will be listed for all subjects with available 
plasma concentrations. Subjects will be excluded from the pharmacokinetic analysis if their data 
do not allow for accurate assessment of the pharmacokinetic (eg, incomplete administration of 
the study agent; concentration data not sufficient for pharmacokinetic parameter calculation due 
to missing pharmacokinetic draws at multiple visits; or early discontinuation from the study). 
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration data presentation. Concentrations below the lowest quantifiable 
concentration will be treated as zero in the summary statistics and for the calculation of 
pharmacokinetic parameters. All subjects and samples excluded from the analysis will be clearly 
documented in the study report. Model-derived exposure parameters may be subjected to further 
explore pharmacokinetic/pharmacodynamic correlation between exposure with relevant clinical 


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or biomarker information. Details of the analyses will be given in a population pharmacokinetic 
analysis plan and the results of the population pharmacokinetic analyses will be presented in a 
separate report.
11.6.
Biomarker Analyses
The MRD assay defining the range of MRD detection will be completed prior to study start; the 
methodology will be described in the appropriate clinical document(s) prior to database lock. 
The MRD-negative rate will be evaluated within and between treatment arms for this study for 
all subjects included in MRD population. Other biomarker analyses will use data from all 
subjects in biomarker population. Analyses will be performed within the treatment group in total 
and stratified by clinical covariates or molecular subgroups using the appropriate statistical 
methods (parametric or non-parametric, univariate or multivariate; for example ANOVA or 
survival analysis, depending on the endpoint). Correlation of baseline expression levels or 
changes in expression levels with time-to-event endpoints may confirm identified resistant 
(or responsive) subgroups. Results may be presented in a separate report.
11.7.
Safety Analyses
All safety analyses will use data for the safety population. The baseline value for safety 
assessment is defined as the value collected at the time closest to, but prior to, the start of 
bendamustine or rituximab or study drug administration. The safety parameters to be evaluated 
are the incidence, intensity, and type of adverse events, clinically significant changes in the 
subject’s physical examination findings, vital signs measurements, and clinical laboratory 
results. Exposure to investigational product and reasons for discontinuation of study treatment 
will be tabulated.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events 
with onset during the treatment phase (ie, treatment-emergent adverse events, and adverse events 
that have worsened since baseline) will be included in the analysis. For each adverse event, the 
percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized by treatment group.
Treatment-emergent adverse events are adverse events that occur after the first dose of study 
treatment, through the Treatment Phase, and for 30 days following the last dose of study 
treatment; any adverse event that is considered study treatment-related regardless of the start date 
of the event; or any event that is present at baseline but worsens in severity or is subsequently 
considered treatment-related by the investigator. Adverse events of special interest with ibrutinib
are major hemorrhage (see Section 12.3.3). Subjects with adverse events of special interest may 
be counted or listed. Adverse events of special interest will be summarized similarly to 
treatment-emergent adverse events.


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The number and percent of subjects with treatment-emergent adverse events will be summarized 
according to intensity (NCI CTCAE, Version 4.03), action taken, and drug relationship as well as 
categorized by System Organ Class and preferred term by treatment group.
Given that the anticipated treatment duration may be different between the 2 treatment groups, 
exposure adjusted incidence rate will also be presented by treatment group if the median 
treatment duration of ibrutinib is 30% longer than the median treatment duration of placebo.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event.
Clinical Laboratory Tests
Hematology and serum chemistry laboratory data up to 30 days after last dose or the end of 
treatment visit date, whichever is later, will be reported in International System of Units (SI). 
Summary statistics (mean, standard deviation, median and range) will be calculated for the raw 
data and for changes from baseline at each timepoint of assessment as well as for the changes 
from baseline to the last value. 
Graphical displays of over-time summaries and shift tables will be presented for the following 
key laboratory parameters: hemoglobin, WBC count, neutrophils, platelets, AST, ALT, total 
bilirubin, creatinine, alkaline phosphatase, and electrolytes (sodium, potassium, calcium, and 
phosphate). The same analysis may be applied to other laboratory parameters.  
Shift tables will summarize by cycle the number of subjects with each baseline NCI CTCAE
grade and changes to the maximum NCI CTCAE grade in the cycle (up to 30 days after last dose 
or the end of treatment visit date, whichever is later).
11.8.
Interim Analyses 
Two interim analyses using classical O’Brien and Fleming33 boundary for both efficacy and 
futility will be conducted after observing approximately 50% and 68% PFS events (progressive 
disease or death).33 The stopping boundaries will be implemented by Lan-Demets spending 
function using East® software v5.3 to control the 1-sided Type I error of 0.025 for the 
comparison of the PFS endpoint. The 1-sided cumulative alpha spend will be 0.002 at the first 
interim, 0.007 at the second interim, and 0.025 at the final analysis. The cumulative Type II error 
spend will be 0.088 at the first interim, 0.141 at the second interim, and 0.225 at the final 
analysis. Based on the enrollment rate as of Amendment INT-4 , the first and second interim 
analyses will take place after approximately 40 and 50 months after the first subject has been 
randomized, respectively. The independent DMC may make recommendations regarding study 
continuation or unblinding the study/stopping placebo treatment if the pre-specified boundary is 
crossed for efficacy or futility, and the sponsor may implement the recommendations.


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11.9.
Independent Data Monitoring Committee
An independent DMC of at least 2 medical experts in the relevant therapeutic area and at least 
1 statistician will be established to monitor data on an ongoing basis to ensure the safety of the 
subjects enrolled in this study.
The independent DMC may recommend stopping the study or unblinding the study/stopping 
placebo treatment for efficacy or futility if the pre-specified stopping boundary is crossed at 
interim analysis, and the sponsor may implement the recommendations. In addition to the 
ongoing safety monitoring and planned interim analyses for efficacy and futility, 3 safety review 
meetings are planned for approximately 2 months after 40 subjects, 200 subjects, and 
400 subjects have been randomized. The safety review will focus on deaths, treatment 
discontinuations, serious adverse events, Grade ≥3 events, and events of special interest. Based 
on the results from these scheduled safety review meetings, the independent DMC chair may 
request additional safety interim analyses and more frequent monitoring. Until the first interim 
safety analysis, all deaths, treatment discontinuations and serious adverse events will be 
reviewed in a blinded fashion by the sponsor’s responsible physician on an ongoing basis to 
identify safety concerns, and the independent DMC will be informed of any new potential 
signals. The plan for monitoring subject safety and evaluating efficacy, and the roles and 
responsibilities of the independent DMC, are detailed in the independent DMC charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event may therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non-investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) product. 
(Definition per International Conference on Harmonisation [ICH]).


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This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For ibrutinib, the expectedness of an adverse 
event will be determined by whether or not it is listed in the Investigator's Brochure. For the 
non-sponsored investigational medicinal products (eg, background therapy) with a marketing 
authorization, the expectedness of an adverse event will be determined by whether or not it is 
listed in the Treanda USPI43 or the Rituxan USPI.37
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.


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12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the NCI CTCAE (version 4.03). The 
investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study treatment that may require expedited reporting and
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug, bendamustine, or rituximab

Suspected abuse/misuse of a sponsor study drug, bendamustine, or rituximab

Inadvertent or accidental exposure to a sponsor study drug, bendamustine, or rituximab

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion), bendamustine, or rituximab
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.


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12.3.
Procedures
12.3.1.
All Adverse Events
All subjects who receive treatment will be considered evaluable for toxicity. All adverse events 
(with the exception of progression of MCL) and special reporting situations, whether serious or 
nonserious, will be reported from the time a signed and dated ICF is obtained until 30 days 
following the last dose of any study treatment or until the start of a subsequent systemic 
anti-MCL therapy, if earlier. Adverse events reported after 30 days following the last dose of any 
study treatment should also be reported if considered related to any study treatment. Resolution 
information after 30 days should be provided. All Grade 3 or Grade 4 adverse events considered 
related to any study treatment must be followed until recovery to baseline or Grade ≤ 1. Cardiac
adverse events of Grade 2 or higher will be followed until improvement to baseline or Grade ≤ 1. 
The unresolved aforementioned events will be followed for a maximum of 6 months. All adverse 
events of special interest as defined in Section 12.3.3 related to bleeding or resulting in bleeding 
complications must be followed until recovery or until there is no further improvement. Serious 
adverse events, including those spontaneously reported to the investigator within 30 days after 
the last dose of any study treatment, must be reported using the Serious Adverse Event Form. 
The sponsor will evaluate any safety information that is spontaneously reported by an 
investigator beyond the time frame specified in the protocol.
Progressive disease of MCL should NOT be reported as an adverse event, but instead 
symptoms/clinical signs of disease progression may be reported. Otherwise, all events that meet 
the definition of a serious adverse event will be reported as serious adverse events, regardless of 
whether they are protocol-specific assessments.
All adverse events, regardless of seriousness, severity, or presumed relationship to any study 
treatment, must be recorded using medical terminology in the source document and the CRF. All 
records will need to capture the details of the duration and the severity of each episode, the 
action taken with respect to the any study treatment, investigator’s evaluation of its relationship 
to the any study treatment, and the subject outcome. Whenever possible, diagnoses should be 
given when signs and symptoms are due to a common etiology (eg, cough, runny nose, sneezing, 
sore throat, and head congestion should be reported as "upper respiratory infection"). 
Investigators must record in the CRF their opinion concerning the relationship of the adverse 
event to all study treatment. All measures required for adverse event management must be 
recorded in the source document and reported according to sponsor instructions. The intensity 
(severity) of adverse events will be assessed using NCI CTCAE Version 4.03.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all serious adverse events that are unlisted (unexpected) and associated 
with the use of the study treatment. The investigator (or sponsor where required) must report 
these events to the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) that approved the protocol unless otherwise required and documented by the 
IEC/IRB. 


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For all studies with an outpatient phase, the subject must be provided with a "wallet (study) card" 
and instructed to carry this card with them for the duration of the study indicating the following: 

Subject name

Subject number

Site number

Study number

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Statement, in the local language(s), that the subject is participating in a clinical study

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event may be attributed to agents other than the study treatment or to factors unrelated
to study conduct

It becomes unlikely that any additional information may be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:


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Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to 
Section 12.1.1, Adverse Event Definitions and Classifications).

A standard procedure for protocol therapy administration will not be reported as a serious 
adverse event. Hospitalization or prolonged hospitalization for a complication of therapy 
administration will be reported as a serious adverse event.

The administration of blood or platelet transfusion. Hospitalization or prolonged 
hospitalization for a complication of such transfusion remains a reportable serious adverse 
event.

A procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling, pharmacokinetic or biomarker blood 
sampling). Hospitalization or prolonged hospitalization for a complication of such 
procedures remains a reportable serious adverse event.

Prolonged hospitalization for technical, practical, or social reasons in the absence of an 
adverse event.

A procedure planned before entry into the study (must be documented in the CRF). 
Prolonged hospitalization for a complication considered to be at least possibly related to the 
study treatment remains a reportable serious adverse event.
12.3.3.
Adverse Events of Interest
Specific adverse events or groups of adverse events will be followed as part of standard safety 
monitoring activities by the sponsor. These events will be reported to the sponsor within 
24 hours of awareness irrespective of seriousness (ie, serious and nonserious adverse events) 
following the procedure described above for serious adverse events and will require enhanced 
data collection.  
12.3.3.1.
Major Hemorrhage
Major hemorrhage is defined as: 

Any treatment-emergent hemorrhagic adverse event of Grade 3 or higher. All hemorrhagic 
events requiring a transfusion of red blood cells should be reported as Grade 3 or higher 
adverse events per NCI CTCAE. 

Any treatment-emergent serious adverse event of bleeding of any grade. 

Any treatment-emergent central nervous system hemorrhage/hematoma of any grade.
12.3.4.
Other Malignancies 
In addition to all routine adverse event reporting, all new malignant tumors, including solid 
tumors, skin malignancies and hematologic malignancies, are to be reported for the duration of 
study treatment and during any protocol-specified follow-up periods including post-progression 
follow-up for overall survival.


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12.3.5.
Pregnancy 
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel 
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form. Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, and congenital 
anomaly) are considered serious adverse events and must be reported using the Serious Adverse 
Event Form. Any subject who becomes pregnant during the study must discontinue further study 
treatment. Because the effect of the study drug on sperm is unknown, pregnancies in partners of 
male subjects included in the study will be reported by the study-site personnel within 24 hours of 
their knowledge of the event using the appropriate pregnancy notification form. Follow-up 
information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will 
be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.


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14.
STUDY DRUG AND BACKGROUND DRUG INFORMATION
For the purposes of this study, ‘study drug’ refers to ibrutinib or placebo.
14.1.
Study Drug - Ibrutinib or Placebo
The ibrutinib supplied for this study will be manufactured and provided under the responsibility 
of the sponsor. Refer to the Investigator's Brochure for a list of excipients.
14.1.1.
Physical Description 
Ibrutinib/placebo capsules are provided as a hard gelatin capsule. Ibrutinib capsules contain
140 mg of ibrutinib. All formulation excipients are compendial and are commonly used in oral 
formulations. Refer to the ibrutinib Investigator's Brochure for a list of excipients. Placebo to 
match capsules will also be provided as a hard gelatin capsule.
14.1.2.
Packaging
To maintain the blind, the ibrutinib and matching placebo capsules will be packaged in opaque 
high-density polyethylene (HDPE) plastic bottles with labels bearing the appropriate label text as 
required by governing regulatory agencies. All study drug bottles will be dispensed in 
child-resistant packaging (bottle caps will be child-resistant).
14.1.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each 
bottle will contain a study-specific label with a unique identification number. The investigational 
product (ibrutinib/placebo) will be blinded.
14.1.4.
Preparation, Handling, and Storage 
The recommended storage condition for ibrutinib/placebo capsules is controlled room 
temperature (15○C to 25○C). Current stability data indicate that the capsules will be stable for the 
duration of the clinical study under the labeled storage conditions. Study staff will instruct 
subjects on how to store medication for at-home use as indicated for this protocol. Refer to the Site 
Investigational Product Manual for additional guidance on ibrutinib/placebo handling and storage 
conditions.
14.2.
Background Therapy – Bendamustine and Rituximab
Bendamustine hydrochloride may be provided in 100 mg single-use vials as a lyophilized 
powder or prescribed by the investigator. Rituximab may be provided in 100 mg or 500 mg 
single-use vials as a solution or prescribed by the treating physician. Bendamustine and rituximab 
labels will contain information to meet the applicable regulatory requirements.
Bendamustine and rituximab must be prepared in an aseptic manner according to local standards 
for handling cytotoxic/cytostatic drugs. Refer to the bendamustine and rituximab local prescribing 
information or the Site Investigational Product Manual for further instructions on preparation, 
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14.3.
Drug Accountability
The investigator is responsible for ensuring that all study treatment received at the site is 
inventoried and accounted for throughout the study. The dispensing of study drug 
(ibrutinib/placebo) to the subject, and the return of study drug (ibrutinib/placebo) from the 
subject (if applicable), must be documented on the drug accountability form. The subject or their 
legally acceptable representatives where applicable, must be instructed to return all original 
containers, whether empty or containing study drug (ibrutinib/placebo). The BR combination and 
R maintenance administered to the subject must be documented on the drug accountability form. 
All study treatment will be stored and disposed of according to the sponsor's instructions. Site 
staff must not combine contents of any study treatment containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drugs and study drug returned by the subject, must be 
available for verification by the sponsor's site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug (ibrutinib/placebo), or used returned study drug for 
destruction, will be documented on the drug return form. When the site is an authorized 
destruction unit and any study treatment supplies are destroyed on site, this must also be 
documented on the drug return form. Potentially hazardous materials such as used ampules,
needles, syringes and vials containing hazardous liquids, should be disposed of immediately in a 
safe manner and therefore will not be retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug (ibrutinib/placebo) must not be 
dispensed again, even to the same subject. Study drug may not be relabeled or reassigned for use 
by other subjects. The investigator agrees neither to dispense the study drug (ibrutinib/placebo) 
from, nor store it at, any site other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Study Protocol

Ibrutinib Investigator Brochure

Ibrutinib study drug diary

Package inserts for bendamustine hydrochloride and rituximab

Revised Response Criteria for Malignant Lymphoma8

Site investigational product manual

Laboratory manual and supplies (for samples and image acquisition)

PRO questionnaires and user manuals: PRO questionnaires will include the FACT-Lym and 
EQ-5D-5L. Sample questionnaires are provided in Attachment 6 and Attachment 7.


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
IWRS manual and supplies

Electronic data capture (eDC) Manual and eCRF completion guidelines

Subject information materials

Informed Consent

Progressive disease notification form (see Section 10.2)

Imaging Manual
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
This is a randomized, double-blind, placebo-controlled study to compare the efficacy and safety 
of ibrutinib in combination with BR to BR alone in subjects with newly diagnosed MCL who are 
65 years of age or older. All subjects will receive active treatment with BR as background 
therapy, which is recommended treatment by NCCN and European Union (EU) MCL Network 
guidelines for the patient population in this study.13,31 The study is blinded to adequately test the 
hypotheses that the addition of ibrutinib will prolong PFS in this subject population and provide 
additional clinical benefit. 
All participating subjects will receive full supportive care and will be followed closely for safety 
and efficacy throughout the study. Efficacy assessments will occur according to the 
internationally accepted Revised Response Criteria for Malignant Lymphoma. Safety 
assessments will occur through regular clinic visits including laboratory analyses.
An independent DMC will be established to review the safety and efficacy of the treatment 
combination and make recommendations as to the future conduct of the study. The sponsor will 
monitor blinded data on an ongoing basis to ensure the safety of the subjects enrolled in this 
study.
The total blood volume to be collected is estimated at 350 mL during the first year, 140 mL 
every year after the first year, and 20 mL at the End of Treatment Visit. The total volume of 
blood includes laboratory assessments associated with screening and treatment including
pharmacokinetic and biomarker samples. Additional MRD samples will be collected for the first 
100 subjects with a CR (Attachment 5). The volume of blood to be drawn is considered to be 
normal and acceptable for subjects participating in a cancer clinical study and is deemed 
reasonable over the time frame of the study.  
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.


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Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments /addenda


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
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug. From Amendment INT-4, these will no longer be provided for bendamustine.

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or trial conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct). At the end of the study, the 
investigator (or sponsor where required) will notify the IEC/IRB about the study completion.
16.2.3.
Informed Consent
Each subject or a legally acceptable representative must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved 
by both the sponsor and by the reviewing IEC/IRB and be in a language that the subject may
read and understand. The informed consent should be in accordance with principles that 
originated in the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the subject will receive for the treatment 
of his or her disease. Subjects will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that the investigator will maintain a subject identification register for the purposes of long-term 
follow-up if needed, and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the subject, to the extent permitted by 


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the applicable law(s) or regulations. By signing the ICF the subject or legally acceptable 
representative is authorizing such access, including permission to obtain information about his or 
her survival status, and agrees to allow his or her study physician to recontact the subject for the 
purpose of obtaining consent for additional safety evaluations, if needed, and subsequent 
disease-related treatments, or to obtain information about his or her survival status.
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for 
study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries. The subject has the right 
to request through the investigator access to his or her personal data and the right to request 
rectification of any data that are not correct or complete. Reasonable steps will be taken to 
respond to such a request, taking into consideration the nature of the request, the conditions of 
the study, and the applicable laws and regulations.
Exploratory biomarker and pharmacokinetic research is not conducted under standards 
appropriate for the return of data to subjects. In addition, the sponsor cannot make decisions as to 
the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to subjects or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.


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16.2.5.
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand ibrutinib, to 
understand MCL, to understand differences in response to drug and to develop tests/assays
related to ibrutinib and MCL. The research may begin at any time during the study or the 
post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw consent for sample storage for research 
(refer to Section 10.3).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.


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17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of any study 
treatment to the study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed, written IEC/IRB approval of the protocol, amendments, 
ICF, any recruiting materials, and if applicable, subject compensation programs. This 
approval must clearly identify the specific protocol by title and number and must be signed 
by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated Clinical Trial Agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness. The subject identification and enrollment log will be 
treated as confidential and will be filed by the investigator in the study file. To ensure subject 
confidentiality, no copy will be made. All reports and communications relating to the study will 
identify subjects by subject identification and date of birth. In cases where the subject is not 
randomized into the study, the date seen and date of birth will be used. The investigator must 


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also complete a subject screening log, which reports on all subjects who were seen to determine 
eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study discussion 
and date of signed informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all adverse events and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; any study treatment 
administration information; and date of study completion and reason for early discontinuation of 
any study treatment or withdrawal from the study, if applicable. In addition, the author of an 
entry in the source documents should be identifiable. At a minimum, the type and level of detail 
of source data available for a subject should be consistent with that commonly recorded at the 
study site as a basis for standard medical care. Specific details required as source data for the 
study will be reviewed with the investigator before the study and will be described in the
monitoring guidelines (or other equivalent document).
17.5.
Case Report Form Completion
Case report forms are provided for each subject in printed or electronic format. 
Electronic data capture will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an electronic CRF, and transmitted in a 
secure manner to the sponsor within the timeframe agreed upon between the sponsor and the 
study site. The electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Study site personnel must complete the CRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible. The investigator must confirm that all data entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or 
study-site personnel must adjust the CRF (if applicable) and complete the query.
If corrections to a CRF are needed after the initial entry into the CRF, this may be done in 
3 different ways:

Study site personnel may make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).


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
Study site manager may generate a query for resolution by the study-site personnel.

Clinical data manager may generate a query for resolution by the study-site personnel. 
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review CRFs for accuracy and completeness during 
on-site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator must permit access to such reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 


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the monitor will compare the data entered into the CRFs with the hospital or clinic records 
(source documents). The nature and location of all source documents will be identified to ensure 
that all sources of original data required to complete the CRF are known to the sponsor and 
study-site personnel and are accessible for verification by the sponsor study-site contact. If 
electronic records are maintained at the study site, the method of verification must be discussed 
with the study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. Findings 
from this review of CRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last visit for the last subject participating in the 
study. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final subject visit at that study site, in the time frame specified in the Clinical Trial 
Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 


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records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding ibrutinib or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including biomarker research data, generated as a result of 
this study, are considered confidential and remain the sole property of the sponsor. The 
investigator agrees to maintain this information in confidence and use this information only to 
accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the clinical study will be used by 
the sponsor in connection with the continued development of ibrutinib and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information 
derived from the clinical studies to be used, the investigator is obligated to provide the sponsor 
with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain CRF data from all study sites that participated in the study. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of exploratory biomarker and 
pharmacokinetic analyses performed after the Clinical Study Report has been issued will be 
reported in a separate report and will not require a revision of the Clinical Study Report. Study 
subject identifiers will not be used in publication of results. Any work created in connection with 
performance of the study and contained in the data that may benefit from copyright protection 
(except any publication by the investigator as provided for below) shall be the property of the 
sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 


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for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as
required by law.


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1992;52(19 Suppl):5541s-5544s.


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Attachment 1: Ann Arbor Classification and the Cotswold Modifications
Stage
Features
I
Involvement of a single lymph node region or lymphoid structure (eg, spleen, 
thymus, Waldeyer’s ring)
II
Involvement of two or more lymph node regions on the same side of the 
diaphragm
III
Involvement of lymph regions or structures on both sides of the diaphragm
IV
Involvement of extranodal site(s) beyond that designated E
For all Stages
A
No symptoms
B
Fever (>38oC), drenching sweats, weight loss (10% body weight over 6 months)
For Stages I to III
E 
Involvement of a single, extranodal site contiguous or proximal to known nodal 
site
Cotswold 
modifications
Massive mediastinal disease has been defined by the Cotswold meeting as a 
thoracic ratio of maximum transverse mass diameter greater than or equal to 33% 
of the internal transverse thoracic diameter measured at the T5/6 intervertebral 
disc level on chest radiography.
The number of anatomic regions involved should be indicated by a subscript 
(eg, II3).
Stage III may be subdivided into: III1, with or without plenic, hilar, celiac, or 
portal nodes;III2, with para-aortic, iliac, mesenteric nodes.
Staging should be identified as clinical stage (CS) or pathologic stage (PS).
A new category of response to therapy, unconfirmed/uncertain complete 
remission (CR) can be introduced because of the persistent radiologic 
abnormalities of uncertain significance.
Armitage JO. Staging non-Hodgkin lymphoma. CA Cancer J Clin. 2005;55(6):368-376.3


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Attachment 2: Eastern Cooperative Oncology Group Performance Status Scale
Grade 
Eastern Cooperative Oncology Group Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self care but unable to carry out any work activities. Up 
and about more than 50% of waking hours
3
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair
5
Dead
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair34


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Approved, Date: 19 December 2019
Attachment 3: Calculating the Simplified MIPI for MCL
For each prognostic factor, 0-3 points were given to each subject and points were summed up to a 
maximum of 11. Subjects with 0-3 points in sum were classified as low risk, subjects with 4-5 points as 
intermediate risk, and subjects with 6-11 points as high risk. ECOG performance status was weighted 
with 2 points if subjects were unable to work or bedridden (ECOG 2-4). LDH was weighted according the 
ratio to the ULN.21
Points
Age, year
ECOG
LDH/ULN
WBC, /uL
0
< 50
0-1
< 0.67
< 6700
1
50-59
-
0.67-0.99
6700-9999
2
60-69
2-4
1.0-1.49
10000-14999
3
70
-
1.5
15000


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Attachment 4: Inhibitors and Inducers of CYP3A
Examples 
of 
inhibitors 
and 
inducers 
of 
CYP3A
can 
be 
found 
at 
the 
following 
websites: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-
inhibitors-and-inducers and http://medicine.iupui.edu/clinpharm/ddis/table.aspx.12,14
The list below reflects
information obtained from the Indiana University, Division of Clinical Pharmacology, Indianapolis, IN website on 
July 2013. 
Inhibitors of CYP3A
Strong inhibitors:
All other inhibitors:
INDINAVIR
amiodarone
NELFINAVIR
NOT azithromycina
RITONAVIR
chloramphenicol
CLARITHROMYCIN
boceprevir
ITRACONAZOLE
ciprofloxacin
KETOCONAZOLE
delaviridine
NEFAZODONE
diethyl-dithiocarbamate
SAQUINAVIR
fluoxetine-metabolite norfluoxetine
TELITHROMYCIN
fluvoxamine
Moderate inhibitors:
gestodene
aprepitant
imatinib
erythromycin
mibefradil
diltiazem 
mifepristone
fluconazole
norfloxacin
grapefruit juice
norfluoxetine
Seville orange juice
star fruit
verapamil
telaprevir
Weak inhibitors:
troleandomycin
cimetidine
voriconazole
a.
Azithromycin is unique in that it does not inhibit CYP3A
Inducers of CYP3A
efavirenz
phenobarbital
nevirapine
phenytoin
barbiturates
pioglitazone
carbamazepine
rifabutin
glucocorticoids
rifampin
modafinil
St. John's wort
oxcarbazepine
troglitazone 


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Attachment 5: Blood Volumes for Laboratory Samples
Blood Samples
Volume per 
Sample 
(mL)
No. of 
samples per 
subject in 
first year
Total 
volume of 
blood (mL)a
in first year
No. of 
samples per 
subject  in 
second year
Total 
volume of 
blood (mL)a
in second 
year
No. of 
samples at 
End of
Treatment
Total 
volume 
(mL)a of 
blood at 
End of 
Treatment
Safety
- Hematologyb
5
19
95
7
35
1
5
- Coagulation (INR/PT and aPTT)
5
1
5
0
0
0
0
- Serum chemistryb
10
10
100
7
70
0
0
Serology (hepatitis)
3
1
3
0
0
0
0
Urine or serum -hCG pregnancy tests
2
1
2
0
0
0
0
Serum IgG, IgM, IgA and beta2-microglobulin
5
4
20
3
15
1
5
Minimal residual diseasec and biomarker samples
6
5
30
1
6
1
6
Additional minimal residual disease samplesd
10
4
40
2
20
0
0
Pharmacokinetic sample
2
9
18
0
0
0
0
Total (Totals with additional MRD samples)c
38 (48)
50 (54)
273 (313)
18 (20)
126 (146)
3
16
a
Calculated as number of samples multiplied by amount of blood per sample.
b
See Section 9.5 for the list of parameters.
c
As of Amendment INT-6, the CR MRD samples will no longer be collected except in subjects whose first assessment of CR is after the issue date of 
Amendment INT-6. The comparative MRD samples (see footnote ‘d’) will continue to be collected in all subjects participating in this assessment.
d
For the first 100 subjects with a CR (excluding subjects at sites in China), additional blood samples will be collected for comparative MRD testing.


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Attachment 6: Sample FACT-Lym (Version 4)


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Approved, Date: 19 December 2019


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Approved, Date: 19 December 2019
Attachment 7: Sample Health Questionnaire EQ–5D–5L


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Attachment 8: Child-Pugh Score for Subjects With Liver Impairment
Measure
1 point
2 points
3 points
Total bilirubin, μmol/L (mg/dL)
<34 (<2)
34-50 (2-3)
>50 (>3)
Serum albumin, g/L (g/dL)
>35 (>3.5)
28-35 (2.8-3.5)
<28 (<2.8)
PT/INR
<1.7
1.71-2.30
>2.30
Ascites
None
Mild
Moderate to Severe
Hepatic encephalopathy
None
Grade I-II (or suppressed 
with medication)
Grade III-IV 
(or refractory)
Points
Class
5-6
A
7-9
B
10-15
C
Sources: 
Child CG, Turcotte JG. Surgery and portal hypertension. In Child CG. The liver and portal hypertension. Philadelphia:Saunders. 
1964; 50-64.
Pugh RN, Murray-Lyon IM, Dawson L, et al. Transection of the oesophagus for bleeding oesophageal varices. The British 
Journal of Surgery, 1973; 60:646-649.


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INVESTIGATOR AGREEMENT
PPD


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date:  7 May 2020
Janssen Research & Development *
Clinical Protocol 
COVID-19 Appendix/DEU-1
A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine 
Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination with Bendamustine and 
Rituximab (BR) in Subjects With Newly Diagnosed Mantle Cell Lymphoma
Protocol PCI-32765MCL3002; Phase 3
JNJ-54179060 (ibrutinib)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc.; Janssen
Infectious Diseases BVBA; Janssen Sciences Ireland UC; or Janssen Research & Development, LLC. The
term “sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
EudraCT NUMBER: 2012-004056-11
Status:
Approved
Date:
7 May 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-RIM-56760, 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
PCI-32765MCL3002 (EDMS-ERI-50002361)
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT01776840


COVID-19 Appendix/DEU-1
JNJ-54179060 (ibrutinib)
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CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date:  7 May 2020
COVID-19 APPENDIX
GENERAL GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by subjects and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for 
study-related subject management in the event of disruption to the conduct of the study. This 
guidance does not supersede any local or government requirements or the clinical judgement of 
the investigator to protect the health and well-being of subjects and site staff. If at any time the 
investigator assesses that the risk of treatment may outweigh the benefits, study treatment will be 
interrupted, and study follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, subjects will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Subjects will also be questioned regarding general 
health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for subjects on study 
treatment, including follow up. Modifications to protocol-required assessments may be permitted 
after consultation between the subject and investigator, and with the agreement of the sponsor. 
Missed assessments/visits will be captured in the clinical trial management system for protocol 
deviations. Discontinuations of study treatment and withdrawal from the study should be 
documented with the prefix “COVID-19-related” in the Comments electronic case report form 
(eCRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
Modifications made to the study conduct as a result of the COVID-19 pandemic should be 
summarized in the clinical study report.


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Status: Approved,  Date:  7 May 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL:
Subject Visits and Assessments

For subjects who are unable to come to the site for Disease Evaluation visits, the visit should 
be postponed and rescheduled as soon as possible.

For subjects who are unable to come to the site for Cycle visits, contact (eg, telephone, 
videoconference, or other channels) with the subject should be made in advance, to collect 
information on the subject’s current health status and any new or ongoing adverse events and 
concomitant medications. The remote method that is used for contact with the subject must 
be allowable per local regulations and fully documented in the subject source record. 
Protocol-specified laboratory assessments and physical examinations should be obtained 
locally, if possible. Where local laboratories are used, it is important to ensure appropriate 
documentation of laboratory reference ranges. After reviewing all available information, and 
if the investigator assesses that continued treatment is acceptable, contact the site manager to 
discuss alternative solutions for the provision of study treatment to subjects (see alternatives 
below). The remote contact with the subject, the local laboratory results, and the sponsor 
discussion should be documented in the subject source record. Similarly, at a minimum, a 
comment must be entered in the Comments eCRF clearly designating as “COVID-19-related” 
and acknowledging the discussion between the investigator and the sponsor.

If the subject is not willing or able to go to a local clinic/laboratory, remote contact 
(eg, telephone, videoconference, or other channels) with the subject is recommended, as well 
as a thorough review of the subject’s medical history, prior labs, and most recent disease 
evaluation. The remote method chosen must be allowable per local regulations and fully 
documented in the subject source record. If appropriate, treatment should be interrupted until 
new laboratory assessments are made. However, if the investigator assesses that continued
treatment is acceptable despite the absence of new laboratory tests, contact the site manager 
to discuss alternative solutions for the provision of study medication to subjects (see possible 
alternatives below). Proper documentation of all discussions and decisions should be made in 
the subject source record and in the Comments eCRF.

If any change in subject status is identified that may impact the subject’s safety, then study 
treatment should be interrupted until the subject can be assessed. Any changes in study 
treatment (dose, frequency, interruption) needs
to be clearly documented
as 
“COVID-19-related”. When pandemic conditions improve, travel restrictions are lifted, and 
the subject is willing and able to come to the clinic, subjects should be scheduled for an 
in-clinic, follow-up visit.

All deviations from protocol-required assessments should be documented in detail within the 
subject’s source record and should be clearly designated as “COVID-19-related”. It must be 
documented if a visit is conducted remotely. Source documentation should detail how each 
assessment was collected (eg, remote vs. on-site, central vs. local laboratory, vital signs taken 
at home by caretaker vs. delegated in-home nursing).


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Status: Approved,  Date:  7 May 2020
Study Drug Supply
If a subject is unable to travel to the site for a scheduled visit where study drug would be dispensed, 
the following alternate measures should be discussed with the study monitor and may be 
considered to ensure continuity of treatment, upon sponsor’s approval:

A caregiver or family member may pick up study drug on behalf of the subject if first 
discussed and agreed by the subject. The conversation with the subject must be documented 
in the subject source records. The subject must name the individual who will pick up study 
drug on their behalf. This is necessary for site staff to confirm the study drug is provided to 
the appropriate individual, ensure proper chain of custody of study drug, and to maintain 
subject privacy. Identification of who will pick up the study drug must be confirmed and 
documented in the subject source record.

Investigative site staff may deliver study drug directly to the subject’s home. The chain of 
custody and transit conditions must be clearly documented within the subject source record.

If no other alternative is feasible, direct-to-patient shipment of study drug from the site may 
be considered with prior approval from the sponsor. Site staff need to obtain permission from 
the subject and record this in the subject source record for direct-to-patient shipments. It is 
important to note this process is not allowed by the health authorities in all countries and a 
specific approval process must be followed with the sponsor before moving forward. If 
requested by the site, the sponsor will investigate local requirements and confirm health 
authority requirements for direct-to-patient shipment. If approval is granted by the sponsor, 
specific procedures including shipment conditions, preferred courier services, and 
documentation requirements will be communicated by the sponsor to the site.
If a subject is able to come to the site for a Cycle visit but anticipates being unable to come to the 
next Cycle visit, the investigator may dispense study treatment for the current cycle and an 
additional cycle, after agreement with the sponsor’s medical monitor. Prior to continuing treatment 
with the additional study treatment, the subject should obtain protocol-specified laboratory 
assessments and physical examinations locally, if possible, and the investigator should conduct a 
remote contact as described above. After reviewing all available information, if the investigator 
assesses that continued treatment is acceptable, the subject may continue treatment using the 
previously supplied additional study treatment. Proper documentation of all discussions and 
decisions should be made in the subject source record and in the Comments eCRF.
For subjects who have reason to believe they have been exposed to COVID-19 but do not 
yet have a confirmed diagnosis and/or are not showing symptoms of infection:

The investigator should consider the risk/benefit of continuing ibrutinib based on the 
individual subject’s underlying condition and the potential risks associated with COVID-19.

If the subject becomes symptomatic at any point, refer to guidance below for subjects with 
symptomatic COVID-19 infection.


COVID-19 Appendix/DEU-1
JNJ-54179060 (ibrutinib)
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Status: Approved,  Date:  7 May 2020
For subjects who have been diagnosed with COVID-19:

The investigator should contact the sponsor’s responsible medical officer to discuss plans for 
study treatment and follow-up.

The investigator should consider the risk/benefit of continuing ibrutinib based on the nature 
and status of the subject’s underlying condition and the potential risks associated with 
COVID-19.

As with all infections, the investigator should follow the protocol guidance which is to 
interrupt therapy for Grade 3 or higher non-hematologic AE (see Section 6.4.3), and resume 
once infection has resolved to Grade 1 or baseline (recovery). Given that severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new pathogen, a more cautious 
approach would be appropriate, with interruption for confirmed cases of SARS-CoV-2
infection of any grade.
On-site Monitoring Visits
In case on-site monitoring visits are not possible, as per institution policies, the sponsor’s site 
managers may contact the investigator to arrange remote monitoring visits. Additional on-site 
monitoring visits may be needed in the future to catch up on source data verification.
All of the above measures are recommended for consideration on a temporary basis during the 
COVID-19 pandemic to enable continuity of treatment and to ensure that subject assessments, 
particularly those assessing relapse and safety, continue as outlined in the protocol without 
imposing health risk to subjects, their families, and site staff. Every effort should be made to 
complete all protocol-required assessments. Investigators should use their clinical judgment and 
risk/benefit assessment in determining if a subject can continue study treatment in the absence of 
on-site clinic visits. If remote visits are not possible, or if in the investigator’s judgment, 
appropriate safety monitoring is not feasible in a remote setting, the investigator should consider 
temporarily interrupting study treatment (for a maximum of 28 consecutive days, unless reviewed 
and approved by the sponsor) or discontinuing study treatment.


COVID-19 Appendix/DEU-1
JNJ-54179060 (ibrutinib)
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Status: Approved,  Date:  7 May 2020
INVESTIGATOR AGREEMENT
PPD

SAP_001.pdf: 
1
Approved, Date: 22 December 2021
Statistical Analysis Plan
A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the 
Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in 
Combination with Bendamustine and Rituximab (BR) in Subjects With 
Newly Diagnosed Mantle Cell Lymphoma
Protocol Number: PCI-32765MCL3002; Phase 3
JNJ-54179060 (Ibrutinib)
Status:
Approved
Date:
22 December 2021
Prepared by:
Janssen Research & Development, LLC
Document No.:
EDMS-ERI-130634570
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP).
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information 
is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or confidential.
NCT01776840


JNJ-54179060 (Ibrutinib)
PCI-32765MCL3002
Statistical Analysis Plan 
2
Approved, Date: 22 December 2021
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
1.
INTRODUCTION.................................................................................................................................. 8
1.1.
Trial Objectives ................................................................................................................................ 8
1.2.
Trial Design ...................................................................................................................................... 9
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 10
1.4.
Sample Size Justification ............................................................................................................... 10
1.5.
Randomization and Blinding .......................................................................................................... 11
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 11
2.1.
Study Treatment and Study Medication......................................................................................... 11
2.2.
Analysis Sets.................................................................................................................................. 11
2.3.
Baseline Definitions........................................................................................................................ 12
2.4.
Cycles............................................................................................................................................. 12
2.5.
Visit Windows................................................................................................................................. 12
2.6.
Study Day and Cycle Day .............................................................................................................. 12
2.7.
Pooling Algorithm for Analysis Centers ...................................................................................... 13
2.8.
Missing and Partial Dates .............................................................................................................. 13
2.9.
Definition of Subgroups.................................................................................................................. 14
2.10.
Exposure Related Definitions......................................................................................................... 15
2.11.
Other General Definitions............................................................................................................... 15
Year and Month .......................................................................................................................... 15
Age.............................................................................................................................................. 15
Time from Initial Diagnosis to Randomization ............................................................................ 16
Tumor Bulk and Tumor Burden at Baseline ............................................................................... 16
Date of Response/Best Response ............................................................................................. 16
Date of Progression.................................................................................................................... 16
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 16
3.1.
Data Monitoring Committee ........................................................................................................... 16
3.2.
Interim Analysis.............................................................................................................................. 16
4.
SUBJECT AND TREATMENT INFORMATION................................................................................ 17
4.1.
Disposition Information................................................................................................................... 17
4.2.
Demographics and Baseline Characteristics ................................................................................. 17
4.3.
Concomitant Medications............................................................................................................... 18
4.4.
Protocol Eligibility and Major Protocol Deviations.......................................................................... 18
4.5.
Extent of Exposure......................................................................................................................... 19
4.6.
Medical History............................................................................................................................... 19
5.
EFFICACY ......................................................................................................................................... 19
5.1.
Analysis Specifications................................................................................................................... 21
Level of Significance................................................................................................................... 21
Data Handling Rules................................................................................................................... 21
General Analysis Considerations ............................................................................................... 21
5.2.
Primary Efficacy Endpoint.............................................................................................................. 22
Progression Free Survival .......................................................................................................... 22
Primary Estimand ....................................................................................................................... 22
Analysis Methods........................................................................................................................ 23
Primary Analysis...................................................................................................................... 23
Sensitivity and Supplementary Analyses ................................................................................ 23
5.2.3.2.1.
Sensitivity Analysis of Homogeneous Baseline Hazard ...................................................... 23
5.2.3.2.2.
Sensitivity Analysis of Disease Assessment Follow up ....................................................... 23
5.2.3.2.3.
Sensitivity Analysis of PD Assessment................................................................................ 23
5.2.3.2.4.
Supplementary Analysis of Estimand 2: .............................................................................. 24


JNJ-54179060 (Ibrutinib)
PCI-32765MCL3002
Statistical Analysis Plan 
3
Approved, Date: 22 December 2021
5.2.3.2.5.
Supplementary Analysis of Estimand 3 ............................................................................... 24
5.2.3.2.6.
Supplementary Analysis of Estimand 4 ............................................................................... 24
Subgroup Analysis of PFS....................................................................................................... 24
5.3.
Key Secondary Efficacy Endpoints ................................................................................................ 25
Complete Response ................................................................................................................... 25
Time-to-Next Treatment (TTNT)................................................................................................. 25
Overall Survival........................................................................................................................... 25
Post-hoc Power Analysis of OS............................................................................................... 25
Primary Estimand of OS.......................................................................................................... 26
Supplementary Analysis of Estimand 2:.................................................................................. 28
Supplementary Analysis of Estimand 3:.................................................................................. 28
Supplementary Analysis of Estimand 4:.................................................................................. 28
Overall Response Rate............................................................................................................... 28
Rate of Minimal Residual Disease Negative-Response............................................................. 29
Time to Worsening in the Lym Subscale of FACT-Lym ............................................................. 30
5.4.
Exploratory Efficacy Endpoint ........................................................................................................ 30
6.
SAFETY............................................................................................................................................. 30
6.1.
Adverse Events .............................................................................................................................. 30
All Adverse Events...................................................................................................................... 31
6.2.
Adverse Events of Interest............................................................................................................. 32
6.3.
Deaths............................................................................................................................................ 32
6.4.
Exposure-Adjusted Incidence Rates.............................................................................................. 32
Restriction on the First Event ..................................................................................................... 32
Duration of Exposure: Censored & Non-censored ..................................................................... 33
Incidence Rate per Subject ........................................................................................................ 33
Average EAIR per Preferred Term ............................................................................................. 33
Average EAIR per SOC.............................................................................................................. 33
Average EAIR on a Global Level................................................................................................ 34
6.5.
Clinical Laboratory Tests................................................................................................................ 34
Creatinine Clearance.................................................................................................................. 34
Analysis of Lymphocytosis.......................................................................................................... 35
6.6.
Electrocardiogram (ECG)............................................................................................................... 35
6.7.
Other Safety Parameters ............................................................................................................... 35
7.
PATIENT-REPORTED OUTCOME................................................................................................... 35
8.
SIGNIFICANT CHANGES FROM PROTOCOL................................................................................ 36
REFERENCES............................................................................................................................................ 37
ATTACHMENT 1: VISIT WINDOW FOR PRO ANALYSIS ....................................................................... 38


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AMMENDMENT HISTORY
December 20, 2021
Added post hoc power analysis for OS including information fraction for interim updates.
November 14, 2021 
Updated further analysis plan for OS.
July 13, 2021
Clarified Histology Group and TP53 Mutation categories.  Added “s” to the abbreviation of MIPI, 
for simplified mantel cell lymphoma international prognostic index.   
Administrative/Consistency: 

Accepted two tracked changes remaining in prior approved version (“mutation” versus 
“mutated”).  

Minor updates for font size and punctuation.

Corrected spacing (e.g., “5cm” changed to “5 cm”). 

Abbreviation DOR changed to DoR, aligning with format of “DoR” and “DoCR” and text. 

Added abbreviation for EuroQol five-dimensional questionnaire (EQ-5D-5L).
July 8, 2021
Updated references and corrected grammar, punctuation, and formatting. Clarified “sponsor”.
Capitalization of Ibrutinib corrected to be lowercase, except when the first word in a sentence and 
in the cover page.
Changed treatment “arm” to “group” for consistency and CSR/manuscript(s) standards.
SAP reconciled against protocol and DPS, requiring additions/deletions.
Renamed and updated Section 8 (formerly COVID-19 analyses) to address significant changes 
from protocol.
Analysis Sets: Added

Definition for PK population.

Statement for region- and country-specific reproduction of analysis/outputs for regulatory 
submissions, per request.
Removed the reporting disposition for region, country, site.
Updates associated with primary or key secondary endpoints:

Added the definition of per-protocol as an Analysis Set, as well as updating Table 3 and 
Section 5.2.3.2.6 as a Supplementary analysis.

Updated hierarchy of testing for key secondary endpoints, per Janssen and Pharmacyclics 
joint agreement.

Replaced “final” analysis with “primary” analysis.

Updated Table 3 – added “Supplementary” to “Sensitivity” efficacy analyses, adding 
COVID related analyses to the list.

Incorporated estimand framework for primary endpoint.

Added a statement for the hierarchical rules associated with statistical tests for key 
secondary endpoints.

Re-ordered hierarchical order of statistical tests.


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
Added COVID-19 to section covering OS.

Clarified use of investigator assessed (versus IRC assessed) for study endpoints.

Clarified analysis of MRD negativity rate. Specified exclusion criteria for sample 
inclusion relative to CR subjects and sample processing requirements.

Updated time to next treatment to include hyphens, for consistency within and across 
other documents.
Subgroup Analysis (Section 2.9):

Added forest plot for OS and ORR subgroup analyses.

Added TP53 and histology subgroup analysis. A separate forest plot will contain these 
two variables for endpoints for PFS, OS, and ORR.
COVID-19 analyses are included in each appropriate section (versus Section 8.0).
Removed the word “improvement” in Section 5.3.6 (TTW).
Moved to other sections: details to analyzing AE data from the Follow-Up Phase to the AE 
section, time to response and duration of response.
Other updates for AEs:

Removed analysis for duration of lympohocycits.

Updated test for ATC and generic term in AE section.

Added incidence and prevalence.

MedDRA updated to 24.0.

Updated AESI to be “AEI” (AEs of interest) and noted that the list will be updated at 
time of final DB lock.
Expanded Appendix table for timing of PROs to include post-PD collection during follow-
up. Clarified restart of timing based on date of PD and all other rows indicate pre-PD data 
collection. Corrected calculations presented in the table for rows associated with Week 12.
Miscellaneous Additions: “under accelerated approval” in the Introduction, mention of region-
specific subgroup analyses for regulatory submission purposes, summary of annual incidence 
rates, demographics and analysis of TP53 mutation status (PFS) and Histology Group, NE to the 
order of response categories used for analysis, duration of CR (DoCR), summary and listing of 
subsequent anti-cancer treatment, and analysis of FACT-G in the PRO section.
Miscellaneous Clarifications/Updates: major protocol deviations are reviewed and classified by 
clinical team, groupings for concomitant medications, use of non- versus un-stratified, use of 
electronic case report forms (eCRFs), imputation rule for last dose date, replaced “body system” 
with “system organ class”, changed “Ibr” to be consistent with CSR outputs (i.e., “Ibrutinib” or 
“ibrutinib”), and updated text associated with the FACT-Lym subscale score to the standard 
reference of “FACT-LymS”.
October 20, 2020
Added descriptive summary of COVID-19 pandemic impact and sensitivity and/or supplementary 
analysis of efficacy endpoint.
Updated interim analysis boundaries based on observed PFS events (information).
Other editorial changes for clarity.


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ABBREVIATIONS
AE(s)
adverse event (s)
AEI
AEs of interest
ALT
alanine aminotransferase
ALC
absolute lymphocyte counts
ANC
absolute neutrophil count 
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BR
bendamustine and rituximab
BSA
body surface area
BTK
Bruton’s tyrosine kinase 
CI
confidence interval 
CNS
central nervous system
CR
complete response
CrCL
creatinine clearance
CRF
case report form 
CT
computed tomography (scan)
DMC
data monitoring committee
DoCR
duration of complete response
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EQ-5D
EuroQol
EQ-5D-5L
EuroQol five-dimensional questionnaire
FACT-G
functional assessment of chronic illness therapy general
FACT-Lym
functional assessment of cancer therapy-lymphoma
Hgb
hemoglobin
Ig
immunoglobulin
INR
international normalized ratio
ITT
intent-to-treat (population)
IPCW
inverse probability of censoring weighting
LDH
lactic acid dehydrogenase 
LymS
lymphoma specific additional concerns subscale
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
sMIPI
simplified MCL international prognostic index
MRD
minimal residual disease
MRI
magnetic resonance imaging 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
overall response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PFS2
progression-free survival after initiation of subsequent antineoplastic therapy
PR
partial response
PRO
patient-reported outcome(s)
PT
preferred term
RPSFTM
rank-preserving structural failure time models
SAP
statistical analysis plan
SD
stable disease
SMQ
standardized MedDRA query
SOC
system organ class
TEAE
treatment-emergent adverse event
TOI
trial outcome index score


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TTNT
time-to-next treatment
TTW
time to worsening
WBC
white blood cell (count)
1.
INTRODUCTION
Ibrutinib (JNJ-54179060: PCI-32765) is a Bruton’s tyrosine kinase (BTK) inhibitor currently 
being co-developed by Janssen Research & Development, LLC (JRD) and Pharmacyclics, LLC. 
Janssen Research & Development, LLC (JRD) is the study sponsor. It has been approved by the 
US Food and Drug Administration as monotherapy for patients with previously treated mantle cell 
lymphoma (MCL), under accelerated approval, and in the EU for patients with relapsed or 
refractory MCL. The MCL3002 study is designed to evaluate whether the addition of ibrutinib to 
standard treatment (bendamustine and rituximab [BR] followed by rituximab [R] maintenance) 
will improve the outcome of subjects with newly diagnosed MCL. This statistical analysis plan 
(SAP) contains definitions of analysis sets, derived variables, data handling rules and statistical 
methods for the analysis of efficacy, safety, and patient reported outcomes. Details of the study 
conduct and data collection can be found in the study protocol amendment INT-7 and electronic 
case report forms (eCRFs). Any changes to the protocol analysis plan, including additional 
analyses are documented here.
1.1.
Trial Objectives

The primary objective of the study is to evaluate whether the addition of ibrutinib to BR 
will result in prolongation of investigator-assessed progression-free survival (PFS) in 
subjects with newly diagnosed MCL who are 65 years of age or older.  

Secondary objectives include evaluation of:
o
Overall survival (OS) 
o
Complete response (CR) rate (investigator assessed)
o
Overall response rate (ORR; CR+ partial response [PR]) (investigator assessed)
o
Patient-reported lymphoma symptoms and concerns as measured by the lymphoma 
(Lym) subscale of the Functional Assessment of Cancer Therapy-Lymphoma 
(FACT-LymS) 
o
Rate of minimal residual disease (MRD)-negative response
o
Time-to-next treatment (TTNT)
o
Duration of response (DoR)
o
Safety of Ibrutinib when combined with BR
o
The pharmacokinetics of ibrutinib and explore the potential relationships between 
ibrutinib metrics of exposure with relevant clinical, pharmacodynamic, or 
biomarker information.


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1.2.
Trial Design
This is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study to compare the 
efficacy and safety of ibrutinib in combination with BR versus placebo + BR in subjects with 
newly diagnosed MCL who are 65 years of age or older. Approximately 520 subjects will be 
randomized in a 1:1 ratio and stratified by simplified MCL international prognostic index (sMIPI) 
score (low risk [0-3] vs. intermediate risk [4-5] vs. high risk [6-11]). 
Subject eligibility will be determined up to 30 days prior to randomization. The Treatment Phase 
will extend from randomization until discontinuation of all study treatment or study end. A cycle 
is defined as 28 days. All subjects will receive open-label BR chemoimmunotherapy for a 
maximum of 6 cycles; subjects with a CR or PR will continue to receive open-label rituximab 
(R) maintenance every second cycle for a maximum of 12 additional doses (i.e., Cycles 8, 10, 12, 
14, 16, 18, 20, 22, 24, 26, 28, and 30). In addition to the BR therapy, all subjects will receive 
blinded study drug (ibrutinib or placebo). Subjects randomized to treatment group A will receive 
placebo capsules, and subjects randomized to treatment group B will receive ibrutinib capsules.  
Study drug will be administered once daily continuously until disease progression, unacceptable 
toxicity, or study end. 
Subjects with stable disease (SD) after initial chemoimmunotherapy (BR+ibrutinib/placebo) 
should continue treatment with ibrutinib/placebo until disease progression, unacceptable toxicity, 
or study end. Subjects with progressive disease (PD) must discontinue all study treatment. For 
subjects who discontinue background BR therapy and do not have PD, treatment with study drug 
(ibrutinib/placebo) will continue until disease progression or unacceptable toxicity. Placebo will 
be stopped when the study is unblinded for the clinical cutoff for the primary analysis of PFS.
Radiological assessments (computed tomography [CT]/magnetic resonance imaging [MRI]) will 
be performed at Screening, and every 12 weeks in the first 12 months after the start of study 
treatment. Positron emission tomography (PET) scan is optional at Screening but mandatory at the 
time of maximal tumor reduction, defined as the time of CR or when 2 consecutive CT scans show 
no further tumor reduction, and at suspected disease progression, if a new lesion was detected on 
CT at suspected disease progression. After the first 12 months, scans will be performed every 16 
weeks until disease progression or the clinical cutoff for the primary analysis of PFS, whichever 
comes first. Subjects who discontinue treatment prior to disease progression (for other reasons 
such as an adverse event [AE]) must continue to have regularly scheduled CT scans/efficacy 
assessments. 
Four analyses are planned. The first 3 analyses will be based on approximately 50%, 68%, and 
100% of the total planned 265 PFS events, respectively. The interim analyses and the primary 
analysis of PFS will take place at these 3 clinical cutoffs, respectively; subject treatment 
assignment will be unblinded for the primary analysis of PFS. The last clinical cutoff will occur at 
the end of the study, when 60% of the randomized subjects have died, or the sponsor terminates 
the study, whichever comes first. Assessment of tumor response and progression will be conducted 
in accordance with the Revised Response Criteria for Malignant Lymphoma [1]. 


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After the clinical cutoff for the primary analysis of PFS, all subjects without PD will continue 
disease assessments according to standard of care until disease progression. 
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis of the study is that ibrutinib in combination with BR compared with 
placebo + BR will prolong PFS in subjects with newly diagnosed MCL who are 65 years of age 
or older.
The statistical hypotheses are as follows: 
H0: The PFS distributions of the experimental treatment group, ST(t), and the placebo group, SP(t), 
are equal at all time points t:
ST(t) = SP(t), for all t > 0
Versus
H1: The PFS distributions of the experimental treatment group, ST(t), are greater than the placebo 
group, SP(t), at least one time point t:
ST(t) > SP(t), for some t > 0
These hypotheses will be tested using stratified log-rank test and assessed within the context of a 
group sequential testing design as described in Sections 3.
1.4.
Sample Size Justification
This study is designed to evaluate the effect of treatment on PFS and is powered for this endpoint. 
The sample size for the study is calculated based on the following assumptions:
1. 1:1 randomization ratio between 2 treatment groups
2. Target hazard ratio of 0.7. Assuming the median PFS for the control group (BR+placebo) is 
42 months from randomization, a target hazard ratio of 0.7 corresponds to an 18-month 
increase in median PFS for the treatment group (ibrutinib+BR) relative to the control (i.e., 60 
months vs. 42 months, respectively)
3. Approximately 77% power 
4. One-sided overall significance level of 0.025
5. Two interim analyses for both efficacy and futility at approximately 50% and 68% of the 
planned PFS events, respectively, with the stopping boundary based on the O’Brien-Fleming 
[2] spending function 
Using the above assumptions, the study will enroll approximately 520 subjects (about 260 subjects 
in each group) to observe 265 events.  As of Amendment INT-4, based on actual enrollment, the 
current projections are to reach 265 events at 72 months after the first patient was enrolled.


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1.5.
Randomization and Blinding
Central randomization will be implemented in this study. Subjects will be randomly assigned to 1 
of 2 treatment groups based on a computer-generated randomization schedule prepared before the 
study by or under the supervision of the sponsor. The randomization will be balanced by using 
randomly permuted blocks and will be stratified by the simplified sMIPI score (low risk [0-3] vs. 
intermediate risk [4-5] vs. high risk [6-11]).  
This randomization scheme is implemented within the interactive web response system (IWRS) 
that dictates the treatment assignment and matching study drug kits for the subject throughout the 
Treatment Phase (Section 2.5). Subjects randomized to treatment are not to be replaced with 
another subject, should they discontinue treatment for any reason.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Study Treatment and Study Medication
For the purpose of the analysis, the term “study treatment” refers to all 3 drugs, ibrutinib/placebo, 
bendamustine, and rituximab. The term “study medication or study drug” refers to 
ibrutinib/placebo.
2.2.
Analysis Sets
The analysis sets are:

Intent-to-Treat (ITT) population: defined as all subjects randomized into the study and 
who will be classified according to the assigned treatment group, regardless of the actual 
treatment received. This population will be used for all efficacy analyses, analyses of 
disposition, demographic, baseline disease characteristics and patient-reported outcome 
(PRO) endpoints.

Per-protocol (PP) population:  all randomized subjects except for those as described 
below:
o
did not meet all inclusion and exclusion criteria
o
did not receive the treatment to which they were randomized
o
had less than 75% of study treatment compliance
o
had no post-baseline efficacy assessment and stay on study for more than 175 days
Subjects in this analysis set will be analyzed according to the treatment to which they are 
randomized.

Safety Population: defined as all randomized subjects who receive at least one dose of 
ibrutinib or placebo. This population will be used for all safety analyses and analyses of 


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exposure. All subjects will be analyzed according to the treatment which they actually 
received.

Pharmacokinetic-evaluable Population: defined as subjects who have received at least 1 
dose of ibrutinib/placebo and have at least 1 pharmacokinetic sample obtained 
posttreatment.
Additional analysis sets for subjects enrolled within specific regions or counties may be used for 
regional regulatory filing purposes, as requested.
2.3.
Baseline Definitions
Unless specified otherwise, the baseline value is defined as the last non-missing value collected 
on or before the administration of the first dose of study treatment.  For subjects who have been 
randomized but not treated with any dose, the randomization date will be used as the reference 
date for the baseline value calculation.
2.4.
Cycles
In defining treatment cycles in a combination therapy setting, the entire combination must be taken 
into account.  Therefore, the nominal cycles as defined in the protocol and recorded on the eCRFs 
will be used in the statistical analyses.
2.5.
Visit Windows
Visit window will be based on phases and cycles:

Screening Phase: prior to the first dose of study treatment.

Treatment Phase: Between the date of the first dose of study treatment and the date of the 
last dose of study treatment. As noted above, the term “study treatment” refers to all of the 
drugs used in the combination treatment.  

End-of-treatment Phase: Between the date of the last dose of all study treatment +1 and 
the date of the last dose of all study treatment + 30 days. The assessments performed during 
the ‘End of Treatment Visit’ will be included in this phase.

Follow-up Phase: After the End-of-Treatment Phase until the study cutoff. A cycle-based 
analysis may be performed for safety parameters during the treatment up to the date of the 
last dose of study treatment + 30 days or the end of treatment visit, whichever comes later. 
2.6.
Study Day and Cycle Day
Assessments will be presented chronologically by cycle day or study day as follows: 
For efficacy data, the randomization date is considered as the reference date (Day 1). For safety 
data, the date of the first dose of study treatment (the randomization date for subjects who have 
been randomized but not treated) will be used as the reference date (Day 1).


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Reference date (Day 1) = randomization date (for efficacy data), or first dose date of study 
treatment (for safety data).
Study Day = assessment date – reference date + 1 for assessment performed on or after the 
reference date; assessment date – reference date for assessment performed before the reference 
date. 
Cycle Day = assessment date - date of the first dose for the cycle + 1. 
2.7.
Pooling Algorithm for Analysis Centers 
The data from all investigative sites will be pooled for all analyses. 
2.8.
Missing and Partial Dates
In general, imputation of missing dates will be made for AE onset date, AE resolution date, date 
of death, start and end dates of prior, concomitant, and subsequent therapies, and the date of the 
initial diagnosis according to the following rules. The start date will be imputed before the end 
date.  

If date is completely missing, no imputation will be made. 

If year is missing, no imputation will be made.

If only year is present, but month and day are missing, then June 30th will be used.

If only day is missing, but year and month are available, then the 15th of the month will be 
used. 
However, the above imputations will be modified by the following rules:

For the initial diagnosis, if such imputed date is on or after the randomization date, then 
randomization date - 1 will be used. 

If such imputed date for prior therapies or the initial diagnosis is on or after the 
randomization date, then randomization date - 1 will be used. If such imputed date for 
subsequent therapies is before the date of the last dose, then the date of the last dose +1 
will be used.

If the last dose end date is missing, the end of treatment date will be used as the last dose 
date.

The imputed start date for subsequent therapies will be adjusted sequentially using the 
following steps:
o
If the imputed start date is before the treatment discontinuation date (or last dose date 
if no treatment discontinuation date), but in the same year and month, then the treatment 


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discontinuation date or the last dose date +1 if no treatment discontinuation date will 
be used. 
o
If subsequent therapy end date is not missing and is before the imputed subsequent 
therapy start date, then the subsequent therapy end date will be used as the start date.

If the imputed date is for a date of death and is before the last date that the subject is known 
to be alive, the latter date will be used.

The imputed AE start date will be adjusted sequentially using the following steps:
o
If the imputed date is in the same year and month as the first dose date, but the 
imputed day is before the day of the first dose date, then the first dose date will be 
used, or 
if it is in the same year and month as the first dose date, but the day after the last 
dose date + 30 days, then the last dose date + 30 days will be used. 
o
If the AE end date is not missing, and the imputed AE start date is after the AE end 
date, then the AE end date will be used.
o
If the imputed AE start date is after the date of death, then the date of death will be 
used.
o
If the imputed AE start date is in the same month and year but after the first 
subsequent therapy start date, then the first subsequent therapy start date will be 
used.

If the imputed date is for an AE end date and is after the death date, then the date of death 
will be used, or if the imputed AE end date is before the AE start date, then the AE start 
date will be used.

The AE imputation rule will be used for concomitant medications.
2.9.
Definition of Subgroups
Table 1:
Subgroup Definition
Subgroup
Definition of Group
Analysis Type
Sex
Male, Female
E, S 
Race
White, Non-White
E 
Race
White, Asian, Others
S
Age
<70, ≥70  
E, S
Baseline ECOG
0 vs. 1 or 2
E, S
Simplified MCL international 
prognostic index (sMIPI)
Low risk [0-3],
Intermediate risk [4-5],
High risk [6-11]
E
Tumor bulk (largest diameter)
≥ 5 cm, < 5 cm
E


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Baseline TP53a
Unmutated vs. Mutated
E
Histology Groupb
Blastoid/Pleomorphic vs. 
Non-Blastoid/Non-Pleomorphicd vs. 
Unknown
E
Hepatic Impairmentc
Normal vs. Mild or Moderate
S
Renal function impairment
CRCL≥ 60 mL/min vs. 
CRCL<60mL/min
S
Concomitant use of CYP3A inhibitor 
Any vs. None; Strong vs. Other
S
E= efficacy (primary, other endpoints such as OS and ORR); S= Safety (AEs); 
a.
An exploratory analysis of the effect of treatment on PFS by TP53 mutation status will be performed in subjects 
having known baseline TP53 mutation status (i.e., subset of the ITT population).
b.
An exploratory analysis of the effect of treatment on PFS by histology will be performed.
c.
Hepatic impairment is based on NCI ODWG Liver function Classification.
d.
Includes diffuse, nodular, and other histology types.
2.10.
Exposure Related Definitions
Number of treatment cycles = the last cycle number - the first cycle number + 1. 
For ibrutinib/placebo, dosing information includes the total dose received (the sum of the total 
dose), the total prescribed dose (treatment duration in days multiplied by 560), the average dose 
level per administration (the ratio of the total dose received and the treatment duration) and the 
relative dose intensity (the total dose received divided by the total expected dose level up to the 
last dose date).
For background therapy (BR), dosing information includes the total dose received (the sum of the 
actual dose administered), the total prescribed dose, the average dose level per administration (the 
ratio of total dose and treatment duration in cycles or doses) and relative dose intensity: 
  	
	  	
	 	 
	   ℎ  
Dose reduction for ibrutinib/placebo due to AE is defined as prescribing a lower dose level due to 
AE (420 mg/day [level 1 reduction] or 280 mg/day [level 2 reduction] or 140 mg/day [level 3 
reduction]). For each subject, use the highest level of dose reduction to summarize categories -
‘One dose reduction’, ‘Two dose reductions’ and ‘Three dose reductions’. 
2.11.
Other General Definitions
Year and Month
1 year equals 365.25 days, and 1 month equals 30.4375 days. 
Age
Age in years will be calculated at the date of informed consent signed.  


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Time from Initial Diagnosis to Randomization
Time from initial diagnosis to randomization in months will be calculated as (date of 
randomization - date of initial diagnosis)/30.4375, and the result will be rounded to the first 
decimal place. A partially missing initial diagnosis date will be imputed based on the rules 
provided in Section 2.78 of the SAP. 
Tumor Bulk and Tumor Burden at Baseline
Tumor bulk is defined as the largest diameter of a measurable tumor lesion assessed by 
investigator.  
Tumor burden is defined as the sum of the product of diameters of all measurable lesions at 
baseline by investigator.  
Date of Response/Best Response
Date of first observed response/best response (CR or PR).
Date of Progression 
Date of first observed progression.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
3.1.
Data Monitoring Committee 
An independent data monitoring committee (DMC) is established to monitor data on an ongoing 
basis to ensure the safety of the subjects enrolled in this study. At the interim analyses, the DMC 
may make recommendations regarding study continuation if the pre-specified stopping boundary 
is crossed for efficacy or futility. In addition to the planned interim analyses, the committee will 
meet periodically to review ongoing safety data. After the review, the DMC will make 
recommendations regarding the conduct of the study. The details are provided in the DMC charter. 
3.2.
Interim Analysis
Two interim analyses were planned using group sequential testing design, scheduled to be 
conducted when approximately 50% and 68% of the PFS events (PD or death) have occurred.  
The O’Brien-Fleming boundaries [2] as implemented by Lan-DeMets spending function is used 
to control the one-sided Type I error of 0.025 for the comparison of the PFS endpoint. The efficacy 
and futility monitoring plan is summarized in Table 2. The actual type I error rates to spend at each 
analysis may differ depending on the actual information fraction.
Table 2:
Stopping Boundaries and Corresponding Observed p-Values and Hazard Ratios
Analysis
PFS 
Events 
(info)
Anticipated 
Time to 
Analysis 
Anticipated 
Enrollment 
(n)
Cumulative Error
Stopping Boundary
Alpha
Beta
p-value (one-sided)
Observed Hazard Ratio
Superiority
Futility
Superiority
Futility 
Superiority
Futility
Interim 1
134 
(50%)
40 months
520
0.002
0.088
<0.0016
≥0.2429
<0.599
≥ 0.886


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Actual
140 
(52.8%)
0.002
0.098
<0.002
≥0.212
<0.613
≥ 0.873
Interim 2
180
(68%)
50 months
520
0.007
0.141
<0.0060
≥0.1180
<0.686
≥0.837
Actual
186 
(70.2%)
0.007
0.151
<0.007
≥0.104
<0.695
≥0.830
Primary
265
(100%)
72 months
520
0.025
0.225
<0.0229
≥0.0229
<0.781
≥ 0.781
Actual
0.025
0.229
<0.023
≥0.023
<0.780
≥ 0.780
Alpha is Type I error of 0.025 (one-sided). Superiority and futility boundaries are based on O’Brien-Fleming [2] boundaries.
Assuming enrollment rate 35/month.
4.
SUBJECT AND TREATMENT INFORMATION 
Analyses of disposition, demographic and baseline disease characteristics will be conducted on the 
ITT population. Analyses of the extent of exposure and concomitant therapy will be conducted on 
the safety population. No statistical testing is planned.
Unless otherwise specified, all continuous endpoints will be summarized using descriptive 
statistics, which will include the number of subjects with a valid measurement (n), mean, standard 
deviation (SD), median, minimum, and maximum. All categorical endpoints will be summarized 
using frequencies and percentages. Percentages will be calculated by dividing the number of 
subjects with the characteristic of interest by the number of subjects in the analysis population.
4.1.
Disposition Information
Disposition information will be summarized for the ITT population.  The number of subjects 
ongoing and discontinued study treatment as well as their reasons for treatment discontinuation 
will be summarized. Disposition due to COVID-19 will also be summarized and listed.
Descriptive statistics will be provided for the time on study. Time on study is defined the same 
way as OS with reversed censoring, i.e., a subject who died will be censored at the date of death.  
Based on this definition, time on study is the same as length of follow up. The Kaplan-Meier 
method will be used to estimate the median time on study.
4.2.
Demographics and Baseline Characteristics
All demographic and baseline characteristics will be summarized for the ITT population using 
descriptive statistics. Subject enrollment will be summarized by region, site, and country. The 
following demographics and baseline disease characteristics information will be summarized for 
ITT subjects:

Demographics: Age (continuous and grouped as <70 or ≥70 years), sex (male or female), 
race, region, ethnicity

Baseline disease characteristics: Time from the initial diagnosis to randomization, Serum 
β2 microglobulin, stage of MCL at study entry (II or III or IV), type of histology, simplified 
sMIPI score (low risk vs. intermediate risk vs. high risk), Eastern Cooperative Oncology 
Group (ECOG) performance status score, endoscopy, hepatic impairment, renal function 


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impairment, histology group (grouped as Blastoid/Pleomorphic vs. Non-Blastoid/Non-
Pleomorphic vs Unknown), and TP53 (Unmutated vs. Mutated)

Extent of disease: Number of lesions, extranodal disease, tumor bulk (grouped as <5 cm, 
≥5 cm), tumor burden, baseline lymphoma symptoms, bone marrow involvement, and 
baseline lactic acid dehydrogenase (LDH)

Hematology: hemoglobin (Hgb), white blood cell count (WBC), absolute neutrophil count 
(ANC), and platelets

Chemistry: sodium, potassium, creatinine clearance (CrCL), creatinine, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactic 
acid dehydrogenase (LDH), total bilirubin, albumin, calcium, magnesium, phosphate, and 
uric acid

Vital signs: height (cm), weight (kg), temperature (C°), systolic blood pressure, diastolic 
blood pressure, heart rate, body surface area (BSA)

Coagulation: Prothrombin international normalized ratio (INR), and Activated partial 
thromboplastin time (aPTT)
4.3.
Concomitant Medications
Use of concomitant therapies other than antineoplastic agents or other systemic therapies for MCL 
between treatment start and the end of the study will be provided by ATC class and drug generic 
term. Multiple medication usage by a subject will be counted only once for that therapeutic class. 
Concomitant medications are defined as medications that were taken at any time on treatment (i.e., 
from the date of the first dose of study treatment through 30 days after the last dose of study 
treatment). However, subgroup analysis by CYP3A inhibitors will use a different time window 
(concomitant medication starting date within the range of the first dose date and last dose date of 
study treatment).
Following concomitant medications of special interest will also be provided:

Anti-coagulation and anti-platelets

CYP3A inhibitors/inducers 

Growth factors/cytokines: Referred to medications coded to ATC level 3 Text = "other 
anti-anemic preparations" or ATC level 4 Text = "colony stimulating factors"

Transfusions: Referred to those medications that are coded to B05AX
4.4.
Protocol Eligibility and Major Protocol Deviations
Subjects with major protocol deviations will be listed by treatment group. Protocol deviations will 
be based on clinical review primarily on the following aspects (but not limited to): (1) eligibility 
criteria, (2) treatment compliance, (3) subject safety (4) efficacy assessment deviation.  Protocol 
deviations will be closely monitored during the execution of the study, and the final set of protocol 
deviation criteria will be finalized before database lock. The major protocol deviations will be 
reviewed and/or classified based on clinical review of the protocol deviations.


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Major protocol deviations due to COVID-19 will be summarized and listed by treatment group.
Listing of minor protocol deviations due to COVID-19 will also be provided. Summary table and
listing of study assessment compliance will be presented.
4.5.
Extent of Exposure
Descriptive statistics (n, mean, standard deviation, median, and range) will be provided for the 
total number of cycles, treatment duration and dosing information for all study treatments 
(Ibrutinib/placebo, BR).  
The number and percentage of subjects with dose reductions due to AEs will be summarized. 
Subjects with dose interruptions (missing dose 7 consecutive days) will also be presented.
Details of the exposure-related definition is specified in Section 2.10.
4.6.
Medical History
Abnormal medical history findings reported by investigator will be summarized by system organ 
class (SOC) and preferred term (PT).
5.
EFFICACY
Analysis of efficacy endpoints will be conducted on the ITT population. Table 3 summarizes the 
efficacy endpoints and analysis methods to be performed. The analyses on PROs are detailed in 
Section 7.


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Table 3:
Summary of Efficacy Analyses to be Performed
Endpoint
Analysis
Analysis Method
Population
Primary
PFS assessed 
by investigator
Primary
Stratified log-rank test, stratified Cox regression 
model, all PD and death considered as events 
regardless of subsequent antineoplastic therapy; 
evaluation of censoring reasons
ITT
Sensitivity/Supplementary 

Unstratified log-rank test, Unstratified Cox 
regression model; 

Subjects who received subsequent 
therapy are censored at the last disease 
assessment showing no evidence of PD 
before the use of subsequent anticancer 
therapy 

Subjects censored at the last disease 
assessment before PFS event if they 
progress or die after missing >=2 planned 
consecutive disease assessments 

IRC assessed PFS by stratified log-rank 
test and stratified Cox regression model; 
concordance rate between the IRC-
determined PD and investigator-
determined PD

Subject censored at the last disease 
assessment before pre-PD death due to 
COVID-19. (This supplementary analysis 
would only be conducted if subject (pre-
PD) death due to COVID-19 is >5% of 
total PFS events.)

Subjects restricted to the defined PP 
analysis set. (This supplementary analysis 
would only be conducted if the PP 
population is less than 90% subjects in 
the ITT population.) 
ITT, unless 
otherwise 
noted.
Subgroup (See Section 
2.9)
Covariate-adjusted 
analysis of PFS  
Unstratified Cox regression model within each 
subgroup
A selected set of potential prognostic variables 
obtained at or before baseline as covariates in 
unstratified Cox regression models: sex, race, age 
group, baseline ECOG, sMIPI score, tumor bulk
ITT
ITT
Key Secondary
CR rate
CMH Chi-square test
ITT 
Rate of Minimal 
Residual 
Disease-
Negative 
Response
CMH Chi-square test
ITT 


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Endpoint
Analysis
Analysis Method
Population
Overall Survival
Stratified log-rank test, stratified Cox regression 
model
ITT
Overall 
Response Rate 
CMH Chi-square test
ITT 
Time-to-Next 
Treatment
Stratified log-rank test, stratified Cox regression 
model
ITT
Patient-Reported 
Outcome
Descriptive summary, mixed model with repeated 
measurements, stratified log-rank test, stratified 
Cox regression model
ITT
5.1.
Analysis Specifications
Level of Significance
All statistical tests will be performed at a two-sided significance level of 0.05, unless otherwise 
specified. All interval estimation will be reported using two-sided 95% confidence intervals (CIs).
Statistical inference on the primary endpoint, PFS, at the interim and primary analyses will be 
conducted at a one-sided significance level of 0.025, under group sequential testing design per 
O’Brien-Fleming [2] boundaries, as specified in Section 3.  
If the primary endpoint achieves statistical significance, tests of key secondary endpoints will be 
performed at the two-sided significance level of 0.05 in a sequential hierarchical manner based on 
a closed testing procedure. The hypothesis for a secondary endpoint will be tested only if the null 
hypotheses for the primary endpoint and for the preceding secondary endpoints are rejected. The 
key secondary endpoints will be ranked in sequence according to the hierarchical order specified 
below: 
1. Complete response (CR) rate (investigator assessed)
2. Time-to-next treatment (TTNT)
3. Overall survival 
4. Overall response rate (CR+PR) (investigator assessed)
5. Rate of MRD-negative response 
6. Time to worsening (TTW) in the Lym subscale of FACT-Lym (FACT-LymS)
Data Handling Rules
Unless specified otherwise, missing values will not be imputed. 
General Analysis Considerations
For continuous variables, number of observations, means, standard deviations, medians, and 
ranges will be used. For discrete variables, frequency will be summarized. For time-to-event 
variables, Kaplan-Meier estimates will be provided. 


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5.2.
Primary Efficacy Endpoint 
Progression Free Survival
The primary endpoint of PFS is assessed by the investigator. PFS is defined as the duration from 
the date of randomization to the date of disease progression or relapse from CR (as assessed by 
the investigator) or the date of death, whichever occurs first.  Subjects who are progression free 
and alive will be censored at the time of their last disease assessment. Subjects with no 
post-baseline disease assessment will be censored on the randomization date.
Primary Estimand
Primary Trial Objective: To demonstrate the superiority of ibrutinib+BR to that of placebo+BR, 
including R maintenance, in terms of PFS in subjects with newly diagnosed MCL.
Estimand Scientific Question of Interest: What is the effect on PFS of assigning subjects to 
ibrutinib+BR vs. BR? 
This primary estimand is the main clinical quantity of interest to be estimated in this study, which 
is defined by the following five attributes [3]:
Population: subjects with newly diagnosed MCL
Treatment: ibrutinib+BR vs. placebo+BR, both including R maintenance therapy for patients 
achieving response
Variable: PFS (PD is assessed by the investigator)
Population-level summary: Kaplan-Meier estimates of PFS, hazard ratio of ibrutinib+BR vs. 
placebo+BR
Intercurrent events and handling strategies: treatment discontinuation, use of subsequent 
anticancer therapy, death due to COVID-19
Intercurrent Events
Name of Strategy for Addressing Intercurrent Events and Its 
Description
Treatment discontinuation (due to AE or 
other reasons other than AE or 
worsening of disease)
Treatment policy strategy: use time to PD or death, regardless 
of whether or not treatment discontinuation had occurred.
Use of subsequent anticancer therapy
Treatment policy strategy: use time to PD or death, regardless 
of whether or not used subsequent anti-cancer therapy.
Hypothetical strategy: subjects are censored at the last disease 
assessment showing no evidence of PD before the use of 
subsequent anti-cancer therapy.
Death due to COVID-19
Composite variable strategy: consider (pre-PD) death as a PFS 
event.
Hypothetical strategy: subjects are censored at the last disease 
assessment before (pre-PD) death due to COVID-19.


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Analysis Methods
Primary Analysis
Assumptions:
Non-informative censoring assumed for all types of censoring
Distinct baseline hazard for each stratum, common proportional hazard ratio across strata
Primary Estimator:
A stratified Cox regression model with study intervention as the sole explanatory variable 
will be performed, with sMIPI as a stratification factor.
Hazard ratio and its 95% CIs will be estimated.
The treatment policy strategy is adopted for handling the intercurrent events of treatment 
discontinuation and use of subsequent anti-cancer therapy. The composite variable strategy 
is adopted for handling the intercurrent events of pre-PD death (PFS event) due to COVID-
19. 
Decision making will be based on the stratified log-rank test for statistical significance. Kaplan-
Meier method will be used to estimate the distribution of PFS for each treatment group. The non-
stratified Cox regression model may be used to analyze the treatment effect on PFS after adjusting 
for covariates (selected demographics and baseline characteristics) as appropriate. The potential 
prognostic factors can be found in Section 2.9. 
Sensitivity and Supplementary Analyses
5.2.3.2.1.
Sensitivity Analysis of Homogeneous Baseline Hazard
Assumptions:
Identical baseline hazard for each stratum and common proportional hazard ratio across 
strata.
Sensitivity Estimator:
A unstratified Cox regression model with study intervention as the sole explanatory variable 
will be performed.
5.2.3.2.2.
Sensitivity Analysis of Disease Assessment Follow up
Assumptions:
Non-informative censoring assumed for all types of censoring.
Sensitivity Estimator:
A stratified Cox regression model with study intervention as the sole explanatory variable 
will be performed, subjects will be censored at the last disease assessment if they 
progress or die after missing ≥ 2 consecutive planned disease assessment visits.
5.2.3.2.3.
Sensitivity Analysis of PD Assessment
Assumptions:
No potential reader-evaluation bias in PD assessment.
Sensitivity Estimator:


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
A stratified Cox regression model with study intervention as the sole explanatory 
variable will be performed, with sMIPI as a stratification factor.

The concordance rate between the IRC-determined PD and investigator-determined PD 
will be evaluated. The number and percentage of PD events and non-PD cases 
determined by investigator and by IRC will be cross-tabulated. 
5.2.3.2.4.
Supplementary Analysis of Estimand 2:
Estimand 2 is defined to support the primary estimand. The only attribute that changes from the 
definition of the primary estimand is how the handling strategy is adopted for the use of 
subsequent anti-cancer therapies.
Estimand 2:
Hypothetical strategy: if all subjects had continued treatment as planned and had not used 
any subsequent anti-cancer therapies.
Under the estimand 2, time to PD or death will be censored at the last disease assessment 
showing no evidence of PD before the use of subsequent anti-cancer therapy. Same 
analyses described in primary estimator will be applied.
5.2.3.2.5.
Supplementary Analysis of Estimand 3
Estimand 3 is defined to support the primary estimand. The only attribute that changes from the 
definition of the primary estimand is how the handling strategy is adopted for the death due to 
COVID-19:
Estimand 3:
Hypothetical strategy: if all subjects had continued treatment as planned and had not died 
from COVID-19.
Under the estimand 4, time to PD or death will be censored at the last disease assessment 
before pre-PD death due to COVID-19. Same analyses described in primary estimator will 
be applied, however, this supplementary analysis would only be conducted if subject (pre-
PD) death due to COVID-19 is >5% of total PFS events.
5.2.3.2.6.
Supplementary Analysis of Estimand 4
Estimand 4 is defined to support the primary estimand. The only attribute that changes from the 
definition of the primary estimand is the analysis set from ITT to PP population.
Estimand 4:
Under the estimand 4, same analyses described in primary estimator will be applied, 
however, this supplementary analysis would only be conducted if the PP population is < 
90% of the ITT population.
Subgroup Analysis of PFS
Subgroup analysis will be performed for the selected potential prognostic variables (as listed in 
Section 2.9) to assess the consistency and robustness of the treatment benefit for PFS.  The 
non-stratified log-rank test analysis method for PFS will be used for each of the subgroup analysis. 
Median PFS with 95% CI, and hazard ratio between the two treatment groups within each subgroup 
and their 95% CI will be calculated using non-stratified Cox regression model. Subgroup analysis 
will be presented graphically in a forest plot.  


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5.3.
Key Secondary Efficacy Endpoints  
Complete Response
Complete response rate is defined as the proportion of subjects who achieve CR (based on 
investigator assessment) on or prior to the initiation of subsequent anticancer therapy.  The rates 
will be compared between groups using Cochran-Mantel-Haenszel (CMH) Chi-square 
methodology, adjusted for the stratification factor sMIPI score used at the randomization. Time to 
CR will be analyzed for subjects with CR and is defined as the interval between the date of 
randomization and the date of initial documentation of a CR. Duration of complete response 
(DoCR) is defined as the interval between the date of initial CR until disease progression or death 
from any cause, whichever occurs first, for subjects who achieved CR. DoCR will be summarized 
descriptively using the Kaplan-Meier method, and no inferential comparison will be made between 
treatment groups. Both the CR rate and DoCR by IRC assessment will also be summarized.
Time-to-Next Treatment (TTNT)
Time-to-next treatment (TTNT) is measured from the date of randomization to the start date of 
any anti-lymphoma treatment subsequent to study treatment. Stem cell transplant is included as at 
type of anti-lymphoma subsequent treatment. Subjects without subsequent treatment will be 
censored at the date of the last contact.
TTNT will be analyzed using the same analysis methods as used for PFS. The number of subjects 
with subsequent anti-cancer therapy will be summarized by therapy type. A listing of subjects with 
subsequent anti-cancer therapy will also be provided. 
Overall Survival
Overall survival (OS) is defined as the time from the date of randomization to the date of death 
from any cause. If the subject is alive, or the vital status is unknown, the subject will be censored 
at the date the subject was last known to be alive. 
Post-hoc Power Analysis of OS
In addition to the OS analysis with the hierarchical testing at the time of primary analysis of PFS, 
patients will continue to be followed, and the OS analysis will be updated periodically (when 50%, 
55% and 60% of randomized subjects have died) until the study end, as specified in the protocol. 
No formal hypothesis testing will be performed. Post-hoc power analysis of OS under various 
scenarios of hazard ratios (HRs) and median OS (with the assumption of exponential distribution)
were conducted at the time of primary analysis of PFS. As shown in Table 4, the power for testing 
the OS effects with HRs of 0.80 and 0.85 are approximately 50% and 30%, respectively, at the 
protocol specified study end, when 60% of subjects have died (314 OS events). Although the 
additional analyses of OS were not intended to be part of group sequential testing to control for 
overall Type I error, information fraction was calculated based on the number of subjects have 
died at a given analysis. Assuming the number of OS events at the study end is 314, and noting at 
the time of the primary PFS analysis 40.3% of subjects had died (approximately an information 
fraction of 67.2% for OS), for subsequent planned OS analyses, when 50% and 55% of subjects 


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have died, these would correspond to information fractions of approximately 83.3% and 91.7%, 
respectively.
Table 4. Post-hoc power analysis of OS
Hazard 
Ratio
Median OS for 
Placebo+BR
Median OS for 
Ibrutinib+BR
No. of OS 
Events at 
Study End
Power for 
OS (%)
Fixed Sample 
Size
Study 
Duration 
(months)
OS Event 
Projection at 
Primary 
Analysis of PFS
0.8
72
90
314
50.6
523
116.1
249
0.85
76.5
90
314
30.1
523
119.4
244
0.8
84
105
314
50.6
523
133.8
223
0.85
89.25
105
314
30.1
523
137.7
218
0.8
96
120
314
50.6
523
151.6
201
0.85
102
120
314
30.1
523
156.0
197
1. The post-hoc power analysis is calculated for a fixed sample size design of 523 subjects with no formal interim analysis. 2. The 
observed average accrual rate of 27.5 per month and variance of log hazard ratio under null hypothesis are used.
The conditional probabilities of observing HR < 1 at future additional OS analyses under various 
assumptions of HRs for the remainder of study were estimated [4] based on the observed HR for
OS at the time of primary analysis of PFS, see Table 5.
Table 5. Conditional probability of HR < 1 at further OS analyses
      Probability of HR < 1 with Additional OS Analysis (%)
Observed HR at Primary 
Analysis of PFS (211 OS 
Events)
Assumed HR for 
the Remainder of 
Study
262 OS Events1
(83.3% 
information)
288 OS Events1
(91.7% 
information)
314 OS Events1
(100% 
information)
1.07 (95% CI 0.81, 1.40)
0.8
44.0
56.3
64.2
1.07 (95% CI 0.81, 1.40)
0.85
36.5
47.3
54.5
1.07 (95% CI 0.81, 1.40)
0.9
29.8
38.9
45.1
1.07 (95% CI 0.81, 1.40)
0.95
24.1
31.5
36.4
1.07 (95% CI 0.81, 1.40)
1
19.3
25.0
28.8
1 The specified number of 262, 288, 314 OS events are approximately 50%, 55%, 60% of the number of subjects randomized 
in the study.
Primary Estimand of OS
The primary estimand of OS is defined by the following five attributes:
Population: subjects with newly diagnosed MCL
Treatment: ibrutinib+BR vs. placebo+BR both including R maintenance therapy for patients 
achieving response
Variable: OS


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Population-level summary: Kaplan-Meier estimates of OS, hazard ratio of ibrutinib+BR vs. 
placebo+BR
Intercurrent events and handling strategies: treatment discontinuation, use of subsequent 
anticancer therapy (including treatment cross-over to ibrutinib or other BTK inhibitors as 
monotherapy), death due to COVID-19, death due to competing risks
Intercurrent Events
Name of Strategy for Addressing Intercurrent Events and Its 
Description
Treatment discontinuation (due to AE or 
other reasons other than AE or 
worsening of disease)
Treatment policy strategy: use time to death, regardless of 
whether or not treatment discontinuation had occurred
Use of subsequent anti-cancer therapy
Treatment policy strategy: use time to death, regardless of 
whether or not subsequent anti-cancer therapy had been 
used 
Hypothetical strategy: if all subjects had continued 
treatment as planned and had not used any subsequent anti-
cancer therapies (or had not received ibrutinib or other 
BTK inhibitors monotherapy)
Death due to COVID-19
Composite variable strategy: consider death due to COVID-
19 as an OS event
Hypothetical strategy: subjects are censored at the date of 
death due to COVID-19
Death due to competing risks
Composite variable strategy: consider death due to reasons 
other than progressive disease or treatment-emergent 
adverse events as an OS event
Hypothetical strategy: consider death due to reasons other 
than progressive disease or treatment-emergent adverse 
events as a competing risk event
Primary Estimator:
A stratified Cox regression model with study intervention as the sole explanatory variable 
will be performed, with sMIPI as a stratification factor. Un-stratified log-rank test and un-
stratified Cox regression model will not be performed as number of events is more than 
10% of the ITT analysis set.
Hazard ratio and its 95% CIs will be estimated.
The treatment policy strategy is adopted for handling the intercurrent events of treatment 
discontinuation and the use of subsequent anti-cancer therapy. The composite variable 
strategy is adopted for handling the intercurrent events of death due to competing risk 
including COVID-19. 
The un-stratified Cox regression model may be used to analyze the treatment effect on OS after 
adjusting for covariates (selected demographics and baseline characteristics) as appropriate. The 
forest plot will be used to assess OS within factors listed in Section 2.9.  


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Supplementary Analysis of Estimand 2:
Estimand 2 is defined to support the primary estimand. The only attribute that changes from the 
definition of the primary estimand is how the handling strategy is adopted for the use of 
subsequent anti-cancer therapies.
Estimand 2:
Hypothetical strategy: if all subjects had continued treatment as planned and had not used 
any subsequent anti-cancer therapies (or had not used ibrutinib or other BTK inhibitors as 
monotherapy).
Under the estimand 2, the inverse probability of censoring weighting (IPCW) analysis [5]
will be used to adjust for the use of subsequent anti-cancer therapies. The rank-preserving 
structural failure time models (RPSFTM) [6] will be used to adjust for treatment crossover 
to ibrutinib or other BTK inhibitors as monotherapy from the placebo+BR arm. 
Supplementary Analysis of Estimand 3:
Estimand 3 is defined to support the primary estimand. The only attribute that changes from the 
definition of the primary estimand is how the handling strategy is adopted for the death due to 
COVID-19:
Estimand 3:
Hypothetical strategy: if all subjects had continued treatment as planned and had not died 
from COVID-19.
Under the estimand 3, the time to death will be censored at the date of death due to COVID-
19. This supplementary analysis would only be conducted if subject deaths due to COVID-
19 are greater than 5% of the total OS events.
Supplementary Analysis of Estimand 4:
Estimand 4 is defined to support the primary estimand. The only attribute that changes from the 
definition of the primary estimand is how the handling strategy is adopted for the death due to 
reasons other than progressive disease or treatment-emergent adverse events:
Estimand 4: Hypothetical strategy: if all subjects had continued treatment as planned and 
had not died from competing risks.
Under the estimand 4, death will be distinguished by causes of death: due to progressive 
disease or treatment-emergent adverse events vs. competing risks (including COVID-19). 
Cumulative incidence function with the associated Gray’s test [7] and competing risks 
regression analysis [8] will be used for the competing risk analysis.
Overall Response Rate
Overall response rate (ORR) is defined as the proportion of subjects who achieve either CR or PR 
as the best overall response as assessed by investigator. The order of the overall response category 
is: CR>PR>SD>PD>NE. The maximum category of overall response is the best overall response. 
The overall response category will be derived based on a response assessment performed on or 
before the start of subsequent anti-cancer therapy. Subjects without documented subsequent anti-


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cancer therapy (and/or the start date of anti-cancer therapy is missing) will be considered as not 
having received subsequent anti-cancer therapy.
ORR will be estimated according to the crude proportion of confirmed responders (PR or better) 
based on the best overall response and summarized by treatment group. ORR will be compared 
between treatment groups using CMH test adjusted for the randomization stratification factor.  The 
relative risk and its 95% CI are to be presented as well. A subgroup analysis will be performed 
using a forest plot for efficacy factors listed in Section 2.9, including the binomial estimate of ORR 
and 95% CIs for each pre-defined subgroup.
Duration of response (DoR) is defined as the interval between the date of initial documentation of 
a response including PR and the date of first documented evidence of PD or death. The censoring 
rule for DoR is the same as PFS. Only subjects who achieved a PR or better will be included in 
the analysis of duration of response. DoR will be summarized descriptively using the Kaplan-
Meier method, and no inferential comparison will be made between treatment groups.
Time to response will be analyzed for subjects with CR/PR and is defined as the interval between 
the date of randomization and the date of initial documentation of a response. Descriptive 
summaries will be provided for the time to response.
For ORR based on IRC assessment, the same analysis methods as used for the investigator 
assessment of overall response will be used.
Rate of Minimal Residual Disease Negative-Response
Rate of MRD-negative response is defined as the proportion of subjects who reach MRD-negative 
disease status, (i.e., <1 MCL cell per 10,000 leukocytes for detection using the MRD assay), as 
assessed by flow cytometry of a bone marrow and/or peripheral blood sample, and whose response 
is CR. Within the same visit, if both the bone marrow and the peripheral test results are available, 
the positive bone marrow test overrules the negative peripheral blood test.  Subjects with missing 
MRD data are considered non-responders. The CMH chi-square test adjusted for the stratification 
factor will be used to compare the MRD negativity rate between treatment groups, chi-square test 
will be used for un-stratified tests, and the Fisher’s exact test may be used if the rate in any 
treatment group is too small.
Samples excluded from MRD analysis include those meeting the following criteria:

Assay processed > 5 days from collection date

Collected either without investigator assessed CR occurring or > 30 days prior to first 
occurrence of investigator assessed CR

Collected after investigator assessed PD

MRD samples taken after global INT-6 implementation date (16Aug2019) 


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Time to Worsening in the Lym Subscale of FACT-Lym
Time to worsening in the Lym subscale of the FACT-Lym (FACT-LymS) is defined as the interval 
from the date of randomization to the start date of the worsening through study discontinuation. 
Worsening is defined by a 5 or greater point reduction from baseline in the FACT-LymS. Death 
(due to any cause) and missing data due to very ill subjects as noted on the eCRF will also be 
considered as worsening. Subjects who have not met the definition of worsening will be censored 
at the last PRO assessment. Subjects with no baseline assessment or on-study assessment will be 
censored at the date of randomization.
Further details are provided in Section 7.
5.4.
Exploratory Efficacy Endpoint
PFS2 is defined as the duration from the date of randomization to the date of the earliest of the 
following 3 types of events: PD that occurs after the first subsequent anti-cancer therapy, death at 
any time on study from any cause, the start of second subsequent anti-cancer therapy.  Those who 
do not receive subsequent antineoplastic therapy or do not experience the event as specified above 
are censored at the last investigator assessed disease assessment. PFS2 will be analyzed using the 
ITT population and using the same analysis method as used for PFS.
6.
SAFETY
Safety will be analyzed using the incidence and severity of AEs and laboratory tests.  Analyses 
will be based on the safety analysis set (Section 2.2). Descriptive statistics and frequency tables 
will be reported and used for all safety data.  Inferential statistics are not planned to be performed 
on safety data. Summary table and listing for treatment-emergent COVID-19 AEs will also be 
presented.
The baseline value for safety analyses is defined as the value collected at the time closest to and 
prior to the start of study treatment. For the analysis of lab measurements for safety parameters by 
cycle, mean values within each cycle will be used. For the analysis of lab grade for safety 
parameters by cycle, the worst grade within each cycle will be used. Annual incidence and 
prevalence rates of safety events will be reported.
Unless otherwise stated, safety data will be summarized by treatment group.
6.1.
Adverse Events
Category
Analysis
Sorted By
Drug-
Related 
TEAE
General
Overall summary

Treatment-emergent AEs 
(TEAEs)
SOC+ PT;
PT
toxicity grade + PT
toxicity grade



Serious TEAEs
SOC+ PT + toxicity grade;
PT+ SOC
Toxicity grade +PT



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Category
Analysis
Sorted By
Drug-
Related 
TEAE
Grade 3 or worse TEAE
PT+ SOC
PT


TEAEs leading to treatment 
discontinuation 
(Ibrutinib/placebo, BR)
PT + SOC
PT
TESAEs leading to treatment 
discontinuation 
(Ibrutinib/placebo, BR)
PT+SOC
TEAEs leading to death
PT + SOC
PT
Grade 3 or worse serious TEAE
PT+SOC
TEAEs leading to dose reduction/ 
(Ibrutinib/placebo, BR; reduction 
is only for Ibrutinib/placebo/B)
PT + SOC
PT


TESAEs leading to dose 
reduction (Ibrutinib/placebo/B)
PT+SOC
AEs of Interest (Hemorrhagic 
events)
PT 
Other safety observations (e.g., 
other malignancies)a
PT 
Other safety observations (i.e., not 
noted above)a
PT + toxicity grade;
SOC+PT + toxicity grade
Deaths during treatment emergent 
period and within 30 days of last 
dose
Reason for death
Subgroup (See 
Section 2.9)
Overall summary
TEAEs
SOC+ PT
Exposure adjusted 
incidence rate 
Overall summary
TEAEs
SOC+ PT+ toxicity grade;
PT+ toxicity grade
Serious TEAEs
SOC+ PT + toxicity grade;
PT+ toxicity grade
a)
To be finalized at the date of final database lock.  See Section 6.2.
All Adverse Events
The verbatim terms used in the eCRFs by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA 24.0). The severity of AEs is assessed 
using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) 
Version 4.03. 
Drug-related AEs are those assessed by investigator as being possible, probable, or very likely 
related to study drug. 


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Treatment-emergent AEs (TEAEs) will be summarized and are defined as those events that 1) 
occur after the first dose of study treatment, through the treatment phase, and for 30 days following 
the last dose of study treatment or until subsequent anti-cancer therapy if earlier; 2) any event that 
is considered study treatment-related regardless of the start date of the event; or 3) any event that 
is present at baseline but worsens in severity or is subsequently considered drug-related by the 
investigator.
TEAEs will be summarized by SOC and PTs, by NCI CTCAE toxicity grade, by relationship to 
study drug, and by action taken. For each TE AE, the percentage of subjects who experience at 
least 1 occurrence of the given event will be summarized. Tables will be sorted by frequency in 
incidence (the highest to lowest incidence). The same summary will be provided for serious TE 
AEs, and drug-related serious TEAEs, as well as TEAEs leading to treatment discontinuation, 
death, and dose reduction.
6.2.
Adverse Events of Interest
AEs of Interest (AEIs) and other safety observations (e.g., other malignancies) will be summarized 
by treatment group.
Hemorrhagic events will be identified by hemorrhage Standardized MedDRA Query (SMQ) 
excluding laboratory terms and be tabulated. Major hemorrhage is a subset of hemorrhagic events 
which are grade ≥ 3 or serious or belong to central nervous system (CNS) hemorrhage/hematoma.
Other malignancies are defined as new malignant tumors including solid tumors, skin malignancies 
and hematologic malignancies and are to be reported by investigators for the duration of study 
treatment and during any protocol-specified follow-up periods including post-progression follow-
up for OS. Summary tables for other malignancies occurring during the study and during the 
treatment-emergent reporting period by PT will be provided, categorized by 3 groups:  non-
melanoma skin cancer, melanoma skin cancer, and non-skin cancer. 
In addition, AEIs classified as Other Safety Observations at the date of the final database lock will 
be summarized. 
6.3.
Deaths
Incidences of deaths during the treatment emergent period and within 30 days after last dose are 
to be reported, along with the primary cause of death.  
6.4.
Exposure-Adjusted Incidence Rates
Restriction on the First Event
To adjust for unequal lengths of study treatment duration among subjects, and potentially between 
treatment groups, exposure adjusted incidence rate (EAIR) may also be summarized if the median 
treatment duration of one group is 30% longer than that of the other group. An overall summary 
of EAIRs will be presented.  EAIRs for AEs and serious AEs will also be summarized by SOC 
and PT.


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The analysis restricts the occurrence of the first event per subject and ignores the existence of later 
(multiple) events, as these cannot be assumed to occur independent of previous events (e.g., 
subjects suffering from infections may have in general a higher risk of having other complications 
and may even have a higher risk of getting other infections). For this reason, the EAIR should be 
interpreted as 'rate until the first event occurs'. Rates estimated from several subjects can be 
averaged on the level of a PT, of an SOC, or on a global level.
Duration of Exposure: Censored & Non-censored
The EAIR for a subject is derived from the duration of treatment exposure for that subject. When 
averaging incidence rates, a subject's duration of exposure is given either by 
a.
time to the earliest onset of the TEAE (non-censored data), or
b.
total duration of treatment, for subjects who did not experience the AE in question (censored 
data). 
Depending on whether a subject has an AE or not, the duration of exposure will be used for the 
denominator in its non-censored or censored form, respectively.
Incidence Rate per Subject
The incidence rate for a specific event of a patient is the reciprocal of time t when the first event 
occurs:
 =

 .
Average EAIR per Preferred Term
The EAIR for a specific PT is an average over all patients as described before, i.e.,
 ! =
∑
!#$#%&,
(
)*
∑
%&,
(
)*
, 
whereby the TEAE enters the sum in the numerator unweighted (TEAEi =1, otherwise TEAEi =0), 
and the duration of exposure enters the denominator as:
 = +    , if occurring (non-censored data)
  	 	  	 if no event occurs (censored data)
Average EAIR per SOC
The average EAIR per SOC considers the first event per patient per SOC only, and only one 
(the corresponding) exposure time in the denominator (where the denominator in the EAIRSOC
depends on the number of PTs per SOC):
/01 =
∑
!#$#234,
(
)*
∑
234,
(
)*
, 
Note: This EAIR is an incidence rate per SOC.


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Average EAIR on a Global Level
The average EAIR on a global level considers the overall first event per patient only, and only one 
(the corresponding) exposure time in the denominator (where the denominator in the EAIRglobal
depends on the overall number of PTs):
567896 =
∑
!#$#
(
)*
∑

(
)*
,
Whereby, TEAEi represents the first TEAE among all TEAEs of patient i and ti as before the 
time when the TEAE occurs (non-censored data) or the total duration of treatment, if no event 
occurs (censored data).
6.5.
Clinical Laboratory Tests
Laboratory data of hematology and serum chemistry up to 30 days after the last dose or the start 
of subsequent anticancer therapy, whichever is earlier, will be reported in SI units. Applicable 
laboratory results will be graded according to NCI CTCAE version 4.03. Note, toxicity grading 
for creatinine increase will be based on the NCI CTCAE v4.03 criteria but limited only to the part 
based on the upper limit of normal (ULN); the other part that is based on the change from baseline 
will not be used for toxicity grading. Toxicity grading for all other laboratory parameters will be 
based on the NCI CTCAE v4.03 criteria as is. Generic normal ranges will be applied whenever 
reference ranges are not available. The following laboratory tests will be analyzed: 

Hematology: hemoglobin, WBC, ANC, absolute lymphocyte counts (ALC), and platelets

Chemistry: sodium, magnesium, creatinine, CrCL, AST, ALT, alkaline phosphatase, LDH, 
total bilirubin, albumin, potassium, calcium, phosphate, uric acid

Other: IgG, IgM, IgA
Descriptive statistics (mean, standard deviation, median and range) will be calculated for the raw 
data and for their changes from baseline at each time point of assessment as well as for the changes 
from baseline to the last value. Parameters will be summarized by toxicity grade. Change from 
baseline to the worst grade during the treatment will be provided as shift tables for selected 
parameters. In addition, treatment-emergent worsening in toxicity grade will be summarized for 
selected hematology parameters. Worst toxicity for hematology and clinical chemistry during 
treatment will also be summarized for both groups. 
Creatinine Clearance
CrCL is calculated using the Cockcroft-Gault formula:
            
   for males, the factor is 1 instead of 0.85
A shift summary from baseline to worst on-treatment toxicity grade for CrCL will be provided.


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Analysis of Lymphocytosis
A descriptive summary of ALC, with and without lymphocytosis, time to lymphocytosis, and 
duration of lymphocytosis will be provided by treatment.  Lymphocytosis is defined as ALC 
increasing ≥ 50% from baseline and achieving a level ≥ 5x109/L. For subjects with lymphocytosis, 
resolution of lymphocytosis is defined as 1) a decrease of the ALC value to baseline level or lower, 
or 2) or an achievement of an ALC value that is < 5x109/L, whichever occurs first. Time to peak 
ALC is defined as the number of weeks from the first dose date of study drug to the highest ALC 
value within the first 9 months of the first dose of study drug.  Time to lymphocytosis is defined 
as the interval between the date of the first dose and the date the subject had lymphocytosis for the 
first time and will be presented in weeks. 
6.6.
Electrocardiogram (ECG) 
Abnormal electrocardiogram (ECG) findings will be summarized. An abnormal finding is 
considered to be treatment-emergent if it occurred during the treatment and up to 30 days after the 
last dose of study treatment or the start of the subsequent therapy, whichever is earlier.
6.7.
Other Safety Parameters
Frequencies of ECOG scores will be reported over time. Descriptive statistics of the change in 
ECOG scores from baseline will also be provided. 
7.
PATIENT-REPORTED OUTCOME
Patient-reported outcome assessments using the Functional Assessment of Cancer Therapy –
Lymphoma (FACT-Lym) [9] and the five level EuroQol five-dimensional questionnaire (EQ-5D-
5L) will be analyzed to examine if the subjects’ perspective of response to treatment are 
accompanied by measurable changes in disease symptoms and health status. Time to clinically 
meaningful worsening in the FACT-Lym lymphoma subscale is also included as one of the key 
secondary objectives of this study.
The FACT-Lym and EQ-5D-5L questionnaires will be administered on Day 1 of every cycle 
during the first 6 cycles, then every 12 weeks in the first 12 months after the first dose of study 
treatment. Thereafter, PROs will be performed every 16 weeks.  During the first 6 cycles, if a PRO 
assessment was conducted, but the cycle was subsequently delayed, the PRO assessment should 
be repeated on Day 1 of the cycle when the treatment is resumed. The FACT-Lym will be 
performed until disease progression, death, or clinical cut-off, whichever comes first. The EQ-5D-
5L will be performed until death or study end.
For both instruments, descriptive statistics (mean, standard deviation, median and range) will be 
calculated for the raw data and for their changes from baseline at each time point of assessment.  
Compliance rates for both instruments will also be summarized. Compliance rates defined as the 
number of questionnaires received as a percentage of the number expected per protocol-specified 
collection schedule are assessed for FACT-Lym and EQ-5D (EuroQol).
For the FACT-Lym, the primary interest is the lymphoma symptoms subscale (FACT-LymS), 
however, other FACT subscales will also be examined, including:


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
The four individual domain scores of the FACT-G (Physical Well-being, Family/Social 
Well-being, Emotional Well-being, Functional Well-being) 

The Trial Outcome Index score (TOI): Physical and Functional domains of the FACT-G 
items plus FACT-LymS)

FACT-G total score (total of Physical, Family/Social, Emotional, and Functional Well-
being subscales)

The FACT-Lym total score (FACT-G plus FACT-LymS)
In the event of missing item(s) in a FACT-Lym assessment, the subscale scores will be computed 
according to the FACT scoring and administration guidelines by multiplying the sum of the 
subscale by the number of items in the subscale, then dividing by the number of items actually 
answered. 
Time to clinically meaningful worsening and improvement in the FACT-LymS subscale of the 
FACT-Lym is defined as the interval from the date of randomization to the start date of the 
worsening and improvement separately. Instrument validation has found the minimum important 
difference (MID) for the FACT-LymS to be in the range of 3 to 5 points, with 5 being the more 
conservative [9, 10]).  Worsening and improvement is defined by a 5 or greater point reduction 
and increase from baseline in the Lym lymphoma subscale, respectively [9, 11]. Death and missing 
data due to being very ill as noted on the eCRF will also be considered as worsening.  Subjects 
who have not met the definition of worsening will be censored at the last FACT-Lym assessment. 
Subjects with no worsening event and with no baseline assessment or on-study assessment will be 
censored at the date of randomization. Time to worsening in FACT-LymS will be estimated using 
Kaplan-Meier methods. The hazard ratio for Ibrutinib relative to placebo and its associated 95% 
CI will be calculated based on the stratified Cox proportional hazards model by the stratification 
factor at randomization. The best and worst change of the FACT-LymS TOI score and FACT-Lym 
total score from baseline to post-baseline may be explored using waterfall plots. 
Exploratory analyses may be conducted to examine time to worsening according to clinical 
response status (i.e., responder vs. non-responder) or by patient baseline characteristics of interest 
(i.e., ECOG performance status). 
For the EQ-5D-5L and FACT-LymS, a mixed effects model with repeated measures analysis will 
be conducted estimating the change from baseline at each time point between two treatments. ITT 
subjects who have a baseline value and at least 1 post-randomization value are included in the 
analysis. Change from baseline will be fitted to a mixed -effects model including subjects as a 
random effect, and baseline value, treatment indicator, time, treatment-by-time interaction, and 
stratification factors as fixed effects.
8.
SIGNIFICANT CHANGES FROM PROTOCOL
Primary analysis is updated with the framework of estimand and summary of COVID-19 impact 
has been added. Post-hoc power analysis of OS has also been added.


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REFERENCES 
1.
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. Journal of Clinical 
Oncology 2007; 25: 579-586.
2.
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 35(3):549-556.
3.
ICH E9 (R1) Addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical 
principles for clinical trials, November 2019.
4.
Wiener, L.E., Ivanova A., Koch G.C. Methods for clarifying criteria for study continuation at interim analysis. 
Pharmaceutical Statistics 2020; 19:720–732.
5.
Robins, J.M., Finkelstein, D.M. Correcting for Noncompliance and Dependent Censoring in an AIDS Clinical 
Trial with Inverse Probability of Censoring Weighted (IPCW) Log Rank Tests. Biometrics 2000; 56(3):779-788.
6.
Robins, J.M., Tsiatis, A.A. Correcting for non-compliance in randomized trials using rank preserving structural 
failure time models. Communications in Statistics-Theory and Methods 1991; 20(8):2609-2631.
7.
Gray, R.J. A class of k-sample tests for comparing the cumulative incidence of a competing risk. Annals of 
Statistics 1988; 16, 1141-1154.
8.
Fine, J.P. and Gray, R.J. A proportional hazards model for the subdistribution of a competing risk. Journal of the 
American Statistical Association 1999; 94, 496-509.
9.
Carter GC, Liepa A, Zimmerman AH, Morschhauser F. Validation of the Functional Assessment of Therapy –
Lymphoma (FACT-LYM) in patients with relapsed/refractory mantle cell lymphoma. Poster presented at: 
Annual Meeting of American Society of Hematology, December 7, 2008; San Francisco, California. 
10.
Hlubocky F.J., Webster K., Cashy J., Beaumont J., and Cella D., “The Development and Validation of a Measure 
of Health-Related Quality of Life for Non-Hodgkin’s Lymphoma: The Functional Assessment of Cancer 
Therapy—Lymphoma (FACT-Lym),” Lymphoma, vol. 2013, Article ID 147176, 9 pages, 2013. 
doi:10.1155/2013/147176.
11.
Cella D, Webster K, Cashy J, et al. Development of a Measure of Health-Related Quality of Life for Non-
Hodgkin’s Lymphoma Clinical Research: The Functional Assessment of Cancer Therapy – Lymphoma (FACT-
Lym) [abstract]. ASH. 2005; 106. Abstract 750. 


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ATTACHMENT 1: VISIT WINDOW FOR PRO ANALYSIS
Details for target date for each scheduled visit and time interval between scheduled visits are 
provided in the table below:
Week Number 
Pre-PD
Start Day
Target Day
End Day
Baseline (weeks 1-4)
-30
1
1
Cycle 2 (weeks 5-8)a
2
29
42
Cycle 3 (weeks 9-12)a
43
57
70
Cycle 4 (weeks 13-16)a
71
85
98
Cycle 5 (weeks 17-20)a
(X-1)*28-13=99
(X-1)*28+1=113
(X-1)*28+14=126
Cycle 6 (weeks 21-24)a
127
141
183
Every 12 weeks up to 12 months
Week 33b
183
225
266
Week 45b
(Y-1)*7-41=265
(Y-1)*7+1=309 
(Y-1)*7+42=350
Week 57b
349
393
449
Every 16 weeks thereafter 
Week 73c
449
505
560
Week 89c
(Y-1)*7-55=561
(Y-1)*7+1=617
(Y-1)*7+56=672
Week 105c
673
729
784
Week 121c
785
841
896
Week 137c
897
953
1008
Week 153 and up c
1009
1065
1120
Week Number
Post-PDd
Start Day
Target Day
End Day
Week 16e
50
106
161
Week 32e
(Y-1)*7-55=162
218
(Y-1)*7+56=273
Week 48e
274
330
385
a.
Target day in cycle = (X-1)*28+1 where X is cycle number, (X-1)*28-13 for start day 
and (X-1)*28+14 for end day.
b.
Target day in week= (Y-1)*7+1 where Y is week number, (Y-1)*7-40 for start day and 
(Y-1)*7+41 for end day.
c.
Target day in week = (Y-1)*7+1 where Y is week number, (Y-1)*7-55 for start day and 
(Y-1)*7+56 for end day.
d.
At PD, sites should attempt to administer the EQ-5D-5L in survival follow-up every 16 
weeks (up to 3 times), unless death or study end occurs first.
e.
Using date of PD as the relative date for counting number of weeks:  Target date post-PD 
in week = (Y-1)*7+1 where Y is week number, (Y-1)*7-55 post-PD for start day and (Y-
1)*7+56 post-PD for end day.