Clinical trial NCT01974440
Conditions: Lymphoma
Keywords: Lymphoma Follicular lymphoma Marginal zone lymphoma Indolent Non-Hodgkin lymphoma PCI-32765 Ibrutinib Bendamustine Rituximab Cyclophosphamide Doxorubicin Vincristine Prednisone R-CHOP
Sponsor: Janssen Research & Development, LLC
Start date: 2014-01-31; Completion date: 2023-06-21
Enrollment: 403 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of PCI-32765 (ibrutinib) administered in combination with either bendamustine and rituximab (BR) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in adult participants with previously treated indolent Non-Hodgkin lymphoma.

Detailed description:
This is a randomized (individuals assigned to study treatment by chance), double-blind (individuals and study personnel will not know the identity of study treatments), 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 in approximately 400 adult participants with follicular lymphoma or marginal zone lymphoma. The study will include the following phases: Screening, Treatment, and a Post-treatment Follow-up. Eligible participants will be randomly assigned in a 1:1 ratio to either treatment Arm A (background immune-chemotherapy + placebo) or treatment Arm B (background immune-chemotherapy + 560 milligram \[mg\] of ibrutinib). All participants will receive 6 cycles of background immune-chemotherapy with either BR or R-CHOP in combination with either placebo (Arm A) or ibrutinib (Arm B). Selection of background immune-chemotherapy will be based on prior treatment history and cardiac function. After completion of background immune-chemotherapy, study drug (ibrutinib or placebo) will continue until disease progression, unacceptable toxicity, or study end, whichever comes first. Assessment of tumor response and progression will be conducted in accordance with the Revised Response Criteria for Malignant Lymphoma. Serial pharmacokinetic (study of what a drug does to the body) blood samples will be collected. Safety will be assessed throughout the study.

Arms: arm 1: Treatment Arm A = background immune-chemotherapy (bendamustine and rituximab \[BR\] or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone \[R-CHOP\]) for 6 cycles + placebo. arm 2: Treatment Arm B = background immune-chemotherapy (BR or R-CHOP) for 6 cycles + PCI-32765 (Ibrutinib).
Interventions: intervention 1: Bendamustine intervention 2: Rituximab intervention 3: Cyclophosphamide intervention 4: Doxorubicin intervention 5: Vincristine intervention 6: Prednisone intervention 7: PCI-32765 (Ibrutinib) intervention 8: Placebo
Intervention descriptions: intervention 1: 90 milligram per meter square (mg/m\^2) administered intravenously on Days 1 to 2 of Cycles 1 to 6. intervention 2: 375 mg/m\^2 administered intravenously on Day 1 of Cycles 1 to 6. intervention 3: 750 mg/m\^2 administered intravenously on Day 1 of Cycles 1 to 6. intervention 4: 50 mg/m\^2 administered intravenously on Day 1 of Cycles 1 to 6. intervention 5: 1.4 mg/m\^2 (maximum total 2 mg) administered intravenously on Day 1 of Cycles 1 to 6. intervention 6: 100 mg administered orally on Days 1 to 5 of Cycles 1 to 6. intervention 7: 560 mg (4\*140 mg) capsules administered orally once daily, continuously starting on Cycle 1, Day 1. intervention 8: Placebo (4 capsules) matched to ibrutinib administered orally once daily, continuously starting on Cycle 1, Day 1.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 29 August 2022
Janssen Research & Development *
Clinical Protocol
A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine 
Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination with Either Bendamustine and 
Rituximab (BR) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and 
Prednisone (R-CHOP) in Subjects with Previously Treated Indolent Non-Hodgkin 
Lymphoma (iNHL)
Protocol PCI-32765FLR3001; Phase 3
AMENDMENT INT-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, 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 2 and Phase 3 clinical studies.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2013-003093-27
Status:
Approved
Date:
29 August 2022
Prepared by:
Janssen Research & Development, LLC 
EDMS Number:
EDMS-ERI-69165703, 4.0
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.
NCT01974440


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
2
Approved, Date: 29 August 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 14
TIME AND EVENTS SCHEDULE .............................................................................................................. 17
ABBREVIATIONS ...................................................................................................................................... 21
1.
INTRODUCTION................................................................................................................................ 23
1.1.
Indolent Non-Hodgkin Lymphoma ................................................................................................. 23
1.2.
Chemo-immunotherapy Treatment of Previously Treated iNHL.................................................... 23
1.3.
Ibrutinib Background ...................................................................................................................... 25
1.3.1.
Clinical Pharmacokinetic Data.................................................................................................... 26
1.3.2.
Clinical Studies of Ibrutinib ......................................................................................................... 26
1.3.2.1.
Clinical Efficacy of Ibrutinib...................................................................................................... 26
1.3.2.2.
Clinical Safety of Ibrutinib........................................................................................................ 27
1.3.2.2.1.
Hematological Adverse Events ............................................................................................ 27
1.3.2.2.2.
Non-hematological Adverse Events..................................................................................... 28
1.3.2.2.3.
Combination Therapy Studies.............................................................................................. 29
1.4.
Overall Rationale for the Study...................................................................................................... 31
2.
OBJECTIVES AND HYPOTHESIS ...................................................................................................32
2.1.
Objectives ...................................................................................................................................... 32
2.2.
Hypothesis ..................................................................................................................................... 33
3.
STUDY DESIGN AND RATIONALE .................................................................................................33
3.1.
Overview of Study Design.............................................................................................................. 33
3.2.
Study Design Rationale.................................................................................................................. 36
4.
SUBJECT POPULATION.................................................................................................................. 38
4.1.
Inclusion Criteria ............................................................................................................................ 38
4.2.
Exclusion Criteria ........................................................................................................................... 40
4.3.
Prohibitions and Restrictions ......................................................................................................... 41
5.
TREATMENT ALLOCATION AND BLINDING.................................................................................42
6.
DOSAGE AND ADMINISTRATION ..................................................................................................43
6.1.
Study Treatment............................................................................................................................. 43
6.2.
BR Administration .......................................................................................................................... 45
6.2.1.
Bendamustine Hydrochloride Dose Modifications......................................................................45
6.2.2.
Rituximab Dose Modifications .................................................................................................... 46
6.3.
R-CHOP Administration ................................................................................................................. 46
6.3.1.
Rituximab Dose Modifications .................................................................................................... 46
6.3.2.
Cyclophosphamide Dose Modifications......................................................................................46
6.3.3.
Doxorubicin Dose Modifications ................................................................................................. 47
6.3.4.
Vincristine Dose Modifications.................................................................................................... 48
6.3.5.
Prednisone (or Equivalent) Dose Modifications ......................................................................... 48
6.4.
Delay of Chemotherapy ................................................................................................................. 48
6.5.
Study Drug Administration ............................................................................................................. 49
6.5.1.
Study Drug (Ibrutinib or Placebo) Dose Modifications................................................................49


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
3
Approved, Date: 29 August 2022
7.
TREATMENT COMPLIANCE............................................................................................................ 51
8.
CONCOMITANT THERAPY.............................................................................................................. 51
8.1.
Concomitant Medications to be used with Caution........................................................................ 51
8.2.
Prohibited Concomitant Medications ............................................................................................. 54
8.3.
Medications Permitted During Treatment ...................................................................................... 54
9.
STUDY EVALUATIONS .................................................................................................................... 54
9.1.
Study Procedures........................................................................................................................... 54
9.1.1.
Overview..................................................................................................................................... 54
9.1.2.
Screening Phase ........................................................................................................................ 55
9.1.3.
Treatment Phase ........................................................................................................................ 55
9.1.4.
Posttreatment Phase (Follow-Up) .............................................................................................. 56
9.1.5.
Clinical Cutoffs............................................................................................................................ 57
9.2.
Efficacy........................................................................................................................................... 58
9.2.1.
Evaluations ................................................................................................................................. 58
9.2.1.1.
Radiographic Image Assessments (CT/MRI)..........................................................................58
9.2.1.2.
Positron Emission Tomography (PET Scan)........................................................................... 59
9.2.1.3.
Bone Marrow Assessment....................................................................................................... 59
9.2.1.4.
Fluid Aspiration at Other Sites of Disease............................................................................... 59
9.2.1.5.
Physical Examination .............................................................................................................. 59
9.2.1.6.
Patient-Reported Outcomes.................................................................................................... 59
9.2.2.
Endpoints.................................................................................................................................... 60
9.2.3.
Efficacy Criteria........................................................................................................................... 61
9.2.3.1.
Assessment of Disease Response and Progressive Disease ................................................ 61
9.2.3.2.
Definition of Measurable and Assessable Disease ................................................................. 61
9.2.3.3.
Response Categories .............................................................................................................. 62
9.3.
Pharmacokinetics........................................................................................................................... 64
9.3.1.
Evaluations ................................................................................................................................. 64
9.3.2.
Analytical Procedures................................................................................................................. 64
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 64
9.4.
Biomarkers and Minimal Residual Disease ...................................................................................64
9.5.
Safety Evaluations ......................................................................................................................... 65
10.
SUBJECT COMPLETION/WITHDRAWAL.......................................................................................68
10.1.
Completion ..................................................................................................................................... 68
10.2.
Discontinuation of Study Treatment............................................................................................... 68
10.3.
Withdrawal From the Study............................................................................................................ 69
11.
STATISTICAL METHODS................................................................................................................. 69
11.1.
Subject Information ........................................................................................................................ 69
11.2.
Sample Size Determination ........................................................................................................... 70
11.3.
Efficacy Analyses ........................................................................................................................... 70
11.3.1.
Primary Endpoint ........................................................................................................................ 71
11.3.2.
Secondary Endpoints.................................................................................................................. 71
11.3.3.
Exploratory Efficacy Endpoints................................................................................................... 72
11.3.4.
Patient-Reported Outcomes ....................................................................................................... 72
11.4.
Pharmacokinetic Analyses............................................................................................................. 72
11.5.
Biomarker Analyses ....................................................................................................................... 73
11.6.
Safety Analyses ............................................................................................................................. 73
11.7.
Interim Analysis.............................................................................................................................. 74
11.8.
Data Monitoring Committee ........................................................................................................... 74
12.
ADVERSE EVENT REPORTING ...................................................................................................... 75
12.1.
Definitions ...................................................................................................................................... 75
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 75
12.1.2.
Attribution Definitions.................................................................................................................. 76
12.1.3.
Severity Criteria .......................................................................................................................... 77


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
4
Approved, Date: 29 August 2022
12.2.
Special Reporting Situations.......................................................................................................... 77
12.3.
Procedures..................................................................................................................................... 77
12.3.1.
All Adverse Events...................................................................................................................... 77
12.3.2.
Serious Adverse Events ............................................................................................................. 78
12.3.3.
Adverse Events of Special Interest............................................................................................. 79
12.3.3.1.
Major Hemorrhage................................................................................................................... 79
12.3.4.
Pregnancy................................................................................................................................... 80
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 80
13.
PRODUCT QUALITY COMPLAINT HANDLING..............................................................................80
13.1.
Procedures..................................................................................................................................... 80
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................80
14.
STUDY DRUG INFORMATION......................................................................................................... 81
14.1.
Physical Description of Study Drugs.............................................................................................. 81
14.2.
Packaging ...................................................................................................................................... 81
14.3.
Labeling.......................................................................................................................................... 81
14.4.
Preparation, Handling, and Storage............................................................................................... 81
14.5.
Drug Accountability ........................................................................................................................ 81
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 82
16.
ETHICAL ASPECTS ......................................................................................................................... 82
16.1.
Study-Specific Design Considerations........................................................................................... 82
16.2.
Regulatory Ethics Compliance....................................................................................................... 82
16.2.1.
Investigator Responsibilities ....................................................................................................... 82
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 83
16.2.3.
Informed Consent ....................................................................................................................... 84
16.2.4.
Privacy of Personal Data ............................................................................................................ 85
16.2.5.
Country Selection ....................................................................................................................... 86
16.2.6.
Long-Term Retention of Samples for Additional Future Research ............................................ 86
17.
ADMINISTRATIVE REQUIREMENTS ..............................................................................................86
17.1.
Protocol Amendments.................................................................................................................... 86
17.2.
Regulatory Documentation ............................................................................................................ 86
17.2.1.
Regulatory Approval/Notification ................................................................................................ 86
17.2.2.
Required Prestudy Documentation............................................................................................. 87
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................87
17.4.
Source Documentation................................................................................................................... 88
17.5.
Case Report Form Completion ...................................................................................................... 88
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 89
17.7.
Record Retention ........................................................................................................................... 89
17.8.
Monitoring ...................................................................................................................................... 90
17.9.
Study Completion/Termination....................................................................................................... 90
17.9.1.
Study Completion ....................................................................................................................... 90
17.9.2.
Study Termination....................................................................................................................... 90
17.10.
On-Site Audits ................................................................................................................................ 91
17.11.
Use of Information and Publication................................................................................................ 91
REFERENCES............................................................................................................................................ 93
INVESTIGATOR AGREEMENT ............................................................................................................... 102


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
5
Approved, Date: 29 August 2022
LIST OF ATTACHMENTS
Attachment 1:
Sample Questionnaire FACT-Lym .............................................................................96
Attachment 2:
Sample Health Questionnaire EQ-5D-5L ...................................................................97
Attachment 3:
Cockcroft-Gault Formula for Estimating Creatinine Clearance ................................ 100
Attachment 4:
Inhibitors and Inducers of CYP3A ............................................................................ 101
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Time and Events Schedule until the study Primary Analysis.................................................... 17
Table 2:
Time and Events Schedule After the study Primary Analysis................................................... 20
Table 3:
Descriptive Summary of Responses to Agents Evaluated for the Treatment of Indolent 
non-Hodgkin Lymphoma...........................................................................................................24
Table 4:
Dose Modification for Cyclophosphamide and Doxorubicin for Hematological 
Toxicities ................................................................................................................................... 47
Table 5:
Dose Modification of Doxorubicin for Hepatic Function Impairment......................................... 47
Table 6:
Dose Modification for Vincristine Hepatic Function Impairment ............................................... 48
Table 7:
Ibrutinib / Placebo Dose Modifications for Ibrutinib Toxicities for Events not Specified 
in Table 8 .................................................................................................................................. 50
Table 8:
Ibrutinib / Placebo Dose Modifications for Cardiac Failure or Cardiac Arrhythmias................. 51
Table 9:
Dose Modifications for Ibrutinib for Subjects Receiving Concomitant CYP3A Inhibitors ......... 52
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 35
Figure 2:
Background Chemotherapy Decision Tree...............................................................................44


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
6
Approved, Date: 29 August 2022
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
10 October 2013
Amendment INT-1
10 December 2014
Amendment INT-2
10 August 2015
Amendment INT-3
29 August 2022
Amendments are listed beginning with the most recent amendment.
Amendment INT-3 (29 August 2022)
The overall reason for the amendment: To update the dose modification guidance and the data that is being 
collected after the clinical cutoff for the primary analysis.
Applicable Section(s)
Description of Change(s)
Time and Events 
Schedule
Title update in Table 1 to define Time and Events Schedule up to clinical cutoff for the 
primary analysis and the time and events schedule after clinical cutoff for primary 
analysis.
New table (Table 2) added to define the time and events schedule after clinical cutoff 
for primary analysis.
Time and Events 
Schedule
9.2.3.1 Assessment of 
Disease Response and 
Progressive Disease
The text “Efficacy Assessments” in Table 1 was update to “Disease Evaluations”
6.5.1 Study Drug 
(Ibrutinib or Placebo) 
Dose Modifications
Text was added to indicate that no dose escalation is allowed following dose reduction.
Text was added to specify Grade 2 and 3 toxicities.
Table 8 was added to describe ibrutinib/placebo dose modifications for cardiac failure 
or cardiac arrhythmias.
8.1 Concomitant 
Medications to be used 
with Caution
Revised text and added a new table (Table 9) to provide updated guidance for dose 
modification for ibrutinib when used concomitantly with CYP3A inhibitors.
Links updated for examples of inhibitors, inducers and substrates.
9.1.5 Clinical Cutoff
9.2.1.6 Patient-Reported 
outcomes
Text was added to describe Table 2 and Time and Events Schedule after clinical cutoff 
for primary analysis, where Patient-Reported Outcomes were removed after the study 
primary analysis
9.4 Biomarkers and 
Minimal Residual 
Disease
Text was added to indicate that minimal residual disease will be collected until clinical 
cutoff for primary analysis and not after.
Throughout the protocol
Minor errors and inconsistencies were corrected, and minor clarifications were added.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
7
Approved, Date: 29 August 2022
Amendment INT-2 (10 August 2015)
This amendment is considered to be non-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, 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. This amendment also 
aligns the French and Japanese protocols with the Global protocol, and clarifies the schedule for patient-reported 
outcome assessments. 
Applicable Section(s)
Description of Change(s)
Rationale: Clinical safety information for ibrutinib has been updated for consistency with both the ibrutinib IB and 
other protocols within the ibrutinib clinical development program.
1.3.2.2. Clinical Safety of 
Ibrutinib;
1.3.2.2.1. Hematological 
Adverse Events;
1.3.2.2.2. Non-
Hematological Adverse 
Events
Clinical safety information for ibrutinib has been updated to show currently available 
data for both 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, 
tumor lysis syndrome has been added to the non-hematological adverse event section.
Rationale: Enhanced reporting, monitoring, and review of safety events were performed during Cycle 1 for the first 
10 Japanese subjects that completed Cycle 1. As this action has been completed, the additional safety monitoring in 
the country-specific Japanese amendment is no longer applicable, and the Japanese protocol can align with the 
Global protocol.
12.4. Reporting, 
Monitoring, and Review 
of Safety Events for 
Japanese 
Subjects; Synopsis: 
Safety Evaluations;
Attachment 5.
These sections of the country-specific amendment for Japan are no longer applicable. 
Rationale: The country-specific amendment for France limits ibrutinib treatment to 3 years. As marketing 
authorization for ibrutinib has been received by the European Commission, and no new safety signals have been 
detected with longer-term use of ibrutinib as reported in the current Investigator Brochure, the country-specific 
amendment for France is no longer applicable. Data are not available that evaluate the safety or efficacy of 
discontinuing treatment in those patients who are responding to therapy. Therefore, the French protocol can align 
with the Global protocol where subjects are receiving continuous treatment until disease progression or 
unacceptable toxicity.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
8
Approved, Date: 29 August 2022
Synopsis Overview of 
Study Design; Synopsis 
Dosage and 
Administration; Time 
and Events Schedule; 3.1.
Overview of Study 
Design; Figure 1; 6.1.
Study Treatment (Study 
Drug); 6.4. Delay of 
Chemotherapy; 9.1.3.
Treatment Phase; 10.2.
Discontinuation of Study 
Treatment  
These sections of the country-specific amendment for France are no longer applicable.
Rationale: The schedule for patient-reported outcome assessments for has been clarified in the Time and Events 
Schedule.
Time and Events 
Schedule
The timing of PRO assessments have been clarified to state that assessments will be 
taken approximately every 24 weeks, to coincide with a  visit starting at Week 40, during 
the Post-Chemotherapy Period in the Treatment Phase and Prior to PD in the Follow-up 
Phase.
Rationale: A correction has been made to the criteria used to determine complete response. 
9.2.3.3. 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: To update the name of the co-development company for ibrutinib from Pharmacyclics, Inc to 
Pharmacyclics LLC.
Synopsis; 1. Introduction
Pharmacyclics, Inc has been replaced by 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: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
9
Approved, Date: 29 August 2022
Amendment INT-1 (10 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 remove requirement that only ~70% of subjects can receive 1 of the 
background chemotherapies as well as to implement several administrative clarifications. Updates on safety-
related information (eg, monitoring for ocular symptoms and atrial fibrillation; potential risks; and guidance on 
co-administration with certain concomitant medications) have been implemented to align with the current 
Investigator’s Brochure (IB).
Applicable Section(s)
Description of Change(s)
Rationale In most countries that are actively recruiting subjects, bendamustine has only recently been available. 
Therefore, the majority of subjects with relapsed disease who are enrolled in this study have received previous 
treatment with R-CHOP or similar regimens.
3.1 Overview of Study Design; 
5 Treatment Allocation and 
Blinding;
6.1 Study Treatment
Removed the requirement limiting the number of subjects randomized to 1 of 
the background chemotherapy regimens to no more than 70% of total subjects. 
Replaced with “The sponsor will strive towards an adequate number of subjects 
randomized into either of the background chemotherapy regimens.”
Rationale: Instructions specific to ibrutinib/placebo administration have been updated. Restrictions for ibrutinib 
dosing relative to meal time has been deleted (ie, 30 minutes before eating or at least 2 hours after a meal).
Synopsis (Dosage and 
Administration);
3.1 Overview of Study Design;
6.5 Study Drug Administration
Changed the time of dosing to “approximately the same time each day”, 
independent of meal time.
Rationale: Potential risks associated with ibrutinib have been updated based on the 2014 IB (version 8.0) and new
risks (cytopenia, diarrhea) have been added. Important new information is provided below (see Section 1.3.2.2 for 
a complete description of each risk). 
1.3.2.2 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.
Lymphocytosis and 
Leukostasis
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A 
high number of circulating lymphocytes (400,000/μL) may confer increased risk. 
Subjects should be closely monitored.
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 Section 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. There is no evidence of QT prolongation with 
increasing plasma concentrations of ibrutinib.
Diarrhea
Approximately one-third of subjects treated with ibrutinib monotherapy and 
two-thirds treated with combination therapy reported diarrhea.
Infections
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.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
10
Approved, Date: 29 August 2022
Rash
Rash has been commonly reported in subjects treated with either single agent 
ibrutinib or in combination with chemotherapy. Most rashes were mild to moderate 
in severity. Subjects should be closely monitored for signs and symptoms suggestive 
of Stevens-Johnson Syndrome. 
Rationale: To provide further clarification and guidance to investigators for medications permitted during study.
8.3 Medications Permitted 
During Treatment
Clarified medications permitted during the study (eg, antiemetics, standard 
supportive care medications, prophylaxis for tumor lysis syndrome for subjects 
considered at risk, neutrophil growth factors, use of anti-microbial prophylaxis). 
Hepatitis B surface antigen positive subjects should receive appropriate prophylaxis 
according to local standards (eg, lamivudine).
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 serious adverse event, or any central nervous system 
hemorrhage/hematoma. Section 12.3.3.2 was deleted, as it is now captured within the new definition of major 
hemorrhage (third bullet).
Synopsis (Safety 
Evaluations); 9.5 Safety 
Evaluations (Adverse 
Events of Interest); 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 events 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
(Electrocardiograms)
Electrocardiograms may be repeated at any time during the study, as clinically 
indicated, particularly in subjects with arrhythmic symptoms (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 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.
!
Statement that concomitant use of ibrutinib and anticoagulants or medications that inhibit platelet function 
may increase the risk of bleeding.
!
Instructions for digoxin administration relative to ibrutinib administration added.
!
Clarification to instructions for anticoagulation therapy (eg, atrial fibrillation).


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
11
Approved, Date: 29 August 2022
8.1 Precautions with 
Concomitant Medications
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). 
Administration of ibrutinib with rifampin, a strong CYP3A inducer, decreases 
ibrutinib plasma concentrations 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.
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.
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: 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.
Time and Events Schedule
(footnote e); 
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: On November 13, 2013 the FDA approved IMBRUVICA® (ibrutinib) for the treatment of adult patients 
with MCL who have received at least 1 prior therapy. Therefore, the statement regarding ibrutinib not being
approved has been modified.
Synopsis; 
1. Introduction
Added statement on initial marketing approval of ibrutinib and clarified that ibrutinib 
has not been approved for marketing for the treatment of follicular lymphoma in any 
country.
Rationale: Immune modulation is a key part of follicular lymphoma response, especially with regard to the T-cell 
phenotypic changes. It is likely that the immune changes induced by ibrutinib, particularly the reported Th2->Th1 
repolarization, may play a major role in response or resistance. This collection is being added to compare immune 
changes after 1 cycle of ibrutinib treatment to baseline.
Time and Events Schedule
(including footnote n)
Added additional biomarker sample on Cycle 2 Day 1.
Rationale: Administrative corrections or clarifications were made throughout the protocol.
Throughout the protocol 
References to CYP3A4/5 have been corrected to CYP3A.
Synopsis (Overview of 
Study Design)
Corrected incorrect treatment descriptions for each treatment arm - placebo and 
ibrutinib were reversed.
Synopsis (Biomarker 
Evaluations); 9.4 
Biomarkers and Minimal
Residual Disease
Deleted need for bone marrow sample for confirmation of CR for central analysis, 
as analysis is only done locally.
Clarification of blood sampling and analysis for biomarkers and residual disease.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
12
Approved, Date: 29 August 2022
Time and Events Schedule
Clarification footnotes added:
!
Added window of ∀2 days and ∀4 days for the Chemotherapy and 
Post-Chemotherapy Periods, respectively.
!
Only a limited symptom-directed physical examination is required during 
treatment, including inquiry of ocular symptoms.
!
Progression needs to be confirmed by the sponsor medical monitor before 
subsequent therapy is started.
!
Clarified text on screening evaluations for Hepatitis B and C.
!
Clarified that during the Follow-up phase, assessments may be performed up 
to 16 weeks for subjects who had not progressed.
!
Clarified that response assessments may be repeated as clinically indicated to 
confirm response or progression.
Table 1
Correction made to CR/CRu rate for van Oers Blood 2006 data.
1 Introduction
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: 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.
1.2 Chemo-immunotherapy 
Treatment of Previously 
Treated iNHL
Moved sentence referring to current ibrutinib IB from Section 1.2 to a more 
appropriate location (ie, Section 1.3, Ibrutinib Background).
1.3.1 Clinical 
Pharmacokinetic Data
Correction to number of subjects exposed to mild/moderate inhibitors, per current 
IB. 
1.3.2.2.3 Combination 
Therapy Studies
Updated OSU 1002 and PCI-32765DBL1002 study summaries per current 
publications.
4.1 Inclusion Criteria
Clarified that evidence of and clinical signs of pathological transformation cannot 
be present at initial histological diagnosis (Criterion 2); Other minor editorial 
clarifications implemented based on site and monitor feedback (Criteria 3 and 4). 
Revised units for consistency across the protocol for absolute neutrophil count and 
platelets (Criterion 7).
4.2 Exclusion Criteria;
Section 9.5 Safety 
Evaluations
Streamlined text on exclusion of subjects with a history of HIV or active Hepatitis B 
and C infection (Criterion 12).
6.1 Study Treatment
Definition of BR sensitivity added. 
8 Concomitant Therapy
Deleted statement causing confusion at sites: Modification of an effective preexisting 
therapy should not be made for the explicit purpose of entering a subject into the 
study.
8.1 Concomitant 
Medication to be Used with 
Caution
Deleted 4th paragraph, as pharmacokinetic collections for subjects who received 
moderate or strong CYP inhibitors are not being performed in this study.
9.1.2 Screening Phase
Clarified wording on confirmation of FL or MZL disease at screening.
9.1.3 Treatment Phase
Clarified when PRO questionnaires should be administered.
9.1.4 (Posttreatment Phase 
[Follow-up]); 9.2.3.1 
Assessment of Disease 
Response and Progressive 
Disease
Clarified that progression needs to be confirmed by the sponsor medical monitor 
before subsequent therapy is started.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
13
Approved, Date: 29 August 2022
9.2.1.3 Bone Marrow 
Assessment
Clarified that repeat bone marrow evaluation includes bone marrow aspirate and 
biopsy.
9.2.1.6 Patient-reported 
Outcomes
Corrected typographical error: EQ-5D-5L includes 5 separate questions, not 
questionnaires.
9.5 Echocardiogram and 
MUGA Scans
Clarified that an echocardiogram or MUGA scan is mandatory at screening for all 
subjects, not just those who are assigned to receive R-CHOP.
10.2 Discontinuation of 
Study Treatment
Clarified that subjects with radiographic progression without clinical progression 
who have not started alternate therapy may continue to receive study treatment at the 
discretion of the investigator.
11.3.4 Patient-Reported 
Outcomes
Clarified that descriptive statistics will also be performed for Fact-Lym.
11.8 Data Monitoring 
Committee
Increased the safety review times from 1 month to 2 months.
12.3.1 All Adverse Events
Clarified the interval of adverse event collection (ie, until 30 days after the last dose 
of ibrutinib or the start of subsequent systemic anticancer therapy if earlier).
References
References updated based on additions/deletions made.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
14
Approved, Date: 29 August 2022
SYNOPSIS
A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor, 
PCI-32765 (Ibrutinib), in Combination with Either Bendamustine and Rituximab (BR) or Rituximab, 
Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects with Previously 
Treated Indolent Non-Hodgkin Lymphoma (iNHL)
Ibrutinib (IMBRUVICA®; PCI-32765; JNJ-54179060) is a first-in-class, potent, orally-administered 
covalently-binding small molecule inhibitor of Bruton’s tyrosine kinase currently being co-developed by 
Janssen Research & Development, LLC and Pharmacyclics LLC for the treatment of B-cell malignancies.
The initial approval of ibrutinib was received on 13 November 2013 by the United States Food and Drug 
Administration for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at 
least 1 prior therapy. Ibrutinib has not been approved for marketing for the treatment of follicular lymphoma 
(FL) in any country.
OBJECTIVES AND HYPOTHESIS
Primary Objectives
The primary objective of this study is to evaluate whether the addition of ibrutinib to bendamustine and 
rituximab (BR) combination or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
(R-CHOP) combination will result in prolongation of progression-free survival (PFS) compared with either 
BR or R-CHOP alone in subjects with previously treated iNHL (follicular lymphoma [FL] or marginal zone
lymphoma [MZL]).
Secondary Objectives
The secondary objectives are to compare treatment groups in terms of overall survival, complete response 
rate (CR), overall response rate ORR (CR + partial response [PR]), duration of response, patient-reported 
lymphoma symptoms and concerns as measured by the Lym subscale of the Functional Assessment of 
Cancer Therapy-Lymphoma (FACT-Lym), and safety of ibrutinib when combined with BR or R-CHOP.
Exploratory Objectives
The exploratory objectives are to evaluate time-to-next treatment, minimal residual disease (MRD) negative 
rate in FL subjects, and patient-reported outcomes (PRO) related to general health status utilizing EuroQol 
(EQ-5D-5L), to characterize the pharmacokinetics of ibrutinib and to explore the potential relationships 
between ibrutinib metrics of exposure with relevant clinical or biomarker information.
Hypothesis
The primary hypothesis of the study is that ibrutinib in combination with either BR or R-CHOP compared 
with either BR or R-CHOP alone will prolong PFS in subjects with previously treated iNHL (FL or MZL).
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study in approximately 
400 subjects with FL or MZL. The study will include a Screening Phase, a Treatment Phase, and a 
Posttreatment Follow-up Phase.
Eligible subjects will be stratified by background chemotherapy treatment, refractory versus relapsed 
disease, iNHL histology, and number of prior lines of therapy. Subjects will be randomized in a 1:1 ratio to 
either Treatment Arm A (background chemotherapy + placebo) or Treatment Arm B (background 
chemotherapy + 560 mg of ibrutinib). All subjects will receive
6 cycles of background 
chemoimmunotherapy with either BR or R-CHOP in combination with either placebo (Arm A) or 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
15
Approved, Date: 29 August 2022
ibrutinib (Arm B). Selection of background therapy will be based on prior treatment history and cardiac
function. After completion of background therapy, study drug (ibrutinib or placebo) will continue until 
disease progression, unacceptable toxicity, or study end. 
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 further conduct of the study.
SUBJECT POPULATION
Key eligibility criteria include: 18 years of age or older; histologically confirmed (by central laboratory) 
diagnosis of B-cell iNHL, with histological subtype limited to the following (a) FL Grade 1, 2, or 3a or (b) 
MZL (splenic, nodal, or extra-nodal); disease which has relapsed or was refractory (failure to achieve PR 
or CR after the most recent treatment) after prior chemoimmunotherapy; at least 1 prior treatment with a 
CD20 antibody combination chemotherapy regimen; at least 1 measurable site of disease according to 
Revised Response Criteria for Malignant Lymphoma; Eastern Cooperative Oncology Group performance 
status grade 0 or 1.
DOSAGE AND ADMINISTRATION
Study drug (ibrutinib 560 mg or placebo) will be administered orally at approximately the same time each
day along with background chemotherapy. Background BR (28-day cycles) consists of bendamustine 
hydrochloride 90 mg/m2 intravenously (IV) on Days 1 and 2 of Cycles 1 to 6 and rituximab 375 mg/m2 IV 
on Day 1 of Cycles 1 to 6. Background R-CHOP (21-day cycles) consists of rituximab 375 mg/m2 IV, 
cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, and vincristine 1.4 mg/m2 IV [maximum total 
2 mg] on Day 1 of Cycles 1 to 6 along with prednisone 100 mg orally on Days 1 to 5 of Cycles 1 to 6. Study 
drug will continue to be administered beyond Cycle 6 until disease progression, unacceptable toxicity, or 
study end.
EFFICACY EVALUATIONS/ENDPOINTS
Assessment of tumor response and progression will be conducted in accordance with the Revised Response 
Criteria for Malignant Lymphoma. Efficacy evaluations may include computed tomography scans, 
magnetic resonance imaging, positron emission tomography using [18F]-fluorodeoxyglucose, bone marrow 
aspirate and biopsy, physical examination including lymphoma B symptoms, or other procedures as 
necessary. Subject lymphoma related symptoms and concerns will be measured by the lymphoma subscale 
of the FACT-Lym and health status will be measured by the EQ-5D-5L.
The primary endpoint is PFS as assessed by the treating physician. Subjects who discontinue treatment 
prior to disease progression will have regularly scheduled disease evaluations until disease progression, 
death, or study end, whichever occurs first. For all subjects, survival and subsequent antineoplastic therapy 
data will be collected until death, lost to follow-up, withdrawal of consent, or study end.
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. Pharmacokinetic parameters (eg, oral 
clearance) and/or metrics of systemic exposure (eg, area under the plasma concentration-time curve [AUC], 
maximal plasma concentration [Cmax]) will be evaluated. Parameters describing the potential relationships
between ibrutinib metrics of exposure with relevant clinical or biomarker information will also be 
evaluated.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
16
Approved, Date: 29 August 2022
BIOMARKER EVALUATIONS
For subjects with FL who have achieved CR, blood samples will be collected at scheduled disease 
assessment visits for assessment of MRD, until clinical cutoff for the primary analysis. A portion of the 
formalin-fixed, paraffin-embedded tissue block or slides obtained at baseline may be used for central 
assessment of MRD.
SAFETY EVALUATIONS
Safety evaluations include: adverse event monitoring, physical examinations, evaluation of changes to
concomitant medications, and clinical laboratory parameters (hematology, coagulation, serum chemistry,
serum immunoglobulin [IgG, IgM, IgA], and beta2-microglobulin). Adverse events that occur between the
signing of the informed consent through 30 days after subjects have completed study treatment will be
collected. 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 an adverse event of special interest and will require enhanced 
reporting and data collection.
STATISTICAL METHODS
The study will enroll approximately 400 subjects (about 200 subjects to each arm), based on the following 
considerations: 
!
1:1 randomization ratio between the 2 treatment arms; 
!
Target hazard ratio of 0.7. Assuming the median PFS for the control arm (BR or R-CHOP + placebo) 
is 20 months from randomization, a target hazard ratio of 0.7 corresponds to an 8.6-month increase in 
median PFS for the treatment arm (BR or R-CHOP +ibrutinib) relative to the control (ie, 20.0 months
versus 28.6 months, respectively); 
!
Minimum 80% power; 
!
2-sided overall significance level of 0.05; 
!
One interim analysis for efficacy at 60% of the planned total PFS events.
Three clinical cutoffs are planned. The first 2 clinical cutoffs will occur when approximately 151 and 
252 PFS events have been observed, respectively. The interim analysis and the primary analysis (ie, final 
analysis of the primary endpoint PFS) will take place at these 2 clinical cutoffs, respectively. The last cutoff 
will occur at the time of the end of study, when approximately 50% of the randomized subjects have died, 
or the sponsor terminates the study, whichever comes first. 
The primary efficacy analysis will be based on PFS and will be performed using the ITT population, which 
is defined as all randomized subjects. The Kaplan-Meier method will be used to estimate the distribution 
of PFS for each treatment group. The stratified log-rank test will be used to compare survival curves of PFS 
between the 2 treatment groups. Hypothesis testing for the interaction between background therapy and 
treatment will be performed.
Adverse events will be summarized and listed. Summary statistics and graphical displays may be presented 
for clinical laboratory parameters. Descriptive statistics of changes from baseline for vital signs and 
physical examination will be summarized.






JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
19
Status: Approved,  Date: 29 August 2022
a.
Slides or tumor block for confirmation of diagnosis may be either newly obtained or from previous biopsy; any remaining sample may be used for MRD and 
biomarker evaluations for FL subjects only.
b.
Additional pregnancy tests may be performed, 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.
c.
Window of ±2 days.
d.
May be repeated during the study when clinically warranted.
e.
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).
f.
Window of ±4 days.
g.
EQ-5D-5L and lymphoma subscale of the FACT-Lym should be completed prior to any assessments, and before being clinically evaluated by the study nurse or 
physician. Following disease progression, collect once approximately 24 weeks after PD, preferably in person but acceptable via telephone contact with subject.
h.
At screening within 60 days of randomization; may be repeated as clinically indicated to confirm response or progression.
i.
Maximal tumor reduction defined as time of CR or when 2 consecutive CT scans show no further tumor reduction.
j.
Progression needs to be confirmed by the sponsor medical monitor before subsequent therapy is started.
k.
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 drug.
l.
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 negative for Hepatitis surface antigen but positive for Hepatitis B core antibody do not require PCR testing and may be included in the study 
with prophylaxis. All other subjects who test positive for Hepatitis B core antibody must have Hepatitis B DNA by PCR performed and confirmed as negative 
prior to randomization, and may be included in the study following consultation with an infectious disease specialist. 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.
m. Predose sample to be obtained on Day 1 in Cycles 1, 2 and 3, and postdose on Day 1 in Cycles 1 and 2, at 1 hour (window 45-75 minutes), 2 hours (window 
1.5-2.5 hours), and 4 hours (window 3.5-6 hours) following dosing.
n.
Day 1 of Cycle 1, Day 1 of Cycle 2, and at the time of suspected disease progression; or at EOT for subjects without disease progression.
o.
May be performed up to 16 weeks.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
20
Status: Approved,  Date: 29 August 2022
Table 2:
Time and Events Schedule After the study Primary Analysis
Treatment Phase 
Posttreatment 
Follow-up Phase
Every 8 weeks
(∀4 days) 
End of Treatment 
Visit
(Within 30 days 
after last dose)
Prior to Disease 
Progression 
(Every 24 weeks ∀4 
weeks)
Following Disease 
Progression 
(Every 24 weeks 
∀4 weeks)
Administer ibrutinib 
#------------------------------Continuous-------------------------∃
Dispense ibrutinib
X
Check drug accountability
X
X
SAEs; Grade ≥3 AEs; AEs resulting in 
dose interruption, reduction, or 
discontinuation; major hemorrhagesa
#---- Continuous from informed consent to 30 days after the last dose of study treatment 
or until the start of a subsequent systemic anti-lymphoma therapy, if earlier ----∃
Prohibited concomitant medications and 
concomitant medications related to SAEs
#---- Continuous from informed consent to 30 days after the last dose of study treatment 
or until the start of a subsequent systemic anti-lymphoma therapy, if earlier ----∃
New malignanciesb
#----------------------------------------------------------------------- Continuous ------------------------------------------------------------------------∃
Laboratory assessments
Per standard of care. Record in eCRF if indicative of the onset and recovery from an 
adverse event
Vital signs (heart rate and blood 
pressure)
Assess at each visit. Record in eCRF if indicative of the onset and recovery from an 
adverse event
Physical examination
X
X
Per standard of care
Disease evaluations
#----------------------------------------------------Per standard of care------------------------------------------------------∃
Survival status
Xc
X
Subsequent anti-lymphoma therapiesd
X
X
a
Lower grade AEs may be reported by the investigator if considered relevant or important. 
b
New malignancies of any grade should be reported throughout the study on the New Malignancies eCRF and (if treatment-emergent) on the Adverse Event eCRF.
c
Contact the subject as needed to assess survival status so that a disease evaluation or survival contact occurs at least every 24 (∀4) weeks.
d
Best response as well as progressive disease on subsequent anti-lymphoma therapy will be collected.
Key: AE = adverse event; eCRF = electronic case report form; SAE = serious adverse event.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
21
Status: Approved,  Date: 29 August 2022
ABBREVIATIONS
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-24
area under the concentration-time curve from 0 to 24 hours post dose
AUClast
area under the concentration-time curve to the last quantifiable concentration
BCL2
B-cell lymphoma 2
BCR
B-cell antigen receptor 
BR
bendamustine and rituximab
BTK
Bruton’s tyrosine kinase 
CI
confidence interval
CLL
chronic lymphocytic leukemia
Cmax
maximum plasma concentration
CNS
central nervous system
CRF
case report form
CYP
cytochrome P450
CR(s)
complete response(s)
CT
computed tomography
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DOR
duration of response
ECG
electrocardiogram
eDC
electronic data capture
EOT
end-of-treatment
EQ-5D-5L
EuroQol; European Quality of Life Questionnaire
EU
European Union
FACT-Lym
Functional Assessment of Cancer Therapy-Lymphoma
FCR
fludarabine, cyclophosphamide, rituximab
FFPE
formalin fixed, paraffin-embedded
FL
follicular lymphoma
GCP
Good Clinical Practice
GTD
greatest transverse diameter
HBV
hepatitis B virus
β-hCG
beta human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s brochure
IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
Ig
immunoglobulin
iNHL
indolent non-Hodgkin lymphoma
INR/PT
international normalized ratio/prothrombin time
ITT
intent-to-treat
IRB
Independent Review Board
IWRS
interactive web response system
IV
intravenous(ly)
IVRS
interactive voice response system
MCL
mantle cell lymphoma
MRD
minimal residual disease
MRI
magnetic resonance imaging
MUGA
multiple uptake gated acquisition
MZL
marginal zone lymphoma


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
22
Status: Approved,  Date: 29 August 2022
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin lymphoma
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PET
positron emission tomography
PFS
progression-free survival 
P-gp
P-glycoprotein
PI3K
phosphoinositide 3-kinase
PP
per protocol
PQC
product quality complaint
PR(s)
partial response(s)
aPTT
activated partial thromboplastin time
R-CHOP
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
R-CVP
rituximab, cyclophosphamide, vincristine, and prednisone
REAL
Revised European-American Lymphoma
SLL
small lymphocytic lymphoma
SPD
sum of the product of the diameters
TTNT
time-to-next treatment
TTW
time to worsening
ULN
upper limit of normal
WBC
white blood cell
WM
Waldenström’s macroglobulinemia


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
23
Status: Approved,  Date: 29 August 2022
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 and 
Pharmacyclics LLC for the treatment of B-cell malignancies. 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. The initial approval of ibrutinib was 
received on 13 November 2013 from the United States (US) Food and Drug Administration (FDA) 
for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least 
1 prior therapy. Ibrutinib has not been approved for marketing for the treatment of follicular 
lymphoma (FL) in any country. Ibrutinib and PCI-32765 and “ibrutinib” refer to the same 
molecule; hereafter, “ibrutinib” will be used.
1.1.
Indolent Non-Hodgkin Lymphoma
Indolent non-Hodgkin lymphoma (iNHL) was initially defined within the Revised European 
American Lymphoma (REAL) classification and comprises FL, small lymphocytic lymphoma 
(SLL), marginal zone lymphoma (MZL), and lymphoplasmacytic lymphoma/Waldenström’s 
macroglobulinemia (WM). These lymphomas are generally highly responsive to a variety of 
therapies, but are considered incurable with conventional therapies. The majority of patients with 
indolent lymphomas will relapse and suffer substantial morbidity as well as mortality related to 
the persistence or recurrence of their disease. Together, FL and MZL account for the vast majority 
of all indolent lymphomas.
Follicular lymphoma is the one of the most common types of non-Hodgkin lymphoma (NHL)
accounting for approximately 22% of cases (NHL Classification Project 1997) and for about 70% 
of indolent lymphomas (NHL Cyber family web site). Most cases have a t(14;18) translocation, 
which juxtaposes B-cell lymphoma 2 (BCL2) with the IgH locus and results in the deregulated 
expression of BCL2 (NCCN 2013). Marginal zone lymphomas are a group of B-cell malignancies 
originating from B lymphocytes that are normally present in the marginal zone of the lymphoid 
follicles of the spleen, lymph nodes, and lymphoid tissue (Kahl 2008). Marginal zone lymphomas 
account for approximately 10% of all NHLs (NHL Classification Project 1997).
1.2.
Chemo-immunotherapy Treatment of Previously Treated iNHL
For patients with relapsed iNHL, there are several choices of therapy. Treatment choices depend 
on stage of disease, symptoms, patient age, overall ability to withstand the associated side effects 
of the regimen, and comorbidities. Treatment guidelines provided by both the National 
Comprehensive Cancer Network (NCCN 2013) and the European Society for Medical Oncology 
(Dreyling 2011) provide similar evidence-based recommendations.
When treatment is given, initial therapy may include rituximab (Rituxan®) as a single agent or in 
combination with 1 or more cytotoxic drugs. Response rates in excess of 85% are observed with 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
24
Status: Approved,  Date: 29 August 2022
many different combinations (Peterson 2003; Hiddemann 2005; Marcus 2007; Czuczman 2005; 
Rummel 2012). In addition, when rituximab is used as maintenance treatment, the response rate 
and disease-free interval increase (Colombat 2001; Hainsworth 2003; Salles 2010).
For patients with relapsed iNHL, 2 of the most common/most representative treatment regimens 
in the relapsed setting are bendamustine and rituximab (BR) and rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone (R-CHOP). The use of chemoimmunotherapy regimens 
such as R-CHOP and BR regimens in the relapsed setting is primarily informed by published 
frontline data. A summary of results from studies in patients with iNHL treated with either BR or 
R-CHOP is provided in Table 3.
Table 3:
Descriptive Summary of Responses to Agents Evaluated for the Treatment of Indolent non-
Hodgkin Lymphoma
Rummel et al
JCO 2005
Robinson et al 
JCO 2008
Fowler et al
JCO 2011
Friedberg et al
Blood 2011
Van Oers et al
Blood 2006
N
63
67
63
30
234
Population
Relapsed low-
grade lymphoma
Relapsed low-
grade lymphoma
R/R FL
R/R iNHL and 
MCL (n=7)
R/R FL
Rituximab 
Exposed
0%
40%
100%
100%
0%
Regimen
BR
BR
BR + bortezomib
BR + bortezomib
R-CHOP
CR/CRu
60%
55%
53%
52%
30%
Median PFS 
(months)
24
23
15
19
33
BR=bendamustine and rituximab; CR=complete response; CRu=complete response unconfirmed; FL=follicular lymphoma; 
iNHL=indolent non-Hodgkin lymphoma; MCL=mantle cell lymphoma; PFS=progression-free survival; R-CHOP=rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone; R/R=relapsed/refractory.
In a Phase 2 clinical study of 63 subjects with iNHL and MCL in the relapsed and refractory 
setting, the combination of BR has been shown to be efficacious with an overall response rate 
(ORR) of 90%, complete response (CR) rate of 60%, and median progression-free survival (PFS) 
of 24 months (Rummel 2005). These data were confirmed in a follow up study of 67 patients with 
relapsed indolent NHL or MCL (Robinson 2008), with a PFS of 23 months. Notably, all patients 
in the Rummel study and most in the Robinson study were rituximab naïve. More relevant to 
current clinical practice are the results from 2 clinical studies evaluating BR+Velcade®
(bortezomib) in treating rituximab exposed and relapsed iNHL patients (Fowler 2011; 
Friedberg 2011). In these studies, the median PFS ranged from 15 to 19 months, in contrast to the 
longer median PFS observed in rituximab-naïve populations. In the VERTICAL study, 63 subjects 
with relapsed FL were treated with bendamustine at 90 mg/m2 in combination with rituximab and 
bortezomib with an ORR of 88% (53% CR) and median PFS of 14.9 months (Fowler 2011). A 
similar regimen was studied in 30 subjects with relapsed iNHL (n=23) and MCL (n=7) with an 
ORR of 83% (52% CR) (Friedberg 2011). The 2-year PFS for the response evaluable population 
was 47%.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
25
Status: Approved,  Date: 29 August 2022
The role of R-CHOP treatment in patients with relapsed/refractory FL has been evaluated 
(van Oers 2006). About 80% of patients had received only 1 prior treatment, almost equally 
consisting of single-agent therapy (mainly chlorambucil) or polychemotherapy. No patients had 
received prior rituximab. Patients were randomized to remission induction with 6 cycles of 
standard CHOP (n=231) or R-CHOP (n=234). With a median follow-up of 39.4 months, median 
PFS was 33.1 months for the R-CHOP group versus 20.2 months for the CHOP group (p<0.001).
This study also demonstrated improved PFS among patients who received rituximab maintenance 
therapy after achieving CR or partial response (PR) (van Oers 2010). Maintenance rituximab is 
often incorporated into front-line regimens. The added benefit, however, appears to be limited to 
rituximab naïve patients and is not standard in the relapsed setting (NCCN 2013).
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.
1.3.
Ibrutinib Background
For the most current comprehensive nonclinical and clinical information regarding ibrutinib, 
including information on adverse drug reactions, refer to the latest version of the ibrutinib 
Investigator's Brochure and supplements/addenda.
Nonclinical Studies
Ibrutinib binds covalently to a cysteine residue (Cys-481) in the BTK active site (Pan 2007). The 
covalent bond formed between ibrutinib and Cys-481 is highly stable, resulting in sustained 
inhibition of the target. Ibrutinib, based on available clinical exposure data, is extensively 
metabolized. The contribution of metabolites to the overall activity is unknown. The mechanism 
of action of ibrutinib can be summarized as follows:
BTK Target Inhibition
!
Ibrutinib forms a stable covalent bond specifically with Cys-481 in the BTK active site.
!
Ibrutinib is a highly potent BTK inhibitor with half-maximal inhibitory concentration (IC50) 
of 0.39 nM.
!
Oral administration of ibrutinib at 420 to 560 mg once daily results in sustained target 
inhibition, while circulating drug is rapidly cleared. 
Antitumor Activity
!
Ibrutinib inhibits B-cell receptor (BCR) and chemokine-receptor signaling pathways in 
malignant B cells. 
!
Ibrutinib disrupts integrin-dependent B-cell migration and adhesion in vitro.
!
Ibrutinib promotes egress of malignant B cells from tissues and prevents homing of these cells 
to tissues.
Thus, ibrutinib, via a mechanism of BTK inhibition, overcomes the BCR-
and 
chemokine-controlled retention of malignant B cells in their supportive microenvironments, and 
thereby is able to disrupt the pathogenesis of several B-cell malignancies.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
26
Status: Approved,  Date: 29 August 2022
1.3.1.
Clinical Pharmacokinetic Data
In vitro preclinical data show that ibrutinib is metabolized primarily by cytochrome P450 
(CYP) 3A4/5. Its bioavailability is variable and relatively low (data on file). In healthy fasted 
subjects, significant pharmacokinetic interactions were observed in drug-drug interaction (DDI) 
studies with ketoconazole (PCI-32765CLL1002) and rifampin (PCI-32765CLL1010), a strong 
CYP3A inhibitor and inducer, respectively. In a study with 18 healthy male subjects dosed with 
120 mg ibrutinib alone followed by 40 mg ibrutinib in combination with 400 mg once daily oral 
ketoconazole, dose-normalized area under the plasma concentration-time curve (AUC) to the last 
quantifiable concentration (AUClast) and maximum plasma concentration (Cmax) of ibrutinib 
increased by 24-fold and 29-fold, respectively. In another study with healthy males and females 
dosed with 560 mg ibrutinib alone (n=18) followed by ibrutinib in combination with 600 mg once 
daily oral rifampin (n=17), AUClast and Cmax of ibrutinib decreased by 10-fold and 13-fold, 
respectively.
There is no intra-patient DDI data comparing ibrutinib exposure with and without concomitant 
CYP3A inhibitors. However, exposure data from 37 subjects taking concomitant mild and/or 
moderate inhibitors did not reveal major differences in absolute exposures. Approximately 90% 
of the subjects treated with mild and/or moderate CYP3A inhibitors had ibrutinib exposure within 
the range of those (n=76) who did not receive the inhibitors. For those subjects with exposure 
above this range, the ibrutinib AUC was still ≤2-fold the upper limit of the range observed in 
absence of inhibitors. No exposure data for concomitant administration of ibrutinib with strong 
inhibitors (treatment with strong inhibitors on study was after the pharmacokinetic sampling 
period) of CYP3A is available in these subjects. Clinical safety data in subjects treated with mild, 
moderate, or strong CYP3A inhibitors did not reveal a meaningful increase in adverse events.
Guidance on concomitant use of ibrutinib/placebo with CYP3A inhibitors or inducers is provided 
in Section 8.1.
In a food effect study in 43 healthy subjects (PCI-32765CLL1001), administration of ibrutinib in 
a fasted condition resulted in approximately 60% of exposure (AUClast) as compared to 
administration either 30 minutes before or 2 hours after a meal (the recommended dosing 
conditions). When ibrutinib was taken 30 minutes after a high fat breakfast (fed condition), the 
exposure (AUClast) was comparable to the recommended dosing conditions of either 30 minutes 
before or 2 hours after a meal.
1.3.2.
Clinical Studies of Ibrutinib
1.3.2.1.
Clinical Efficacy of Ibrutinib
Efficacy results from Study PCYC-04753 suggest that ibrutinib has activity as a single-agent in 
the treatment of subjects with relapsed or refractory iNHL. Currently a large, multicenter study 
(PCI-32765FLR2002) of ibrutinib in chemoimmunotherapy resistant FL is ongoing.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
27
Status: Approved,  Date: 29 August 2022
Study PCYC-04753
Study PCYC-04753 was a multicenter, open-label, dose-escalation, Phase 1 study of ibrutinib in 
recurrent B-cell malignancies (relapsed or refractory NHL, chronic lymphocytic leukemia (CLL), 
and WM with a minimum of 6 subjects per cohort). Five dose levels (1.25, 2.5, 5.0, 8.3, and 
12.5 mg/kg/day) were administered. In these dosing cohorts, each treatment cycle consisted of 
28 consecutive days of once daily dosing followed by a 7-day rest period. Two additional dose 
groups at 8.3 mg/kg/day and 560 mg/day (fixed dose) were also evaluated using a 35-day cycle 
with no rest period ("continuous dosing" and “fixed” cohorts, respectively). 
Sixteen subjects with a diagnosis of FL were enrolled and treated in Study PCYC-04753 
(PCYC 04753 CSR). Median age was 60 years (range, 41 to 71 years). Equal numbers of male and 
female subjects were enrolled (n=8). Median time since initial diagnosis was 54 months (range, 
19 to 186 months). Subjects had received a median of 3 prior therapies (range, 1 to 6 therapies). 
Approximately one third (31%) had received prior radiotherapy.
Of the 11 subjects with FL included in the efficacy evaluable population, 3 subjects (27%) had a 
best response of CR, and 2 subjects (18%) had a best response of PR, for an ORR of 45%. Five 
subjects (45%) had stable disease and 1 subject (9%) had progressive disease. Median time on 
ibrutinib was 6.7 months (range, 0.2 to 17.1 months). Median PFS was 13.4 months. Median 
follow-up time was 8.8 months (range, 3.3 to 17.3 months). Three subjects with MZL were also 
enrolled, with 1 PR noted. The median PFS for all 3 subjects was 7 months (95% confidence 
interval [CI]: 2-9 months).
1.3.2.2.
Clinical Safety of Ibrutinib
As of 6 April 2015, 1071 subjects have been treated with ibrutinib monotherapy and 423 subjects 
have been treated with ibrutinib combination therapy in sponsor-initiated clinical studies in B-cell 
lymphomas. Because ibrutinib is in clinical development, its 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.
1.3.2.2.1.
Hematological Adverse Events
Cytopenias
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. 
Lymphocytosis and Leukostasis
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥50% increase from 
baseline and an absolute count >5,000/μL), often associated with reduction of lymphadenopathy, 
has been observed in most subjects with CLL/SLL treated with ibrutinib. This effect has also been 
observed in some subjects with MCL treated with ibrutinib. This observed lymphocytosis is a 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
28
Status: Approved,  Date: 29 August 2022
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 few weeks 
of ibrutinib therapy (median time 1.1 weeks) and typically resolves within a median of 8.0 weeks 
in subjects with MCL and 18.7 weeks in subjects with CLL/SLL.
A large increase in the number of circulating lymphocytes (eg, >400,000/ μL) has been observed 
in some subjects. Lymphocytosis appeared to occur in lower incidence and at lesser magnitude in 
subjects with CLL/SLL receiving ibrutinib in combination with chemoimmunotherapy. 
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high number 
of circulating lymphocytes (>400,000/μL) may confer increased risk. Subjects should be closely 
monitored. Administer supportive care including hydration and/or cytoreduction as indicated.
1.3.2.2.2.
Non-hematological Adverse Events
Bleeding-related Events
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, epistaxis, 
and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria (see also Section 12.3.3.1). Subjects were excluded from 
participation in specific ibrutinib Phase 2 and 3 studies if they required warfarin or other vitamin K 
antagonists. 
Subjects in the current study will be monitored closely for hemorrhagic adverse events (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 8.1.
Atrial Fibrillation
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. 
Periodically monitor subjects clinically for atrial fibrillation. Subjects who develop arrhythmic 
symptoms (eg, palpitations, lightheadedness) or new onset of dyspnea should be evaluated 
clinically and if indicated, have an electrocardiogram (ECG) performed. For atrial fibrillation that 
persists, consider the risks and benefits of ibrutinib treatment and follow the dose modification 
guidelines.
There is no evidence of QT prolongation with increasing plasma concentrations of ibrutinib. 
Guidance on the use of medications known to cause QT prolongation is provided in Section 8.1. 
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 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
29
Status: Approved,  Date: 29 August 2022
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 described in Section 6.5.1.
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. Although causality has not been established, cases of progressive multifocal 
leukoencephalopathy have occurred in subjects treated with ibrutinib. Subjects should be 
monitored for symptoms (fever, chills, weakness, confusion) and appropriate therapy should be 
instituted as indicated.
Second Primary 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 PCYC-1112-CA. Most rashes were mild to moderate in severity. One 
case of Stevens-Johnson Syndrome (SJS) was reported in a subject with CLL. The subject received 
ibrutinib (420 mg/day) and was also receiving various antibiotics and medications for gout 
(allopurinol) known to be associated with SJS. Subjects should be closely monitored for signs and 
symptoms suggestive of 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.
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.
1.3.2.2.3.
Combination Therapy Studies
The safety of ibrutinib administered with rituximab-containing therapy has also been evaluated in 
2 clinical studies, (Study PCYC1108-CA and Study PCI-32765DBL1002), and in an 
investigator-initiated study (Study OSU10052). These data suggest that ibrutinib can be combined 
with these regimens at their usual doses.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
30
Status: Approved,  Date: 29 August 2022
Study PCYC 1108-CA
In Study PCYC-1108-CA, ibrutinib (420 mg/day) is administered to subjects with CLL/SLL in 
combination with either the FCR regimen (fludarabine, cyclophosphamide, and rituximab) or the 
BR regimen. Bendamustine plus rituximab is administered intravenously (IV) for a maximum of 
6 cycles. One cycle is 28 days. Subjects receive bendamustine 70 mg/m² on Day 1 and 2 of each 
cycle. For Cycle 1 only, rituximab is given at a dose of 375 mg/m2 on Day 1; alternatively, the 
rituximab dose could be divided between Day 1 and Day 2 per institution standards for subjects 
considered at risk for infusion reactions. Rituximab is given at a dose of 500 mg/m² on Day 1 of 
subsequent cycles of therapy.
Thirty subjects received ibrutinib in combination with BR. All subjects reported 1 or more 
treatment-emergent adverse events. The most common adverse events have been diarrhea 
(21 subjects; 70.0%), nausea (20 subjects; 66.7%), and fatigue (14 subjects; 46.7%). Neutropenia 
was the most common hematologic toxicity (12 subjects; 40.0%), followed by thrombocytopenia 
(5 subjects; 16.7%), and anemia and febrile neutropenia (2 subjects each; 6.7%). Many of the 
adverse events occurring in greater than 10% of subjects reflect the adjunctive chemotherapy.
Overall, 66.7% of subjects have experienced at least one Grade 3 or 4 event during treatment. The 
most common were neutropenia (12 subjects; 40%), fatigue and maculopapular rash (3 subjects 
each; 10.0%), and thrombocytopenia, febrile neutropenia, and cellulitis (2 subjects each; 6.7%).
Overall, 20% of treated subjects have experienced at least 1 serious adverse event. Febrile 
neutropenia and cellulitis were the most common serious events reported in 2 (6.7%) subjects each. 
The system organ classes most frequently affected with a serious adverse event have been Blood 
and Lymphatic system (6.7%) and Infections (6.7%). No serious adverse events in the Hepatic, 
Renal, or Cardiac system organ classes have been reported. Four (13.3%) subjects experienced a 
serious adverse event deemed related to ibrutinib— including febrile neutropenia reported in 
2 (6.7%) subjects, and cellulitis and tumor lysis syndrome, reported in 1 (3.3%) subject each. In 
general, the serious adverse events reported to date have been commensurate with the disease state 
of this population.
There were no treatment-emergent adverse events resulting in premature discontinuation of 
ibrutinib therapy. Events leading to discontinuation of bendamustine and/or rituximab were 
reported in 20% of subjects, of which neutropenia was the most commonly reported in this 
category (3 subjects, 10.0%). No subjects died during the study and within 30 days of last study 
treatment.
This study demonstrated that ibrutinib can be safely combined with BR. The toxicity profile of 
combination ibrutinib and BR is similar to that of BR alone (O’Brien 2012).
Study OSU 10052 (Investigator-initiated Study of BR in Combination with Ibrutinib)
This study (Study OSU 10052) was an investigator-initiated Phase 1 study of ibrutinib in 
combination with BR in subjects with relapsed/refractory NHL. Treatment consisted of rituximab 
at a dose of 375 mg/m2 on Day 1, bendamustine 90 mg/m2 on Days 1 and 2, and escalating doses 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
31
Status: Approved,  Date: 29 August 2022
of ibrutinib (280 or 560 mg) on Days 1 to 28 every 28 days for 6 cycles, followed by ibrutinib 
alone until progression. Forty-eight subjects (37 males) with a median age of 62 (range 23 to
84 years) previously treated with a median of 3 prior therapies (range 1 to 10 prior therapies) were 
enrolled. Histologies included MCL (n=17), diffuse large B-cell lymphoma (DLBCL, n=16), 
transformed NHL (n=2), FL (n=12), and MZL (n=1) (Maddocks 2014). 
No dose-limiting toxicities (DLTs) have been observed. Subjects received a median of 8 cycles, 
with 26 subjects completing 6 cycles and continuing ibrutinib alone in Cycles 7 to 34. Grade 3 and 
4 toxicities included lymphopenia (77%), neutropenia (33%), rash (25%), and thrombocytopenia 
(19%). The recommended Phase 2 dose of ibrutinib in combination with R-bendamustine in 
subjects with NHL is 560 mg.
Study PCI-32765DBL1002
Study PCI-32765DBL1002 was an open-label, nonrandomized, multicenter, dose-escalation study 
to establish the recommended Phase 2 dose of ibrutinib combined with standard R-CHOP therapy 
in subjects with newly diagnosed CD20-positive B-cell NHL, including DLBCL, FL, and MCL. 
Subjects were assigned to cohorts of increasing oral daily doses of ibrutinib (280, 420, and 
560 mg) administered in combination with R-CHOP. Of the 33 subjects treated with the 
ibrutinib+R-CHOP combination in Study PCI32765DBL1002; 21 subjects received the 
recommended Phase 2 dose of 560 mg/day.
In the all treated population (N=33), all subjects had at least 1 adverse event and 27 (82%) had 
Grade 3 or higher adverse events (Younes 2014). The most common Grade 3 or higher adverse 
events included neutropenia (73%, 24 subjects), thrombocytopenia (21%, 7 subjects), and febrile 
neutropenia and anemia (18% each, 6 subjects). The most frequently reported serious adverse 
events were febrile neutropenia (18%, 6 subjects) and hypotension (6%, 2 subjects). 
Thirteen (39%) of 33 subjects had an adverse event leading to dose modification of any of the 
study drugs; 3 (9%) subjects had serious adverse events leading to dose reduction (Grade 3 febrile 
neutropenia and pyrexia, Grade 3 febrile neutropenia, and Grade 3 diarrhea, in 1 subject each). 
Eleven (34%) of 32 subjects had single-dose reductions of vincristine and 1 subject (3%) each had 
1 or 2 dose reductions of cyclophosphamide, doxorubicin, or prednisone; no rituximab dose 
reductions were noted. Five (16%) subjects had an ibrutinib dose reduction. Nine (27%) subjects 
had an adverse event leading to treatment discontinuation of 1 or more study drug. One subject 
died during the study, but cause of death (suicide) was considered unrelated to treatment.
1.4.
Overall Rationale for the Study
With conventional chemotherapy, even if combined with radiotherapy, advanced-stage iNHL is 
incurable (Relander 2010). Responsiveness to therapy and duration of response both decline with 
repeated treatments, with death generally resulting from the disease (Montoto 2007). For patients 
with significant tumor burden or progressive disease, chemoimmunotherapeutic options are 
preferred (NCCN 2013). Chemoimmunotherapy regimens such as R-CHOP and BR are the most 
commonly used regimens in the relapsed setting, primarily informed by published frontline data.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
32
Status: Approved,  Date: 29 August 2022
Outcomes of chemoimmunotherapy in the relapsed setting are poor, regardless of the background 
chemotherapy selected, particularly for patients with prior exposure to rituximab-containing 
chemoimmunotherapy. While there are a number of available therapies for patients with previously
treated iNHL, these agents provide limited clinical benefit to these patients, and none of these 
treatments are curative, highlighting the need for novel, well-tolerated, effective treatment options. 
Hence, there is a medical need for new treatments that can be combined with existing therapies to 
provide durable clinical benefit without added toxicities.
Ibrutinib, a first-in-class, potent, BTK inhibitor, has demonstrated promising activity in patients 
with iNHL in Phase 1 studies and in an ongoing Phase 2 study in 110 subjects with 
chemoimmunotherapy-resistant FL (Study PCI-32765FLR2002). Phase 1 combination studies 
PCYC-1108, OSU 10052, and PCI-32765DBL1002 have demonstrated that ibrutinib can be safely 
combined with chemoimmunotherapy regimens such as BR and R-CHOP. These data suggest that 
targeting BTK is a novel, safe, and potentially effective therapeutic approach in iNHL.
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 (BR) combination or rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone (R-CHOP) combination will result in prolongation of PFS compared with either BR or 
R-CHOP alone in subjects with previously treated iNHL (FL or MZL).
Secondary Objectives
The secondary objectives are to compare treatment groups in terms of the following:
!
overall survival (OS)
!
complete response rate (CR)
!
overall response rate (ORR [CR+PR])
!
duration of response (DOR)
!
patient-reported lymphoma symptoms and concerns as measured by the Lym subscale of 
the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)
!
safety of ibrutinib when combined with BR or R-CHOP 
Exploratory Objectives
The exploratory objectives are to evaluate:
!
time-to-next treatment (TTNT)
!
minimal residual disease (MRD) negative rate in FL subjects
!
patient-reported outcomes (PROs), related to general health status, utilizing EuroQol 
(EQ-5D-5L)


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
33
Status: Approved,  Date: 29 August 2022
!
pharmacokinetics of ibrutinib and explore the potential relationships between ibrutinib
metrics of exposure with relevant clinical or biomarker information
2.2.
Hypothesis
The primary hypothesis of this study is that ibrutinib in combination with either BR or R-CHOP 
compared with either BR or R-CHOP alone will prolong PFS in subjects with previously treated
iNHL (FL or MZL).
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 or R-CHOP to BR alone or R-CHOP alone 
in subjects with previously treated iNHL (FL or MZL).
The study will include a Screening Phase, Treatment Phase, and Posttreatment Follow-up Phase. 
Subject eligibility will be determined up to 30 days prior to randomization. The Treatment Phase 
will extend from randomization until study drug discontinuation. 
All subjects will receive background therapy with either BR or R-CHOP. Selection of background 
therapy will be based on prior treatment history and cardiac function. The sponsor will strive 
towards an adequate number of subjects randomized into either of the background chemotherapy 
regimens.
Approximately 400 eligible subjects will be stratified by (1) background chemotherapy treatment, 
(2) refractory versus relapsed disease, (3) iNHL histology, and (4) number of prior lines of therapy 
(for definitions see Section 11.3.1). Subjects will be randomized in a 1:1 ratio to either Treatment 
Arm A (background chemotherapy + placebo) or Treatment Arm B (background chemotherapy +
560 mg of ibrutinib). Study drug will be administered orally at approximately the same time each 
day and on a continuous schedule until disease progression, unacceptable toxicity, or study end, 
whichever comes first. 
The Posttreatment Follow-up Phase will begin once a subject discontinues study drug (ibrutinib or 
placebo). Subjects who discontinue for reasons other than disease progression must continue 
disease evaluations according to the Time and Events Schedule. The Posttreatment Follow-up 
Phase will continue until death, loss to follow up, consent withdrawal, or study end, whichever 
occurs first. 
Three clinical cutoffs are planned. The first 2 clinical cutoffs will occur when approximately 
151 and 252 PFS events have been observed, respectively. The interim analysis and the final 
analysis of the primary endpoint PFS will take place at these 2 clinical cutoffs, respectively. The 
last cutoff will occur at the time of the end of study, when approximately 50% of the randomized 
subjects have died, or the sponsor terminates the study, whichever comes first. Investigators will 
be informed when the cutoffs are to occur. All available data prior to the time of a clinical cutoff 
will be included in each of the respective analyses. The sponsor will ensure that subjects benefiting 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
34
Status: Approved,  Date: 29 August 2022
from treatment with ibrutinib are able to continue treatment after the end of the study. 
Assessment of tumor response and progression will be conducted in accordance with the Revised 
Response Criteria for Malignant Lymphoma (Cheson 2007). The investigator will evaluate sites 
of disease by radiological imaging, physical examination, or other procedures as necessary. The 
primary efficacy analysis of PFS will be based on investigator 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. At some visits, blood samples will be drawn for assessment of pharmacokinetic 
parameters and for MRD. 
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 further conduct of the study 
(see Section 11.8). Details regarding the composition and procedures will be provided in the DMC 
charter.
A diagram of the study design is provided below in Figure 1.




JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
36
Status: Approved,  Date: 29 August 2022
3.2.
Study Design Rationale
Study Population
Selection of iNHL (FL or MZL) subjects for this study was based on the promising activity seen 
in Phase 1 studies.
An ongoing Phase 2 study
(Study PCI-32765FLR2002)
in 
chemoimmunotherapy-resistant subjects is expected to confirm the activity seen in Phase 1. While 
there are a number of available therapies for patients with previously treated iNHL, these agents 
provide limited clinical benefit to these patients, and none of these treatments are curative, 
highlighting the need for novel, well-tolerated, effective treatment options. Thus, there is a medical 
need for newer treatments that can be combined with existing therapies to provide durable clinical 
benefit without added toxicities.
Study Treatment
The choice of chemoimmunotherapeutic regimen used in the relapsed setting is informed by the 
frontline regimen used, the remission duration, and depends on the efficacy of prior regimens 
(Dreyling 2011). Given the increased use of bendamustine-containing regimens in frontline 
therapies, patients who relapse from bendamustine are commonly treated with other 
chemoimmunotherapeutic regimens such as R-CHOP (NCCN 2013).
A survey of treatment practices among 43 US-based community oncologists was conducted in 
patients with newly diagnosed FL (n=186) and relapsed FL (n=133) between 2008 and 2010 
(Gregory 2010). R-CHOP was the most commonly used regimen in patients with newly diagnosed 
FL. An increased use of BR for the frontline treatment of FL was noted from 2008 to 2010, 
suggesting that community oncologists are rapidly incorporating clinical trial results into practice. 
Of note, there was evidence of substantial BR uptake following the landmark Rummel presentation
(Rummel 2005), with 31% of those patients who initiated treatment in 2010 receiving BR 
compared with less than 5% of those who commenced therapy in 2008 or 2009. Rituximab 
monotherapy was the most common treatment in patients with relapsed FL, followed by R-CVP
(rituximab, cyclophosphamide, vincristine, and prednisone), BR, and R-CHOP. The therapies that 
were used by these physicians in the front-line and relapsed settings broadly corresponded to 
published literature and were supported by treatment guidelines.
Dose Rationale
The 560 mg daily dose of ibrutinib was selected as the recommended dose in combination with 
BR or R-CHOP based on clinical data from Studies PCYC-04753, PCYC-1108-CA, OSU 10052, 
and PCI-32765DBL1002.
The pharmacokinetic and pharmacodynamic relationship between BTK active-site occupancy and 
ibrutinib exposure was evaluated in Study PCYC-04753. Data from Study PCYC-04753 showed 
that although ibrutinib is rapidly eliminated from the plasma after oral administration, once daily 
dosing with ibrutinib was adequate to sustain maximal pharmacodynamic activity for 24 hours 
post-dose at dose levels ≥2.5 mg/kg (191 mg). In addition, the analysis of pharmacokinetic and 
pharmacodynamic profiles showed that BTK active-site occupancy was saturated or near saturated 
(>95%) at AUC values of ≥160 ng•h/mL. In Study PCYC-04753, >85% of subjects who received 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
37
Status: Approved,  Date: 29 August 2022
dosages ≥2.5 mg/kg/day had Day 1 area under the concentration time curve from 0 to 24 hours 
(AUC0-24) values ≥160 ng•h/mL, indicating that the vast majority of patients who receive a dose 
of either 420 mg/day or 560 mg/day will achieve full BTK site occupancy. Since the 
pharmacokinetic of ibrutinib is highly variable, it is critical to ensure that also exposures on the 
lower end of the range are sufficiently high to guarantee full occupancy.
Clinical activity has been observed in FL patients in Study PCYC-04753. Of the 11 subjects with 
FL included in the efficacy evaluable population, 3 subjects (27%) had a best response of CR, and 
2 subjects (18%) had a best response of PR, for an ORR of 45%. Median time on ibrutinib was 
6.7 months (range, 0.2 to 17.1 months). Median PFS was 13.4 months. Median follow-up time was 
8.8 months (range, 3.3 to 17.3 months). With the caveat of small numbers, duration of response 
and progression free survival subjects were favoring 5 mg/kg/day (Fowler 2012). Three subjects 
with MZL were also enrolled, with 1 PR noted. The median PFS for all 3 subjects was 7 months 
(95% CI: 2 to 9 months).
The safety profile of 560 mg dosing in combination with BR or R-CHOP is acceptable. In a phase 
1 study where Ibrutinib at a dose of 560 was combined with BR no DLTs were observed 
(Blum 2012). During a dose escalation study of ibrutinib (280, 420, and 560 mg) in combination 
with R-CHOP, DLTs were observed at different dose levels, however, MTD was not reached 
(DBL1002). The Study Evaluation Team recommended 560 mg ibrutinib + R-CHOP for 
evaluation in Phase 2.
Based on these data and for consistency across the lymphoma program, the 560 mg dose has been 
selected for this study.
The assessment of pharmacokinetics is important in understanding both safety and efficacy in this 
patient population. 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 determination of subject-covariates that influence the pharmacokinetics 
of the drug, this may provide supportive evidence for the efficacy and safety analyses, help in 
deriving dosing regimens not directly studied in clinical studies, and identify at-risk subjects who 
require a dose-adaptation.
Blinding, Control, Treatment Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active treatment. 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
clinical endpoints.
Subjects will be stratified by (1) background 
chemoimmunotherapy treatment, (2) refractory versus relapsed disease, (3) iNHL histology, and 
(4) number of prior lines of therapy (for definitions see Section 11.3.1).


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
38
Status: Approved,  Date: 29 August 2022
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 30 days before randomization. Computed 
tomography/magnetic resonance imaging (CT/MRI), positron emission tomography (PET), and
bone marrow aspirate/biopsy may be performed up to 60 days before randomization.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. Waivers to the protocol inclusion and exclusion criteria will not be 
granted. Investigators must ensure that all inclusion and exclusion criteria have been satisfied at 
screening. Retesting during the Screening Period is allowed. A subject is considered eligible if the 
last observation before randomization satisfies the inclusion and exclusion criteria. If a subject's 
status changes (including laboratory results or receipt of additional medical records) after 
screening but before randomization such that he or she no longer meets all eligibility criteria, then 
the subject should be excluded from participation in the study. If there is a question about the 
inclusion or exclusion criteria below, the investigator should consult with the appropriate sponsor 
representative before obtaining randomization for a subject in the study. 
Minimum criteria for the availability of documentation supporting the eligibility criteria are 
described in Section 17.4, Source Documentation.
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, Sample 
Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study.
1.
Subject must be 18 years of age or older (or the legal age of consent in the jurisdiction 
in which the study is taking place).
2.
Criterion modified per Amendment INT-1:
2.1 Have both of the following
!
Histologically confirmed diagnosis of B-cell iNHL, with histological subtype 
limited to the following at initial diagnosis and without evidence of pathological 
transformation or clinical signs suggesting transformation
a.
follicular lymphoma (FL) Grade 1, 2, or 3a
b.
marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)
!
Prior to randomization, diagnosis must be confirmed by review of local pathology 
report. If report from local laboratory is not available or insufficient, diagnosis must 
be confirmed by central pathology laboratory, as described in Section 9.1.2.
3
Criterion modified per Amendment INT-1:
3.1 At least 1 prior treatment with a CD20 antibody combination chemoimmunotherapy 
regimen


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
39
Status: Approved,  Date: 29 August 2022
4
Criterion modified per Amendment INT-1:
4.1 Disease that has relapsed or was refractory after prior chemoimmunotherapy. 
Refractory disease is defined as failing to achieve PR or better after the most recent 
treatment. 
5.
At least 1 measurable site of disease according to Revised Response Criteria for 
Malignant Lymphoma (Cheson 2007) (ie, 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 
dimensions).
6.
Eastern Cooperative Oncology Group performance status grade 0 or 1.
7.
Criterion modified per Amendment INT-1:
7.1 Hematology values must be within the following limits:
a.
absolute neutrophil count (ANC) ≥1,500/μL independent of growth factor 
support
b.
platelets ≥100,000/μL or ≥50,000/μL if bone marrow involvement 
independent of transfusion support
8.
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 creatinine clearance (CCr) 
≥30 mL/min/1.73m2 (please refer to Attachment 3)
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. For females, these restrictions apply for 6 months after the last dose of 
bendamustine, 12 months after the last dose of rituximab or 1 month after the last dose 
of study medication, whichever is later. Men must also agree not to donate sperm during 
and after the study. 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 medication, whichever is later.
10.
Women of childbearing potential must have a negative serum (&-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 and are willing to participate in the study.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
40
Status: Approved,  Date: 29 August 2022
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
1.
Prior nitrosoureas within 6 weeks, other chemotherapy within 3 weeks, therapeutic 
anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 
10 weeks, radiation therapy within 3 weeks, or major surgery within 4 weeks of 
randomization.
2.
Prior treatment with ibrutinib or other BTK inhibitors. Subjects who progressed or 
become refractory while on treatment with phosphoinositide 3-kinase (PI3K) inhibitors 
are excluded. However, subjects who are responding to PI3K inhibitors but had 
treatment discontinued due to toxicity, or subjects who relapsed after stopping
PI3K treatment, are eligible.
3.
Received a prior allogeneic hematopoietic stem cell transplant. Prior autologous 
hematopoietic stem cell transplant is allowed.
4.
Unable to receive either BR or R-CHOP background chemotherapy, based on prior 
treatment history and cardiac function. Refer to Figure 2.
5.
Known CNS lymphoma.
6.
Diagnosed or treated for malignancy other than iNHL (FL or MZL), 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 carcinoma in situ without evidence of disease
7.
History of stroke or intracranial hemorrhage within 6 months prior to randomization.
8.
Requires anticoagulation with warfarin or equivalent Vitamin K antagonists 
(eg, phenprocoumon).
9.
Criterion modified per Amendment INT-1:
9.1 Requires treatment with strong CYP3A inhibitors (see Section 8.1)
10.
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.
a.
subjects receiving R-CHOP are excluded if left ventricular ejection fraction is 
below institutional normal limits


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
41
Status: Approved,  Date: 29 August 2022
11.
Vaccinated with live, attenuated vaccines within 4 weeks of randomization.
12.
Criterion modified per Amendment INT-1:
12.1 Known history of human immunodeficiency virus (HIV) or active Hepatitis C 
virus (HCV; RNA polymerase chain reaction [PCR]-positive) or active Hepatitis B 
virus (HBV; DNA PCR-positive) infection or any uncontrolled active systemic 
infection requiring IV antibiotics (see Section 9.5). Subjects with PCR-negative 
HBV are permitted in the study.
13.
Known anaphylaxis or immunoglobulin E (IgE)-mediated hypersensitivity to murine
proteins or to any component of rituximab including polysorbate 80 and sodium citrate 
dehydrate.
14.
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.
15.
Received investigational agents within 4 weeks prior to randomization or concurrent 
enrollment in another therapeutic investigational clinical treatment study.
4.3.
Prohibitions and Restrictions
Ibrutinib may increase risk of bleeding with invasive procedures or surgery. 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.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
42
Status: Approved,  Date: 29 August 2022
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 (1) background chemotherapy treatment, 
(2) refractory versus relapsed disease, (3) iNHL histology, and (4) number of prior lines of therapy 
(for definitions see Section 11.3.1). The sponsor will strive towards an adequate number of subjects 
randomized into either of the background chemotherapy regimens. 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
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 concentration) 
will be handled with special care to ensure that the integrity of the blind is maintained and the 
potential for bias is minimized. This can 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 case report form 
(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.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled evaluations. After treatment is unblinded, subjects assigned to ibrutinib will continue to 
receive open-label study drug; placebo will be discontinued.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
43
Status: Approved,  Date: 29 August 2022
At the time of the interim analysis, 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 analysis.
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. 
!
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).
6.
DOSAGE AND ADMINISTRATION
6.1.
Study Treatment
Study Drug
Subjects will be randomized in a 1:1 ratio to either Treatment Arm A or Treatment Arm B. 
Treatment with the study drug will start on Study Day 1 and 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 every day along with background 
chemotherapy.
Treatment Arm B: 
560 mg (4 x 140-mg capsules) of ibrutinib will be administered orally once daily every day along 
with background chemotherapy.
In Treatment Arm A and Treatment Arm B, subjects will receive either BR or R-CHOP as the 
background therapy for 6 cycles unless progression of disease or unacceptable toxicity is 
encountered prior to Cycle 6. Background therapy will be determined based on prior treatment 
history and cardiac function, as outlined in Figure 2. Once the background therapy regimen has 
been selected, subjects may not be switched to the other regimen. “BR sensitive” is defined as 
response lasting ≥24 months from the start of treatment to relapse.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
44
Status: Approved,  Date: 29 August 2022
Figure 2:
Background Chemotherapy Decision Tree
A.
B.
C.
BR=bendamustine and rituximab; LLN=lower limit of normal; LVEF=left ventricular ejection fraction; PI=principal investigator; 
R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
45
Status: Approved,  Date: 29 August 2022
In order to achieve an adequate balance between the background chemotherapy treatments, the 
sponsor will strive towards an adequate number of subjects randomized into either of the 
background chemotherapy regimens.
BR regimen (28 day cycles):
!
bendamustine hydrochloride 90 mg/m2 IV on Days 1 and 2 of Cycles 1 to 6
!
rituximab 375 mg/m2 IV on Day 1 of Cycles 1 to 6
R-CHOP regimen (21 day cycles):
!
rituximab 375 mg/m2 IV on Day 1 of Cycles 1 to 6
!
cyclophosphamide 750 mg/ m2 IV on Day 1 of Cycles 1 to 6
!
doxorubicin 50 mg/m2 IV on Day 1 of Cycles 1 to 6
!
vincristine 1.4 mg/m2 IV [maximum total 2 mg] on Day 1 of Cycles 1 to 6
!
prednisone 100 mg orally on Days 1 to 5 of Cycles 1 to 6
Note: In either regimen, rituximab may be administered separately on Day 1, followed by the 
remaining intravenous chemotherapy drugs on Day 2 (and Day 3 for bendamustine), at the 
investigator’s discretion.
6.2.
BR Administration
Investigators should refer to the package inserts for the storage and handling, and detailed 
instructions on the administration of bendamustine hydrochloride and rituximab, respectively. 
BR is administered IV, per institutional standards, at the dosages described above in Section 6.1.
Doses of bendamustine hydrochloride and rituximab should be reduced or held in accordance with 
the dose modification guidelines in the respective product labels, as described below.
6.2.1.
Bendamustine Hydrochloride Dose Modifications
Bendamustine hydrochloride administration should be delayed in the event of 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 hematologic events, bendamustine hydrochloride may be 
reinitiated after blood counts have improved (ANC ∋1 x 109/L [∋1,000/μL]; platelets ∋75 x 109/L 
[∋75,000/μL]), at the discretion of the investigator. 
In addition, dose reduction may be warranted as follows:
!
Dose modifications for Grade 4 hematologic toxicity: the dose should be reduced to 60 mg/m2
on Days 1 and 2 of each cycle. If Grade 4 toxicity recurs, the dose should be reduced to 
45 mg/m2 on Days 1 and 2 of each cycle.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
46
Status: Approved,  Date: 29 August 2022
!
Dose modifications for clinically significant Grade ∋3 non-hematologic toxicity: the dose 
should be reduced to 60 mg/m2 on Days 1 and 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.
6.2.2.
Rituximab Dose Modifications
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 should be held for any Grade 4 
toxicity or for any rituximab-related, clinically significant, unmanageable Grade 3 adverse events.
Rituximab may be held for a maximum of 28 consecutive days for a drug-related toxicity. 
Discontinue rituximab permanently if it cannot be restarted within 28 days due to drug-related 
toxicity. If rituximab is discontinued for toxicity, treatment with bendamustine hydrochloride 
and/or ibrutinib or placebo may be continued.
6.3.
R-CHOP Administration
Investigators should refer to the local prescribing information for storage and handling, and
detailed instructions on the administration of rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone (or equivalent). Rituximab biosimilar drugs are not permitted in this 
study. All IV drugs should be administered per institutional standards at the dosages described 
above in Section 6.1. Refer also to the study Investigational Product Procedures Manual.
6.3.1.
Rituximab Dose Modifications
Please refer to Section 6.2.2.
6.3.2.
Cyclophosphamide Dose Modifications
Dose adjustments for cyclophosphamide must follow the provided prescribing information. The 
most common adverse events experienced with cyclophosphamide are hematological toxicities; 
myelosuppression with leucopenia, anemia, and thrombocytopenia may occur. The lowest 
leukocyte and platelet levels occur in the first to second week after treatment is started. Recovery 
usually occurs within 3 to 4 weeks after treatment is started. Following treatment with 
cyclophosphamide, hemorrhagic cystitis and hematuria can occur. These may necessitate 
interruption of dosing.
To start a cycle with cyclophosphamide, ANC must be ∋1,000/μL and platelets ∋75,000/μL. The 
cycle may be delayed up to 2 weeks until the above values are documented on Day 1 of the cycle. 
Subjects who develop hematological toxicities thought to be causally related to cyclophosphamide 
must have their dose adjusted on Day 1 of the subsequent cycle according to Table 4.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
47
Status: Approved,  Date: 29 August 2022
Table 4:
Dose Modification for Cyclophosphamide and Doxorubicin for Hematological Toxicities
ANC and Neutropenia [μL]
(any time during cycle)
Platelet count [μL]a
Dose Given
(on next cycle)
∋1,000/μL
>75,000/μL
100% of the designated dose
>500/μL and no febrile neutropenia
>50,000/μL
100% of the designated dose after 
recovery of ANC to 1,500/μL and 
platelets to 100,000/μL
<500/μL and/or febrile neutropenia 
(ANC <500/μL + fever ∋38.5)C)
N/A
Initiate G-CSF for all subsequent 
cycles
<500/μL and/or febrile neutropenia (ANC <500/μL 
+ fever ∋38.5)C despite growth factors
<50,000/μL
25% dose reduction for 
subsequent cycles
Recurrence of <500/μL and/or febrile neutropenia 
(ANC <500/μL + fever ∋38.5)C despite growth 
factors
Recurrence of 
<50,000/μL
Additional 25% dose reduction for 
subsequent cycles
Third episode of <500/μL and/or febrile neutropenia 
(ANC <500/μL + fever ∋38.5)C despite growth 
factors and 2 dose reductions
Third episode of 
<50,000/μL
Discontinue
ANC=absolute neutrophil count; G-CSF=granulocyte colony stimulating factor; N/A=not applicable
a
Dose reductions due to low platelet counts are not required in subjects with thrombocytopenia due to bone 
marrow infiltration from lymphoma who entered the study with platelet counts <75,000/μL.
6.3.3.
Doxorubicin Dose Modifications
Dose adjustments for doxorubicin must follow the provided prescribing information. The 
recommended lifetime cumulative dose limit of doxorubicin is 450 to 550 mg/m2. The maximum 
dose given for each subject in this study will be 300 to 400 mg/m2, depending on the number of 
cycles given.
Dose-limiting toxicities of doxorubicin therapy are mucositis, myelosuppression, and 
cardiotoxicity. Myelosuppression includes leucopenia, thrombocytopenia, and anemia, reaching 
nadir at 10 to 14 days after treatment. Cardiotoxicity includes arrhythmia that may occur directly 
after administration and ECG changes may last up to 2 weeks after administration. Cardiotoxicity 
may, however, occur several weeks or months after administration.
Doxorubicin is metabolized by the liver and excreted in bile. Impairment of liver function results 
in slower excretion of the drug and consequently increased retention and accumulation in the 
plasma and tissues, resulting in enhanced clinical toxicity. Doxorubicin dosage must be reduced if 
hepatic function is impaired according to Table 5: 
Table 5:
Dose Modification of Doxorubicin for Hepatic Function Impairment
Serum Bilirubin Levels
Recommended Dose
2.0–3.0 mg/dL
50% normal dose
>3.0 mg/dL
25% normal dose
These dose reductions are not required in subjects with Gilbert syndrome and in cases where the 
increase of bilirubin is due to non-hepatic reasons. Dose reductions due to hematological toxicities 
should be performed as indicated in Table 4.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
48
Status: Approved,  Date: 29 August 2022
6.3.4.
Vincristine Dose Modifications
Dose adjustments for vincristine must follow the provided prescribing information. The vincristine 
dosage must be reduced if hepatic function is impaired according to Table 6:
Table 6:
Dose Modification for Vincristine Hepatic Function Impairment
Serum Bilirubin Levels
Recommended Dose
2.0–3.0 mg/dL
75% normal dose
>3.0 mg/dL
50% normal dose
Vincristine doses should be re-escalated when hyperbilirubinemia improves. These dose 
reductions are not required in subjects with Gilbert syndrome and in cases where the increase of 
bilirubin is due to non-hepatic reasons.
Neurologic toxicity is the most common adverse event experienced with vincristine and is related 
to dose and age. In case of severe neurotoxicity (Grade 3), vincristine should not be administered, 
especially if there are signs of paresthesia or paresis. Treatment may be resumed at 50% of the 
dose when symptoms subside. Vincristine should be reduced by 25% for any episode of 
ileus/constipation requiring hospitalization. Vincristine should be permanently discontinued for 
Grade 4 neuropathy of any type.
6.3.5.
Prednisone (or Equivalent) Dose Modifications
Dose adjustments for prednisone (or equivalent) must follow the provided prescribing information. 
In regions where prednisone is not marketed or available, prednisolone will be used. By definition, 
high-dose prednisone or equivalent will be used in this study at 100 mg. Subjects administered 
high-dose prednisone or equivalent should be monitored carefully as there is a relatively higher 
risk of developing or exacerbating some conditions (eg, bacterial infections, viral infections, 
systemic mycoses, hypertension, diabetes mellitus, and gastrointestinal conditions such as peptic 
ulcers, pancreatitis, and diverticulitis).
In the event that a subject develops an adverse event related to prednisone or equivalent and is not 
able to tolerate 100 mg as required per protocol, the dose should be adjusted to a level specific to 
that subject but should be no less than 80 mg per day (so that the subject still receives a high dose 
of prednisone [or equivalent]). In exceptional circumstances, a subject may not tolerate sudden 
steroid withdrawal after 5 days of prednisone or equivalent therapy. In such an instance, a tapering 
regimen of prednisone (or equivalent) is indicated.
6.4.
Delay of Chemotherapy
The start of a new cycle may be delayed on a weekly basis until recovery of toxicity to a level 
allowing continuation of therapy. A subject whose cycle is delayed should be assessed weekly for 
resolution of toxicity. It is not always easy to assess the role of any 1 agent in these events; 
therefore, it is at the investigators discretion to decide if 1 or more agents are responsible and take 
action as described in Section 6.2 through Section 6.3. If toxicity persists after a 2-week cycle 
delay, that is related to 1 specific chemoimmunotherapy drug (eg, bendamustine, doxorubicin, 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
49
Status: Approved,  Date: 29 August 2022
etc.), the offending drug should continue to be withheld and the new cycle should be started with 
the remaining drugs. If chemotherapy is delayed, treatment with study drug should be continued 
during the delay phase unless criteria for stopping study drug are also met (see Section 6.5). If 
there is a delay in the start of a new cycle of more than 28 days due to insufficient recovery from 
toxicity (with all chemoimmunotherapy drugs withheld), subjects will permanently discontinue 
chemoimmunotherapy. However, the start of a new cycle after more than a 4-week delay (with all 
drugs withheld) may occur if there is clear clinical benefit and only after approval by the sponsor. 
Subjects who discontinue chemoimmunotherapy without disease progression will continue study 
drug until disease progression or unacceptable toxicity.
The following parameters must be met on the first day of each cycle of chemotherapy (other than 
Cycle 1):
!
platelet count ∋75,000 cells/∗L (prior platelet transfusion is allowed)
!
subjects with thrombocytopenia due to bone marrow infiltration from lymphoma are allowed 
to have ∋50,000 cells/∗L on the first day of the cycle
!
hemoglobin ∋8 g/dL (∋4.96 mmol/L) (prior red blood cell transfusion or recombinant human 
erythropoietin use is allowed)
!
ANC ∋1,000 cells/∗L (growth factor use is allowed, eg, granulocyte colony stimulating factor 
or granulocyte-macrophage colony-stimulating factor)
6.5.
Study Drug Administration
Ibrutinib (4 capsules for a dose of 560 mg) or placebo should be administered orally with a glass 
of water at approximately the same time each day. The capsules should be swallowed whole with 
water and should not be opened, broken, or chewed. Avoid grapefruit and Seville oranges with 
ibrutinib treatment. Ibrutinib administration should continue until disease progression or until no 
longer tolerated by the subject. If a dose 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.
One bottle of study drug will be administered at Cycles 1 to 6. Subjects will return in 3 or 4 weeks 
for their Cycle 7 visit. Starting at Cycle 7, 2 bottles of study drug will be administered. 
Post-chemotherapy period visits (dispensing of study drug, safety assessments, and clinical lab 
assessments) can occur earlier to align with efficacy assessments. At each study visit, sufficient 
study drug required for treatment until the next visit should be dispensed. Unused study drug 
dispensed during previous visits must be returned and drug accountability records updated. 
Returned capsules cannot 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.
6.5.1.
Study Drug (Ibrutinib or Placebo) Dose Modifications
Treatment with study drug should be held for any unmanageable, potentially study drug-related 
toxicity that is Grade ∋3 in severity. Study drug may be held for a maximum of 28 consecutive 
days for drug-related toxicity. Study drug should be discontinued permanently in the event of a 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
50
Status: Approved,  Date: 29 August 2022
drug-related toxicity lasting more than 28 days. 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. Changes must be recorded in the Dosage Administration page 
of the CRF.
The below actions in Table 7 and Table 8 should be taken for the following drug related toxicities:
!
Grade 3 or greater neutropenia with infection or fever 
!
Grade 4 neutropenia (ANC <0.5 x 109/L [ie, <500/∗L]) for >14 days
!
Grade 3 thrombocytopenia (platelets <50 x 109/L [ie, <50,000/∗L]) in the presence of 
significant bleeding
!
Grade 4 thrombocytopenia (platelets <25 x 109/L [ie, <25,000/∗L])
!
Grade 3 or greater non-hematological toxicity (noting specific Table 8 recommendations for 
Grade 3 or higher cardiac failure and cardiac arrhythmias).
!
Grade 2 cardiac failure (Table 8)
!
Any other Grade 4 or unmanageable Grade 3 hematological toxicity.
Table 7:
Ibrutinib / Placebo Dose Modifications for Ibrutinib Toxicities for Events not Specified in 
Table 8
Occurrence
Action
First
Hold study drug until recovery to Grade ≤1 or baseline; may restart at 
original dose levela
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
a.
When resuming treatment, restart at the same or lower dose based on benefit-risk evaluation. If the 
toxicity reoccurs, reduce daily dose by 140 mg.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
51
Status: Approved,  Date: 29 August 2022
Table 8:
Ibrutinib / Placebo Dose Modifications for Cardiac Failure or Cardiac Arrhythmias 
Events
Occurrence
Action
Grade 2 cardiac failure
First
Hold study drug until recovery to Grade ≤1 or baseline; 
restart at 1 dose level lower (3 capsules [ie, 420 mg 
daily])
Second
Hold study drug until recovery to Grade ≤1 or baseline; 
restart at 1 dose level lower (2 capsules [ie, 280 mg 
daily])
Third
Discontinue study drug
Grade 3 cardiac arrhythmias
First
Hold study drug until recovery to Grade ≤1 or baseline; 
restart at 1 dose level lower (3 capsules [ie, 420 mg 
daily])a
Second
Discontinue study drug
Grade 3 or 4 cardiac failure
Grade 4 cardiac arrhythmias
First
Discontinue study drug
a.
Evaluate the benefit-risk before resuming treatment.
7.
TREATMENT COMPLIANCE
The study drug 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. Administration of the study drug must be recorded 
in the subject’s source documents. The study drugs may not be used for any purpose other than 
that outlined in this protocol, including other human studies, animal investigations, or in vitro 
testing.
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 pharmacy manual/study site 
investigational product manual.
8.
CONCOMITANT THERAPY
Concomitant therapies must be recorded throughout the study beginning with signing of informed 
consent to 30 days after the last dose of study drug. All therapies (prescription or over-the-counter 
medications, including vaccines, vitamins, herbal supplements; non-pharmacologic therapies such 
as electrical stimulation, acupuncture, special diets, exercise regimens) different from the study 
drug must be recorded in the CRF. Recorded information will include a description of the type of 
the drug, treatment period, dosing regimen, route of administration, and indication.
8.1.
Concomitant Medications to be used with Caution
Concomitant Use of Ibrutinib /Placebo and CYP3A Inhibitors/Inducers Drugs
Ibrutinib is metabolized primarily by CYP3A (Section 1.3.1). Concomitant use of ibrutinib and 
drugs that strongly or moderately inhibit CYP3A can increase ibrutinib exposure and strong 
CYP3A inhibitors should be avoided.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
52
Status: Approved,  Date: 29 August 2022
Co-administration of ketoconazole, a strong CYP3A inhibitor, in 18 healthy subjects increased
exposure (Cmax and AUC0-last) of ibrutinib by 29- and 24-fold, respectively. In a dedicated
drug-drug interaction study in patients with B-cell malignancies, co-administration of
voriconazole increased Cmax and AUC by 6.7-fold and 5.7-fold, respectively. In clinical studies,
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. Voriconazole and posaconazole can be used concomitantly with IMBRUVICA as per
dose recommendations in Table 9. All other strong inhibitors of CYP3A (eg, ketoconazole,
indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole,
nefazodone, and cobicistat) should be avoided and an alternative with less CYP3A inhibitory
potential should be considered. If the benefit outweighs the risk and a strong CYP3A inhibitor
must be used, see recommended dose modifications in the table below. In patients with B-cell
malignancies, co-administration of CYP3A inhibitor erythromycin increased Cmax and AUC by
3.4-fold and 3.0-fold, respectively. If a moderate CYP3A inhibitor (eg, fluconazole, erythromycin, 
amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, imatinib, 
verapamil, amiodarone, dronedarone) is indicated, reduce the dose as per recommended dose 
modifications in Table 9. 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.
Table 9:
Dose Modifications for Ibrutinib for Subjects Receiving Concomitant CYP3A Inhibitors
Co-administered Drug
Recommended Ibrutinib Dose for the Duration of the 
Inhibitor Use a
!
Mild CYP3A inhibitors
No dose adjustment required
!
Moderate CYP3A inhibitors
280 mg once daily
!
Voriconazole
!
Posaconazole at doses less than or equal 
to suspension 200 mg BID
140 mg once daily
!
Other strong CYP3A inhibitors
!
Posaconazole at higher doses b
Avoid concomitant use and consider alternative with less 
CYP3A inhibitory potential.
If these inhibitors will be used short-term (such as antiinfectives 
for 7 days or less), interrupt ibrutinib.
If the benefit outweighs the risk, and long-term dosing with a 
CYP3A inhibitor is required (more than 7 days), reduce 
ibrutinib dose to 140 mg once daily for the duration of the 
inhibitor use.
a.
Monitor for adverse reactions to ibrutinib and interrupt or modify dose as recommended.
b.
Posaconazole at higher doses (posaconazole suspension 200 mg three times daily or 400 mg twice daily, 
posaconazole IV injection 300 mg once daily, and posaconazole delayed-release tablets 300 mg once daily).
Key: BID = twice a day; CYP = cytochrome P450.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
53
Status: Approved,  Date: 29 August 2022
Administration of ibrutinib with rifampin, a strong CYP3A inducer, decreases ibrutinib plasma 
concentrations 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-inducers
and
https://medicine.iu.edu/internal-
medicine/specialties/clinical-pharmacology/drug-interaction-flockhart-table.
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-glycoprotein (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 gastrointestinal tract, 
narrow therapeutic range P-gp substrates such as digoxin should be taken at least 6 hours before 
or after ibrutinib.
Concomitant Use of QT Prolonging Agents
Any medications known to cause QT prolongation should be used with caution; periodic 
monitoring with ECGs and electrolytes should be considered.
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. Consultation with the sponsor’s Medical Monitor is recommended. Subjects should 
be observed closely for signs and symptoms of bleeding. No dose reduction is required when study 
drug is restarted.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
54
Status: Approved,  Date: 29 August 2022
8.2.
Prohibited Concomitant Medications
Any concurrent chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy 
are prohibited. 
Corticosteroids are allowed when used to premedicate or manage rituximab infusion-related 
reactions or contrast allergies, as well as short courses (<14 days) of corticosteroid treatment for 
non-cancer related medical reasons (ie, treatment for autoimmune cytopenias) at doses not to 
exceed 100 mg/day of prednisone or equivalent. Otherwise, corticosteroid dosages equivalent to 
prednisone >20 mg/day are not permitted; routine infusion premedication with corticosteroid doses 
of >100 mg IV prednisolone (or equivalent) is also not permitted.
8.3.
Medications Permitted During Treatment
Antiemetics are permitted if clinically indicated. Standard supportive care medications are 
permitted, including pre-medication for rituximab and bendamustine infusions per the rituximab 
and bendamustine package inserts, respectively. Prophylaxis for tumor lysis syndrome may be 
administered to subjects considered to be at risk. Use of neutrophil growth factors (filgrastim and 
pegfilgrastim) are permitted per the ASCO guidelines or according to the institution’s guidelines 
(Ozer 2000). Use of anti-microbial prophylaxis (eg, pneumocystis pneumonia prophylaxis with 
sulfamethoxazole and trimethoprim or equivalent), according to the institution’s guidelines, is 
recommended. Hepatitis B surface antigen positive subjects should receive appropriate 
prophylaxis according to local standards (eg, lamivudine).
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The
Time and Events Schedule summarizes the frequency and timing of efficacy,
pharmacokinetic, biomarker, PROs, and safety measurements applicable to this study.
Additional serum or urine pregnancy tests may be performed, 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.
Total blood volume for the study is approximately 20 mL for clinical laboratory assessments at 
the start of each cycle of chemotherapy and 15 mL every 8 weeks thereafter plus 20 mL at the 
End-of-Treatment (EOT) and every 12 weeks in Follow-up prior to PD, 20 mL for 
pharmacokinetics in Cycles 1 and 2 plus 2 mL in Cycle 3, and 2 mL for pregnancy testing at
screening [for women of childbearing potential only]).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
55
Status: Approved,  Date: 29 August 2022
9.1.2.
Screening Phase
All subjects must sign an informed consent form (ICF) prior to the conduct of any study-related 
procedures. During this phase, eligibility criteria will be reviewed and a complete clinical 
evaluation will be performed as specified in the Time and Event Schedule. Screening procedures 
will be performed up to 30 days (60 days for CT, MRI, PET, and bone marrow biopsy and aspirate) 
before randomization. Laboratory tests noted in the inclusion criteria must be within the limits 
specified prior to randomization. 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. 
During the Screening Phase, eligibility criteria will be reviewed and a complete clinical evaluation 
will be performed as specified in the Time and Events Schedule. This evaluation will include a 
complete medical history, including confirmation of iNHL (FL or MZL) diagnosis (based on 
paraffin embedded biopsy tissue block or slides, preferably of lymph node origin), and relevant 
laboratory reports, key features of disease, and prior cancer therapy. The subject’s baseline 
cardiovascular status will be assessed by an ECG.
Subjects will be required to have confirmation of disease (FL or MZL) prior to randomization. A
report from the local laboratory may be acceptable to demonstrate diagnosis of FL or MZL and
must be sent to the central laboratory and the sponsor for review and confirmation of the diagnosis. 
For subjects who do not have this report available or the report is deemed not acceptable by the 
central laboratory, a tumor tissue block or slides must be sent to the central laboratory and 
confirmation of iNHL (FL or MZL) diagnosis must be obtained from the central laboratory prior 
to randomization.
For subjects with MZL, if diagnosis was approved based on the local pathology report, a 
formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained slides must still be sent to the 
central laboratory after randomization for central confirmation of the diagnosis.
For subjects with FL, if diagnosis is determined from review of the local pathology report, a 
minimum of 5 unstained slides, sectioned at a thickness of 5 μm, must still be sent to the central 
laboratory for MRD analysis. 
The screening bone marrow biopsy will be obtained to document bone marrow involvement with 
lymphoma and does not need to be shipped to the central laboratory.
9.1.3.
Treatment Phase
The Treatment Phase will begin at randomization and will continue until study drug 
discontinuation due to disease progression, or unacceptable toxicity, whichever occurs first. 
Subjects should start study drug treatment within 72 hours after randomization. The last 
measurements taken on Day 1 of Cycle 1 before administration of study drugs or at screening 
(whichever value was last) will be defined as the baseline values for safety assessments and 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
56
Status: Approved,  Date: 29 August 2022
treatment decisions. Laboratory values that are obtained prior to Cycle 1, Day 1 should be repeated 
if they were collected more than 5 days prior to the start of study drug (ibrutinib or placebo). These 
values should be consistent with the values in the inclusion and exclusion criteria in order for the 
subject to receive treatment. 
The FACT-Lym and EQ-5D-5L will be collected at the beginning of the clinic visits, preferably, 
before any procedures or physician interactions. After the PRO questionnaires have been 
administered, a symptom-directed physical examination (including lymphoma B symptoms and 
ocular changes) will be conducted (see Section 9.5). Laboratory testing scheduled for the same 
visit should be conducted preferably, after the PRO questionnaires have been administered. 
Adverse events and changes to concomitant medications will be recorded. Subjects will be 
evaluated throughout this phase for possible toxicities. Dose modifications will be made as 
according to criteria described in the protocol (see Section 6.2, 6.3, and 6.5.1).
Adverse events and changes to concomitant medications will be recorded. Subjects will be 
evaluated throughout this phase for possible toxicities. Dose modifications will be made as 
according to criteria described in the protocol (see Section 6). 
All subjects will visit the study site on Day 1 of the first 6 cycles. Subjects receiving BR will return 
on Day 2 of the first 6 cycles to receive bendamustine. Each cycle is 28 days for BR and 21 days 
for R-CHOP. When all evaluations have been completed at each of these visits, and it has been 
determined that the subject may continue to receive treatment, chemoimmunotherapy with either 
BR or R-CHOP will be administered IV and 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. After the end of 
chemotherapy, clinic visits for study-related procedures will occur every 8 weeks. Clinical 
evaluations and laboratory studies may be repeated more frequently, if clinically indicated. If a 
subject shows signs of progression on physical examination or laboratory assessment, the subject 
may continue study treatment until progression is confirmed by CT scan. If progressive disease is 
diagnosed, then the subject will discontinue study drug, complete the End-of-Treatment Visit 
within 30 days after the last dose of study drug, and enter the Posttreatment Follow-up Phase.
End of Treatment
An EOT Visit will be scheduled within 30 days after the last dose of study drug 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 
progression, adverse event, or other reasons and enter the Posttreatment Follow-up Phase should 
have the EOT Visit completed before starting any subsequent anti-lymphoma treatment. If a 
subject is unable to return to the site for the EOT Visit, the subject should be contacted to collect 
adverse events that occur within 30 days after the last dose of study drug.
9.1.4.
Posttreatment Phase (Follow-Up)
The Posttreatment Follow-up Phase is the time between the EOT Visit and the end of study 
participation or end of study. 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
57
Status: Approved,  Date: 29 August 2022
Progression-free survival is the primary endpoint for this study. Therefore, for subjects who 
discontinue treatment prior to disease progression, it is imperative that the regularly scheduled 
disease assessments are performed throughout the Posttreatment Follow-up Phase until disease 
progression, death, or study end, whichever occurs first, as outlined in Section 9.2.1. Evidence of 
disease progression should be done in accordance with the Revised Response Criteria for 
Malignant Lymphoma and it has to be documented at the time at which it is first detected 
(Cheson 2007). 
For all subjects who reach progression, the sponsor medical monitor should be notified within 
24 hours of the investigator becoming aware of the progression. Progression needs to be confirmed 
by the sponsor medical monitor before subsequent therapy is started. Following disease 
progression, contact will be made to determine survival status and subsequent antineoplastic 
therapy every 24 weeks until death, lost to follow-up, withdrawal of consent, or study end. If the 
information on survival status and subsequent therapy is obtained via telephone contact, then 
written documentation of the communication must be available for review in the source 
documents. If the subject has died, then the date and cause of death will be collected and 
documented on the CRF.
Following disease progression, the PROs will be performed once after approximately 24 weeks. 
Subjects who visit the site for the follow-up assessments should complete the PRO questionnaires
at that time. If the PROs are 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 questionnaires. If the subject is unable to complete the PROs during the Post-treatment Phase, 
the reason for not completing the questionnaire will be documented (ie, too ill, subject refused).
9.1.5.
Clinical Cutoffs
Three clinical cutoffs are planned. The first 2 clinical cutoffs will occur when approximately 
151 and 252 PFS events have been observed, respectively. The interim analysis and the primary 
analysis (ie, final analysis of the primary endpoint PFS) will take place at these 2 clinical cutoffs, 
respectively; subject treatment assignment will be unblinded and placebo treatment will be stopped
at the primary analysis. The last cutoff will occur at the time of the end of study, when 
approximately 50% of the randomized subjects have died or the sponsor terminates the study, 
whichever comes first. The end of study clinical cutoff is chosen to ensure reasonable maturity of 
the survival data and allow estimation of median OS. Investigators will be informed when the 
clinical cutoffs are to occur.
The Time and Events Schedule after clinical cutoff for the primary analysis is shown in Table 2. 
The following data will continue to be collected for all subjects after the clinical cutoff for the 
primary analysis
survival data, best response and progressive disease on subsequent 
anti-lymphoma therapy, and reports of new malignancies. Subjects without progressive disease 
will continue to have disease assessments according to standard of care, until disease progression.
In addition, the following data will be collected for subjects still receiving study treatment after 
the clinical cutoff for the primary analysis: study drug administration, adverse events during 
treatment and within 30 days after last dose that are either serious, Grade ≥3 or result in dose 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
58
Status: Approved,  Date: 29 August 2022
interruption, reduction, or discontinuation; major hemorrhages (see Section 12.3.3.1), new
malignancies of any grade; concomitant medications associated with a serious adverse event, and 
laboratory assessments and vital signs indicative of the onset and recovery from an adverse event. 
Where allowed by local law, public records may be used to document death for the purpose of 
obtaining survival status.
9.2.
Efficacy
9.2.1.
Evaluations
Eligible subjects must have at least 1 measurable site of disease by radiological assessment 
(Cheson 2007). Efficacy evaluations will be conducted as specified in the Time and Events 
Schedule (Table 1 and Table 2) and may include the following: CT scans, MRI, PET using 
[18F]-fluorodeoxyglucose (FDG), bone marrow aspirate and biopsy, physical examination 
including lymphoma B symptoms, or 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. Subject lymphoma related symptoms and concerns will be measured by 
the lymphoma subscale of the FACT-Lym and health status will be measured by the EQ-5D-5L. 
9.2.1.1.
Radiographic Image Assessments (CT/MRI)
Efficacy assessments with CT scans with IV contrast of the neck (full neck views must be 
obtained), chest, abdomen, and pelvis and any other location where disease was present at 
Screening will be performed at every evaluation. Subjects who are intolerant of IV CT contrast 
agents will have CT scans performed with oral contrast. Contrast is required unless otherwise 
contraindicated. 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; however, the CT scanning must be done according to the imaging requirements 
provided to the radiologist in the radiology manual to ensure that an optimized CT 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 neck, chest, abdomen, and pelvic CT scans. 
Brain MRI and lumbar puncture are required only if clinically indicated.
Radiological assessments will be performed at Screening, Week 12, Week 24, and then every 
16 weeks for 3 years, thereafter every 24 weeks (±7-day window for all assessments) until disease 
progression, death, or the clinical cutoff for the final analysis of the primary endpoint, whichever 
comes first. Assessments should be scheduled on a calendar basis; interruptions of treatment will 
not affect when scans are obtained. 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 until disease progression, death, or clinical cutoff for the final 
analysis of the primary endpoint, whichever occurs first. 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
59
Status: Approved,  Date: 29 August 2022
9.2.1.2.
Positron Emission Tomography (PET Scan)
Whole body FDG-PET scan (skull base to the proximal femur) will be performed at screening and 
at the time of maximal tumor reduction (eg, CR or 2 consecutive CT scans showing no further 
tumor reduction). 
Assessment of PET results is based on published criteria (Juweid 2007). 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 
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 start of treatment must have a 
repeat bone marrow evaluation (ie, bone morrow aspirate and biopsy) at the time of CR (preferably 
within 30 days of the initial documentation of CR). If bone marrow involvement is confirmed with 
morphology, immunohistochemistry does not need to be performed.
9.2.1.4.
Fluid Aspiration at Other Sites of Disease
If diagnosis of disease progression is based solely on sites of disease with fluid accumulation 
(ascites, pleural or pericardial effusions), a diagnostic sample of fluid must be obtained and
cytology or flow cytometry confirmation of the presence of lymphoma is required. 
9.2.1.5.
Physical Examination 
During the Screening, Treatment, and Posttreatment Follow-up Phases (see Time and Event 
Schedules for exact procedures), subjects should have physical examinations to evaluate possible 
presence of palpable lymph nodes, tumor masses, or enlargement of spleen and liver. 
Symptom-directed questions will be asked to evaluate for presence of B-symptoms. 
9.2.1.6.
Patient-Reported Outcomes
Two PRO instruments, the lymphoma subscale of the FACT-Lym and EQ-5D-5L, will be 
administered up to the clinical cutoff for the primary analysis, at the timepoints specified in Table 1
of the Time and Events Schedule; no PROs will be assessed after clinical cutoff for primary 
analysis (Table 2). The FACT-Lym (Attachment 1) was originally developed to assess functional 
status and well-being of patients with NHL (Eremenco 2004). The lymphoma scale of the FACT-
Lym includes 15 items and scores range from 0 to 60, with each item scored on a 5-point scale 
from 0 (not at all) to 4 (very much). Higher scores represent better health status with respect to 
fewer disease related symptoms and fewer disease related concerns of patients. In patients with 
FL, the lymphoma subscale has been shown to differ according to disease state. Patients who have 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
60
Status: Approved,  Date: 29 August 2022
relapsed disease report more disease-related symptoms and concerns than patients who are either 
newly diagnosed, in partial or complete remission, or completely disease free (Pettengell 2008). 
Carter et al (2008) and Cella et al (2005) reported a minimal important change score for the 
Lym subscale in a relapsed/refractory MCL population ranges 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.
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome 
(Attachment 2). 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 (Rabin 2011). For purposes of 
this study, the EQ-5D-5L will be used to generate utility scores for use in cost effectiveness
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). The scores for the 5 separate 
questions are categorical and should not be analyzed as cardinal numbers. However, 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.
9.2.2.
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 are progression-free and alive or have unknown status 
will be censored at the last tumor assessment.
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.
!
Duration of response (CR or PR) is defined as duration 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. Subjects who are progression-free and 
alive or have unknown status will be censored at the last tumor assessment.
!
Time to worsening (TTW) in the Lym subscale of the FACT-Lym is defined as the time from 
the date of randomization to the start date of the worsening of patient symptoms. Worsening 
is defined by a 5-point decrease from baseline in patient symptoms.
!
Safety parameters of ibrutinib when combined with either BR or R-CHOP.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
61
Status: Approved,  Date: 29 August 2022
Exploratory Endpoints
!
Time-to-next treatment is measured from the date of randomization to the start date of any 
anti-lymphoma treatment subsequent to the study treatment. Subjects without subsequent 
treatment will be censored at the date of the last site visit.
!
Minimal residual disease negative rate is defined as the proportion of FL subjects who reach 
MRD-negative disease status.
!
The mean change from baseline in EQ-5D-5L scores for each post baseline assessment.
!
Frequency of biomarkers associated with resistance to ibrutinib in subjects who develop 
resistance compared to those who respond
!
Pharmacokinetic parameters (eg, oral plasma clearance, oral volume of distribution at steady 
state) or metrics of systemic exposure (eg, AUC, minimum observed serum concentration) of 
ibrutinib after oral daily dosing. Parameters describing the potential relationships between 
ibrutinib metrics of exposure with relevant clinical, or biomarker information.
9.2.3.
Efficacy Criteria
9.2.3.1.
Assessment of Disease Response and Progressive Disease
Disease evaluations, for the purpose of the study result analyses, will be performed by the 
investigators according to the Revised Response Criteria for
Malignant Lymphoma 
(Cheson 2007). All efficacy assessments must continue until disease progression (even if 
subsequent therapy is started), withdrawal of consent from study participation, or clinical cutoff 
for final analysis of the primary endpoint PFS. For all subjects with disease progression, the 
sponsor medical monitor should be notified within 24 hours of the investigator becoming aware 
of the progression. Progression needs to be confirmed by the sponsor medical monitor before 
subsequent therapy is started.
9.2.3.2.
Definition of Measurable and Assessable Disease
Eligible subjects must have at least 1 measurable site of disease by radiological assessment. 
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.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
62
Status: Approved,  Date: 29 August 2022
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 gastrointestinal 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.
9.2.3.3.
Response Categories
The response categories being used to assess efficacy are based on the Revised Response Criteria 
for Malignant Lymphoma (Cheson 2007).
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 gastrointestinal 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.
!
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.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
63
Status: Approved,  Date: 29 August 2022
!
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 the appearance of any of the criteria 
noted below:
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.
!
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. 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
64
Status: Approved,  Date: 29 August 2022
!
Cytology confirmation of lymphoma 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) cytologic confirmation of the
presence of lymphoma is required.
9.3.
Pharmacokinetics
9.3.1.
Evaluations
In both treatment arms, blood samples will be collected from all subjects for determination of 
plasma concentrations of ibrutinib and the PCI-45227 metabolite (if possible and judged relevant)
according to the Time and Events Schedule. These sparse samples will be used for the development 
of a population-based pharmacokinetic model.
Subjects should refrain from taking the study drug on the morning of study visits designated for 
pharmacokinetic sampling until instructed to do so at the site. Subjects 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, area under the plasma concentration-time curve 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 and Minimal Residual Disease
Blood samples for biomarker evaluations will be collected from all subjects on Day 1 of Cycle 1, 
Day 1 of Cycle 2 and at the time of suspected disease progression, preferably within 24 to 48 hours 
of the last dose of ibrutinib, or the EOT Visit for subjects who discontinue treatment without 
disease progression.
A portion of the FFPE tissue block or slides collected for confirmation of disease for FL subjects 
prior to randomization may be used for central assessment of MRD and for biomarker analyses. If 
the FFPE tissue block or slides were not needed for confirmation of diagnosis, additional tissue or 
slides will need to be sent to the central laboratory for MRD analysis. For subjects with FL, blood 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
65
Status: Approved,  Date: 29 August 2022
samples for MRD will be collected on Day 1 of Cycle 1. For those subjects with FL who have 
achieved CR, blood samples will be collected at subsequent scheduled disease assessment visits 
for assessment of MRD (see Time and Events Schedule Table 1) until clinical cutoff for the 
primary analysis. Thereafter samples will no longer be collected for MRD analysis (Table 2). A 
portion of the bone marrow sample collected to confirm CR may be assessed for MRD, if available.
Current technologies, designed to identify and track patient-specific B-cell clones, will be used to 
assess MRD. Specific amplification and sequencing of the CDR3 region of the B-cell receptor 
affords identification (over-represented clones at baseline) and sensitive tracking (post-treatment) 
of a patient’s specific clones. 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 PCR (qRT-PCR), gene expression profiling, 
microRNA (miRNA), methylation, mutational and RNA sequencing (RNASeq) analyses, or other 
similar technologies utilized for analysis of ribonucleic acid (RNA) or somatic deoxyribonucleic 
acid (DNA) analysis. The blood samples may also be used for secreted protein or flow cytometry 
analyses to characterize immune response changes to the treatment. Genes identified in previous 
studies with ibrutinib will 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.
Biomarker and MRD analyses are dependent on the availability of appropriate assays and clinical 
response rates. Samples will be collected only at sites where local regulations and shipping 
logistics permit. 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 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 data.
Additional Collections
If it is determined at any time before study completion that additional material is needed from a 
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.
9.5.
Safety Evaluations
The study will include the following evaluations of safety and tolerability according to the 
timepoints provided in the Time and Event schedule. Any clinically significant abnormalities 
persisting at the end of treatment will be followed by the investigator until resolution or until a 
clinically stable endpoint is reached or until the end of the study.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
66
Status: Approved,  Date: 29 August 2022
Adverse Events
All adverse events will be reported from the time a signed and dated ICF is obtained until 30 days 
following the last dose of study drug. Adverse events reported after 30 days following the last dose 
of study drug should also be reported if considered related to ibrutinib/placebo. Progressive disease 
of lymphoma should not be reported as an adverse event, but instead, the clinical symptom(s) that 
is associated with disease progression should be reported. All events that meet the definition of a 
serious adverse event will be reported as serious adverse events.
The sponsor will evaluate any safety information that is spontaneously reported by an investigator 
beyond the time frame specified in the protocol. 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. Adverse events 
will be graded according to the NCI-CTCAE, Version 4.03. 
All deaths, treatment discontinuations, and serious adverse events will be reviewed by the 
sponsor’s responsible physician, who will be blinded to treatment group. Review will be performed 
on an ongoing basis to identify potential safety concerns for further review by the DMC.
Adverse Events of Interest
Major hemorrhage has been identified as an adverse event of special interest and will require
enhanced reporting and data collection (See Section 12.3.3 for details).
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. 
Blood samples to assess the safety of study drug 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 first dose 
of study drug. 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 study drug (dose change, 
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 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 the Time 
and Events Schedule:


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
67
Status: Approved,  Date: 29 August 2022
!
Hematology Panel
-hemoglobin
-absolute neutrophil count
-white blood cell (WBC) count
- absolute lymphocyte count
-platelet count
!
Coagulation Studies 
-aPTT (activated partial thromboplastin time)
-INR/PT (international normalized ratio/prothrombin time)
!
Serum Chemistry Panel
-sodium
-AST
-potassium
-ALT
-creatinine
-lactate dehydrogenase
-total bilirubin
-alkaline phosphatase
-albumin
!
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 negative for 
Hepatitis surface antigen but positive for Hepatitis B core antibody do not require PCR testing 
and may be included in the study with prophylaxis. All other subjects who test positive for 
Hepatitis B core antibody must have Hepatitis B DNA by PCR performed and confirmed as 
negative prior to randomization, and may be included in the study following consultation with 
an infectious disease specialist. 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.
Carriers of Hepatitis B should be closely monitored for clinical and laboratory signs of active HBV 
infection and for signs of hepatitis during and for several months following rituximab treatment.
!
Pregnancy test (serum β-hCG or urine): for women of childbearing potential only
!
Beta2- microglobulin and serum immunoglobulin levels (IgG, IgM, IgA)
Vital Signs
Temperature, heart rate, and blood pressure will be recorded at Screening and at the timepoints
shown in the Time and Events Schedule. 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 chemotherapy 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 Time and 
Events Schedule.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
68
Status: Approved,  Date: 29 August 2022
Physical Examination 
The Screening physical examination will include, at a minimum, the general appearance of the 
subject, height and weight, examination of the skin, ears, nose, throat, lungs, heart, abdomen, 
extremities, musculoskeletal system, lymphatic system, and nervous system. During the Treatment 
Phase, limited symptom-directed physical examination and weight assessment is required. Review 
of symptoms 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. An assessment 
of lymphoma B-symptoms (fever, night sweats and weight loss), change in status of lymph nodes, 
liver and spleen should also be conducted. 
Echocardiogram or Multiple Uptake Gated Acquisition (MUGA) scans
An echocardiogram or multiple uptake gated acquisition (MUGA) scan is mandatory at screening 
for all subjects. Subjects who will receive R-CHOP must have left ventricular ejection fraction 
within institutional normal limits at screening. Echocardiogram may be performed thereafter, at 
any time during the study, as clinically indicated.
Electrocardiograms
Electrocardiogram will be performed for all subjects during Screening. Abnormalities noted at 
screening should be included in the medical history. Electrocardiograms may be repeated at any 
time during the study, as clinically indicated, particularly in subjects with arrhythmic symptoms 
(palpitations, lightheadedness, or new onset dyspnea).
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, or has not been lost to follow up or withdrawn consent before the end of the study.
10.2.
Discontinuation of Study Treatment
If a subject's study treatment must be discontinued before the end of the treatment regimen, this 
will not result in automatic withdrawal of the subject from the study.
A subject's study treatment (ibrutinib or placebo) should be discontinued if:
!
the investigator believes that for safety reasons (eg, adverse event) it is in the best interest of 
the subject to discontinue study treatment
!
the subject becomes pregnant
!
the subject experiences overt disease progression or relapse; however, if the subject has 
radiographic progression without clinical progression and alternate therapy is not initiated, 
study treatment may continue at the discretion of the investigator
!
unacceptable toxicity


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
69
Status: Approved,  Date: 29 August 2022
!
the subject refuses further treatment with the study drug
!
administration of study drug is interrupted for more than 4 weeks due to drug-related toxicities
!
a serious protocol violation has occurred that may compromise subject safety, as determined 
by the principal investigator or the sponsor
If a subject discontinues background chemotherapy, they will continue to receive study drug 
(ibrutinib or placebo) until one of the reasons for discontinuation of study drug given above is met. 
If a subject discontinues study drug only, they will continue to receive background chemotherapy 
until completion of 6 cycles unless disease progression or unacceptable toxicity is encountered.
End-of-Treatment and posttreatment assessments should be obtained and scheduled disease 
assessments should be continued until they complete the study.
If a subject discontinues study treatment (both study drug and background chemotherapy), EOT 
and posttreatment assessments should be obtained and scheduled assessments should be continued
until they complete the study.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:
!
lost to follow-up
!
withdrawal of consent
!
the sponsor discontinues the study
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. If a subject 
withdraws from the study before the end of the treatment phase, EOT assessments should be 
obtained.
11.
STATISTICAL METHODS
Statistical analysis will be performed 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:
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.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
70
Status: Approved,  Date: 29 August 2022
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. Details of 
the exact criteria defining this population will be specified in the statistical analysis plan.
Biomarker population: All randomized subjects with biomarker data collected.
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/R-CHOP +
placebo) is 20 months from randomization (Fowler 2011; Friedberg 2011), a target hazard 
ratio of 0.7 corresponds to an 8.6 months increase in median PFS for the treatment arm 
(BR/R-CHOP + ibrutinib) relative to the control (ie, 20 months versus 28.6 months, 
respectively)
c.
minimum 80% power 
d.
2-sided overall significance level of 0.05
e.
one interim analysis for efficacy at 60% of the planned total PFS events 
Using the above assumptions and based on a uniform accrual rate of approximately 26 subjects
per month, the study will enroll approximately 400 subjects (about 200 subjects to each arm) to 
observe 252 events in approximately 43 months from the first subject randomized. The length of 
time required to observe the targeted number of events would be longer if subjects were to 
withdraw from the study before events were observed.
The data cutoffs based on the interim and primary analysis (ie, final analysis of the primary 
endopoint PFS) will be when about 151 and 252 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 20 months to 28.6 months), the 
study has at least 80% power assuming a statistical significance level of 5% (2-sided).
11.3.
Efficacy Analyses
Descriptive statistics and subject listings will be used to summarize the data. For continuous 
variables, number of observations, means, standard deviations, medians, and ranges will be used.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
71
Status: Approved,  Date: 29 August 2022
For discrete variables, frequency will be summarized. Specific details will be provided in the 
Statistical Analysis Plan.
Comparisons between the 2 treatment arms will be performed as follows: for the continuous 
variables representing change from baseline to a particular postbaseline timepoint, analysis of 
variance will be used. For discrete variables, Cochran-Mantel-Haenszel Chi-square test will be 
used. For time-to-event variables, stratified log-rank test and stratified Cox proportion hazard 
model will be used unless if specified otherwise. All tests will be conducted at a 2-sided alpha 
level of 0.05 and 95% CI will be provided, unless stated otherwise.
11.3.1.
Primary Endpoint
The primary efficacy analysis will be based on the PFS and will be performed using the ITT 
population, which is defined as all randomized subjects. The Kaplan-Meier method will be used 
to estimate the distribution of PFS for each treatment group. The stratified log-rank test will be 
used to compare survival curves of PFS between the 2 treatment groups. The median PFS will be 
provided for each treatment group and the hazard ratio for (BR or R-CHOP) + ibrutinib relative to 
(BR or R-CHOP) + placebo and its associated 95% CI will be calculated based on the 
Cox proportional hazards model stratified by the following stratification factors:
!
background treatment (either BR or R-CHOP), 
!
iNHL histology (FL or MZL), 
!
refractory or relapsed disease (refractory defined as failing to achieve PR or better after the 
most recent treatment),
!
prior lines of therapy (1 or >1 line of therapy. Separate lines of therapy are defined as different 
regimens that are separated by disease progression, refractory disease, or relapsed disease). 
Hypothesis testing for the interaction between background therapy and treatment will be 
performed. If a significant interaction is observed, then the statistical inference for the treatment 
benefit will be made for each background therapy separately.
Subgroup analysis will be provided. The sensitivity analyses for PFS using different censoring 
mechanisms based on the ITT population, as well as analyses based on the PP population, will be 
performed similarly. Detailed PFS censoring rules and other sensitivity analyses will be specified 
in the Statistical Analysis Plan.
11.3.2.
Secondary Endpoints
For the secondary efficacy endpoints, OS will be compared using the stratified log-rank test. The 
Kaplan-Meier method will be used to estimate the distribution of OS for each treatment group. 
The hazard ratio for (BR or R-CHOP) + ibrutinib relative to (BR or R-CHOP) + placebo and its 
associated 95% CI will be calculated based on the stratified Cox proportional hazards model. The 
CR rate and ORR will be summarized and comparison of the rates between the 2 treatment groups 
will be performed using the Cochran-Mantel-Haenszel chi-square test adjusted for the stratification 
factors. The distribution of duration of response will be estimated using the Kaplan-Meier product 
limit method for those subjects with CR or PR. Multiplicity adjustments will be made for the 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
72
Status: Approved,  Date: 29 August 2022
hypothesis testing of secondary endpoints. Details will be specified in the statistical analysis plan.
See Section 11.3.4 for details on the secondary endpoint FACT-Lym PRO analyses.
11.3.3.
Exploratory Efficacy Endpoints
Time-to-next treatment is measured from the date of randomization to the start date of any 
anti-lymphoma treatment subsequent to the study treatment. Subjects without subsequent 
treatment will be censored at the date of the last site visit. The distribution of time-to-next treatment 
will be estimated using the Kaplan-Meier product limit method. See Section 11.3.4 for details on 
the exploratory endpoint EQ-5D-5L PRO analyses.
11.3.4.
Patient-Reported Outcomes
Time to worsening (TTW) on the Lym subscale of the FACT-Lym is defined from the date of 
randomization to the start date of the worsening of patient symptoms. Worsening is defined by a 
5-point decrease from baseline in patient symptoms. The analysis of TTW will be analyzed using 
log-rank test. The distribution of TTW will be estimated using the Kaplan-Meier product limit 
method.
Descriptive statistics (number of observations, mean, standard deviation, median, minimum, 
maximum) of FACT-Lym subscale and EQ-5D-5L scores will be calculated for baseline and 
postbaseline assessments, as well as change from baseline to postbaseline assessments. Other 
exploratory analyses may be performed as appropriate.
11.4.
Pharmacokinetic Analyses
The plasma concentration data for ibrutinib and, if possible and judged relevant, PCI-45227 at 
each timepoint will be summarized using descriptive statistics. 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 per treatment 
group. Subjects will be excluded from the pharmacokinetic analysis if their data do not allow for 
accurate assessment of the pharmacokinetic parameters (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 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.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
73
Status: Approved,  Date: 29 August 2022
11.5.
Biomarker Analyses
The MRD negative rate will be evaluated in FL subjects within and between treatment arms of this 
study. Biomarkers identified in other studies of ibrutinib will be explored in samples collected for 
MRD assessment. 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). Results may be presented in a separate report.
11.6.
Safety Analyses
All safety analyses will be based on the safety population and will be performed by the treatment 
actually received. 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 current Medical Dictionary for Regulatory Activities. 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. 
Treatment-emergent adverse events are adverse events that occur after the first dose of study drug, 
and within 30 days following the last dose of study drug; any adverse event that is considered 
study drug-related regardless of the start date of the event; or any adverse event that is present at 
baseline but worsens in severity or is subsequently considered drug-related by the investigator. 
The number and percent of subjects with treatment-emergent adverse events will be summarized 
according to intensity (NCI-CTCAE, Version 4.03) and drug relationship as well as categorized 
by system organ class and preferred term. 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 serious adverse event.
Clinical Laboratory Tests
Hematology and serum chemistry laboratory data up to 30 days after last dose or EOT visit date, 
whichever is later, will be reported in International System of Units. 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 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. Shift tables from baseline to worst value on study (from treatment 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
74
Status: Approved,  Date: 29 August 2022
start to 30 days after the last dose or the End-of-Treatment Visit date, whichever is later) will also 
be provided. The worst toxicity grade during the study will be tabulated.
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, and blood pressure (systolic and diastolic) 
values and changes from baseline will be summarized at each scheduled time point. The percentage 
of subjects with values beyond clinically important limits will be summarized.
Electrocardiogram data at baseline will be summarized.
Physical Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
Physical examination findings will be summarized at each scheduled time point. Descriptive 
statistics will be calculated at baseline and for observed values and changes from baseline at each 
scheduled time point. Frequency tabulations of the abnormalities will be made.
11.7.
Interim Analysis
An interim analysis using classical O’Brien & Fleming boundary for efficacy will be conducted 
after observing approximately 60% (151) PFS events (PD or death) (O’Brien 1979). The stopping 
boundaries will be implemented by Lan-Demets spending function using East® software v5.3 to 
control the 2-sided Type I error of 0.05 for the comparison of the PFS endpoint. The 2-sided 
cumulative alpha spent will be 0.0076 at the interim and 0.05 at the final analysis. Assuming the 
enrollment rate is 26 subjects per month, the interim analysis will take place approximately 
25 months after the first subject has been randomized. The independent DMC may make 
recommendations regarding study continuation if the pre-specified boundary is crossed for 
efficacy. The roles and responsibilities of the DMC will be detailed in the DMC Charter.
11.8.
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 unblinded data on an ongoing basis to ensure the safety 
of the subjects enrolled in this study and evaluate efficacy.
In addition to the planned interim analysis for efficacy, 3 safety review meetings are planned that 
will occur approximately 2 months after 80 subjects have been randomized (20% of expected 
enrollment), 2 months after 200 subjects have been randomized, and 2 months after all 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 DMC chair may request additional safety interim analyses 
and more frequent monitoring. The plan for monitoring subject safety and evaluating efficacy, and 
the roles and responsibilities of the DMC, will be detailed in the DMC Charter.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
75
Status: Approved,  Date: 29 August 2022
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 can 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])
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*


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
76
Status: Approved,  Date: 29 August 2022
*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.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must be 
reported as a serious and unexpected suspected adverse reaction even if it is a component of the 
study endpoint (eg, all-cause mortality).
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 BR and R-CHOP, the 
expectedness of an adverse event will be determined by whether or not it is listed in the applicable 
package insert.
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.
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).


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
77
Status: Approved,  Date: 29 August 2022
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 drug that may require expedited reporting and/or safety 
evaluation include, but are not limited to:
!
overdose of a sponsor study drug
!
suspected abuse/misuse of a sponsor study drug
!
inadvertent or accidental exposure to a sponsor study drug
!
medication error involving a sponsor product (with or without subject/patient exposure to the 
sponsor study drug, eg, name confusion)
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.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until 30 days after the last dose of ibrutinib or 
the start of subsequent systemic anticancer therapy if earlier. Serious adverse events, including 
those spontaneously reported to the investigator within 30 days after the last dose of study drug, 
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.
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 for the entire follow-up period including post-progression follow-up for OS.
Progressive disease (for which there are protocol-specific assessments), should NOT be reported 
as an adverse event, but instead symptoms/clinical signs of unexpected disease progression are to 
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.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
78
Status: Approved,  Date: 29 August 2022
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the CRF. 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 study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
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 drug. 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. 
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:
!
study number
!
statement, in the local language(s), that the subject is participating in a clinical study
!
investigator's name and 24-hour contact telephone number
!
local sponsor's name and 24-hour contact telephone number (for medical staff only)
!
site number
!
subject number
!
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


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
79
Status: Approved,  Date: 29 August 2022
!
the event returns to baseline, if a baseline value/status is available
!
the event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct
!
it becomes unlikely that any additional information can 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:
!
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility)
!
Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.
!
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, scans, sampling for laboratory 
tests, bone marrow sampling) or protocol therapy administration. Hospitalization or prolonged 
hospitalization for a complication of such procedures remains a reportable serious adverse 
event.
12.3.3.
Adverse Events of Special 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 events 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.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
80
Status: Approved,  Date: 29 August 2022
12.3.4.
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.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
81
Status: Approved,  Date: 29 August 2022
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drugs
Study drugs (ibrutinib and placebo) are provided as a hard gelatin capsules containing 140 mg of 
PCI-32765 or placebo. All formulation excipients are compendia and are commonly used in oral 
formulations. Refer to the Investigator's Brochure for a list of excipients.
14.2.
Packaging
Study drugs are packaged in opaque high-density polyethylene plastic bottles with labels bearing 
the appropriate label text as required by governing regulatory agencies. All bottles will utilize child 
resistant packaging.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Study 
drug supplies will contain a study-specific label with a unique identification number.
14.4.
Preparation, Handling, and Storage
The recommended storage condition for study drug capsules is controlled room temperature (15oC 
to 25oC). 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 pharmacy 
manual/study site investigational product manual for additional guidance on study drug handling 
and storage conditions.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the return 
of study drug from the subject (if applicable), must be documented on the drug accountability 
form. Subjects or their legally acceptable representatives where applicable, must be instructed to 
return all original containers, whether empty or containing study drug. All study drug will be stored 
and disposed of according to the sponsor's instructions. Study-site personnel must not combine 
contents of the study drug 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 drug, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the drug return form. When the study site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
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 must not be dispensed again, even to the 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
82
Status: Approved,  Date: 29 August 2022
same subject. Whenever a subject brings his or her study drug to the study site for pill count, this 
is not seen as a return of supplies. Study drug may not be relabeled or reassigned for use by other 
subjects. The investigator agrees neither to dispense the study drug 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:
!
Protocol
!
Investigator Brochure
!
Pharmacy manual/study site investigational product manual]
!
Laboratory manual and laboratory supplies
!
PRO questionnaires 
!
Revised Response Criteria for Malignant Lymphoma (Cheson 2007)
!
IVRS/IWRS Manual
!
Electronic data capture (eDC) Manual and CRF completion guidelines
!
Sample ICF
!
Subject information materials
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected is considered to be normal and acceptable for subjects 
participating in a cancer clinical study and is deemed reasonable over the timeframe 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.
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. 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
83
Status: Approved,  Date: 29 August 2022
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
!
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


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
84
Status: Approved,  Date: 29 August 2022
!
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 study 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 can 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 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 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
85
Status: Approved,  Date: 29 August 2022
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 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.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
86
Status: Approved,  Date: 29 August 2022
16.2.5.
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.
16.2.6.
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 FL and/or 
MZL, to understand differential drug responders, and to develop tests/assays related to ibrutinib 
and FL and/or MZL. 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 their consent for their samples to be 
stored for research (refer to Section 10.3).
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.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
87
Status: Approved,  Date: 29 August 2022
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:
!
protocol and amendment(s), if any, signed and dated by the principal investigator
!
A copy of the dated and signed (or sealed, where appropriate per local regulations), 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 (or sealed, where appropriate per local 
regulations) 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


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
88
Status: Approved,  Date: 29 August 2022
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 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; study drug administration information; and 
date of study completion and reason for early discontinuation of study drug 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).
Subject- and investigator-completed scales and assessments designated by the sponsor will be
recorded directly into an electronic device and will be considered source data.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. 
Electronic Data Capture (eDC) 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 verify that all data entries in the CRFs are accurate and correct.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
89
Status: Approved,  Date: 29 August 2022
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 can be done in 3 different 
ways:
!
Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).
!
Study site manager can generate a query for resolution by the study-site personnel.
!
Clinical data manager can 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, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
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 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
90
Status: Approved,  Date: 29 August 2022
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/institution 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, 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 assessment 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 assessment 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:


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
91
Status: Approved,  Date: 29 August 2022
!
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 
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 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, and direct transmission of 
clinical laboratory data from a central laboratory into the sponsor's database. 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 biomarker 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 can benefit from copyright protection (except any publication by the 


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
92
Status: Approved,  Date: 29 August 2022
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 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.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
93
Status: Approved,  Date: 29 August 2022
REFERENCES
1.
Blum KA, Christian B, Flynn J, et al. A phase I trial of the Bruton’s Tyrosine Kinase (BTK) inhibitor, ibrutinib 
(PCI-32765), in combination with rituximab (R) and bendamustine in patients with relapsed/refractory 
non-Hodgkin’s lymphoma (NHL). Blood. 2012;120:Poster.
2.
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 Am Soc Hematology; 7 December 2008; San Francisco, California.
3.
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]. Am Soc Hematology. 2005;106:Abstract 750.
4.
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 
2007;25(5):579-586.
5.
Colombat P, Salles G, Brousse N, et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line 
therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. 
Blood. 2001;97:101-106.
6.
Czuczman MS, Koryzna A, Mohr A, et al. Rituximab in combination with fludarabine chemotherapy in 
low-grade or follicular lymphoma. J Clin Oncol. 2005;23(4):694-704.
7.
Dreyling M, Ghielmini M, Marcus R, Salles G, Vitolo U. Newly diagnosed and relapsed follicular lymphoma: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 
2011;22(Supplement 6):vi59–vi63.
8.
Eremenco S, Webster K, Kubkova L, Bowman, L, Cella, D. Development and multilingual validation of the 
FACT-Lymphoma instrument. Quality of Life Research. 2004;13(9):1501.
9.
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of 
Medicine. Available at: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed July 31, 2013.
10.
Fowler N, Kahl BS, Lee P, et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or 
refractory follicular lymphoma: the Phase II VERTICAL study. J Clin Oncol. 2011;29(25):3389-3395.
11.
Fowler N, Advani R, Sharman J, et al. ASH Abstract. The Bruton’s tyrosine inhibitor ibrutinib (PCI-32765) is 
active and tolerated in relapsed follicular lymphoma. Blood. 2012;120:Abstract 156.
12.
Friedberg JW, Vose JM, Kelly JL, et al. The combination of bendamustine, bortezomib, and rituximab for 
patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood.
2011;117(10):2807-2812.
13.
Gregory SA, Cheson BD, Czuczman MS, Love N. Management of follicular lymphoma in the up-front and 
relapsed settings. Oncology. 2010;24:1-5.
14.
Hainsworth JD. First-line and maintenance treatment with rituximab for patients with indolent non-Hodgkin’s 
lymphoma. Semin Oncol. 2003;30(1)Supp2:9-15.
15.
Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of 
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for 
patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a 
prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 
2005;106:3725-3732.
16.
Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of 
lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. 
J Clin Oncol. 2007;25(5):571-578.
17.
Kahl B, Yang D. Marginal zone lymphomas: management of nodal, splenic, and MALT NHL. Hematology 
Am Soc Hematol Educ Program. 2008:359-364.
18.
Maddocks K, Christian B, Jaglowski S, et al. A phase 1/1b study of combined rituximab, bendamustine, and 
ibrutinib in patients with previously untreated and relapsed/refractory non-Hodgkin's lymphoma. Blood. 2014
(Blood First Edition Paper, prepublished online 29 October 2014; DOI 10.1182/blood-2014-08-597914).


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
94
Status: Approved,  Date: 29 August 2022
19.
Marcus R, Hagenbeek A. The therapeutic use of rituximab in non-Hodgkin's lymphoma. Eur J Haematol. 
2007;67:5-14.
20.
Montoto S, Canals C, Rohatiner AZ, et al. Long-term follow-up of high-dose treatment with autologous 
haematopoietic progenitor cell support in 693 patients with follicular lymphoma: an EBMT registry study. 
Leukemia. 2007;21(11):2324-2331.
21.
National comprehensive clinical network clinical practice guidelines in oncology (NCCN guidelines). 
Non-Hodgkin’s Lymphomas, Version 3.2012. Available at 
http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed 27 June 2013.
22.
Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study 
Group classification of non-Hodgkin’s lymphoma. Blood. 1997;89(11):3909-3918.
23.
Non-Hodgkin Lymphoma CyberFamily website. Available at: 
http://www.nhlcyberfamily.org/types/follicular.htm. Accessed: 12 September 2013.
24.
O'Brien SM, Barrientos JC, Flinn IW, et al. Combination of the Bruton's tyrosine kinase (BTK) inhibitor 
PCI-32765 with bendamustine (B)/rituximab (R) (BR) in patients (pts) with relapsed/refractory (R/R) chronic 
lymphocytic leukemia (CLL): Interim results of a phase Ib/II study [abstract]. ASCO. 2012;Abstract 6515.
25.
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549-556.
26.
Ozer H, Armitage JO, Bennett CL, et al. 2000 update of recommendations for the use of hematopoietic 
colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol. 2000;18:3558-3585.
27.
Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. 
Chem Med Chem. 2007;2(1):58-61.
28.
Peterson BA, Petroni GR, Frizzera G, et al. Prolonged single-agent versus combination chemotherapy in 
indolent follicular lymphomas: a study of the cancer and leukemia group Br J Clin Oncol. 2003;21:5-15.
29.
Pettengell R, Donatti C, Hoskin P, et al. The impact of follicular lymphoma on health-related quality of life.
Annals of Oncology. 2008;19:570–576.
30.
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-tablesubstrates-
inhibitors-and-inducers. Accessed 26 August 2022.
31.
Department of Medicine Clinical Pharmacology Drug Interactions Flockhart Table. Available at 
https://medicine.iu.edu/internal-medicine/specialties/clinical-pharmacology/drug-interaction-flockhart-table. 
Accessed 26 august 2022.
32.
Rabin R, Oemar M, Oppe M, Janssen B, Herdman, M. EuroQol. EQ-5D-5L User’s Guide (Version 1.0). 
April 2011.
33.
Relander T, Johnson NA, Farinha P, Connors JM, Sehn LH, and Gascoyne RD. Prognostic factors in follicular 
lymphoma. J Clin Oncol 2010;28(17):2902-2913. Erratum in: J Clin Oncol. 2010;28(30):4664.
34.
Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine plus rituximab 
in patients with relapsed indolent B-cell and mantle cell non-Hodgkin’s lymphoma. J Clin Oncol.
2008;26(4):4473-4479.
35.
Rummel M. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of 
mantle cell and low-grade non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23:3383-3389.
36.
Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab (B-R) versus CHOP plus 
rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): 
Updated results from the StiL NHL1 study [abstract]. ASCO. 2012;Abstract 3.
37.
Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden 
follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled 
trial Lancet. 2010;377:42–51.
38.
Van Oers MHJ, Klasa R, Marcus ME, et al. Rituximab maintenance improves clinical outcome of 
relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during 
induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006;108:3295-3301.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
95
Status: Approved,  Date: 29 August 2022
39.
Van Oers MHJ, Van Glabbeke, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant
follicular non-Hodgkin lymphoma: long-term outcome of the EORTC 20981 phase 3 randomized intergroup 
study. J Clin Oncol. 2010;28:2853-2858.
40.
Younes A, Thieblemont C, Morschhauser F, et al. Combination of ibrutinib with rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell 
non-Hodgkin lymphoma: a non-randomised, phase 1b study. Lancet Oncol. 2014;15(9):1019-1026.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
96
Status: Approved,  Date: 29 August 2022
Attachment 1: Sample Questionnaire FACT-Lym


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
97
Status: Approved,  Date: 29 August 2022
Attachment 2: Sample Health Questionnaire EQ-5D-5L


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
98
Status: Approved,  Date: 29 August 2022




JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
100
Status: Approved,  Date: 29 August 2022
Attachment 3: Cockcroft-Gault Formula for Estimating Creatinine Clearance
Ccr =
(140 – age) x Body Weight (kg)
(Serum creatinine mg/dL) x 72
Note:
!
Multiply by 0.85 for women
!
Use with caution in cirrhosis and muscle wasting
!
To convert ∗mol (micromoles)/L of creatinine to mg/dL, divide by 88.4.
Cockroft D, Gault MK. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765FLR3001 Amendment INT-3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
101
Status: Approved,  Date: 29 August 2022
Attachment 4: Inhibitors and Inducers of CYP3A
Examples of inhibitors and inducers of CYP3A can be found at the following website: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx and 
http://www.pharmacologyweekly.com/content/pages/online-drug-therapy-tables. 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 



SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Approved, Date: 15 June 2022
Janssen Research & Development *
Statistical Analysis Plan
A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine 
Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination with Either Bendamustine and 
Rituximab (BR) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and 
Prednisone (R-CHOP) in Subjects with Previously Treated Indolent Non-Hodgkin 
Lymphoma (iNHL)
Protocol PCI-32765FLR3001 (SELENE); Phase 3
PCI-32765 (ibrutinib)
Status:
Approved
Date:
15 June 2022
Prepared by:
Janssen Research & Development, LLC  
Document No.:
EDMS-ERI-68097552, 6.0
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.
NCT01974440


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Approved, Date: 15 June 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 3
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 5
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Trial Objectives ................................................................................................................................ 6
1.2.
Trial Design ...................................................................................................................................... 7
1.3.
Statistical Hypotheses for Trial Objective ........................................................................................ 9
1.4.
Sample Size Justification ................................................................................................................. 9
1.5.
Randomization and Blinding ............................................................................................................ 9
2.
GENERAL ANALYSIS DEFINITIONS ..............................................................................................10
2.1.
Study Treatment and Study Drug .................................................................................................. 10
2.2.
Baseline Definitions........................................................................................................................ 10
2.3.
Study Day and Cycle Day .............................................................................................................. 10
2.4.
Pooling Algorithm for Analysis Centers.......................................................................................... 11
2.5.
Imputation of Missing Dates ....................................................................................................... 11
2.6.
Analysis Sets.................................................................................................................................. 12
2.6.1.
Efficacy Analysis Set(s) .............................................................................................................. 12
2.6.2.
Safety Analysis Set..................................................................................................................... 12
2.6.3.
Pharmacokinetics (PK) Analysis Set .......................................................................................... 12
2.7.
Definition of Subgroups.................................................................................................................. 12
2.8.
Other General Definitions............................................................................................................... 13
2.8.1.
Year and Month .......................................................................................................................... 13
2.8.2.
Age.............................................................................................................................................. 13
2.8.3.
Time from Initial Diagnosis to Randomization ............................................................................ 13
2.8.4.
Treatment-emergent Adverse Event Period............................................................................... 14
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 14
3.1.
Data Monitoring Committee ........................................................................................................... 14
3.2.
Interim Analysis.............................................................................................................................. 14
4.
SUBJECT INFORMATION................................................................................................................ 15
4.1.
Disposition Information................................................................................................................... 15
4.2.
Demographics and Baseline Characteristics ................................................................................. 15
4.3.
Medical History............................................................................................................................... 15
4.4.
Extent of Exposure......................................................................................................................... 16
4.5.
Protocol Deviations ........................................................................................................................ 16
4.6.
Prior and Concomitant Medications ............................................................................................... 16
5.
EFFICACY ......................................................................................................................................... 17
5.1.
Analysis Specifications................................................................................................................... 17
5.1.1.
Level of Significance................................................................................................................... 17
5.1.2.
Data Handling Rules................................................................................................................... 18
5.1.3.
General Analysis Considerations ............................................................................................... 18
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 18
5.2.1.
Definition..................................................................................................................................... 18
5.2.2.
Primary Estimand ....................................................................................................................... 18
5.2.3.
Analysis Methods........................................................................................................................ 19
5.2.3.1.
Primary Analysis...................................................................................................................... 19
5.2.3.2.
Sensitivity and Supplementary Analyses ................................................................................20


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Approved, Date: 15 June 2022
5.2.3.2.1.
Sensitivity Analysis of Disease Assessment Follow up .......................................................20
5.2.3.2.2.
Supplementary Analysis of Estimand 2: ..............................................................................21
5.2.3.2.3.
Supplementary Analysis of Estimand 3 ...............................................................................21
5.2.3.3.
Subgroup Analyses of PFS ..................................................................................................... 21
5.3.
Secondary Endpoints..................................................................................................................... 21
5.3.1.
Overall Survival........................................................................................................................... 21
5.3.2.
Complete Response Rate and Overall Response Rate.............................................................23
5.3.3.
Time to Worsening in the Lym Subscale....................................................................................23
5.3.4.
Duration of Response................................................................................................................. 24
5.4.
Exploratory Endpoints.................................................................................................................... 24
5.4.1.
Time-to-Next Treatment.............................................................................................................. 24
5.4.2.
Minimal Residual Disease (MRD) Negative Rate....................................................................... 24
5.4.3.
Progression-free Survival on Next-Line Therapy (PFS2)........................................................... 24
6.
SAFETY............................................................................................................................................. 25
6.1.
Adverse Events .............................................................................................................................. 25
6.2.
Adverse Events of Special Interest................................................................................................ 25
6.3.
Other Safety Observations............................................................................................................. 25
6.4.
Death.............................................................................................................................................. 26
6.5.
Clinical Laboratory Tests................................................................................................................ 26
6.5.1.
Creatinine Clearance.................................................................................................................. 26
6.5.2.
Analysis of Lymphocytosis.......................................................................................................... 26
6.6.
Other Safety Parameters ............................................................................................................... 27
7.
PATIENT REPORTED OUTCOMES................................................................................................. 27
8.
PHARMACOKINETICS ..................................................................................................................... 28
APPENDIX 1 CHANGE TO PROTOCOL PRE-PLANNED ANALYSIS .................................................... 29
1.
COVID-19 IMPACT............................................................................................................................ 29
REFERENCES............................................................................................................................................ 30
LIST OF IN-TEXT TABLES
Table 1:
Subgroups................................................................................................................................. 13
Table 2:
Two-stage Group Sequential Design for Progression-free Survival......................................... 14
Table 3:
Estimated Crossing Boundary in Hazard Ratio and p-value Scales for the Planned OS 
Analysis..................................................................................................................................... 22




PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Approved, Date: 15 June 2022
ABBREVIATIONS
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ASCT
autologous stem cell transplant
AST
aspartate aminotransferase
BR
bendamustine, rituximab
BSA
body surface area
CI
confidence interval
COVID-19
Coronavirus Disease 2019
CR(s)
complete response(s)
CRF
case report form 
CSR
clinical study report
CT
computed tomography
DMC
data monitoring committee
DOR
duration of response
ECOG
Eastern Cooperative Oncology Group
EQ-5D-5L
EuroQol questionnaire
FACT-Lym
Functional Assessment of Cancer Therapy-Lymphoma
FACT-LymS
FACT-Lym Lymphoma Symptom Subscale
FL
follicular lymphoma
IF
information fraction
Ig
Immunoglobulin
HR
hazard ratio
iNHL
indolent Non-Hodgkin Lymphoma
INR
international normalized ratio
ITT
intent-to-treat
LDH
lactic acid dehydrogenase 
MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimal residual disease
MZL
marginal zone lymphoma
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 on next-line therapy
PK
Pharmacokinetics
PP
per-protocol
PR
partial response
PRO
patient-reported outcomes
R-CHOP
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SUV
standardized uptake values
TTNT
time-to-next-treatment
TTW
time to worsening
ULN
upper limit of normal
WBC
white blood cell (count)


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Approved, Date: 15 June 2022
1.
INTRODUCTION
The FLR3001 study is part of a comprehensive clinical development program to evaluate the safety 
and efficacy of ibrutinib (JNJ-54179060: PCI-32765) in subjects with B-cell malignancies. This 
randomized, double-blind, placebo-controlled, multicenter, Phase 3 study was designed to evaluate 
the efficacy and safety of ibrutinib in combination with bendamustine and rituximab (BR) or 
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in subjects 
with previously treated indolent Non-Hodgkin Lymphoma (iNHL). 
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, data 
handling rules, and statistical methods for the analysis of efficacy, safety, biomarkers, and 
pharmacokinetics. Details of the study conduct, and data collection can be found in the study 
protocol amendment INT-2 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 either BR or 
R-CHOP will result in prolongation of progression free survival (PFS) compared with either BR 
or R-CHOP alone in subjects with previously treated iNHL (follicular lymphoma [FL] or marginal 
zone lymphoma [MZL]).
The secondary objectives are the evaluation of treatment groups in terms of the following:
!
Overall survival (OS)
!
Complete response (CR) rate 
!
Overall response rate, ORR (CR + partial response [PR]) 
!
Duration of response (DOR)
!
Patient-reported lymphoma symptoms and concerns as measured by the Functional 
Assessment of Cancer Therapy-Lymphoma Symptom Subscale (FACT-LymS) of the 
Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)
!
Safety of ibrutinib when combined with BR or R-CHOP
The exploratory objectives include the evaluation of the following:
!
Time-to-next treatment (TTNT)
!
Minimal residual disease (MRD) negative rate in FL subjects
!
Patient-reported outcomes (PRO), related to general health status, utilizing EuroQol 
(EQ-5D-5L)
!
Pharmacokinetics of ibrutinib and explore the potential relationships between ibrutinib
metrics of exposure with relevant clinical or biomarker information


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Approved, Date: 15 June 2022
1.2.
Trial Design
FLR3001 is a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study to 
compare the efficacy and safety of ibrutinib in combination with either BR or R-CHOP to placebo 
plus BR or R-CHOP in subjects with previously treated iNHL (FL or MZL). 
All subjects received background therapy of either 6 cycles of BR or 6 cycles of R-CHOP. 
Selection of background therapy was based on prior treatment history and cardiac function and
was in the judgment of the investigator. Approximately 400 eligible subjects were stratified by (1) 
backbone chemotherapy treatment either BR or R-CHOP, (2) refractory vs relapsed disease (stable 
disease [SD]/progressive disease [PD] vs CR/PR as best response to last prior chemotherapy),
(3) iNHL histology (FL vs MZL), and (4) number of prior lines of therapy (1 vs >1).  Subjects 
were randomized in a 1:1 ratio to either Treatment Arm A (background therapy + placebo) or 
Treatment Arm B (background therapy + 560 mg of ibrutinib). Study drug was administered orally
approximately at the same time each day and on a continuous schedule until disease progression, 
unacceptable toxicity, or study end, whichever came first. 
Three clinical cut-offs were planned. The first 2 clinical cut-offs were planned to occur when 
approximately 151 and 252 PFS events had been observed, respectively. The interim analysis and 
the primary analysis of the primary endpoint PFS were to take place at these 2 clinical cutoffs, 
respectively. The last cutoff will occur at the time of the end of study, when approximately 50% 
of the randomized subjects have died or the Sponsor terminates the study, whichever comes first. 
Subject participation includes a Screening Phase, a Treatment Phase, and a Posttreatment Follow-
up Phase. Subject eligibility is determined up to 30 days prior to randomization. The Treatment 
Phase extends from randomization until study drug discontinuation. The Posttreatment Follow-up 
Phase begins once a subject discontinues study drug and continues until death, loss to follow up, 
consent withdrawal, or study end, whichever occurs first. 
Assessment of tumor response and progression is conducted in accordance with the Revised 
Response Criteria for Malignant Lymphoma.1 The investigator evaluates sites of disease by
radiological imaging, physical examination, or other procedures as necessary.  The primary 
efficacy analysis of PFS is based on investigator assessment.  The assessments are performed at 
Screening, Week 12, Week 24, and then every 16 weeks until 3 years, and every 24 weeks 
thereafter until disease progression, or death, whichever comes first. Subjects who discontinue 
treatment for reasons other than disease progression (for reasons such as an adverse event [AE]) 
must continue to have regularly scheduled computed tomography (CT) scans/efficacy assessments 
according to the Time and Events Schedule until disease progression, death, or the clinical cutoff 
for the final analysis of the primary endpoint, whichever occurs first.
At each site visit, subjects are evaluated for toxicity. Safety evaluations include adverse event 
monitoring, physical examinations, concomitant medication usage, and clinical laboratory
parameters. At some visits, blood samples are drawn for assessment of pharmacokinetic
parameters and for MRD.


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
8
Approved, Date: 15 June 2022
An independent Data Monitoring Committee (DMC) was formed and constituted according to 
regulatory agency guidelines. The independent DMC reviewed the unblinded safety and efficacy 
of the treatment combination and made recommendations as to the further conduct of the study at 
designated milestones. Details regarding the composition and procedures are provided in the DMC 
charter.
A diagram of the study design is provided below in Figure 1.
Figure 1:
Schematic Overview of the Study


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
9
Approved, Date: 15 June 2022
1.3.
Statistical Hypotheses for Trial Objective
The statistical hypotheses are described as follows:
H0: Null hypothesis, the PFS distributions of the experimental treatment group, ST(t), and the 
placebo group, SP(t), are the same at all time points t:
ST(t) = SP(t), for all t ≥ 0
versus
H1: Alternative hypothesis, the PFS distributions of the experimental treatment group, ST(t), are 
stochastically different than the placebo group, SP(t):
ST(t) ≠ SP(t), for some t ≥ 0.
1.4.
Sample Size Justification
This study was designed to evaluate the effect of treatment on PFS and was powered for this 
endpoint. The sample size for the study was calculated based on the following considerations:
a.
1:1 randomization ratio between 2 treatment groups
b. Target hazard ratio (HR) of 0.7. Assuming the median PFS for the control arm (background 
therapy + placebo) is 20 months from randomization, a target HR of 0.7 corresponds to an 
8.6-month increase in median PFS for the treatment group (background + ibrutinib) relative 
to the control (ie, 28.6 months versus 20 months, respectively)
c.
Minimum 80% power
d. 2-sided overall significance level of 0.05
e.
One interim analysis for efficacy at 60% of the planned total PFS events
Using the above assumptions, the study enrolled approximately 400 subjects (about 200 subjects 
to each arm) to observe 252 PFS events to achieve 80% power for PFS endpoints. The planned 
data cutoffs were based on the interim and primary analysis of PFS when approximately 151 and 
252 PFS events, respectively, had occurred.
1.5.
Randomization and Blinding
Central randomization was implemented in this study. Subjects were randomly assigned to 1 of 
the 2 treatment groups based on a computer-generated randomization schedule prepared before the 
study and under the supervision of the sponsor. The randomization was balanced by using 
randomly permuted blocks and stratified by (1) background therapy treatment (BR vs R-CHOP),
(2) refractory vs relapsed disease, (3) iNHL histology (FL vs MZL), and (4) number of prior lines 
of therapy (1 vs >1). The sponsor strived towards an adequate number of subjects randomized into 
either of the background therapy regimens. Subjects were randomized in a 1:1 ratio to either


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
10
Approved, Date: 15 June 2022
Treatment Arm A (background therapy + placebo) or Treatment Arm B (background 
therapy + 560 mg of ibrutinib).
In this double-blind placebo-controlled study, subjects, investigators, and the sponsor’s study team 
members will remain blinded to treatment assignment until the database has been locked for 
writing the clinical study report (CSR). Personnel who may be unblinded during the study are:
!
The independent DMC, the independent unblinded biostatisticians
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 (SAE)
!
In case of an urgent safety concern, site personnel and the sponsor may be 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)
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Study Treatment and Study Drug
For the purpose of analysis, the term “study treatment” refers to the background therapy (BR or 
R-CHOP) and ibrutinib/placebo.  The term “study drug” refers to ibrutinib/placebo. Outputs will 
be provided by treatment group (ie, ibrutinib + background therapy, placebo + background 
therapy).
2.2.
Baseline Definitions
Unless otherwise specified, the baseline value is defined as the last available (non-missing) value 
collected on or prior to the administration of the first study treatment, except for efficacy variables, 
for which the randomization date is used to define baseline. For subjects who have been 
randomized but not treated with any dose, the randomization date is used as the reference date for 
baseline value calculation.
2.3.
Study Day and Cycle Day
For efficacy data, the randomization date is considered as the reference date (Day 1). For safety 
data, date of first dose of study treatment is used as the reference date (Day 1).
Reference date (Day 1) = randomization date (for efficacy data), or first dose date of study 
treatment (for safety data).


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11
Approved, Date: 15 June 2022
Study day is calculated as follows:
Study Day (if on or after reference date) = assessment date – reference date +1, 
Study Day (if before reference date) = assessment date – reference date, 
Cycle Day = assessment date - date of the first dose for the cycle + 1. 
2.4.
Pooling Algorithm for Analysis Centers
The data from all investigative sites is pooled for all analyses.
2.5.
Imputation of Missing Dates
In general, imputation of missing dates is made for AE onset date, AE resolution date, date of 
death, start and end dates of prior, concomitant, and subsequent therapies, date of 
progression/relapse on the last prior therapy, date of second progressive disease, and date of initial 
diagnosis according to the following rules. Start date is imputed before end date.  
!
If the date is completely missing, no imputation is made. 
!
If the year is missing, no imputation is made.
!
If only the year is present, but the month and day are missing, then June 30th is used.
!
If only the day is missing but the year and month are available, then the 15th of the month is
used. 
The above imputations are modified by the following rules:
!
For initial diagnosis if such imputed date is on or after the randomization date, then 
randomization date - 1 day is used. 
!
If such imputed date for prior therapies or initial diagnosis is on or after the randomization 
date, then randomization date - 1 day is used. If such imputed date for subsequent therapies is 
before date of last dose, then date of last dose +1 day is used.
!
The imputed start date for subsequent therapies is 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 discontinuation date or last dose date if no treatment discontinuation date
is 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 is 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 is used.


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
12
Approved, Date: 15 June 2022
!
The imputed AE start date is adjusted sequentially using the following steps:
o
If the imputed date is in the same year and month but before the first dose date, then 
the first dose date is used, or if it is in the same year and month but after the last dose 
date + 30 days, then the last dose date + 30 days is used. 
o
If AE end date is not missing and the imputed AE start date is after the AE end date, 
then the AE end date is used.
o
If the imputed AE start date and is after date of death, then date of death is used
o
If the imputed AE start date is in the same month and year but after the 1st subsequent 
therapy start date, then 1st subsequent therapy start date is used.
!
If the imputed date is for an AE end date and is after the death date, then the death date is
used, or if the imputed AE end date is before the AE start date, then the AE start date is used.
!
The AE imputation rule is used for concomitant medication.
2.6.
Analysis Sets
2.6.1.
Efficacy Analysis Set(s)
The Intent-to-Treat (ITT) analysis set is defined as all randomized subjects. Subjects in this 
analysis set are analyzed according to the treatment to which they are randomized. The ITT 
analysis set is used to summarize the study population and characteristics, efficacy, and PRO data.
2.6.2.
Safety Analysis Set
The Safety analysis set is defined as all randomized subjects who received at least 1 dose of study 
drug. Safety data are analyzed according to the actual treatment received. 
2.6.3.
Pharmacokinetics (PK) Analysis Set
This analysis set is defined as all randomized subjects who received at least 1 dose of ibrutinib and 
had at least 1 pharmacokinetic sample obtained.  
2.7.
Definition of Subgroups
The subgroup variables and the cutoff values are summarized in Table 1.


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
13
Approved, Date: 15 June 2022
Table 1:
Subgroups
Subgroup
Definition of Group
Analysis Type
Sex
Male, Female
E, S, D
Race
White, Non-White
E, S, D
Region
Asia, Other
E, S, D
Age
<65, ≥65  
E, S, D
Baseline ECOG
0, 1 or 2
E, S, D
Background therapy treatment
BR, R-CHOP
E, S, D
Number of lines of prior therapy
1, >1
E
Disease status
Refractory, relapsed
E
iNHL histology
FL, MZL
E,S,D
Baseline extra nodal site involvement
Yes, no
E
Prior autologous stem cell transplant 
(ASCT)
Yes, no
E
Baseline LDH
Normal, elevated
E
Baseline PET SUV
Mild to moderate SUV, high SUV
E
Tumor bulk (largest diameter)
≤6 cm, >6 cm 
E
PRIMA PI2
Low, Medium, High risk 
E
POD243
>24, <= 24
E
Hepatic impairment (based on NCI criteria)
Normal vs Mild vs Moderate/ Severe
liver dysfunction
S
Renal impairment 
Creatinine clearance <60, ≥60
S
Concomitant use of CYP3A inhibitor 
Strong/Moderate, all remaining 
subjects
S
Concomitant use of CYP3A inhibitor 
Strong, all remaining subjects
S
BR=bendamustine, rituximab; CIT=chemoimmunotherapy; CYP=cytochrome P450; E=efficacy; S=safety (adverse 
events); D=demographic and baseline disease characteristics, ECOG=Eastern Cooperative Oncology Group; 
FL=follicular lymphoma; LDH=lactic acid dehydrogenase; PET= positron emission tomography; MZL=marginal 
zone lymphoma; NCI=National Cancer Institute; PRIMA PI=simplified index based on beta 2 microglobulin and 
bone marrow involvement for patients treated with immunochemotherapy; POD24=progression of disease (POD) 
within 2 years of first line of CIT therapy; R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone SUV=standardized uptake values
2.8.
Other General Definitions
2.8.1.
Year and Month
For the analyses purpose it’s assumed 1-year equals to 365.25 days and 1 month equals to 30.4375 
days.
2.8.2.
Age
Age in years is calculated at the date the informed consent is signed.
2.8.3.
Time from Initial Diagnosis to Randomization
Time from initial diagnosis to randomization in months is calculated as (date of randomization -
date of initial diagnosis)/30.4375 and the result is rounded to the first decimal place. Partially 
missing initial diagnosis date is imputed based on the rules provided in Section 2.5 of the SAP. 


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
14
Approved, Date: 15 June 2022
2.8.4.
Treatment-emergent Adverse Event Period
In general, the treatment-emergent period is defined as the time from first dose date through 
30 days after last dose date, or day before subsequent antineoplastic therapy, whichever occurs 
first.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
3.1.
Data Monitoring Committee
An independent DMC was established to monitor data on an ongoing basis to ensure the safety of 
subjects enrolled in this study and to evaluate the efficacy of the treatment at the time of interim 
analysis. The committee met periodically to review study data, to assess the evidence of benefit or 
adverse effects of ibrutinib, and to monitor the conduct of the study. After the review, the DMC 
was to make recommendations regarding the conduct of the study including stopping the study for 
efficacy, if the pre-specified stopping boundary is crossed at the interim analysis. The details 
regarding the DMC responsibilities, authorities, and procedures are provided in a separate DMC 
charter.
3.2.
Interim Analysis
An interim analysis using the classical O’Brien-Fleming boundary for efficacy was planned to be 
conducted after observing approximately 60% (151) PFS events (PD or death).4 The stopping 
boundaries were implemented using Lan-DeMets spending function with the parameter 
resembling the conservative O’Brien-Fleming boundary using East® software (version 5.3) to 
control the 2-sided Type I error of 0.05 for the comparison of the PFS endpoint. The interim 
analysis was conducted after 163 PFS events were observed.  Details of the efficacy monitoring 
plan are summarized in Table 2.
Table 2:
Two-stage Group Sequential Design for Progression-free Survival
Analysis
Information 
Fraction
Number of 
PFS 
Events
Monitoring 
Boundary Based on 
Observed HR
2-sided 
Nominal 
Significance 
Level
2-sided
Cumulative 
Alpha
Planned Interim
60%
151
0.646
0.0076
0.0076
Actual Interim 
65%
163
0.674
0.0116
0.0116
Final
100%
252
0.778
0.0476
0.05
PFS=progression-free survival, HR=hazard ratio
The 2-sided nominal significance level and cumulative alpha in this table are based on a 2-sided log-rank test and are 
updated using the software package East® v6.5 (Cytel Software Corp., Cambridge, MA). The significance level for the 
final analysis is based on the actual information fraction for the interim analysis.
At the preplanned interim analysis, the independent DMC made the recommendation of continuing 
the study as the pre-specified boundary for efficacy was not crossed.  


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
15
Approved, Date: 15 June 2022
4.
SUBJECT INFORMATION
4.1.
Disposition Information
Disposition information will be summarized for the ITT analysis set, including the number and 
percentage of subjects who are randomized, treated, and discontinued treatment as well as their 
reason for discontinuation. The tabulation of the above information will be provided by treatment
group and combined.
Descriptive statistics will be provided for the time on study. Time on study will be defined the 
same way as OS with reversed censoring, ie, subject who died is censored. 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 demographics and baseline characteristic variables will be summarized for the ITT analysis set 
by treatment group and combined, unless otherwise specified. No formal statistical hypothesis 
testing is planned.
!
Demographic and baseline characteristics data: age (continuous and grouped as <65, or ∀65 
years), sex, race, ethnicity, weight, height, blood pressure, temperature, heart rate, and body 
surface area (BSA)
!
Disease characteristics at baseline: iNHL histology (FL or MZL), time from initial diagnosis 
to randomization, lymphoma-related B-symptoms, lactic acid dehydrogenase (LDH), number 
of lines of prior therapies (continuous and grouped as 1, >1), background therapy received in 
the study (BR or R-CHOP), refractory or relapse to last prior therapy, hepatic impairment, 
creatinine clearance rate (<60 mL/min, ≥60 mL/min), extra nodal disease, Eastern 
Cooperative Oncology Group (ECOG) performance status, tumor bulk (≤6 cm, >6 cm)
!
Hematology: hemoglobin, white blood cell (WBC) count, absolute neutrophil count (ANC), 
absolute lymphocyte count (ALC), and platelet count
!
Chemistry: creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
total bilirubin
!
Coagulation: Prothrombin
international normalized ratio (INR), Activated partial 
thromboplastin time (aPTT)
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 and range. 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.
4.3.
Medical History
Abnormal medical history findings reported by the investigator will be summarized by body 
system by treatment group and combined, based on the ITT analysis set.


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
16
Approved, Date: 15 June 2022
4.4.
Extent of Exposure
Extent of exposure will be summarized for the safety analysis set.  Descriptive statistics (n, mean, 
standard deviation, median and range) will be provided for the treatment duration (the interval 
between date of first dose and date of last dose of study drug), and study drug dosing information 
including total dose received (the sum of total dose), dose intensity (the ratio of total dose and 
treatment duration) and relative dose intensity (the ratio of dose intensity and 560 mg).    
For each component of the background therapy, dosing information will include total number of 
cycles received, total dose received (the sum of actual dose administered), dose intensity (the ratio 
of total dose and number of cycles), and relative dose intensity (the ratio of dose intensity and 
planned total cumulative dose for the specific drug per cycle). For vincristine, relative dose 
intensity will be considered as 100% for those subjects who received 2 mg since dosing is 
independent of basal surface area if dose >2 mg.  
For each of the study drug and background therapy components, dose reduction information will 
be summarized for the number of subjects with any dose reduction (at least 1 reported dose 
reduction), as well as the frequency and reason of dose reduction.  Number and percentage of 
subjects with cycle delays will also be presented.
AEs leading to dose reduction will be summarized for each component of the study treatment.  
4.5.
Protocol Deviations
Subjects with major protocol deviations will be summarized and listed, as appropriate, by 
treatment group. Protocol deviations are based on clinical review primarily on the following 
aspects (but not limited to): (1) eligibility criteria, (2) treatment compliance, (3) subject safety, and 
(4) efficacy assessment deviations. Protocol deviations are closely monitored during the execution 
of the study and the final set of protocol deviation criteria is finalized before database lock. The 
major protocol deviations are reviewed and/or classified based on clinical review of the protocol 
deviations.
4.6.
Prior and Concomitant Medications
Prior and concomitant medications will be summarized for the ITT analysis set by the World 
Health Organization Drug Dictionary therapeutic class, pharmacological class, and preferred term.
Medications administered prior to the first dose of study drug, or any component of the background 
therapy treatment is considered prior medications. Concomitant therapies include those taken on 
or after the first dose of study drug or any component of the background therapy treatment through 
30 days after the last dose.   
The following concomitant medications of special interest will also be summarized:
!
Anti-coagulation and anti-platelets.
!
Cytochrome P450 (CYP)3A inhibitors/inducers


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
17
Approved, Date: 15 June 2022
!
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
5.
EFFICACY
Unless specified otherwise all efficacy analyses are based on the ITT analysis set. 
5.1.
Analysis Specifications
5.1.1.
Level of Significance
In general, all tests are performed at a 2-sided significance level of 0.05, unless otherwise specified. 
All interval estimations are reported using 2-sided 95% confidence intervals (CIs). Statistical 
inference on the primary endpoint, PFS, is conducted at 2-sided overall significance level of 0.05, 
under group sequential testing design per O’Brien-Fleming boundaries, as specified in Section 3.
PFS will be updated at the time of protocol-specified final analysis of OS.
If the primary endpoint achieves statistical significance at a 2-sided significance level of 0.0476 at 
the final analysis, testing of the secondary endpoints will be performed at the 2-sided significance 
level of 0.05 in a sequential hierarchical manner based on a closed testing procedure. All key 
secondary endpoints are ranked in sequence according to the hierarchical order specified below: 
1. CR rate
2. OS 
3. ORR (CR + PR) 
4. Time to worsening (TTW) in the FACT-LymS
The significance level at the interim and the primary analyses of PFS is determined by the 
alpha-spending function specific to endpoints:  
!
For CR and ORR, the data are expected to be matured at the interim analysis of PFS and are
not expected to change at the final analysis of PFS. Consequently, testing of CR rate and ORR 
endpoints is conducted at 2-sided significance level of 0.05
!
For OS, testing of OS is conducted under group sequential design per O’Brien-Fleming 
boundaries, as specified in Section 5.3
!
For TTW in the FACT-LymS, the information fraction is expected to be the same as for PFS
at the interim analysis. The O’Brien-Fleming alpha-spending function as implemented by the 
Lan-DeMets method is used for alpha spending. The actual alpha is the same as for PFS at the 
interim and at the final analyses of PFS
If the null hypothesis for any endpoint fails to be rejected at the interim analysis, then any 
subsequent endpoint(s) listed in the hierarchical order above will not be tested until the next 
analysis time point, eg, primary analysis of PFS), if applicable. If the null hypothesis for an 


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
18
Approved, Date: 15 June 2022
endpoint is rejected at the interim analysis, it will remain being rejected and will not be re-tested 
at any subsequent time points, if any.
5.1.2.
Data Handling Rules
Unless specified otherwise, missing values will not be imputed.
5.1.3.
General Analysis Considerations
Disease progression and disease response is based on the modified Revised Response Criteria for 
Malignant Lymphoma.1
If the number of subjects in a stratum is small, 1 or more stratification factors will be removed 
from the stratified analysis. In that case, the stratified analysis with fewer stratification factors will 
be considered as the primary analysis. The order of removal is determined by clinical importance
as follows: 
1. Background therapy treatment (BR vs R-CHOP)
2. Refractory vs relapsed disease
3. Number of prior lines of therapy (1 vs >1)
4. iNHL histology (FL vs MZL)
5.2.
Primary Efficacy Endpoint(s)
5.2.1.
Definition
The primary endpoint is the investigator assessed PFS, defined as duration from the date of 
randomization to the date of disease progression or death, whichever is first reported. Subjects 
who are progression-free and alive or have unknown status will be censored at the last adequate 
disease assessment. Subjects with no postbaseline disease assessment will be censored at the
randomization date. Adequate disease assessment is defined as having sufficient evidence to 
correctly indicate that progression has or has not occurred.
5.2.2.
Primary Estimand 
Primary Trial Objective: To demonstrate the superiority of ibrutinib + background therapy (BR 
or RCHOP) to that of placebo + background therapy in terms of PFS in patients with relapsed 
refractory FL or MZL. 
Estimand Scientific Question of Interest: What is the effect on PFS of assigning subjects to 
ibrutinib + background therapy vs placebo + background therapy? 
This primary estimand is the main clinical quantity of interest to be estimated in this study, which 
is defined by the following five attributes.5
Population: Patients with relapsed or refractory FL or MZL.


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
19
Approved, Date: 15 June 2022
Treatment: Ibrutinib+ background therapy vs placebo + background therapy.
Variable: PFS (PD, as assessed by the investigator or death).
Population-level summary: Kaplan-Meier estimates of PFS, HR of ibrutinib + background 
therapy vs placebo+ background therapy.
Intercurrent events and handling strategies: Treatment discontinuation, use of subsequent
anticancer therapy, death due to Coronavirus Disease 2019 (COVID-19).
Intercurrent Events
Name of Strategy for Addressing Intercurrent Events and its 
Description
Treatment discontinuation
Treatment policy strategy: Use time to PD or death, regardless 
of whether treatment discontinuation had occurred.
Use of subsequent anticancer therapy
Treatment policy strategy: Use time to PD or death, regardless 
of whether 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.
5.2.3.
Analysis Methods
5.2.3.1.
Primary Analysis
Assuming a non-informative censoring, distinct baseline hazard for each stratum and a common 
proportional HR across strata, the primary estimator for the primary endpoint is the HR and its 
95% CIs estimated using a stratified Cox regression model with study intervention as the sole 
explanatory variable with (1) background therapy treatment (BR vs R-CHOP), (2) refractory vs 
relapsed disease, (3) iNHL histology (FL vs MZL), and (4) number of prior lines of therapy (1 vs 
>1) as stratification factors.
The treatment policy strategy will be adopted for handling the intercurrent events of treatment 
discontinuation and use of subsequent anti-cancer therapy. The composite variable strategy will 
be adopted for handling the intercurrent events of pre-PD death (PFS event) due to COVID-19. 
However, this analysis would only be conducted if pre-PD COVID-19 related deaths account for 
more than 5% of the total PFS events.
The primary analysis of PFS will be based on the ITT analysis set. The Kaplan-Meier product limit 
method will be used to estimate the distribution and median PFS with 95% CI for each treatment 
group.  The stratified log-rank test will be used to compare PFS distributions of the 2 treatment 
groups. The stratification factors at randomization to be used in the analysis are background


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
20
Approved, Date: 15 June 2022
therapy treatment (BR vs. R-CHOP), refractory vs. relapsed disease, number of prior lines of 
therapy (1 vs. >1), and iNHL histology (FL vs MZL). 
To further explore the potential effect of covariates in the primary analysis, a Multivariate Cox 
Regression analysis may be performed using a selected set of potential prognostic variables 
(obtained at or before baseline) as covariates. Each factor will be assessed individually for 
prognostic values using a univariate Cox model. Factors that are deemed to have prognostic value 
will be included as covariates in a Cox model to assess their significance in the presence of other 
factors. Selection methods will be used to identify the final set of prognostic factors. Treatment 
will then be added to this final model to assess the effect of treatment when adjusted for these 
selected prognostic factors. Potential prognostic factors include, but are not limited to, the 
following.
!
Age (<65 vs ≥65)
!
Gender (male vs female)
!
Race (White vs non-White)
!
Background therapy treatment (BR vs R-CHOP)
!
Number of lines of prior therapy (1 vs >1)
!
Disease status (refractory vs. relapsed)
!
iNHL histology (FL vs MZL)
!
POD24 (>24 vs ≤ 24)
!
PRIMA- PI (Low vs Medium vs High risk)
Concordance between investigator determined PFS and IRC determined PFS will be primarily 
assessed using the Dodd 2-stage test procedure.6 In addition, the AMIT audit method7will be used 
as sensitivity analysis for assessing concordance between IRC and investigator data. Details on the 
study’s imaging audit plan is provided in the study audit plan.
5.2.3.2.
Sensitivity and Supplementary Analyses
5.2.3.2.1.
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.


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
21
Approved, Date: 15 June 2022
5.2.3.2.2.
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 the handling strategy for the use of subsequent anti-cancer 
therapies.
!
Hypothetical strategy: All subjects had continued treatment as planned and had not used any 
subsequent anti-cancer therapies.
Under the estimand 2, time to progression or death is censored at the last disease assessment 
showing no evidence of progression before the start of subsequent antineoplastic therapy. The 
same analyses described in primary estimator will be applied.
5.2.3.2.3.
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 the handling strategy for the death due to COVID-19:
!
Hypothetical strategy:  all subjects had continued treatment as planned and had not died from 
COVID-19.
Under the estimand 3, time to PD or death is censored at the last disease assessment before pre-
PD death due to COVID-19. The same analyses described in primary estimator will be applied, 
however, this supplementary analysis would only be conducted if pre-PD COVID-19 deaths
account for more than 5% of total PFS events.
5.2.3.3.
Subgroup Analyses of PFS
Subgroup analysis will be performed for the subgroups (Section 2.7) to assess the internal 
consistency of the treatment benefit. A forest plot, with HR between the treatment groups within 
each subgroup and its associated 95% CI estimated using non-stratified Cox regression model will 
be presented.
In addition, interaction between treatment and background therapy treatment will be tested at a 
2-sided 0.2 level using a stratified Cox proportional hazards model. If the parameter for the 
interaction term is significant, the inferences on the treatment benefit will be made for each 
background therapy treatment separately.  Secondary Endpoints
5.3.
Secondary Endpoints
5.3.1.
Overall Survival
Definition
Overall survival is defined as the interval between the date of randomization and the date of the 
subject’s death from any cause. If the date of death is unknown, OS will be censored at the date 
the subject was last known to have been alive. Subjects who are known to be alive as of their last 
known status will be censored at their date of last contact. Subjects who are lost in follow-up will 
be censored at the date the subject is last known to have been alive.


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
22
Approved, Date: 15 June 2022
Analysis method
Overall survival will be analyzed using the log-rank test for treatment comparison at the interim 
analyses of OS and the stratified log-rank test at the final analysis of OS. The OS distribution and 
median OS with its 95% CI will be estimated using the Kaplan-Meier product limit method. The 
HR for background therapy + ibrutinib relative to background therapy + placebo and its associated 
95% CI will be calculated based on the Cox proportional hazards model at the interim analyses of 
OS and the stratified Cox proportional hazards model by the stratification factors at randomization
at the final analysis of OS.
Multiplicity adjustment for OS
Inferential hypothesis testing for OS was planned to conducted at 2-sided overall significance level 
of 0.05 according to the hierarchy specified in Section 5.1.1, at different time points under the 
group sequential testing design per O’Brien-Fleming boundaries (Table 3). The first analysis of 
OS was planned to occur at the time of the planned interim analysis for PFS.  The second analysis 
will occur at the time of the planned primary analysis of PFS when 252 PFS events have been 
observed.  The final analysis of OS will be performed at the study end, which is defined as when 
50% of the subjects have died or sponsor terminates the study, whichever comes first. 
Assuming OS follows an exponential distribution and the median OS for the control arm 
(background therapy + placebo) is 6 years from randomization and the HR for the treatment group
(background therapy+ibrutinib) relative to the control is 0.78, it was expected that approximately 
54 and 104 overall survival events will be observed at the time of the first and second analysis of 
OS, respectively. At the interim analysis of PFS, 55 OS events were observed.
The efficacy of OS will not be claimed unless PFS reaches statistical significance.  For the 3 
planned analyses of OS, the type I error rate of the OS will be rigorously controlled using the 
Lan-DeMets spending function with the parameter resembling the conservative O’Brien-Fleming 
boundary which conservatively allocates alpha according to the information fraction (IF) at the 
time of each planned analysis. Information on the estimated boundary for OS is provided in Table 
3.
Table 3:
Estimated Crossing Boundary in Hazard Ratio and p-value Scales for the Planned OS Analysis
OS Analysis
Cumulative 
Number of OS 
Events
Timing (Month)
Calculated 
Boundary HR
Calculated 
Boundary p-value 
(2-sided)
Incremental 
Boundary 
Crossing 
Probability
  1st analysis
    55 (IF = 27.5%)
25
0.33
0.00004
0.0007
  2nd analysis
120 (IF = 60%)
49
0.61
0.0076
0.094
  Final analysis
200
89
0.76
0.0476
0.319
OS=overall survival, HR=hazard ratio, IF=information fraction 


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
23
Approved, Date: 15 June 2022
5.3.2.
Complete Response Rate and Overall Response Rate
Definition
Complete response 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.
Analysis method
Subjects with no postbaseline data will be considered as non-responders. Partial response or CR 
after the start of subsequent therapy will not be considered.  CR rate will be summarized using 
descriptive statistics for categorical data by treatment group.
The relative risk (background therapy +ibrutinib vs background therapy + placebo) adjusted for 
the stratification factors at randomization will be reported along with the associated 95% CI. 
Statistical inference will be evaluated using the Cochran-Mantel-Haenszel (CMH) Chi-square 
statistic, adjusted for the stratification factors at randomization: background therapy treatment (BR 
vs R-CHOP), refractory vs relapsed disease, number of prior lines of therapy (1 vs >1), and iNHL 
histology (FL vs MZL). Logistic regression analysis will also be performed to estimate the odds 
ratio and its associated 95% CI between the 2 treatment groups, adjusted for the stratification 
factors at randomization. 
Overall response rate will be analyzed in a similar fashion as CR rate. A listing of tumor response 
by assessment visit will be provided by treatment group.
5.3.3.
Time to Worsening in the Lym Subscale
Definition
Time to worsening (TTW) in the FACT-LymS is defined from the date of randomization to the 
start date of the worsening of patient symptoms. Worsening is defined by a 5-point decrease from
baseline in patient symptoms. Death and missing data due to very ill as noted on the case report 
form (CRF) 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 date of randomization.
In the event of missing item(s) in a FACT-Lym assessment, the subscale scores are 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 answered. 
Analysis method
The distribution of TTW in the Lym subscale will be estimated using Kaplan-Meir product limit 
method. A stratified log-rank test will be used to compare the distributions of the 2 treatment 
groups. The HR for background therapy + ibrutinib relative to background therapy + placebo and 
its associated 95% CI will be calculated based on the stratified Cox proportional hazards model by 


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
24
Approved, Date: 15 June 2022
the stratification factors at randomization. Further details on patient reported outcomes are 
provided in Section 7.
5.3.4.
Duration of Response
Definition
Duration of response is defined as the interval between the date of initial documentation of a 
response (CR or PR) and the date of first documented evidence of PD (or relapse for subjects who 
experience CR during the study) or death, whichever occurs first. The censoring rule for DOR is 
the same as PFS.
Analysis method
Duration of response will be analyzed for subjects with CR/PR. The distribution of duration of 
response will be estimated using the Kaplan-Meier product limit method. No formal hypothesis 
testing is conducted to compare the treatment groups.  
5.4.
Exploratory Endpoints
5.4.1.
Time-to-Next Treatment
Time-to-next treatment is defined as the duration from the date of randomization to the start date 
of any anti-lymphoma treatment subsequent to the study treatment. Subjects without subsequent 
treatment will be censored at the date of the last site visit.
The distribution of TTNT will estimated using the Kaplan-Meier product limit method. No formal 
hypothesis testing will be conducted to compare the treatment groups.
5.4.2.
Minimal Residual Disease (MRD) Negative Rate
The rate of MRD-negative response among FL subjects will be presented. Rate of MRD-negative 
response is defined as the proportion of FL subjects whose response is CR and who reach MRD-
negative disease status, (ie, <1 FL cell per 10,000 leukocytes for detection using the MRD assay). 
Subjects with missing MRD data and non-CR subjects are considered non-responders. In addition, 
durability of MRD-negative status defined will be presented. No formal hypothesis testing will be 
conducted to compare the treatment groups.
5.4.3.
Progression-free Survival on Next-Line Therapy (PFS2)
Progression-free survival on next-line therapy is defined as the time interval between the date of 
randomization and date of event, which is defined as progressive disease as assessed by 
investigator that starts after the next line of subsequent antineoplastic therapy, or death from any 
cause, whichever first. Those who are alive and for whom a second disease progression has not 
been observed are censored at the last disease assessment without second disease progression. It 
is analyzed using the same analysis methods as used for PFS.


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
25
Approved, Date: 15 June 2022
6.
SAFETY
Safety will be analyzed using the incidence, intensity, and type of AE, laboratory tests. All safety 
analyses will be based on the safety analysis set and performed by the treatment actually received. 
6.1.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AE will be coded using the current 
Medical Dictionary for Regulatory Activities (MedDRA). The severity of AE is assessed in 
National Cancer Institute (NCI) common toxicity criteria for adverse events (CTCAE) 
Version 4.03.
Treatment-emergent AE are (1) AE that occur after the first dose of study drug or any component 
of the background therapy treatment, and within 30 days following the last dose of study drug or 
any component of the background therapy treatment or the start date of a subsequent systemic 
anticancer therapy, whichever is earlier (including both dates), (2) any AE that is considered study 
treatment-related (ie, possibly, probably, or very likely related to study treatment) regardless of 
the start date of the event, (3) any AE that is present at baseline but worsens in severity or is 
subsequently considered study treatment-related by the investigator, or (4) any AE with missing
start date and its end date is during the treatment. 
Treatment-emergent AE will be summarized by system organ class and preferred term, by grade, 
by relationship to study drug, and by action taken. For each 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 (from the highest to lowest incidence in the Total column). The same 
summary will be provided for study drug-related AE, SAE, and study drug-related SAE, as well 
as AE leading to treatment discontinuation and death. Ocular events collected on the CRF will be 
summarized similarly to the treatment-emergent AE.
6.2.
Adverse Events of Special Interest
Major hemorrhage events: a subset of hemorrhagic events which are
!
Grade 3 or higher, or
!
SAE of bleeding of any grade, or
!
central nervous system hemorrhage of any grade
Adverse events of special interest will be summarized similarly to treatment-emergent AE.
6.3.
Other Safety Observations
Other malignancies: 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. Other malignancies will be summarized by preferred term for 
the entire study period and for the treatment-emergent AE period. In addition, AEs of clinical 
interest and other special AEs will be summarized by treatment group.


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
26
Approved, Date: 15 June 2022
6.4.
Death
A summary of the number of deaths since first administration of study drug or any component of 
the background therapy until 30 days after last study drug administration will be provided, along 
with the primary cause of death. A death is a study drug-related death if the primary cause is a 
study drug-related AE. 
6.5.
Clinical Laboratory Tests
Laboratory data for hematology and serum chemistry tests 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 CTC v4.03 criteria but limited only to the part 
based on the ULN, the other part that is based on change from baseline will not be used for toxicity 
grading. Toxicity grading for all other lab parameters will be based on the NCI CTC v4.03 criteria 
as is. Generic normal ranges will be applied whenever reference ranges are not available. Generic 
normal ranges will be applied to hematology using published values.8,9 Local ranges will be used 
for chemistry parameters.
The following laboratory tests will be analyzed: 
!
Hematology: hemoglobin, WBC count, ANC, ALC, and platelet count
!
Chemistry: sodium, potassium, creatinine, AST, ALT, alkaline phosphatase, LDH, total 
bilirubin, and albumin.
!
Beta2-microglobulin, serum immunoglobulin levels (IgG, IgM, IgA)
Descriptive statistics (mean, standard deviation, median, and range) will be calculated for the raw 
data and for change from baseline at each time point of assessment, as well as for change from 
baseline to the last value. Toxicity grade will be summarized for all hematology and chemistry 
parameters except for LDH, which will be summarized by abnormal/normal using standard normal 
ranges provided in the dataset. Change from baseline to the worst grade during the treatment will 
be provided as shift tables for selected parameters.
6.5.1.
Creatinine Clearance
Creatinine clearance (CrCl) is calculated using the Cockroft-Gault formula:
For males, the factor is 1 instead of 0.85
6.5.2.
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 absolute 
lymphocyte counts increasing ≥50% from baseline and achieving level ≥5×109/L For subjects with 
lymphocytosis, resolution of lymphocytosis is defined as (1) a decrease of ALC value to the 
baseline level or lower, or (2) or an achievement of ALC value that is <5×109/L, whichever occurs 


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
27
Approved, Date: 15 June 2022
first. Time to lymphocytosis is defined as the interval between the date of first dose and the date 
subject had lymphocytosis first time and presented in weeks. Duration of lymphocytosis will be 
derived from first time subject had lymphocytosis until it recovered for first time and presented in 
weeks. Subjects who have not recovered will be censored at last lab assessment. 
6.6.
Other Safety Parameters
Frequencies of ECOG score will be reported over time.
7.
PATIENT REPORTED OUTCOMES
Two PRO instruments, the FACT-LymS and EQ-5D-5L will be administered in this study:
The FACT-LymS includes 15 items, and scores range from 0 to 60, with each item scored on a 
5-point scale from 0 (not at all) to 4 (very much). Higher scores represent better health status with 
respect to fewer disease related symptoms and fewer disease related concerns of patients. 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. For purposes 
of this study, the EQ-5D-5L will be used to generate weighted 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). The scores for the 5 separate 
questionnaires are categorical and should not be analyzed as cardinal numbers. However, 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.
For each of the PRO scales, compliance, descriptive statistics (number of observations, mean, 
standard deviation, median, minimum, maximum) of scores at baseline and postbaseline 
assessments, as well as change from baseline to postbaseline assessments will be reported by 
treatment groups. Time to worsening (TTW) in the Lym subscale analysis is specified in 
Section 5.3.3. Exploratory analyses may be conducted to examine time to worsening by clinical 
response status (ie, responder vs. non-responder) or by patient baseline characteristics of interest 
(ie, ECOG performance status).
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 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 FACT-
LymS to be in the range of 3 to 5 points, with 5 being the more conservative.10,11 Worsening and 
improvement is defined by a 5 or greater point reduction and increase from baseline in the Lym 
lymphoma subscale, respectively.11,12 Death will also be considered as worsening.  Subjects who 
have not met the definition of worsening will be censored at the last FACT-LymS assessment. 
Subjects with no worsening event and with no baseline assessment or on-study assessment will be 


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
28
Approved, Date: 15 June 2022
censored at date of randomization. Time to worsening in the FACT-LymS will be estimated using 
Kaplan-Meier methods. The HR for ibrutinib relative to placebo and its associated 95% CI will be 
calculated based on the stratified Cox proportional hazards model by the stratification factors at 
randomization. The best and worst change of the lymphoma subscale from baseline to post-
baseline may be explored using waterfall plot.
For FACT-LymS and EQ-5D-5L score, a mixed effects model with repeated measures analysis 
may be conducted estimating change from baseline at each time point between 2 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 in week as a continuous variable, 
treatment-by-time interaction, and stratification factors at randomization as fixed effects.
8.
PHARMACOKINETICS
The plasma concentration data of ibrutinib and ibrutinib metabolite PCI-45227 at each time point 
will be summarized using descriptive statistics and will be listed for all subjects per treatment 
group, based on the PK analysis set. 
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 (ie, <0.500 ng/mL) will be treated as zero in calculating the summary statistics.


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
29
Approved, Date: 15 June 2022
APPENDIX 1 CHANGE TO PROTOCOL PRE-PLANNED ANALYSIS
1.
COVID-19 IMPACT
Impact of the COVID-19 pandemic is analyzed and presented, including COVID-19 related 
treatment and study disposition, protocol deviations, doses modifications, disease evaluation 
compliance and adverse events is summarized.


PCI-32765 (ibrutinib)
Statistical Analysis Plan PCI-32765FLR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
30
Approved, Date: 15 June 2022
REFERENCES
1.
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol.
2007;25(5):579-586.
2.
Bachy E et al. A Simplified scoring system in de novo follicular lymphoma  treated  initially  with 
immunochemotherapy. Blood, Am Soc Hematology. 2018;132:49-58.
3.
Casullo Cet al. Early Relapse of Follicular Lymphoma after Rituximab plus Cyclophosphamide, Doxorubicin, 
Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis from the National 
LymphoCare Study. Journal of Clinical Oncology, American Society of Clinical Oncology. 2015; 33:2516-
2522.
4.
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549-556.
5.
ICH E9 (R1) Addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical 
principles for clinical trials, November 2019.
6.
Dodd LE, Korn EL, Freidlin B, et al. An audit strategy for progression-free survival. Biometrics. 
2011;671092–671099.
7.
Amit O, Mannino F, Stone AM, et al. Blinded independent central review of progression in cancer. EU J 
Cancer. 2011;47:1772-1778.
8.
Kratz A, Ferraro, M, Sluss, PM, Lewandrowski, KB. Laboratory Reference Values; NEJM. 2004; 351: 1548-
1563. 
9.
Provan D, Singer CRJ., Baglin T, Lilleyman J. Oxford Handbook of Clinical Hematology. Second Edition, 
Oxford University Press. 2004. 
10.
Hlubocky FJ, Webster K, Cashy J, et al. 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. 
11.
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 Am Soc Hematology; 7 December 2008; San Francisco, California.
12.
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]. Am Soc Hematology. 2005;106:Abstract 750.