Clinical trial NCT01855750
Conditions: Lymphoma
Keywords: Lymphoma B-cell lymphoma Non-germinal center B-cell subtype Diffuse large B-cell lymphoma Bruton's tyrosine kinase inhibitor PCI-32765 JNJ-54179060 Ibrutinib Rituximab Cyclophosphamide Doxorubicin Vincristine Prednisone
Sponsor: Janssen Research & Development, LLC
Start date: 2013-09-03; Completion date: 2019-04-05
Enrollment: 838 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate if ibrutinib administered in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improves the clinical outcome in newly diagnosed patients with non-germinal center B-cell subtype (GCB) of diffuse large B-cell lymphoma (DLBCL) selected by immunohistochemistry (IHC) or newly diagnosed patients with activated B cell-like (ABC) subtype of DLBCL identified by gene expression profiling (GEP) or both populations.

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 to compare the efficacy and safety of ibrutinib in combination with R-CHOP versus R-CHOP alone in adult patients newly diagnosed non-GCB DLBCL selected by IHC or newly diagnosed patients with ABC subtype of DLBCL identified by GEP or both populations. The study will include screening, active treatment, and posttreatment follow-up phases. The study will end when 50% of participants have died or 5 years after the last participant is randomized or the sponsor terminates the study, whichever occurs first. Approximately 800 participants will be randomly assigned in a 1:1 ratio to receive either placebo+R-CHOP (treatment arm A) or ibrutinib+R-CHOP (treatment arm B). All participants will receive R-CHOP as background therapy for 6 or 8 cycles (21 days per cycle) prespecified according to local practice. After 4 treatment cycles, an interim response assessment will be performed to evaluate disease progression for each participant. Participants with progressive disease or relapsed disease after complete response will be discontinued from treatment. Participants who discontinue R-CHOP without disease progression will continue study drug (placebo or ibrutinib) until 6 or 8 cycles are completed, disease progression, or unacceptable toxicity, whichever occurs first. After completion of study drug, participants will undergo assessment of tumor response based on the Revised Response Criteria for Malignant Lymphoma. Participants with documented residual disease upon completion of at least 6 cycles of R-CHOP therapy are considered eligible to initiate subsequent antilymphoma therapy. Serial pharmacokinetic samples will be collected before and after dosing, and safety will be monitored throughout the study.

Arms: arm 1: Treatment Arm A = placebo + R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) arm 2: Treatment Arm B = ibrutinib + R-CHOP
Interventions: intervention 1: Ibrutinib intervention 2: Placebo intervention 3: Rituximab intervention 4: Cyclophosphamide intervention 5: Doxorubicin intervention 6: Vincristine intervention 7: Prednisone (or equivalent)
Intervention descriptions: intervention 1: 560 mg capsules administered by mouth once daily (21-day cycles) intervention 2: 4 matched capsules administered by mouth once daily (21-day cycles) intervention 3: 375 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles) intervention 4: 750 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles) intervention 5: 50 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles) intervention 6: 1.4 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles) intervention 7: 100 mg capsules administered by mouth once daily on Day 1 to Day 5 of each cycle

Protocol documents:
Prot_000.pdf: 
1
Approved, Date: 16 October 2017
Janssen Research & Development *
Clinical Protocol
A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine 
Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination with Rituximab, 
Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects With 
Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma
Protocol PCI-32765DBL3001; 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 Pharmaceutica NV; Janssen, Inc; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout 
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information 
page that accompanies the protocol.
This compound is being investigated in Phase 1, 2, and 3 clinical studies.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER:  2013-000959-40
Universal Trial Number: U1111-1139-6222
Status:
Approved
Date:
16 October 2017
Prepared by:
Janssen Research & Development, LLC
EDMS No. & Version: EDMS-ERI-56338574, Version 6.0
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.
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Approved, Date: 16 October 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 19
ABBREVIATIONS ...................................................................................................................................... 28
1.
INTRODUCTION................................................................................................................................ 30
1.1.
Diffuse Large B-cell Lymphoma..................................................................................................... 30
1.1.1.
Standard Treatment for Diffuse Large B-Cell Lymphoma .......................................................... 30
1.1.2.
Classification by Cell of Origen in Diffuse Large B-Cell Lymphoma .......................................... 31
1.2.
Investigational Product Name and Description.............................................................................. 32
1.3.
Summary of Relevant Nonclinical and Clinical Data...................................................................... 32
1.3.1.
Nonclinical Data.......................................................................................................................... 32
1.3.2.
Clinical Pharmacokinetic Data.................................................................................................... 32
1.3.3.
Clinical Efficacy of Ibrutinib in Diffuse Large B-cell Lymphoma ................................................. 34
1.3.3.1.
Study PCYC-04753 ................................................................................................................. 34
1.3.3.2.
Study PCYC-1106-CA ............................................................................................................. 34
1.3.3.3.
Post hoc Analysis .................................................................................................................... 35
1.3.3.4.
Study PCI-32765DBL1002 ...................................................................................................... 35
1.3.4.
Clinical Safety of Ibrutinib ........................................................................................................... 36
1.3.4.1.
Monotherapy Studies............................................................................................................... 37
1.3.4.1.1.
Hematological Adverse Events ............................................................................................ 37
1.3.4.1.2.
Non-Hematological Adverse Events .................................................................................... 37
1.3.4.2.
Combination Therapy Studies ................................................................................................. 39
1.3.4.2.1.
Preliminary Results From Study PCI-32765DBL1002 ......................................................... 39
1.3.4.3.
Treatment Discontinuations..................................................................................................... 41
1.3.5.
Background Therapy .................................................................................................................. 41
1.4.
Overall Rationale for the Study...................................................................................................... 41
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 43
2.1.
Objectives ...................................................................................................................................... 43
2.2.
Hypothesis ..................................................................................................................................... 44
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 44
3.1.
Overview of Study Design.............................................................................................................. 44
3.2.
Study Design Rationale.................................................................................................................. 46
3.2.1.
Study Population......................................................................................................................... 47
3.2.2.
Study Treatments ....................................................................................................................... 47
3.2.3.
Biomarker Collection................................................................................................................... 47
4.
SUBJECT POPULATION.................................................................................................................. 47
4.1.
Inclusion Criteria ............................................................................................................................ 48
4.2.
Exclusion Criteria ........................................................................................................................... 49
4.3.
Prohibitions and Restrictions ......................................................................................................... 50
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 50
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 52
6.1.
Study Treatment............................................................................................................................. 52
6.1.1.
R-CHOP Administration.............................................................................................................. 52
6.1.2.
Ibrutinib or Placebo Administration............................................................................................. 52
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6.2.
Dose Modifications and Dose Delay.............................................................................................. 53
6.2.1.
Rituximab.................................................................................................................................... 54
6.2.2.
Cyclophosphamide ..................................................................................................................... 54
6.2.3.
Doxorubicin................................................................................................................................. 55
6.2.4.
Vincristine ................................................................................................................................... 56
6.2.5.
Prednisone (or Equivalent) ......................................................................................................... 56
6.2.6.
Study Drug (Ibrutinib or Placebo) ............................................................................................... 56
7.
TREATMENT COMPLIANCE............................................................................................................ 57
7.1.
Ibrutinib or Placebo Compliance.................................................................................................... 57
7.2.
R-CHOP Compliance..................................................................................................................... 58
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 58
8.1.
Permitted Medications and Supportive Therapies...................................................................... 58
8.1.1.
Medications Permitted Prior to Study Treatment........................................................................ 59
8.1.1.1.
Pre-treatment Steroids ............................................................................................................ 59
8.1.2.
Medications Permitted During Treatment................................................................................... 59
8.1.2.1.
Uric Acid-lowering Agents ....................................................................................................... 60
8.2.
Prohibited Medications ............................................................................................................... 60
8.2.1.
Concomitant Use of Ibrutinib/Placebo and CYP3A Inhibitors or Inducers ................................. 60
8.2.2.
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib.................................. 61
8.2.3.
Concomitant Use of Ibrutinib/Placebo and QT Prolonging Agents ............................................ 61
8.2.4.
Concomitant Use of Ibrutinib/Placebo and Antiplatelet Agents and Anticoagulants .................. 61
8.2.5.
Radiation Therapy ...................................................................................................................... 62
8.3.
Subsequent Antilymphoma Therapies........................................................................................ 62
9.
STUDY EVALUATIONS .................................................................................................................... 62
9.1.
Study Procedures........................................................................................................................... 62
9.1.1.
Overview..................................................................................................................................... 62
9.1.2.
Pretreatment (Screening) Phase ................................................................................................ 62
9.1.3.
Active Treatment Phase ............................................................................................................. 64
9.1.4.
Posttreatment Follow-up Phase ................................................................................................. 65
9.1.5.
Clinical Cutoffs............................................................................................................................ 66
9.2.
Efficacy........................................................................................................................................... 66
9.2.1.
Evaluations ................................................................................................................................. 66
9.2.1.1.
CT/MRI/PET Scans ................................................................................................................. 66
9.2.1.2.
Bone Marrow Assessment....................................................................................................... 68
9.2.1.3.
Fluid Aspiration at Other Sites of Disease............................................................................... 68
9.2.1.4.
Physical Examination .............................................................................................................. 68
9.2.1.5.
Patient-Reported Outcomes.................................................................................................... 68
9.2.2.
Efficacy Criteria........................................................................................................................... 69
9.2.2.1.
Assessment of Disease Response and Progressive Disease ................................................ 69
9.2.2.2.
Definition of Measurable and Assessable Disease ................................................................. 69
9.2.2.3.
Response Categories .............................................................................................................. 70
9.2.3.
Endpoints.................................................................................................................................... 72
9.3.
Pharmacokinetics........................................................................................................................... 72
9.3.1.
Evaluations ................................................................................................................................. 72
9.3.2.
Analytical Procedures................................................................................................................. 73
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 73
9.4.
Companion Diagnostic and Biomarkers......................................................................................... 73
9.4.1.
Companion Diagnostic................................................................................................................ 73
9.4.2.
Biomarkers.................................................................................................................................. 73
9.5.
Safety Evaluations ......................................................................................................................... 74
9.6.
Sample Collection and Handling.................................................................................................... 77
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 78
10.1.
Completion ..................................................................................................................................... 78
10.2.
Discontinuation of Study Treatment............................................................................................... 78
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10.3.
Withdrawal From the Study............................................................................................................ 78
11.
STATISTICAL METHODS................................................................................................................. 79
11.1.
Analysis Populations...................................................................................................................... 79
11.2.
Subject Information ........................................................................................................................ 80
11.3.
Sample Size Determination ........................................................................................................... 80
11.3.1.
Multiplicity Adjustment for ABC Subtype .................................................................................... 81
11.4.
Efficacy Analyses ........................................................................................................................... 82
11.4.1.
Primary Endpoint ........................................................................................................................ 82
11.4.2.
Secondary Endpoints.................................................................................................................. 83
11.4.2.1.
Progression-free Survival ........................................................................................................ 83
11.4.2.2.
Complete Response ................................................................................................................ 83
11.4.2.3.
Overall Survival ....................................................................................................................... 83
11.4.2.4.
Time to Worsening on the Lym Subscale................................................................................ 83
11.4.3.
Other Exploratory Efficacy Endpoints......................................................................................... 84
11.4.4.
Patient-Reported Outcomes ....................................................................................................... 84
11.5.
Pharmacokinetic Analyses............................................................................................................. 84
11.6.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 85
11.7.
Biomarker Analyses ....................................................................................................................... 85
11.8.
Safety Analyses ............................................................................................................................. 85
11.9.
Interim Analysis.............................................................................................................................. 86
11.10.
Data Monitoring Committee ........................................................................................................... 86
12.
ADVERSE EVENT REPORTING ...................................................................................................... 87
12.1.
Definitions ...................................................................................................................................... 87
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 87
12.1.2.
Attribution Definitions.................................................................................................................. 88
12.1.3.
Severity Criteria .......................................................................................................................... 88
12.2.
Special Reporting Situations.......................................................................................................... 89
12.3.
Procedures..................................................................................................................................... 89
12.3.1.
All Adverse Events...................................................................................................................... 89
12.3.2.
Serious Adverse Events ............................................................................................................. 90
12.3.3.
Adverse Events of Special Interest............................................................................................. 91
12.3.3.1.
Major Hemorrhage................................................................................................................... 92
12.3.4.
Other Malignancies..................................................................................................................... 92
12.3.5.
Pregnancy................................................................................................................................... 92
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 92
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 92
13.1.
Procedures..................................................................................................................................... 93
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 93
14.
STUDY DRUG INFORMATION......................................................................................................... 93
14.1.
Study Drug – Ibrutinib or Placebo.................................................................................................. 93
14.1.1.
Physical Description ................................................................................................................... 93
14.1.2.
Packaging ................................................................................................................................... 93
14.1.3.
Labeling ...................................................................................................................................... 93
14.1.4.
Preparation, Handling, and Storage ........................................................................................... 94
14.2.
Background Therapy (R-CHOP).................................................................................................... 94
14.3.
Drug Accountability ........................................................................................................................ 94
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 95
16.
ETHICAL ASPECTS ......................................................................................................................... 95
16.1.
Study-Specific Design Considerations........................................................................................... 95
16.2.
Regulatory Ethics Compliance....................................................................................................... 96
16.2.1.
Investigator Responsibilities ....................................................................................................... 96
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 97
16.2.3.
Informed Consent ....................................................................................................................... 98
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16.2.4.
Privacy of Personal Data ............................................................................................................ 99
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 99
16.2.6.
Country Selection ..................................................................................................................... 100
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 100
17.1.
Protocol Amendments.................................................................................................................. 100
17.2.
Regulatory Documentation .......................................................................................................... 100
17.2.1.
Regulatory Approval/Notification .............................................................................................. 100
17.2.2.
Required Prestudy Documentation........................................................................................... 100
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 101
17.4.
Source Documentation................................................................................................................. 102
17.5.
Case Report Form Completion .................................................................................................... 102
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 103
17.7.
Record Retention ......................................................................................................................... 103
17.8.
Monitoring .................................................................................................................................... 103
17.9.
Study Completion/Termination..................................................................................................... 104
17.9.1.
Study Completion ..................................................................................................................... 104
17.9.2.
Study Termination..................................................................................................................... 104
17.10.
On-Site Audits .............................................................................................................................. 105
17.11.
Use of Information and Publication.............................................................................................. 105
REFERENCES.......................................................................................................................................... 107
INVESTIGATOR AGREEMENT ............................................................................................................... 122
LIST OF ATTACHMENTS
Attachment 1:
Revised International Prognostic Index.................................................................... 110
Attachment 2:
Decision Tree for Immunohistochemistry Classification of DLBCL.......................... 111
Attachment 3:
Eastern Cooperative Oncology Group Performance Status Scale .......................... 112
Attachment 4:
Body Surface Area Calculation ................................................................................ 113
Attachment 5:
Inhibitors and Inducers of CYP3A ............................................................................ 114
Attachment 6:
Sample FACT-Lym (Version 4) ................................................................................ 115
Attachment 7:
Sample Health Questionnaire EQ–5D–5L................................................................ 118
Attachment 8:
Estimated Blood Volumes for Laboratory Samples.................................................. 121
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Time and Events Schedule – Up to Clinical Cutoff for Primary Endpoint Analysis .................. 23
Table 2:
Dose and Administration Schedule for R-CHOP ...................................................................... 26
Table 3:
Time and Events Schedule – After the Clinical Cutoff for the Primary Endpoint 
Analysis..................................................................................................................................... 27
Table 4:
Study PCYC-1106-CA Efficacy Results.................................................................................... 35
Table 5:
Preliminary Response Data (Study PCI-32765DBL1002)........................................................ 36
Table 6:
Dose Modification for Cyclophosphamide and Doxorubicin for Hematological 
Toxicities ................................................................................................................................... 55
Table 7:
Dose Modification of Doxorubicin for Hepatic Function Impairment......................................... 55
Table 8:
Dose Modification for Vincristine Hepatic Function Impairment ............................................... 56
Table 9:
Ibrutinib/Placebo Dose Modifications........................................................................................ 57
Table 10:
Examples of Possible Study Outcomes Based on Median EFS=12 Months for Non-
cured Subjects .......................................................................................................................... 81
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 46
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Approved, Date: 16 October 2017
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
1 May 2013
Amendment INT-1
21 Dec 2013
Amendment INT-2
5 Aug 2015
Amendment INT-3
16 Oct 2017
Amendments are listed beginning with the most recent amendment.
Amendment INT-3 (16 Oct 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To omit the interim analysis due to a lower than expected event-free 
survival (EFS) event rate observed. To change retrospective analysis of the activated B cell-like (ABC) diffuse 
large B-cell lymphoma (DLBCL) population by gene expression profiling (GEP) from a secondary objective 
to a co-primary objective (ie, in addition to the already pre-specified non-germinal center B cell-like
[non-GCB] DLBCL population by immunohistochemistry [IHC]). The hypothesis and primary endpoint 
analysis were updated to include the ABC by GEP population and the statistical method was clarified.
Applicable Section(s)
Description of Change(s)
Rationale: The sponsor is omitting the interim analysis due to a lower than expected EFS rate and the short time 
between when sufficient EFS events are projected to be reached for the interim analysis (ie, approximately 
270 EFS events) and when the final analysis will be performed (fixed date; clinical cutoff is 30 months after the 
800th subject is randomized).
9.1.5 Clinical Cutoff; 11.3 Sample Size Determination;
11.9 Interim Analysis
Clarified language since the interim analysis is being 
omitted due to the low event rate and short time 
between the interim analysis (event-driven) and final 
analysis (fixed date).
Rationale: Since the initiation of this study, GEP is now a more readily available assay platform used for 
DLBCL subtyping in standard practice using commonly available formalin-fixed paraffin-embedded tissue
(FFPE). Therefore, available tumor samples will be retrospectively analyzed to identify the ABC DLBCL 
population using GEP and the ABC subtype of DLBCL by GEP is being included as part of the primary endpoint 
analysis.
Synopsis (Primary Objective; Secondary Objectives); 
2.1 Objectives (Primary Objectives; Secondary 
Objectives)
Updated to add evaluation of the treatment benefit of 
subjects with the ABC subtype of DLBCL by GEP as a 
primary objective and remove as a secondary objective.
Synopsis (Hypothesis);
2.2 Hypothesis
Updated the study hypothesis to also include 
evaluation of the treatment benefit of subjects with the 
ABC subtype of DLBCL identified by GEP.
Synopsis (Overview of Study Design); 
1.4 Overall Rationale for the Study; 
3.1 Overview of Study Design
Clarified that available tumor samples will be 
retrospectively analyzed to identify the ABC DLBCL 
population using GEP now that this assay platform is 
more readily available; included supportive 
background rationale.
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9.4.1 Companion Diagnostic
Clarified that 
 (a 
diagnostic GEP manufacturer) is developing a GEP
assay for identification of the ABC DLBCL subtype (in 
addition to the already pre-specified IHC assay) that 
will be retrospectively determined using available 
clinical study FFPE tissue specimens.
11.1 Analysis Populations
Clarified definition for the ITT population and added 
the ABC population description.
11.4 Efficacy Analyses
Clarified that the primary endpoint analysis will use the 
Song and Chi method.
11.3.1 Multiplicity Adjustment for the ABC Subtype; 
References
Section added to describe revised statistical method 
(Song and Chi) to be used to analyze the ABC by GEP 
DLBCL population. References added.
Synopsis (Statistical Methods);
11.4.1 Primary Endpoint
Primary endpoint analysis was clarified for ABC by 
GEP population.
Synopsis (Secondary Objectives, Statistical Methods); 
2.1; Objectives; 11.4.2 Secondary Endpoints; 
9.2.3 Endpoints
Updated the hierarchal order of the secondary efficacy 
endpoints (analysis of CR rate before overall survival).
Rationale: To clarify data to be collected after the primary endpoint analysis.
Synopsis (Efficacy Evaluations); 
Table 1 (Time and Events Schedule – Up to Clinical 
Cutoff for Primary Endpoint Analysis
Table 3 (Time and Events Schedule – After the 
Clinical Cutoff for the Primary Endpoint Analysis); 
3.1 Overview of Study Design;
9.1.4 Posttreatment Follow-up Phase
9.2.1 Evaluations; 
9.2.1.1 CT/MRI/PET Scans; 
9.2.1.5 Patient-Reported Outcomes
Renamed and clarified heading in Table 1 to specify 
assessments to be performed up to clinical cutoff for 
primary endpoint analysis; 
Added Table 3 to clarify data to be collected after the 
primary endpoint analysis. Radiological disease 
evaluations are not required after the clinical cutoff for 
the primary endpoint analysis and may be performed as 
clinically indicated (at the discretion of the 
investigator) per local standard of care
Rationale: Clarification to end of study definition was provided.
Synopsis (Overview of Study Design); 
3.1 Overview of Study Design; 
9.1.5 Clinical Cutoff
Clarified definition of end of study: ie, when 50% of 
the randomized subjects have died or 5 years after the 
last subject is randomized or the sponsor terminates 
the study, whichever occurs first.
Rationale: Minor errors were corrected.
Throughout the protocol
Minor grammatical, formatting, or spelling changes 
were made.
References
Updated reference list per revised text.
9.1.4 Posttreatment Follow-up Phase; 
9.2.1.1 CT/MRI/PET Scans
Removed reference to specific assessment timepoints 
to streamline document (retain details in Time and 
Events Schedule)
9.5 Safety Evaluations
Correction made to clarify that adverse events reported 
after 30 days following the last dose of study treatment 
should be reported if considered related to “study 
treatment” (not ibrutinib/placebo)
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Rationale: Updates were made to align with current protocol template as appropriate.
Title page
Updated sponsorship statement.
17.3 Subject Identification, Enrollment, and Screening 
Logs
Clarified that date of birth for subject identification 
(eg, in reports and communications) will only be used 
as allowed by local regulations.
17.11 Publications
Clarified timing for publication of study results. 
Clarified guidelines and criteria used for named 
authors in publications.
Amendment INT-2 (5 Aug 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To clarify protocol recommendations for monitoring of patient 
subgroups who are considered, based on emerging literature, at increased risk of hepatitis B virus reactivation due 
to R-CHOP + ibrutinib/placebo therapy. Additionally, the protocol was updated with new safety-related 
information for consistency with the ibrutinib Investigator’s Brochure.
Applicable Section(s)
Description of Change(s)
Rationale: Subjects who are at increased risk of potentially fatal hepatitis B virus reactivation as a consequence of 
R-CHOP + ibrutinib/placebo anti-B-cell drug treatment should be monitored to guide antiviral therapy.
Time and Events Schedule 
(note ‘n’);
8.1.2. Medications Permitted 
During Treatment;
9.5. Safety Evaluations

Clarified the requirement for hepatitis B DNA by PCR testing at screening, and 
confirmation of a negative finding for this test, to include subjects testing 
positive for hepatitis B surface antigen (in addition to those testing positive for 
hepatitis B core antibody).

Clarified prophylactic antiviral therapy in subjects who are hepatitis B surface 
antigen positive/hepatitis B DNA by PCR negative, according to local 
guidelines.

Added prophylactic antiviral therapy or monitoring in subjects who are hepatitis 
B core antibody positive/hepatitis B DNA by PCR negative, according to local 
guidelines.

Clarified monitoring of hepatitis B carriers during and after anti-B-cell 
treatment, according to local guidelines.
Rationale: To clarify the follow-up period for the interim analysis, as the language is inaccurate in stating that this 
is estimated to occur approximately 6 months after the last subject is enrolled. The interim analysis is event-driven. 
For the second clinical cutoff for the final EFS analysis, we are clarifying that the cutoff will occur 30 months after 
the ‘800th‘ subject is randomized instead of ‘last subject’ randomized.
Synopsis;
9.1.5. Clinical Cutoffs;
11.3. Sample Size 
Determination;
11.9 Interim Analysis
With a study follow-up period of 30 months after the 800th subject is randomized, it 
is anticipated that approximately 419 EFS events will be observed and the study 
will have at least 90% power to show the statistical significance at the overall alpha 
level of 0.025 (1 sided). The interim analysis will occur when approximately 
270 EFS events have been observed. The clinical cutoff for the final EFS analysis 
is 30 months after the 800th subject randomized.
Rationale: To update the Sponsorship statement.
Title page
In the Sponsorship statement, replaced “Janssen R&D Ireland” with “Janssen 
Sciences Ireland UC”.
Rationale: To update the name of the co-development company for ibrutinib from Pharmacyclics, Inc to
Pharmacyclics LLC.
NCT01855750


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765DBL3001 Amendment INT-3
9
Approved, Date: 16 October 2017
Applicable Section(s)
Description of Change(s)
Synopsis;
1. Introduction
Pharmacyclics, Inc has been replaced by Pharmacyclics LLC.
Rationale: A correction has been made to the criteria used to determine complete response.
9.2.2.3. Response Categories
The length of the short axis of previously involved nodes before treatment has been 
corrected from 1.1 cm to 1.0 cm.
Rationale: Language describing health authority approvals for ibrutinib has been made more general, to avoid the 
need for future updates to this text.
Synopsis;
1. Introduction
Rather than describe the current U.S. FDA approvals for ibrutinib, the initial 
approval (adult patients with mantle cell lymphoma who have received at least 
1 prior therapy) is noted instead.
Rationale: The definition for the adverse event of special interest of major hemorrhage has been clarified, and 
intracranial hemorrhage is subsumed within the new definition for major hemorrhage. 
Synopsis Safety Evaluations;
9.5. Safety Evaluations;
12.3.3.1. Major Hemorrhage
Intracranial hemorrhage is no longer mentioned separately from major hemorrhage; 
rather, it is subsumed within the new definition for major hemorrhage.
Rationale: Clarifications have been made to the description of the investigational product, for consistency with the 
ibrutinib Investigator’s Brochure.
1.2. Investigational Product 
Name and Description
Ibrutinib is described as a white to off-white solid, provided in an oral capsule 
formulation.
Rationale: Results from a recent hepatic impairment study performed in non-cancer 526 subjects administered a 
single dose of 140 mg ibrutinib are available and were added to the background section of the protocol.
1.3.2. Clinical 
Pharmacokinetic Data
(Summary of Human 
Pharmacokinetics)
In a hepatic impairment study, data showed an increase in ibrutinib exposure
following single dose administration in subjects with mild, moderate, and severe 
hepatic impairment compared to subjects with normal liver function.
Rationale: Clinical safety information for ibrutinib monotherapy studies has been updated for consistency with both 
the ibrutinib Investigator’s Brochure and other protocols within the ibrutinib clinical development program.
1.3.4. Clinical Safety of 
Ibrutinib;
1.3.4.1.1. Hematological 
Adverse Events;
1.3.4.1.2. Non-Hematological 
Adverse Events
Clinical safety information for ibrutinib monotherapy studies has been updated and 
reorganized 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; rash and tumor lysis syndrome).
Rationale: The timing of required laboratory assessments at screening has been further clarified to minimize 
confusion.
4.1. Inclusion Criteria 
(Criteria 8 and 9)
Inclusion criteria 8 (hematology values) and 9 (biochemical values) specify limits 
that must be met prior to randomization and at baseline. The qualifier ‘within 
14 days’ has been removed from both criteria.
Rationale: This section has been revised to clarify that a short ibrutinib hold (up to 3 days) should be considered for 
intrathecal CNS prophylaxis based upon the subject’s clinical situation, including assessment of underlying 
lymphoma.
4.3. Prohibitions and 
Restrictions
From bullet #2 within this section, the word ‘minor’ has been deleted within ‘minor 
procedures’.
Also within bullet #2, for the list of procedures requiring ibrutinib to be held, 
‘intrathecal CNS prophylaxis’ has been added.
NCT01855750


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765DBL3001 Amendment INT-3
10
Approved, Date: 16 October 2017
Applicable Section(s)
Description of Change(s)
Rationale: Dose modification for hematologic toxicities related to cyclophosphamide and doxorubicin, and 
maximum allowed dose of prednisone administered for reason other than cancer, have been clarified based on 
investigator feedback.
6.2.2. Cyclophosphamide;
6.2.3. Doxorubicin;
Within Sections 6.2.2 and 6.2.3, dose adjustments for hematologic toxicities are 
now recommended rather than mandated.
Rationale: To clarify that chronic use of corticosteroids (ie, prednisone 20 mg/day or its equivalent) is allowed for 
other non-cancer related medical reasons during the treatment phase.
8.2. Prohibited Medications
Chronic use of systemic corticosteroids above that given for R-CHOP 
chemotherapy are prohibited. However, prednisone 20 mg/day or its equivalent is 
allowed for the treatment of adrenal insufficiency or other medical reason that is 
not cancer related.
Rationale: Guidance for certain categories of concomitant medications has been updated for consistency with the 
current ibrutinib Investigator’s Brochure.
8.2.2. Drugs That May Have 
Their Plasma Concentrations 
Altered by Ibrutinib;
8.2.4. Concomitant Use of 
Ibrutinib/Placebo and 
Antiplatelet Agents and 
Anticoagulants
Guidance for administration of ibrutinib with narrow therapeutic range P-gp 
substrates has been added to Section 8.2.2.
Guidance for administration of ibrutinib/placebo in subjects requiring therapeutic 
anticoagulation therapy has been clarified within Section 8.2.4.
Rationale: To avoid enrolling subjects in whom R-CHOP dose reductions are inevitable.
9.1.2. Pretreatment 
(Screening) Phase
Statement has been added requiring investigators to confirm that subjects who are 
80 years old are eligible to receive R-CHOP according to the protocol, without 
preplanned dose reductions.
Rationale: Clarified the minimum criteria that have to be present in the local pathology report for DLBCL 
diagnosis.
9.1.2. Pretreatment 
(Screening) Phase
Requirements for the local pathology report, allowing verification of the DLBCL 
diagnosis, have been clarified.
Rationale: Safety data from a Phase 3, randomized comparator-controlled (ibrutinib versus ofatumumab) study of 
ibrutinib monotherapy in subjects with CLL/SLL (ibrutinib: 195 subjects; ofatumumab: 191 subjects) 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.
9.5. Safety Evaluations
(Physical Examination)
Physical examinations conducted during the Active Treatment Phase will include 
monitoring for ocular symptoms.
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
Text has been expanded to show that in addition to electrocardiograms performed 
for all subjects during Screening, electrocardiograms may be repeated at any time 
during the study, as clinically indicated, especially in subjects with symptoms of 
arrhythmia.
Rationale: For consistency with risk-based monitoring text in current protocol template.
NCT01855750


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765DBL3001 Amendment INT-3
11
Approved, Date: 16 October 2017
Applicable Section(s)
Description of Change(s)
17.8. Monitoring
Three new paragraphs have been added to this section, addressing:
Sponsor will use a combination of monitoring techniques.
Remote contacts.
Central monitoring/central review.
Additionally, text has been added stating that only a sample of data may be 
reviewed.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment INT-1 (21 Dec 2013)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union
The overall reason for the amendment: To remove the biopsy/tissue requirement for confirmation of DLBCL 
diagnosis; update the protocol with new safety-related information and instructions; further clarify study treatment 
dosing instructions; revise operational aspects of the study; and perform minor modifications and formatting 
changes.
Applicable Section(s)
Description of Change(s)
Rationale: Tissue was being collected to both confirm DLBCL diagnosis and to determine the molecular subtype 
(non GCB vs. GCB subtype). Collection of tissue for confirmation of DLBCL diagnosis is no longer required 
(pathology report is sufficient); this will minimize burden to study subjects and clinical sites. The potential benefit 
of confirming the DLBCL diagnosis with the additional biopsy/tissue sample is considered to be small and 
removing central pathology confirmation of DLBCL imparts no risk to the study’s objectives. Alternatively, the 
sponsor will collect local pathology reports to determine the incidence of misdiagnosis and sensitivity analyses to 
the primary analysis will be considered if substantial misdiagnosis is suspected.
Synopsis; Time and Events 
Schedule; 3.1 Overview of 
Study Design; 4.1 Inclusion 
Criteria (criterion 3); 
9.1.2 Pretreatment 
(Screening) Phase; Figure 1
Wording revised to remove requirement for tissue collection at screening for 
confirmation of DLBCL diagnosis. Figure 1 (study schema) updated to reflect this.
Rationale: Clarification that uric acid is part of the chemistry panel on Day 1 of each cycle to allow for monitoring 
of tumor lysis syndrome. Also clarified that biochemistry tests may be repeated as clinically indicated.
Time and Events Schedule
On Day 1 of each cycle starting with Cycle 2: sodium, potassium, creatinine, total 
bilirubin, uric acid, and LDH. Magnesium on Day 1 of Cycles 1 and 2. 
Biochemistry tests may be repeated as clinically indicated.
Rationale: Clarification to the mechanism of action of ibrutinib.
Synopsis;
1 Introduction
Based on current information, the description of the mechanism of action of 
ibrutinib as a potent, orally-administered, covalently-binding small molecule 
Bruton’s tyrosine kinase (BTK) inhibitor has been updated in the protocol.
Rationale: On November 13, 2013 the FDA approved ibrutinib for the treatment of patients with MCL who have 
received at least 1 prior therapy. Therefore, the statement indicating that ibrutinib has not been approved for 
marketing in any country has been deleted and a statement on the current US approval in MCL has been added.
Synopsis; 1 Introduction; 1.2 
Investigational Product Name 
and Description
Added: Ibrutinib (IMBRUVICA™) is approved by the U.S. Food and Drug 
Administration for the treatment of adult patients with mantle cell lymphoma who 
have received at least 1 prior therapy.
NCT01855750


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765DBL3001 Amendment INT-3
12
Approved, Date: 16 October 2017
Applicable Section(s)
Description of Change(s)
Rationale: Clarified that the components of the R-CHOP regimen can be administered over 2 days. 
Table 2, Dose and 
Administration Schedule for 
R-CHOP 
The components of the R-CHOP regimen can be given over 2 days.
Rationale: Updated nonclinical statement on growth inhibition for specificity on DLBCL cell lines and to align 
with current Investigator’s Brochure.
1.3.1 Nonclinical Data
Ibrutinib inhibited the proliferation of cell lines derived from DLBCL patients with 
a median effective concentration of 1 or 2 nM. 
Rationale: The average increase (ie, 26-fold) in ibrutinib exposure when administered in combination with 
ketoconazole was provided in the protocol. The protocol has been updated with the actual increase for the Cmax and 
AUC0-last. A cross-reference to Section 8.2.1 was added for additional guidance on concomitant use of
ibrutinib/placebo with CYP3A inhibitors or inducers. In addition, updated text within Pharmacokinetic and 
Pharmacodynamic subsection of Section 1.3.2 to align with the current Investigator’s Brochure.
1.3.2 Clinical 
Pharmacokinetic Data; 
8.2.1 Concomitant Use of 
Ibrutinib/Placebo and 
CYP3A Inhibitors/Inducers 
Ketoconazole, a strong CYP3A inhibitor, increased ibrutinib exposure (maximum 
observed plasma concentration [Cmax] and area under the plasma concentration 
versus time curve from time zero to the time corresponding to the last quantifiable 
concentration [AUC0-last]) by 29- and 24-fold, respectively.
Bruton's tyrosine kinase remained fully occupied by ibrutinib (≥90% occupancy) 
for at least 24 hours in all subjects in Cohorts 2 through 5 (2.5 to 12.5 mg/kg/day) 
and for the 560 mg continuous dosing cohorts.
Rationale: Updated available efficacy data in subjects with DLBCL from Study PCI-32765DBL1002.
1.3.3.4 Study 
PCI-32765DBL1002; 
Table 4
Response data suggest activity with this regimen, with 18/18 (100%) evaluable 
subjects with DLBCL treated at a dose of 560 mg ibrutinib + R-CHOP achieving a 
response (14 CRs and 4 PRs).
Rationale: Safety data, since the time the original protocol was finalized, have been updated. These data include 
information from the 2013 Investigator’s Brochure, PCYC-04753 CSR, and preliminary safety results for 
Study PCI-32765DBL1002 (data cutoff of 08 July 2013).
1.3.4 Clinical Safety of 
Ibrutinib; 1.3.2 Clinical 
Pharmacokinetic Data
At the time of the original protocol (1 May 2013), safety data for 312 subjects were 
available, which was consistent with the Investigator’s Brochure at the time of 
protocol finalization. Safety data as of 06 Apr 2013 for the 506 subjects treated 
with ibrutinib monotherapy and 130 subjects treated with ibrutinib in combination 
with chemotherapy have been added. Data regarding hemorrhagic adverse events 
occurring in ibrutinib clinical studies have been updated. Preliminary safety data 
for Study PCI-32765DBL1002 was updated (clinical cutoff: 08 July 2013). 
Rationale: Additional new safety information (other malignancies, rashes, and infection) based on studies 
conducted with ibrutinib has been added. Other malignancies occurring in subjects treated in this study will be 
reported and collected on the CRF. A description of other malignancies observed in subjects treated with ibrutinib is 
also provided.
NCT01855750


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765DBL3001 Amendment INT-3
13
Approved, Date: 16 October 2017
Applicable Section(s)
Description of Change(s)
Synopsis (Safety 
Evaluations); 1.3.4.4 Other 
Malignancies; 1.3.4.5 Rash; 
1.3.4.6 Infection;
9.1.4 Posttreatment 
Follow-up Phase;  
12.3.4 Other Malignancies
In addition to all routine AE reporting, all new malignant tumors, including solid 
tumors, skin malignancies, and hematologic malignancies, are to be reported for 
the duration of study treatment and during any protocol-specified follow-up periods 
including post-progression follow-up for overall survival.
Mild to moderate rashes have been observed with ibrutinib alone or in combination 
with other drugs. A single case of Stevens-Johnson Syndrome (SJS) was reported 
in a male subject with CLL treated with ibrutinib 420 mg/day. The subject was also 
receiving multiple concomitant medications known to be associated with SJS. 
Subjects should be monitored closely for signs and symptoms suggestive of SJS.
In non-randomized clinical trials, infections (including sepsis, bacterial, viral, or 
fungal infections) were observed in subjects with MCL (≥ Grade 3; 25.2%) and 
CLL/SLL (≥Grade 3; 35.3%). Some of these infections have been associated with 
hospitalization and death. Subjects should be monitored for fever and infections 
and appropriate anti-infective therapy should be instituted as indicated.
Rationale: All imaging evaluations and radiology reports must be readily available if requested by the sponsor; 
images must meet imaging requirements as specified in the radiology manual. Also clarified that a PET/CT may be 
submitted in lieu of a dedicated CT if it is of diagnostic quality.
Synopsis; 3.1 Overview of 
Study Design; 
9.2.1 Evaluations; 
15 Study-Specific Materials
Radiological and PET scans performed prior to the database lock for the final 
analysis of EFS must be transferred to the independent imaging laboratory for 
storage; the scans may be reviewed, if deemed necessary.
A separate CT scan is 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 if it is of diagnostic quality. The CT scanning 
must be done according to the imaging requirements provided in the radiology 
manual to ensure that an optimized examination is done.
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) as well 
as the timing if a dose is missed (ie, up to 6 hours after a meal). Furthermore, instructions for fasting prior to 
collection of pharmacokinetic samples have been deleted.
6.1.2 Ibrutinib or Placebo
Administration
9.3.1 Evaluations
Ibrutinib/placebo capsules should be swallowed whole and should not be opened, 
broken, or chewed. If a dose of study drug is missed it can be taken as soon as 
possible on the same day with a return to the normal schedule the following day. 
The subject should not take extra capsules to make up the missed dose. 
Deleted: 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.
NCT01855750


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765DBL3001 Amendment INT-3
14
Approved, Date: 16 October 2017
Applicable Section(s)
Description of Change(s)
Rationale: Clarified throughout protocol that study treatment may continue if study drug (ibrutinib or placebo) is 
delayed, withheld, or discontinued.
Synopsis; 6.2 Dose 
Modifications and Dose 
Delay; 10.2 Discontinuation 
of Study Treatment 
Subjects who discontinue any component of R-CHOP without disease 
progression will continue study drug (placebo or ibrutinib) until 6 or 8 cycles are 
completed (as pre-specified by each site), disease progression, or unacceptable 
toxicity, whichever occurs first. If study drug is discontinued, any remaining 
study treatment (ie, rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone [or equivalent]) may continue.
If R-CHOP is delayed, treatment with study drug should be continued during the 
delay phase. If the study drug (ibrutinib/placebo) is delayed or withheld, R-CHOP 
treatment may be continued if clinically indicated.
Rationale: Throughout the protocol references to ‘study drug’ - meaning ibrutinib or placebo - versus ‘study 
treatment’ - meaning ibrutinib or placebo plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
have been clarified. Examples or characterization of the changes are provided below.
Synopsis; Time and Events 
Schedule; 1.3.5 Background 
Therapy; 3.1 Overview of 
Study Design; 6 Dosage and 
Administration; 7.1 Ibrutinib 
or Placebo Compliance; 
8 Prestudy and Concomitant 
Therapy; 9.1.3 Active 
Treatment Phase; 
9.3.1 Evaluations; 9.5 Safety 
Evaluations; 
10.2 Discontinuation of 
Treatment; 11.8 Safety 
Analyses; 12.2 Special 
Reporting Situations; 
12.3.1 All Adverse Events; 
12.3.2 Serious Adverse 
Events; 14.3 Drug 
Accountability;
17.2.2 Required Prestudy 
Documentation; 17.4 Source 
Documentation
For the purposes of this study, ‘study drug’ refers to ibrutinib or placebo and 
‘study treatment’ refers to ibrutinib/placebo, rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone (or equivalent).
The Active Treatment Phase will begin at randomization and will continue until 
discontinuation of all study treatment (ie, ibrutinib/placebo, rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone [or equivalent]) due 
to disease progression, initiation of subsequent antilymphoma therapy, 
unacceptable toxicity, withdrawn, or completion of study treatment.
The timeframe for collection of data on concomitant medications and adverse 
events, and study assessment and procedures now reference study treatment 
instead of study drug, where applicable.
An End-of-Treatment Visit will be scheduled within 30 days after the last dose of 
the last study treatment.
The investigator is responsible for ensuring that all study treatment received at 
the site is inventoried and accounted for throughout the study.
Section 1.3.5 heading title renamed from “Study Drugs Used as Background 
Therapy” to “Background Therapy” since “study drug” is defined as ibrutinib or 
placebo.
Rationale: Clarified pre-treatment steroid instructions.
8.1.1.1 Pre-treatment Steroids
If pre-treatment steroids exceed 10 days or 100 mg/day, please consult the medical 
monitor for approval.
Rationale: Instructions for dose modification for cyclophosphamide and doxorubicin for hematological toxicities 
was updated to align with global treatment practices. 
NCT01855750


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765DBL3001 Amendment INT-3
15
Approved, Date: 16 October 2017
Applicable Section(s)
Description of Change(s)
6.2.2 Cyclophosphamide
To start a cycle with cyclophosphamide, ANC must be 1,000/µL and platelets 
75,000/µL. The cycle must be delayed up to 3 weeks (instead of 2 weeks as 
previously specified) until the above values are documented on Day 1 of the cycle.
For ANC <500/µL and/or febrile neutropenia, initiation of G-CSF for all 
subsequent cycles is recommended. 
Dose reductions due to low platelet counts or ANCs are not required in subjects 
with thrombocytopenia or neutropenia due to bone marrow infiltration from 
DLBCL who entered the study with platelet counts <75,000/µL or neutrophil 
counts <1,000 cells/μL.
Rationale: Instructions for Grade 3 or greater neutropenia with infection or fever have been added and instructions 
for any Grade 3 or greater non-hematological toxicity. Specific instructions for nausea, vomiting, and diarrhea have 
been removed.
6.2.6 Ibrutinib or Placebo
Dose modification instructions were added for Grade 3 or greater neutropenia with 
infection or fever and any Grade 3 or greater non-hematological toxicity. 
Rationale: Throughout the protocol, references to CYP3A4/5 have been corrected to CYP3A. Examples are 
provided below.
1.3.2 Clinical 
Pharmacokinetic Data; 
4.1 Exclusion Criteria; 
6.1.2 Ibrutinib or Placebo 
Administration; 6.2.6 Study 
Drug (Ibrutinib or Placebo); 
8.1 Permitted Medications 
and Supportive Therapies; 
8.2.1 Concomitant Use of 
Ibrutinib/ Placebo and 
CYP3A Inhibitors/Inducers; 
Attachment 5
Subjects should avoid consuming food and beverages containing grapefruit or 
Seville oranges for the duration of the study due to CYP3A inhibition.
All concomitant medications for medical conditions other than DLBCL NHL are 
permitted other than those listed as CYP3A inhibitors, as clinically indicated.
Ibrutinib is metabolized primarily by CYP3A.
Rationale: Guidance for the administration of CYP3A inhibitors during ibrutinib/placebo administration is 
provided.
8.2.1 Concomitant Use of 
Ibrutinib/Placebo and 
CYP3A Inhibitors/Inducers; 
Attachment 5, References
Avoid co-administration with strong or moderate CYP3A inhibitors and consider 
alternative agents with less CYP3A inhibition.
A new reference website for inhibitors and inducers of CYP450 enzymes has been 
added.
Rationale: Instructions for drugs that may have their plasma concentrations altered by ibrutinib were added.
8.2.2 Drugs That May Have 
Their Plasma Concentrations 
Altered by Ibrutinib
New text has been added to discuss the effect of ibrutinib as a weak inducer of 
CYP450 isoenzymes and a mild inhibitor of P-gp.
Rationale: QT prolongation is not expected with ibrutinib; however, text regarding the precaution for concomitant 
use of ibrutinib and medications known to cause QT prolongation has been added to align with the current 
Investigator’s Brochure.
8.2.3 Concomitant Use of 
Ibrutinib/Placebo and QT 
Prolonging Agents
Any medications known to cause QT prolongation should be used with caution; 
periodic monitoring with electrocardiograms (ECG) and electrolytes should be 
considered and, if needed, the medical monitor may be contacted.
NCT01855750


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765DBL3001 Amendment INT-3
16
Approved, Date: 16 October 2017
Applicable Section(s)
Description of Change(s)
Rationale: Instructions for concomitant use of ibrutinib and antiplatelet agents, anticoagulants, and supplements 
such as fish oil and vitamin E preparations have been updated. 
8.2.4 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 preparations should be 
avoided. Use ibrutinib with caution in subjects requiring other anticoagulants or 
medications that inhibit platelet function. Subjects with congenital bleeding 
diathesis have not been studied. Ibrutinib should be withheld at least 3 to 7 days 
pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
Rationale: To date, the ocular adverse events observed in subjects with ibrutinib alone do not indicate the need of 
additional monitoring. Therefore, this is no longer a required assessment.
Time and Events Schedule; 
9.1.3 Active Treatment 
Phase; 9.5 Safety 
Evaluations; 12.3.3.2
Intracranial Hemorrhage
Deleted review of ocular changes for physical examinations. The following text has 
been deleted: The examination should also include inquiry of ocular symptoms and 
subjects should be referred to an ophthalmologist for a formal examination if any 
Grade ≥2 symptoms are reported.
Rationale: For subjects without progressive disease after the clinical cutoff, efficacy assessments will continue to 
be collected. Previously, efficacy assessments were to be collected according to the schedule outlined in the 
protocol. This has been changed to comply with the standard of care at the site.
9.2.1.1 CT/MRI/PET Scans
Follow up visits, including CT scans, will be completed every 16 weeks for the 
first 24 months, then every 24 weeks until PD, the clinical cutoff for the primary 
endpoint, or up to 5 years. After that, CT may be performed only as clinically 
indicated per standard of care.
Rationale: Clarified text regarding fluid aspiration for other sites of disease
9.2.1.3 Fluid Aspiration of 
Other Sites of Disease
For sites of disease with fluid accumulation such as 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 before disease 
progression is diagnosed for a subject if the fluid accumulation is the only sign of 
disease progression.
Rationale: Increased window for hematology and clinical chemistry assessments for flexibility at the sites.
Time and Events Schedule; 
9.5 Safety Evaluations
For Cycle 1 Day 1 only, if Screening tests were performed within 5 days of first 
dose of study treatment, then clinical laboratory tests do not need to be repeated. 
For subsequent cycles, samples can be taken within 3 days prior to dosing, 
provided that results are available before study treatment is given.
Rationale: Added details regarding the companion diagnostic procedures for determination of the DLBCL subtype.
9.4 Companion Diagnostic 
and Biomarkers
Added subsections 9.4.1 (Companion Diagnostic) and 9.4.2 (for Biomarkers). A 
companion diagnostic device will be developed in parallel to the clinical study for 
determination of DLBCL subtype. The DLBCL Classification IHC
 
assay used to identify non-GCB and GCB subtypes is based on the Hans algorithm 
(2004) and utilizes a standardized immunohistochemistry protocol. Subtyping will 
be accomplished by determination of the status of CD10, BCL6, and MUM 1. 
Standardized protocols will be implemented at 4 regional central laboratories to 
ensure consistency in testing between each laboratory.
Rationale: Additional information for the Screening Hepatitis B and C sample collection has been added.
NCT01855750


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765DBL3001 Amendment INT-3
17
Approved, Date: 16 October 2017
Applicable Section(s)
Description of Change(s)
Time and Events Schedule;
9.5 Safety Evaluations
Screening for Hepatitis B and C will include the following evaluations: Hepatitis B 
surface antigen, Hepatitis B core antibody, and Hepatitis C antibody. Subjects who 
test positive for Hepatitis B core antibody must have Hepatitis B DNA by PCR 
performed and confirmed as negative prior to randomization. Subjects who test 
positive for Hepatitis C antibody are eligible if previously treated and achieved a 
sustained viral response, defined as a negative viral load for Hepatitis C after 
completion of the treatment for hepatitis.
Rationale: Clarification on post-Screening vital sign procedures provided for completeness and consistency with 
Time and Events Schedule.
9.5 Safety Evaluations (Vital 
Signs)
Heart rate and blood pressure will also be collected on Day 1 of each cycle and at 
the End-of-Treatment Visit.
Rationale: Clarified the study hypothesis method used to determine sample size. In this study, the primary endpoint 
analysis measures a combination of improvement in the cure rate and improvement in the EFS interval among those 
patients who are not cured. A wide range of outcomes may result in a statistically significant difference between the 
groups. 
11.3 Sample Size 
Added text and table to describe the possible clinical outcomes and corresponding 
probability that such outcomes will result in a statistically significant difference 
between the groups, based on a median EFS of 12 months for non-cured subjects.
Rationale: Timing of safety review meetings has been revised for consistency with the Statistical Analysis Plan. 
11.10
Data 
Monitoring 
Committee
At the interim analysis, the DMC may recommend stopping the study for efficacy, 
if the pre-specified stopping boundary is crossed. In addition to the planned interim 
analyses for efficacy, 4 safety review meetings are planned that will occur 
approximately 2 months (not 1 month, as previously stated) after 50, 250, 450, and 
650 subjects have been randomized.
Rationale: The list of study-specific materials provided to the sites has been revised according to company 
operational standards. Some of these items may be provided via other processes. The names of 2 forms have been 
revised.
15 Study-Specific Materials; 
10.2 Discontinuation of 
Study Treatment; 
9.2.2.1 Assessment of 
Disease Response and 
Progressive Disease  
The following materials have been removed from the list: ibrutinib and placebo 
capsules; package inserts for rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone; and the NCI-CTCAE Version 4.03. Added Imaging 
Manual to the list. The Eligibility Notification form was revised to the Diagnosis 
and subtyping report form. The Progressive disease notification form was revised 
to Study Event form.
Rationale: Throughout the protocol, minor grammatical, formatting, or spelling changes were made where 
required, or clarifications, if needed. Examples are provided below. 
Synopsis (Safety 
Evaluations)
Clarified in the synopsis that enhanced reporting of adverse events of interest 
(intracranial hemorrhage, major hemorrhage) will be conducted and data on new 
malignancies will be collected.
5 Treatment Allocation and 
Blinding
Clarified that site personnel and the sponsor may be unblinded if treatment 
assignment information is needed to determine further actions to address an urgent 
safety concern.
9.1.3 Active Treatment Phase
Text on adverse event reporting deleted, as already included in Section 12, Adverse 
Event Reporting.
9.2.1.1 CT/MRI/PET Scans
Clarified timing of End-of-Treatment scans (ie, added: at least 3 weeks but 
preferably 6 to 8 weeks, after the last dose of R-CHOP) as stated in Time and 
Events Schedule.
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Applicable Section(s)
Description of Change(s)
9.5 Safety Evaluations (Vital 
Signs)
Clarified that “abnormal” vital signs considered to be clinically relevant are to be 
documented as adverse events.
12.3.1 All Adverse Events
Periodic reviews of the protocol template are conducted to provide corrections and 
improvements. Instructions for the subject “wallet (study) card” were clarified.
16.2.3 Informed Consent
Clarified that the molecular subtyping informed consent form may be obtained 
separately from the full study informed consent form.
16.2.5 Long-Term Retention 
of Samples for Additional 
Future Research
Clarification was made to explain the meaning of ‘differential drug responders’. 
This was changed to ‘differences in response’ to drug to the following: Samples 
collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand 
ibrutinib, to understand DLBCL, to understand differences in response to drug and 
to develop tests/assays related to ibrutinib and DLBCL.
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SYNOPSIS
A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) 
Inhibitor, PCI-32765 (Ibrutinib), in Combination with Rituximab, Cyclophosphamide, Doxorubicin, 
Vincristine, and Prednisone (R-CHOP) in Subjects With Newly Diagnosed Non-Germinal Center B-Cell 
Subtype of Diffuse Large B-Cell Lymphoma
Ibrutinib (IMBRUVICA; PCI-32765; JNJ-54179060) is a first-in-class, potent, orally-administered, 
covalently-binding small molecule BTK inhibitor 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 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 and PCI-32765 refer to the same molecule; hereafter, ibrutinib 
will be used.
It is increasingly appreciated that the diagnostic category of diffuse large B-cell lymphoma (DLBCL) is 
heterogeneous in terms of morphology, genetics, and biologic behavior. Gene expression profiling (GEP) 
and immunohistochemistry (IHC) are 2 of the assay platforms currently being used for determining cell of 
origin. Gene expression profiling platforms assign specimens into 1 of 3 diagnostic categories: germinal 
center 
B cell-like 
subtype 
(GCB), 
activated 
B cell-like 
subtype
(ABC), 
or 
unclassified. 
Immunohistochemistry divides the population into non-germinal center B cell-like subtype (non-GCB) 
and GCB. Current evidence suggests that patients diagnosed with the non-GCB subtype of DLBCL, as 
compared to the GCB subtype, have inferior outcomes when treated with conventional therapy. 
Identifying and treating the non-GCB subtype with improved therapeutics represents a significant unmet 
medical need. Recently, Phase 1 and 2 studies suggest that ibrutinib is less active in subjects with GCB 
DLBCL and more active in subjects with non-GCB or specifically the ABC subtype. Interestingly, data 
also suggest that ibrutinib shows superior activity among DLBCL patients who are still chemosensitive. 
Together, these findings suggest a potentially important role for ibrutinib as front-line treatment in the 
non-GCB and ABC subtypes. Early data from an ongoing Phase 1 combination study show that ibrutinib 
can be safely combined with R-CHOP. This study will evaluate if ibrutinib in combination with R-CHOP 
improves the outcome in newly diagnosed patients with the non-GCB subtype of DLBCL selected by 
IHC or newly diagnosed patients with ABC subtype of DLBCL identified by GEP or both populations.
OBJECTIVES AND HYPOTHESIS
Primary Objective
To evaluate if the addition of ibrutinib to R-CHOP prolongs event-free survival (EFS) compared with 
R-CHOP alone in subjects with newly diagnosed non-GCB subtype of DLBCL selected by IHC or newly 
diagnosed patients with ABC subtype of DLBCL identified by GEP or both populations.
Secondary Objectives
To compare ibrutinib in combination with R-CHOP versus R-CHOP alone with regard to progression-free 
survival (PFS), complete response (CR) rate, overall survival, patient-reported lymphoma symptoms and 
concerns, and safety. Additional secondary objectives are to characterize the pharmacokinetics of 
ibrutinib and explore the potential relationships between ibrutinib metrics of exposure with relevant 
clinical or biomarker information.
Exploratory Objectives
To evaluate patient-reported outcomes (PROs) related to well-being and general health status utilizing the
Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and EuroQol (EQ-5D-5L)
questionnaires and to explore the relationship between relevant biomarkers with clinical outcomes and 
mechanism of resistance.
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Hypothesis
Ibrutinib in combination with R-CHOP will prolong EFS compared with R-CHOP alone in subjects with 
newly diagnosed non-GCB DLBCL selected by IHC or in subjects with newly diagnosed ABC DLBCL 
identified by GEP or in both populations.
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 R-CHOP versus R-CHOP alone in subjects 18 years 
and older with newly diagnosed non-GCB DLBCL. Prior to randomization, subjects with DLBCL are 
required to submit local pathology reports to a central laboratory for verification of diagnosis. In addition, 
all subjects are required to submit tumor samples to the central laboratory for determination of subtype 
(GCB versus non-GCB) by central IHC. Only subjects with newly diagnosed non-GCB subtype of 
DLBCL, as determined by IHC at a central laboratory, will be enrolled. Approximately 800 eligible 
subjects will be stratified by Revised International Prognostic Index (R-IPI; 1-2 vs. 3-5), region 
(US/Western Europe vs. Rest of World), and number of pre-specified treatment cycles (6 vs. 8 cycles),
then randomized in a 1:1 ratio to receive either placebo+R-CHOP (Treatment Arm A) or 560 mg 
ibrutinib+R-CHOP (Treatment Arm B). Prior to treatment, sites will pre-specify treatment of subjects 
with either 6 or 8 cycles. The study will include a Pretreatment (Screening) Phase prior to randomization, 
an Active Treatment Phase (includes visits at the start of each cycle and an End-of-Treatment Visit
[should occur 30 days after the last dose of the last study treatment]), and a Posttreatment Follow-up 
Phase until death, loss to follow up, consent withdrawal, or study end. It is expected that there will be 
27 months of accrual, and the study will end when 50% of the randomized subjects have died or 5 years 
after the last subject is randomized or the sponsor terminates the study, whichever occurs first. Available 
tumor samples will be retrospectively analyzed to identify the ABC DLBCL population using GEP.
SUBJECT POPULATION
The study population will include subjects 18 years of age and older with newly diagnosed DLBCL and
histological confirmation of the non-GCB subtype (by sponsor approved central laboratory) and Stage II 
(not candidates for local X-ray therapy) to Stage IV disease (by Ann Arbor Classification). Subjects must 
also have at least 1 measurable site of disease; an R-IPI score of 1; and an Eastern Cooperative 
Oncology Group performance status grade of 0, 1, or 2.
DOSAGE AND ADMINISTRATION
All subjects will receive R-CHOP (rituximab 375 mg/m2 intravenous [IV], cyclophosphamide 750 mg/m2
IV, doxorubicin 50 mg/m2 IV, vincristine 1.4 mg/m2 IV [maximum total 2 mg], and prednisone 
[or equivalent] 100 mg orally) as background therapy for 6 or 8 cycles per site preference (21 days per 
cycle). Sites may choose to administer 6 or 8 cycles of treatment based on local practice; once the number 
of cycles is pre-specified by the site, all subjects at individual sites are intended to receive the same
number of treatment cycles (6 or 8; no individual subject adjustment permitted based on interim 
response). Subjects will be randomized in a 1:1 ratio to Treatment Arm A (placebo, 4 capsules orally once 
daily continuously + R-CHOP) or Treatment Arm B (ibrutinib 560 mg [4 x 140 mg capsules orally once 
daily continuously + R-CHOP]) for 6 or 8 cycles, depending on the number of cycles pre-specified by 
each site. Study treatment administration begins on Cycle 1 Day 1 (within 72 hours of randomization) and 
ends on Day 21 of the last cycle, unless the subject experiences unacceptable toxicity or disease 
progression.
Subjects who discontinue any component of R-CHOP without disease progression will continue study 
drug (placebo or ibrutinib) until 6 or 8 cycles are completed (as pre-specified by each site), disease 
progression, or unacceptable toxicity, whichever occurs first. If study drug is discontinued, any remaining 
study treatment (ie, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
[or equivalent]) may continue. Study drug (ibrutinib or placebo) should be held for any unmanageable, 
potentially study drug-related toxicity that is Grade 3 in severity until recovery to Grade ≤1 or baseline. 
Dose reductions are permitted for recurring adverse events (ie, reduce to 420 mg on second occurrence, 
280 mg on third occurrence, then discontinue on fourth occurrence of the same adverse event). Dose
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escalation of study drug is not allowed. Dose modifications for R-CHOP should be done in accordance 
with the respective product labels, unless stated otherwise in the protocol. The start of a new cycle may be 
delayed on a weekly basis (assessed weekly) until recovery of toxicity to a level allowing continuation of 
therapy. If toxicity persists after a 2-week cycle delay that is related to 1 specific drug (eg, vincristine, 
doxorubicin), then the offending drug should continue to be withheld and the new cycle started with the 
remaining drugs. If R-CHOP is delayed, treatment with study drug should be continued during the delay 
phase. If the study drug (ibrutinib/placebo) is delayed or withheld, R-CHOP treatment may be continued 
if clinically indicated.
EFFICACY EVALUATIONS
Disease response will be assessed according to the Revised Response Criteria for Malignant Lymphoma. 
Efficacy assessments will be performed using computed tomography (CT) scans of the neck, chest, 
abdomen, and pelvis with IV and oral contrast as indicated. Whole body positron emission tomography
(PET) scan is recommended but not mandated at baseline, but is required at the end of treatment. 
Magnetic resonance imaging may be used to evaluate sites of disease that cannot be adequately imaged 
using CT. Other sites of disease will be evaluated by radiological imaging, physical examination, or other 
procedures as necessary, including review of hematology and serum chemistry results. After 4 cycles, an 
interim response assessment will be performed to evaluate progression for each subject. After the end of 
treatment (at least 3 weeks, preferably 6-8 weeks after last dose of R-CHOP), all subjects will also have 
an efficacy assessment. During the follow-up phase, all subjects without disease progression including 
those subjects who discontinue study treatment prior to progressive disease (PD) will have efficacy 
assessments every 16 weeks in the first 24 months, then every 24 weeks until PD, the clinical cutoff for 
the primary endpoint, or up to 5 years, whichever occurs first. After that, CT may be performed as 
clinically indicated (at the discretion of the investigator) per local standard of care. Radiological and PET 
scans performed prior to the database lock for the final analysis of EFS must be transferred to the 
independent imaging laboratory for storage; the scans may be reviewed, if deemed necessary.
PHARMACOKINETIC EVALUATIONS
In both treatment arms, sparse samples for the development of a population-based pharmacokinetic 
approach will be collected from all subjects from selected sites and evaluated for ibrutinib and potentially 
for PCI-45227. It is estimated that 200 subjects on ibrutinib are needed to adequately assess this. 
Collection of pharmacokinetic samples will stop when this cutoff point has been reached (or earlier or 
later at the sponsor’s discretion). Pharmacokinetic parameters include oral plasma clearance, area under 
the plasma concentration time curve, minimum observed plasma concentration, maximum observed 
plasma concentration, and others if needed.
BIOMARKER EVALUATIONS
Tumor (from biopsy samples) will be evaluated in all subjects to identify markers predictive of response 
to ibrutinib. Paraffin-embedded, formalin-fixed tumor tissue or cells isolated from blood collections may 
also be subjected to RNA analysis (eg, GEP, quantitative reverse transcription [qRT]– polymerase chain 
reaction [PCR]) or somatic mutational analysis (eg, MiSeq, ExomeSEQ) from all subjects entered within 
this study. Comparison of IHC results may be made to transcriptomic or genomic data from matching 
tumor or blood to correlate molecular subtype and mutational status. Gene expression profiling and 
mutational analysis may also be utilized to identify other signaling pathway markers that may correlate 
with response to treatment (eg, CD79B, TP53, MLL2, CARD11, MYD88,) or other pathways/markers 
that may be up-regulated in the non-GCB subtype of DLBCL (eg, IL-6/STAT3). Other prognostic 
markers that may be analyzed include BCL-2 expression and C-MYC rearrangement. In addition, 
minimal residual disease assessment may be done on serum samples collected at the End-of-Treatment 
Visit and during the Posttreatment phase up to 24 months.
SAFETY EVALUATIONS
Regular periodic medical evaluations will be conducted including adverse event monitoring, physical 
examination, vital signs (temperature, heart rate, and blood pressure), weight evolution, concomitant 
medication usage, and performance status evaluation. Hematology and serum chemistry tests will be 
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performed at regular intervals. A baseline electrocardiogram and left ventricular ejection fraction 
measurement by multiple-gated acquisition scan or echocardiography is required in all subjects. Major 
hemorrhage has been identified as an adverse event of special interest and will require enhanced reporting 
and data collection. Data will also be collected on new malignant tumors occurring during study treatment 
and during any protocol-specified follow-up periods, including post-progression follow-up for overall 
survival.
STATISTICAL METHODS
The primary endpoint of the study is EFS, defined as the duration from the date of randomization to the 
date of disease progression, relapse from CR as assessed by investigator, initiation of subsequent systemic 
antilymphoma therapy for either PET-positive or biopsy-proven residual disease upon completion of at 
least 6 cycles of R-CHOP therapy, or death, whichever occurs first. Assuming 40% and 50% of the 
patients will be cured in the control (placebo+R-CHOP) and treatment (ibrutinib+R-CHOP) arms,
respectively, and the hazard ratio of treatment over the control is 0.75 in the uncured subjects and the 
median EFS for the uncured subjects in the control arm is 12 months, approximately 419 EFS events will 
be observed, with 800 subjects (400 subjects in each arm) to be enrolled in 27 months and a follow-up 
period of 30 months after the 800th subject is randomized. The study is expected to maintain at least 90% 
power, with statistical significance at the overall alpha level of 0.025 (1-sided). The primary endpoint 
EFS will be analyzed using data from the Intent-to-Treat (ITT) population (defined as all subjects 
randomized into the study and classified according to assigned treatment arm) and the ABC population
(identified by GEP). The alpha allocation for the ITT and ABC populations will be based on Song and 
Chi method (details provided in the Statistical Analysis Plan). The stratified log-rank test will be used as 
the primary analysis for treatment comparison. In case there is strong evidence of crossing hazard, other 
test statistics such as Rényi statistics may be used. Secondary endpoints include PFS, CR rate, overall 
survival, time-to-worsening in the Lym subscale of the FACT-Lym, pharmacokinetics, and safety. An 
independent Data Monitoring Committee (DMC) will be commissioned for this study to review the safety
and efficacy of the treatment combination and make recommendations as to the future conduct of the 
study in accordance with the DMC charter.
EudraCT NUMBER:  2013-000959-40
Universal Trial Number: U1111-1139-6222
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Table 1:
Time and Events Schedule – Up to Clinical Cutoff for Primary Endpoint Analysis
Pretreatment 
Phase
Active Treatment Phase (1 Cycle=21 days 2 days)
Posttreatment
Follow-up Phase
Screeninga
Active Treatment
Early Withdrawal/ 
End-of-Treatment Visitb
Prior to PD (CT Q16 wks [±7 d from 
last CT] first 24 mos; then every 
Q24wks [±10 d]) until PD or CCO for 
the Primary Endpoint Analysis
After PD 
(Q16 wks
[±7 d])
30 d before 
randomization
Day 1 of each cycle
Procedures
Informed consent
X
Paraffin-embedded tumor tissue and 
local pathology reportc
X
Fresh tissue biopsy
X (at PD, if feasible)
Eligibility criteria reviewc
X
Demographics/medical 
history/physical examination
X
Limited physical examinationd; vital 
signs (temperature, HR, BP)e
Vital signs
Xe
X
Limited PE only
ECOG performance status
X
X
Height, weight, BSA
Height, weight
Weight, BSAe
Weight only
ECG and echocardiogram or MUGA 
scanf
X
AEs/concomitant medications
<---Continuous from informed consent to 30 d after the last dose of study treatment--->
Disease Evaluations
CT (neck, chest, abdomen, and 
pelvis)g
Xh
End of Cycle 4 onlyi
X (at least 3 wks after last dose of
R-CHOP; 6-8 wks preferred)i
X (for up to 5 years, then only as 
clinically indicated)
Whole body FDG-PET scan
Xh
X (at least 3 wks after last dose of 
R-CHOP; 6-8 wks preferred)i
Bone marrow aspirate and biopsy
Xh
X (if bone marrow positive at baseline)i
PRO (FACT-Lym, EQ-5D-5L)j
X
X
X
Xk
Survival status/subsequent 
antilymphoma therapy
X
X
Laboratory Assessments
Hematology (see Section 9.5)
X
X (weekly)l
X
Coagulation (aPTT, INR/PT)
X
Serum chemistry (see Section 9.5)m
X
Xl
X
Hepatitis B and C serology
Xn
Serum -hCG or urine pregnancy 
test
Xl
X
Beta-2 microglobulin/serum 
immunoglobulin
Xl
X
X (once; done at time of the first follow 
up CT)
PK samples in subset of subjects 
(see Section 9.3.1)o
Cycles 1, 2, and 3
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Pretreatment 
Phase
Active Treatment Phase (1 Cycle=21 days 2 days)
Posttreatment
Follow-up Phase
Screeninga
Active Treatment
Early Withdrawal/ 
End-of-Treatment Visitb
Prior to PD (CT Q16 wks [±7 d from 
last CT] first 24 mos; then every 
Q24wks [±10 d]) until PD or CCO for 
the Primary Endpoint Analysis
After PD 
(Q16 wks
[±7 d])
30 d before 
randomization
Day 1 of each cycle
Blood samples for biomarker 
evaluations
Cycle 1p
Xp
Xp
Drug Administration (within 72 hours of randomization)
R-CHOP
See Dose and 
Administration Table 2
Dispense study drug/check drug 
accountability
X
Study drug:
Arm A: placebo (4 capsules)
Arm B: ibrutinib 560 mg 
(4 capsules)
Continuous until PD, initiation of subsequent antilymphoma therapy, 
unacceptable toxicity, withdrawn, or completion of 6 or 8 cycles (as 
pre-specified by the site), whichever occurs first
AE=adverse event; aPTT=activated partial thromboplastin time; ALT=alanine aminotransferase; AST=aspartate aminotransferase; -hCG=beta-human chorionic gonadotropin; BP=blood 
pressure; BSA=body surface area; CCO=clinical cutoff; CR=complete response; CT=computed tomography; d=day; DLBCL=diffuse large B-cell lymphoma; DNA=deoxyribonucleic 
acid; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=End-of-Treatment; EQ-5D-5L=EuroQol questionnaire; FACT-Lym=Functional Assessment of Cancer 
Therapy-Lymphoma; FDG=[18F]-fluorodeoxyglucose; hr=hour; HR=heart rate; IHC=immunohistochemistry; INR=international normalized ratio; IV=intravenous; LDH=lactate 
dehydrogenase; min=minutes; MRD=minimal residual disease; MRI=magnetic resonance imaging; mos=months; MUGA=multiple-gated acquisition scan; non-GCB=non-germinal center 
B-like DLBCL; PCR=polymerase chain reaction; PD=progressive disease; PE=physical examination; PET=positron emission tomography; PK=pharmacokinetic; PRO=patient-reported 
outcomes; PT=prothrombin time; Q=every; R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-IPI=Revised international prognostic index; wks=weeks.
a
Steroids are permitted prior to randomization (up to 100 mg prednisone or equivalent) for a maximum of 10 days, only after the baseline imaging assessment, baseline laboratory 
assessments, baseline performance status assessment, and baseline R-IPI calculation are performed. Baseline laboratory assessments need to be repeated if performed more than 5 d 
prior to the first dose of study treatment.
b
Early withdrawal=stopping treatment before 6 or 8 complete cycles of study treatment are given, depending on the number of cycles pre-specified by each site. If any component of 
R-CHOP is discontinued for toxicity, study drug may continue up to the pre-specified number of treatment cycles. EOT Visit is required for all subjects; should occur 30 d (+10 d) 
after the last dose of study treatment. If study drug is discontinued, any remaining study treatment (ie, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [or 
equivalent]) may continue. If a subject requires subsequent antilymphoma therapy between the last dose of study treatment and the EOT Visit, then this visit should be completed just 
prior to initiation of subsequent antilymphoma therapy.
c
Biopsy sample (paraffin-embedded tumor tissue) for central pathology determination of the non-GCB subtype of DLBCL and supportive materials (local pathology report) for 
verification of DLBCL diagnosis is required before a patient is considered eligible and can be randomized into the study. Biopsy sample must be sent to the central pathology 
laboratory within 28 d prior to randomization, however; a biopsy extracted from a subject >28 d prior to randomization is permitted. Part of the tumor biopsy block will be used for 
biomarker studies. Bone marrow is not sufficient for confirmation of the non-GCB subtype. 
d
Limited physical examination includes all organ systems previously abnormal or involved with disease and documentation of any clinically relevant organ abnormalities. Lymphoma 
symptoms reported at Screening should be reviewed and recorded during the limited physical examination.
e
BSA calculated and vital signs done prior to dosing on Day 1 of each cycle. If a subject experiences a >10% change in weight from the weight used in the previous BSA calculation, 
then BSA and dose should be recalculated.
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Pretreatment 
Phase
Active Treatment Phase (1 Cycle=21 days 2 days)
Posttreatment
Follow-up Phase
Screeninga
Active Treatment
Early Withdrawal/ 
End-of-Treatment Visitb
Prior to PD (CT Q16 wks [±7 d from 
last CT] first 24 mos; then every 
Q24wks [±10 d]) until PD or CCO for 
the Primary Endpoint Analysis
After PD 
(Q16 wks
[±7 d])
30 d before 
randomization
Day 1 of each cycle
f
Echocardiography or MUGA scan is mandatory at Screening; may be repeated at any time during the study (using same modality), as clinically indicated, either at an assessment visit 
or unscheduled visit.
g
CT may be performed with oral contrast only if the subject is intolerant of IV contrast agents. MRI may be used to evaluate sites of disease that cannot be adequately imaged using CT 
(see Section 9.2.1.1 for details). Evaluation of other sites of disease may be performed by radiological imaging, physical examination, or other procedures as necessary (should be 
performed throughout the study using same method of assessment per subject).
h
CT, MRI, PET, and bone marrow biopsy/aspirate may be performed up to 60 d before randomization (PET at screening is recommended but not mandatory). Morphological (and IHC, 
if warranted) examination of bone marrow is required. For subjects with bone marrow involvement prior to treatment, bone marrow aspirate and biopsy must be repeated once during 
the study to confirm CR (preferably within 30 d of initial CR documentation). Bone marrow at Screening should be performed within 60 d prior to the first dose of study treatment. 
i
Response assessment window: 7 d. Assessments can be repeated if clinically indicated to confirm response or progression.
j
The PRO questionnaires (FACT-Lym and EQ-5D-5L) will be collected at the beginning of the clinic visits, preferably, before any procedures or physician interactions. The first 
FACT-Lym and EQ-5D-5L assessment will be administered prior to the first dose of study treatment.
k
Following disease progression, sites should attempt to administer the EQ-5D-5L every 16 wks for 32 wks.
l
For Cycle 1 Day 1 only, if Screening tests were performed within 5 d of first dose of study treatment, then clinical laboratory tests do not need to be repeated. For subsequent cycles, 
samples can be taken within 72 hours of the scheduled visit, provided that results are available before study treatment is given. Pregnancy test during Screening within 21 d of Cycle 1 
Day 1 does not need to be repeated. 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.
m
At Screening: sodium, potassium, creatinine, AST, ALT, total bilirubin, albumin, uric acid, LDH, and alkaline phosphatase. On Day 1 of each cycle starting with Cycle 2: sodium, 
potassium, creatinine, total bilirubin, uric acid, and LDH. Magnesium on Day 1 of Cycles 1 and 2. Biochemistry tests may be repeated as clinically indicated.
n
Screening for hepatitis B and C will include the following evaluations: hepatitis B surface antigen, hepatitis B core antibody, and hepatitis C antibody. Subjects who test positive for
hepatitis B surface antigen or hepatitis B core antibody must have hepatitis B DNA by PCR performed and confirmed as negative prior to randomization. Hepatitis B surface antigen 
positive subjects who are also hepatitis B DNA by PCR negative should receive prophylactic antiviral therapy (such as entecavir or tenofovir) and be treated according to local 
guidelines. Hepatitis B core antibody positive subjects who are also hepatitis B DNA by PCR negative should receive prophylactic antiviral therapy (such as entecavir or tenofovir) or 
undergo regular monitoring of hepatitis B virus DNA according to local guidelines. Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active 
hepatitis B virus infection and for signs of hepatitis during and following anti-B-cell treatment, according to local guidelines. Consultation with a hepatitis specialist is also 
recommended. 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.
o
Before dosing of study drug (ibrutinib or placebo capsules) on Day 1 of Cycles 1, 2, and 3, and postdose on Cycles 1 and 2 at 1 hr (window 45 to 75 min), 2 hrs (window 1.5 to 
2.5 hrs), and 4 hrs (window 3.5 to 6 hrs) after dosing.
p
Day 1 of Cycle 1 (may be collected up to 5 days), at the time of disease progression, or the EOT Visit for subjects who discontinue study treatment without disease progression. In 
addition, MRD assessment may be done on serum samples collected at the EOT Visit and during the Posttreatment phase up to 24 months.
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R-CHOP will be administered within 72 hours of randomization to subjects in both treatment arms as background therapy according to the
following schedule (21 days per cycle) (Table 2):
Table 2:
Dose and Administration Schedule for R-CHOP
R-CHOP Regimena
Drug
Dose
Day 1
Day 2
Day 3
Day 4
Day 5
Days 6 to 21
Rituximab
375 mg/m2 IV
X
Cyclophosphamide
750 mg/m2 IV
X
Doxorubicin
50 mg/m2 IV
X
Vincristine
1.4 mg/m2 IV (maximum total of 2 mg)
X
Prednisone (or equivalent)b
100 mg orally
X
X
X
X
X
IV=intravenously; R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
a Six or 8 cycles per treatment arm, depending on the number of cycles pre-specified by each site. The components of the R-CHOP regimen can be given over 2 days. 
b In regions where prednisone is not marketed or available, prednisolone will be used.
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Table 3:
Time and Events Schedule – After the Clinical Cutoff for the Primary Endpoint Analysis
Posttreatment Follow-up Phase
Procedures
Survival status (physician visit or 
telephone contact)
Every 24 weeks 14 days until end of study.a
PRO (EQ-5D-5L)
Collect at 24 and 48 weeks 14 days for those subjects who have not progressed at the time of clinical cutoff
(ie, 2 times after the clinical cutoff for the primary endpoint analysis)
Progressive diseaseb/subsequent 
antilymphoma therapy
Every 24 weeks 14 days until end of study (document progressive disease and subsequent antilymphoma therapy dates, if applicable)
New malignancies
Every 24 weeks 14 days until end of study
Adverse events or serious adverse
events and associated concomitant 
medications, if related to study 
treatment
Every 24 weeks 14 days until end of study
EQ-5D-5L=EuroQol questionnaire; PRO=patient-reported outcomes
a
The Posttreatment Follow-up Phase will continue until death, loss to follow up, consent withdrawal, or study end, whichever occurs first. The end of study is defined as when 50% of 
the randomized subjects have died or 5 years after the last subject is randomized or the sponsor terminates the study, whichever comes first.
b
Radiologic disease evaluations may be performed as clinically indicated (at the discretion of the investigator) per local standard of care after the clinical cutoff for the primary endpoint 
analysis.
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ABBREVIATIONS
ABC
activated B cell-like subtype of DLBCL
ACVBP
adriamycin, cyclophosphamide, vindesine, bleomycin, and prednisone
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-24
area under the plasma concentration-time curve from time 0 to 24 hours
AUC0-last
area under the plasma concentration versus time curve from time zero to the time corresponding to 
the last quantifiable concentration
-hCG
beta-human chorionic gonadotropin 
BCR
B-cell receptor
BR
bendamustine + rituximab
BSA
body surface area
BTK
Bruton's tyrosine kinase
CHOP
cyclophosphamide, doxorubicin, vincristine, and prednisone
CI
confidence interval
CL/F
oral plasma clearance
Cmax
maximum observed plasma concentration
Cmin
minimum observed plasma concentration
CNS
central nervous system
CR
complete response
CRF
case report form
CT
computed tomography
CYP
cytochrome P450
Cys
cysteine
DA-EPOCH-R
dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus 
rituximab
DNA
deoxyribonucleic acid
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
eDC
electronic data capture
EFS
event-free survival
EQ-5D-5L
EuroQol questionnaire
Emax
maximum obtainable effect
FACT-G
Functional Assessment of Chronic Illness Therapy-General
FACT-Lym
Functional Assessment of Cancer Therapy-Lymphoma
FCR
fludarabine, cyclophosphamide, and rituximab
FDG
[18F] fluorodeoxyglucose
GCB
germinal center B cell-like subtype of DLBCL
GCP
Good Clinical Practice
GEP
gene expression profiling
GERD
gastroesophageal reflux disease
GI50
50% growth inhibition
GTD
greatest transverse diameter
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HR
hazard ratio
IC50
half maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
Ig
immunoglobulin
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IHC
immunohistochemistry
INR
international normalized ratio
IPI
International Prognostic Index
IRB
Institutional Review Board
ITT
Intent-to-Treat population
IV
intravenous
IWRS
interactive web response system
LC-MS/MS
liquid chromatography/mass spectrometry/mass spectrometry
LDH
lactate dehydrogenase
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose 
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NF-B
nuclear factor-kappa B
NHL
non-Hodgkin’s lymphoma
Non-GCB
non-germinal center B cell-like subtype
ORR
overall response rate
PCR
polymerase chain reaction
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
PLC
phospholipase C gamma
PQC
Product Quality Complaint
PR
partial response
PRO
patient-reported outcome(s)
PT
prothrombin time
qRT
quantitative reverse transcription
R-CHOP
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
R-IPI
Revised International Prognostic Index
RNA
ribonucleic acid
SET
Study Evaluation Team
SJS
Stevens-Johnson Syndrome
SPD
sum of the product of the diameters
t1/2
half-life
Tmax
time of maximum concentration
TTW
time to worsening
ULN
upper limit of normal
U.S.
United States
Vss/F
oral volume of distribution at steady state
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1.
INTRODUCTION
Ibrutinib (IMBRUVICA; PCI-32765; JNJ-54179060) is a first-in-class, potent, orally 
administered, covalently-binding, small molecule Bruton’s tyrosine kinase (BTK) inhibitor 
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 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. Phase 1 and 2 studies suggest that ibrutinib may be less active in subjects 
with germinal center B cell-like (GCB) diffuse large B-cell lymphoma (DLBCL), with an 
acceptable safety profile. Ibrutinib and PCI-32765 refer to the same molecule; hereafter, ibrutinib 
will be used.
1.1.
Diffuse Large B-cell Lymphoma
Diffuse large B-cell lymphoma is an aggressive, although potentially curable, disease. Patients 
typically present with a large, fast growing mass; eg, an enlarged lymph node.50 Only 30% to 
55% of patients achieve durable cure;14 the remaining patients ultimately die of the disease 
despite standard chemotherapy treatment. Chances of survival are reduced for patients with a 
disease onset on or after the age of 60 years, increased lactate dehydrogenase (LDH) levels 
(above normal limits), Eastern Cooperative Oncology Group performance status grade of ≥2, 
Stage III or IV disease, and more than 1 extra nodal disease site.50
Diffuse large B-cell lymphoma accounts for approximately 30% to 58% of all new cases of 
non-Hodgkin’s lymphoma (NHL) diagnosed annually worldwide.49 The incidence of DLBCL is 
approximately 23,911 patients in the United States (U.S.), 16,817 patients in the G5 countries 
(Germany, France, United Kingdom, Italy, and Spain), and 10,636 patients in Japan.30,23 The 
average age at diagnosis is 64 years, with men slightly more affected then women.50 For most 
patients, the origin of DLBCL is unknown. Factors thought to confer increased risk include 
immunosuppression and environmental chemicals. A variety of chromosomal alterations have 
been described in DLBCL. The most common abnormality involves alterations of the BCL-6 
gene at the 3q27 locus, which is critical for germinal center formation. A substantial number of 
DLBCL cases have complex karyotypes.16
1.1.1.
Standard Treatment for Diffuse Large B-Cell Lymphoma
Worldwide, the currently accepted standard regimen for frontline treatment of patients with 
DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). 
Several studies have found the addition of rituximab to CHOP (rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone) and CHOP-like chemotherapies significantly improve 
the clinical outcome of patients with DLBCL.6,44,18,36 A randomized study of CHOP versus 
R-CHOP was performed in 398 newly diagnosed DLBCL patients, 60 to 80 years of age.6 The 
rate of complete response (CR) was significantly higher in the group that received R-CHOP 
compared with the group that received CHOP alone (76% vs. 63%; p=0.005). With a median 
follow up of 2 years, event-free survival (EFS) was 57% in the R-CHOP group and 38% in the 
CHOP group. Results from the 10-year analysis confirmed the benefit of the addition of 
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rituximab to CHOP (10-year progression-free survival [PFS]: 36.5% vs. 20% for R-CHOP and 
CHOP, respectively; 10-year overall survival: 43.5% vs. 27.6%, respectively).7 A pivotal Phase 3 
study of CHOP versus R-CHOP with a second randomization to rituximab maintenance or 
observation in untreated patients 60 years and older with DLBCL also clearly showed that 
R-CHOP chemotherapy significantly prolonged failure-free survival in older DLBCL patients.18
This study also showed that after R-CHOP, no benefit was provided by rituximab maintenance. 
The above 3 studies have established R-CHOP as the standard therapy for DLBCL.
Several other combination therapies have also been tested including DA-EPOCH-R
(dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus 
rituximab),54 ACVBP (adriamycin, cyclophosphamide, vindesine, bleomycin, and prednisone; 
ie, intensive CHOP-like),48,40 and 14-day CHOP,36 but R-CHOP remains the current standard of 
care.32
1.1.2.
Classification by Cell of Origen in Diffuse Large B-Cell Lymphoma
From both biological and clinical perspectives, DLBCL is a heterogeneous disease. To 
understand further the heterogeneity of this disease, gene expression profiling (GEP) has been 
used to investigate the different possible cellular origins of DLBCL. In 2000, Alizadeh and 
colleagues,1 using DNA microarrays, have identified 2 molecularly distinct forms of DLBCL 
that had gene expression patterns indicative of different stages of B-cell differentiation. One type 
expressed genes characteristic of germinal center B-cells (`germinal center B cell-like DLBCL' 
[GCB]); the second type expressed genes normally induced during in vitro activation of 
peripheral blood B-cells (`activated B cell-like DLBCL' [ABC]). Patients with GCB DLBCL had 
a significantly better overall survival than those with ABC DLBCL.1
The 2002 Lymphoma/Leukemia Molecular Profiling Project used DNA microarrays to analyze 
biopsy samples of DLBCL from 240 patients, and found that the better survival rate for the GCB 
subtype was independent of clinical International Prognostic Index (IPI) risk.43 Classification of 
DLBCL has also been shown to be clinically applicable by using a differential immunostaining 
method comprised of BCL-6, CD10, and MUM-1 antigens and an associated algorithm.19
Various studies have shown that this classification, on the basis of the cell of origin, is an 
important independent prognostic factor for patients who are treated with CHOP or CHOP-like 
chemotherapy.19,2,51 Additional biomarkers, such as BCL-2 overexpression, have been shown to 
be significant prognostic factors in ABC DLBCL but not in GCB DLBCL.24 Some researchers
have questioned the value of these prognostic indicators, given that adding rituximab to standard 
chemotherapy appeared to eliminate the prognostic value of the immunohistochemistry
(IHC)-defined GCB and non-germinal center B cell-like (non-GCB) subtypes of DLBCL.33
However, recent large, retrospective studies have since confirmed the prognostic importance of 
subclassification of DLBCL on the basis of the cell of origin even in rituximab-treated patients.17
One study documented that, for patients treated with R-CHOP, the GCB subgroup had a 
significantly better 3-year overall survival than the non-GCB subgroup (85% versus 69%; 
p=0.032).17 The largest dataset to date includes 475 subjects treated with R-CHOP who were 
successfully subclassified using various IHC algorithms (including Hans), that showed high 
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concordance (86.3% to 92.6%) with GEP. Subjects stratified into GCB and non-GCB groups 
using IHC had significantly different 5-year PFS rates.52
1.2.
Investigational Product Name and Description
Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidin-1-yl]-1-
piperidinyl]-2-propen-1-one and has a molecular weight of 440.50 g/mole (anhydrous basis). 
Ibrutinib is a white to off-white solid. It has a single chiral center and is the R-enantiomer. The 
investigational drug product, ibrutinib, is an oral capsule formulation containing micronized 
ibrutinib.
1.3.
Summary of Relevant Nonclinical and Clinical Data
For the most comprehensive nonclinical and clinical information regarding the efficacy and 
safety of ibrutinib, refer to the latest version of the Investigator's Brochure and 
Addenda/Supplements for ibrutinib. The term "sponsor" used throughout this document refers to 
the entities listed in the Contact Information page(s), which will be provided as a separate 
document.
1.3.1.
Nonclinical Data
In vitro studies have shown that ibrutinib binds covalently to a cysteine residue (Cys-481) in the 
BTK active site, leading to potent and irreversible inhibition of BTK enzymatic activity.34 In 
cellular signal transduction assays with a B-cell lymphoma cell line, ibrutinib inhibited 
autophosphorylation 
of 
BTK, 
phosphorylation 
of 
BTK’s 
physiological 
substrate, 
phospholipase-C gamma (PLCγ), and phosphorylation of a further downstream kinase, 
extracellular signal-regulated kinase.22 Ibrutinib inhibited the proliferation of cell lines derived 
from DLBCL patients with a median effective concentration of 1 or 2 nM. 
1.3.2.
Clinical Pharmacokinetic Data
In vitro preclinical data show that ibrutinib is metabolized primarily by CYP3A. Its 
bioavailability is variable and relatively low (data on file). Study PCI-32765CLL1002 was an 
open-label study with a drug-drug interaction cohort of 18 healthy men, in which ibrutinib was 
administered alone at a 120-mg dose or in combination with ketoconazole at a 40-mg dose. 
Results demonstrated that ketoconazole, a strong cytochrome P450 (CYP)3A inhibitor, increased 
ibrutinib exposure (maximum observed plasma concentration [Cmax] and area under the plasma 
concentration versus time curve from time zero to the time corresponding to the last quantifiable 
concentration [AUC0-last]) by 29- and 24-fold, respectively. Terminal half-life was not increased. 
Guidance on concomitant use of ibrutinib/placebo with CYP3A inhibitors or inducers is provided 
in Section 8.2.1.
Study PCI-32765CLL1004 was a mass-balance study in 6 men in which ibrutinib was 
administered as a 140-mg solution admixed with 14C-ibrutinib. Preliminary results from 
Study PCI-32765CLL1004 showed approximately 90% of radioactivity was excreted within
168 hours after administration, with less than 10% accounted for in urine and the remainder in 
feces. A negligible fraction was excreted as unchanged drug.
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Summary of Human Pharmacokinetics
Extensive pharmacokinetic sampling and evaluation have been performed in approximately 
250 subjects receiving ibrutinib across 5 of the above mentioned clinical studies: PCYC-04753, 
PCYC-1102-CA, PCYC-1104-CA, PCYC-1106-CA, and PCYC-1109-CA and results are briefly 
summarized below.
Following oral administration of ibrutinib at doses ranging from 1.25 to 12.5 mg/kg/day, area 
under the plasma concentration-time curve (AUC) values for ibrutinib increased with increasing
dose, but with considerable overlap in values. The coefficient of variation for the AUC ranged 
from 60% to 107% across 3 studies (Studies PCYC-04753, PCYC-1102-CA, and 
PCYC-1109-CA). The mean half-life (t1/2) of ibrutinib across 4 clinical studies ranged from 
4.3 to 8.9 hours, with a median time of maximum concentration (Tmax) of 2 hours. 
Ibrutinib was extensively metabolized to the dihydrodiol metabolite PCI-45227. The metabolite 
to-parent AUC ratio ranged from 1.4 to 3.2. Consistent with the profile observed for ibrutinib, 
there was no apparent accumulation of the metabolite PCI-45227 in the plasma after repeated 
daily oral dosing with ibrutinib. PCI-45227 is a reversible inhibitor of BTK with approximately 
10% of the inhibitory potency of ibrutinib. The effect of renal impairment on drug clearance in 
humans is not known at this time. In a hepatic impairment study, data showed an increase in 
ibrutinib exposure. Following single dose administration of 140 mg ibrutinib under fasted 
conditions, the AUClast of ibrutinib increased 2.7-, 8.2-, and 9.8-fold in subjects with mild 
(Child-Pugh Class A), moderate (Child-Pugh Class B), and severe (Child-Pugh Class C) hepatic 
impairment compared to subjects with normal liver function. The safety of ibrutinib has not been 
evaluated in patients with hepatic impairment.
Pharmacokinetic and Pharmacodynamic Relationship
Ibrutinib binds covalently and irreversibly to Cys-481 near the BTK active site and inhibits the 
enzymatic activity of purified BTK with a half maximal inhibitory concentration (IC50) of 
0.5 nM. In Study PCYC-04753, the BTK active-site occupancy by ibrutinib was measured in the 
peripheral blood samples collected before and at 4 and 24 hours after administration of ibrutinib 
for each subject on Days 1, 8, and 28. The 24-hour samples were collected before dose 
administration the next day. Bruton's tyrosine kinase remained fully occupied by ibrutinib 
(≥90% occupancy) for at least 24 hours in all subjects in Cohorts 2 through 5 (2.5 to 
12.5 mg/kg/day) and for the 560 mg continuous dosing cohorts. Although ibrutinib is rapidly 
eliminated from the plasma after oral administration, once daily dosing with ibrutinib is adequate 
to sustain maximal pharmacodynamic activity for 24 hours post-dosing.
The relationship between the averaged BTK occupancy at 4 and 24 hours postdose (trough 
exposure) and the Day 1 area under the plasma concentration versus time curve from 0 to 
24 hours [AUC0-24] for ibrutinib can be described by a simple maximum obtainable effect (Emax)
model. 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 dosages ≥2.5 mg/kg/day had Day 1 
AUC0-24 values ≥160 ng·h/mL. In Study PCYC-1104-CA, in which ibrutinib was administered to 
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subjects with relapsed/refractory MCL as a fixed dosage of 560 mg/day, 96% of the subjects 
retained steady-state ibrutinib AUC value >160 ng∙h/mL. This result indicates that a dose of 
560 mg/day is adequate to achieve exposures yielding full BTK active-site occupancy in most 
patients with MCL. In addition, this dose was used to establish initial efficacy evaluations in 
Phase 1 and 2.
1.3.3.
Clinical Efficacy of Ibrutinib in Diffuse Large B-cell Lymphoma
Efficacy results from Studies PCYC-04753 and PCYC-1106-CA demonstrate that ibrutinib has 
robust activity as a single agent in subjects with relapsed or refractory DLBCL, with possible 
lower response rates in subjects with the GCB subtype.
1.3.3.1.
Study PCYC-04753
This is a completed, Phase 1, multicenter, open-label, dose escalation study in 66 subjects with 
recurrent NHL. The objectives included studying the safety profile of ibrutinib, identifying the 
maximum tolerated dose (MTD) and optimal dosing schedule, and characterizing efficacy, 
pharmacokinetics, and pharmacodynamics. A minimum of 6 subjects per cohort received 1 of 
5 escalating dose levels of ibrutinib between 1.25 and 12.5 mg/kg for 28 consecutive days in a 
35-day cycle, with the objective of escalating 3 dose levels above that which achieved full BTK 
occupancy based on the fluorescent probe assay. Two additional cohorts received a continuous 
ibrutinib dose of 8.3 mg/kg without a 7-day rest and a fixed continuous dose of 560 mg/day.
Full BTK occupancy was achieved with doses at ≥2.5 mg/kg/day; consequently, per protocol, 
12.5 mg/kg/day was the highest dose cohort evaluated. There were 2 dose-limiting toxicities 
(DLTs) (Grade 2 neutropenia [2.5 mg/kg/day] and Grade 3 hypersensitivity [8.3 mg/kg/day]); 
these events occurred in different dose cohorts, with neither in the highest-dose nor a continuous 
dosing cohort. The MTD of ibrutinib in subjects with B-cell malignancies was not established in 
this study.
Five of 15 subjects with DLBCL (33%) achieved objective responses, 2 CRs and 3 partial 
responses (PRs). The median time on treatment was 8 weeks (range: 2 to 98 weeks). Median PFS 
was 2.5 months (range: 0.7 to 4.6 months) and the median follow-up time was 3.5 months 
(range: 0.8 to 22.5 months).
1.3.3.2.
Study PCYC-1106-CA
This is a Phase 2, multicenter, open-label, single-arm study in subjects with relapsed or
refractory DLBCL. Subjects are enrolled and retrospectively assigned to 1 of 2 cohorts by 
subtype: ABC versus GCB as per central GEP. All subjects have received a continuous fixed 
dose of ibrutinib 560 mg/day. The objectives include studying the efficacy of ibrutinib in 
DLBCL and the safety of this dosing regimen.
The study has completed enrollment. Seventy subjects were enrolled with a median age of 
63 years (range: 28 to 92 years) and a median of 3 prior systemic therapies (range: 1 to 7). 
Median time from diagnosis was 19 months. In a subset of samples, a comparison of the central 
IHC by Hans algorithm to the GEP algorithm that was used in this Phase 2 clinical study 
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(ie, Sensation algorithm; 200 genes) was performed (unpublished data on file).55 Non-GCB by 
central IHC, blinded to the GEP assignment and clinical data, had a 92% concordance (12/13) 
with GEP. For the 60 response evaluable subjects, the overall response rate (ORR) was 21.7% 
(13/60 subjects). Median PFS was 1.64 months (Table 4).55 In the ABC subtype, ORR was 40% 
(10/25 subjects; 95% confidence interval [CI]: 21% to 61%), CR 8% (2/25 subjects), and 
PR 32% (8/25 subjects). Only 1 PR (1/19 subjects; 5.3%) was observed in the GCB subtype and 
none in unclassifiable cases. Thus, while the 2 subgroups were clinically not well balanced, 
ibrutinib showed less activity in the GCB DLBCL subtype (p=0.0126, Fisher’s exact test).55
Table 4:
Study PCYC-1106-CA Efficacy Results
ABC subtype
(n=29)
GCB subtype
(n=20)
Unclassifiablea
(n=16)
Unknownb
(n=5)
Total
(N=70)
Evaluable for Response
25
19
13
3
60
PP ORR (CR+PR)
10 (40%)
1 (5.3%)
0
2 (66.7%)
13 (21.7%)
CR
2 (8%)
0
0
1 (33.3%)
3 (5%)
PR
8 (32%)
1 (5.3%)
0
1 (33.3%)
10 (16.7%)
PFS (months)
2.5
1.28
0.95
NR
1.64
ABC=activated B-like DLBCL; CR=complete response, GCB=germinal center B cell-like DLBCL; NR=not 
reached; ORR=overall response rate; PFS=progression-free survival; PP=per-protocol population; PR=partial 
response
a
Gene expression profiling performed, but not assignable to ABC or GCB subtypes.
b
Gene expression profiling not yet performed or tissue not available.
1.3.3.3.
Post hoc Analysis
A post hoc analysis of pooled data from the DLBCL expansion cohort of Study PCYC-04753 
and Study PCYC-1106-CA was conducted. The effect of a prior response to chemotherapy on 
subsequent response to ibrutinib was assessed for all subjects with DLBCL and for subjects in 
2 subsets of DLBCL, ie, the ABC DLBCL and non-ABC DLBCL subsets. More subjects in the 
ABC DLBCL subset who were chemo-sensitive had a response (11/14 subjects, 78.6%) 
compared with the chemo-sensitive non-ABC DLBCL subset (4/16 subjects, 25.0%). Fewer 
subjects with ABC DLBCL who were chemo-refractory (defined as failure to achieve a response 
to the last prior chemotherapy regimen, ie, a regimen with at least 2 chemotherapeutic agents) 
had a response (4/25 subjects, 16%), but the response was still favorable as compared with the 
chemo-refractory non-ABC DLBCL subset (0/25 subjects, 0%). Based on these results, ibrutinib 
appears to be more active in subjects with chemo-sensitive DLBCL. Therefore, use of ibrutinib 
in earlier lines of therapy and in the non-GCB subtype of DLBCL may have the greatest clinical 
effect.
1.3.3.4.
Study PCI-32765DBL1002
This is a multicenter, dose-escalation and expansion study in subjects with newly diagnosed
CD20-positive B-cell NHL including DLBCL, follicular lymphoma, and MCL. Thirty-three 
subjects have been enrolled in this study of whom 24 subjects have DLBCL; 18 subjects with
newly diagnosed DLBCL were treated at the recommended Phase 2 dose (ibrutinib 560 mg 
daily) in combination with R-CHOP. 
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In the dose-escalation phase of this study, subjects were assigned to cohorts of increasing oral 
daily doses of ibrutinib 280 mg (n=7), 420 mg (n=4), and 560 mg (n=6) administered in 
combination with R-CHOP. A Study Evaluation Team (SET) reviewed all available data upon 
completion of the first cycle for all subjects at each dose cohort to determine DLTs. After the 
recommended Phase 2 dose was determined (560 mg), 16 subjects with newly diagnosed 
DLBCL were enrolled into the expansion cohort. Subjects are allowed to continue to receive 
ibrutinib and R-CHOP up to a maximum of 6 cycles. The study will end 1 year after the last 
subject has completed the End-of-Treatment Visit. The data summarized below are preliminary 
and are subject to change upon study completion and data review.
Preliminary response data based on the final analysis suggest activity with this regimen, with 
18/18 (100%) evaluable subjects with DLBCL treated at a dose of 560 mg ibrutinib + R-CHOP 
achieving a response (14 CRs and 4 PRs; Table 5). While these data are encouraging, they must 
be interpreted in the context of the small sample size, the immaturity of the data, and the known 
response rate of background therapy.
Table 5:
Preliminary Response Data (Study PCI-32765DBL1002)
Dose level
Total
DLBCL
MCL
FL
(n)
CR
PR
(n)
CR
PR
(n)
CR
PR
280 mg
7a
2
2
3
3
1
1
420 mg
4
2
2
0
2
1
1
560 mg (dose escalation)
6b
3
1
2
2
1
1
0
RP2D (560 mg, expansion)
16c
15
13
2
0
0
CR=complete response; DLBCL=diffuse large B-cell lymphoma; FL=follicular lymphoma; MCL=mantle cell 
lymphoma; PR=partial response; RP2D=recommended Phase 2 dose.
a One subject not evaluable for response because the subject refused further treatment after the initial dose 
(only 1 dose of 280 mg taken).
b One subject not evaluable for response, the subject refused further follow up after discontinuation of therapy 
(Cycle 2 Day 8) and was withdrawn from the study.
c One subject not evaluable for response due to serious adverse event (rituximab reaction); subject discontinued 
the study before ibrutinib exposure.
1.3.4.
Clinical Safety of Ibrutinib
As of 6 April 2015, 1071 subjects have been treated with ibrutinib monotherapy 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.
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1.3.4.1.
Monotherapy Studies
1.3.4.1.1.
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 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, >400000/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.
1.3.4.1.2.
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 8.2.4.
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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 8.2.3.
Diarrhea
Diarrhea is the most frequently reported nonhematologic adverse event with ibrutinib 
monotherapy and combination therapy. Other frequently reported gastrointestinal events include 
nausea, vomiting, and constipation. These events are rarely severe and are generally managed 
with supportive therapies including antidiarrheals and antiemetics. Subjects should be monitored 
carefully for gastrointestinal adverse events and cautioned to maintain fluid intake to avoid 
dehydration. Medical evaluation should be made to rule out other etiologies such as Clostridium 
difficile or other infectious agents. Should symptoms be severe or prolonged, ibrutinib treatment 
should be modified as described in Section 6.2.6.
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 medication 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 
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for rashes and treated symptomatically, including interruption of the suspected agent as 
appropriate.
In addition, hypersensitivity-related events erythema, urticaria, angioedema have been reported.
Tumor Lysis Syndrome
Tumor lysis syndrome has been reported with ibrutinib therapy. Subjects at risk of TLS are those 
with high tumor burden prior to treatment. Monitor subjects closely and take appropriate 
precautions.
1.3.4.2.
Combination Therapy Studies
The safety of ibrutinib administered as combination therapy to 130 subjects was evaluated in 
3 clinical studies: Studies PCYC-1108-CA, PCYC-1109-CA, and PCI-32765DBL1002. In
Study PCYC-1108-CA, ibrutinib was administered in combination with either the FCR 
(fludarabine, cyclophosphamide, and rituximab) or the BR chemotherapy regimen 
(bendamustine and rituximab). In Study PCYC-1109-CA, ibrutinib is
administered in
combination with the monoclonal antibody ofatumumab in patients with relapsed and refractory 
CLL. In Study PCI-32765DBL1002, ibrutinib is administered in combination with standard 
R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone).
Across these combination studies, the most common adverse event has been diarrhea (47.7%),
nausea (33.1%), infusion related reaction (29.2%), and fatigue (26.2%). Neutropenia (24.6%) has 
been the most common hematologic toxicity, followed by anemia (20.0%) and thrombocytopenia 
(19.2%).
Adverse events that were Grade 3 or higher in severity were reported in 57.7% of subjects. The 
most common have been hematologic: neutropenia (21.5%), anemia and thrombocytopenia 
(7.7% each), and febrile neutropenia (6.2%). Pneumonia (7.7%) was the most frequently 
reported nonhematologic Grade 3 or higher adverse event.
Overall, 36.2% of treated subjects have experienced at least 1 serious adverse event. The most 
commonly reported serious adverse events were febrile neutropenia and pneumonia (6.2% each), 
cellulitis (3.8%), atrial fibrillation (3.1%), and dehydration and dyspnea (2.3% each).
1.3.4.2.1.
Preliminary Results From Study PCI-32765DBL1002
Preliminary results from an ongoing Phase 1b study in subjects with newly diagnosed NHL, 
Study PCI-32765DBL1002, are summarized below with a data cutoff of 08 July 2013.
The following DLTs were reported during the dose-escalation phase: at the lowest dose level 
(280 mg), 2 DLTs in 2 subjects were reported: Grade 3 syncope that triggered an expansion of 
the cohort to 7 subjects and Grade 3 peri-orbital cellulitis. No DLTs were reported at the 420-mg
dose. Another DLT was reported at the highest dose (560 mg) in a subject who had Grade 2 
gastritis (requiring 7 days dose interruption), and triggered dose cohort expansion. The subject
had a history of well-controlled gastrointestinal disorders (gastroesophageal reflux disease 
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[GERD] and irritable bowel syndrome). The SET agreed further enrollment of 2 additional 
subjects at the 560 mg/day dose level, thus expanding the cohort to 6 evaluable subjects. Once all
6 subjects were evaluated through the first cycle and no additional DLTs were observed, the SET 
re-convened and confirmed that the recommended Phase 2 dose be set at 560 mg 
ibrutinib+R-CHOP, and enrollment of the expansion phase for subjects with newly diagnosed 
DLBCL proceeded.
Preliminary Safety Analysis
As of 08 July 2013, safety data are available for all 33 subjects; 32 subjects were treated with the 
ibrutinib + R-CHOP combination; 1 subject was enrolled but discontinued the study prior to 
ibrutinib exposure due to a rituximab reaction; 21 subjects (18 subjects with DLBCL, 2 subjects 
with MCL, and 1 subject with FL) have received the recommended Phase 2 dose. All 33 subjects
experienced at least 1 treatment-emergent adverse event; the most common were neutropenia 
(67%), nausea (67%), thrombocytopenia (61%), vomiting (49%), anemia (36%), fatigue (30%),
and diarrhea (30%). The most common treatment-emergent adverse events of Grade 3 or higher 
severity were neutropenia (61%), thrombocytopenia (21%), anemia (18%), and febrile 
neutropenia (15%). Serious Adverse Events were reported in 46% of all patients, and most 
common serious adverse events reported were febrile neutropenia (15%) and pyrexia (6%). All 
other SAEs were reported in 1 subject each. The incidence of neutropenia and febrile 
neutropenia reported to date is consistent with treatment with R-CHOP alone, which is has been 
reported at 19% for febrile neutropenia35 and 62% for neutropenia.20 The overall toxicity profile 
in this study is also consistent with the known profiles of R-CHOP and ibrutinib independently. 
Based on the interim data, there appears to be no new or unexpected toxicities or 
additive/synergistic effects of the combination ibrutinib+R-CHOP.
Preliminary Pharmacokinetic Results
Thirty-two subjects have received ibrutinib in combination with R-CHOP. The risks associated 
with ibrutinib and the dihydrodiol metabolite PCI-45227 as potential perpetrators of clearance 
mechanisms of concomitant medications were assessed based on literature review and 
pharmacokinetic measurements in the Phase 1b Study PCI-32765-DBL1002. It was concluded 
that enzymatic drug-drug interactions between ibrutinib or the dihydrodiol metabolite PCI-45227 
and each of the 5 R-CHOP components were unlikely. To confirm this, vincristine 
pharmacokinetic was evaluated in Study PCI-32765DBL1002, as this drug was considered the 
most plausible drug-drug interaction target since CYP3A4 has been shown to be relevant for 
vincristine’s systemic clearance. Preliminary PK analysis of a subset of subjects showed that 
there was no effect of ibrutinib co-administration on vincristine PK. For the other compounds of 
this combination chemotherapy regimen, clinical drug-drug interaction with ibrutinib is not 
expected. Co-administration of R-CHOP and ibrutinib did not affect ibrutinib exposures in a
clinically meaningful way.
Dose Reductions
As of 08 July 2013, 5 of 21 subjects enrolled at the 560-mg dose level reported dose reductions 
of ibrutinib (preliminary data). One subject who had a DLT of gastritis (discussed above) 
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resulting in dose reduction started the second cycle at a reduced dose of 420 mg; the subject 
discontinued the study permanently on Cycle 2 Day 8 due to Grade 2 gastritis. The second 
subject had a dose reduction secondary to increased bleeding time (bleeding time was assessed 
by the Ivy method) without any clinical evidence of bleeding at Cycle 2 Day 1; bleeding time 
was prolonged for 25 minutes at Cycle 2 Day 1). The dose was reduced to 420 mg and the
bleeding time was re-assessed 1 week later as prolonged for 8.5 minutes by the Ivy method. The 
subject continued on the 420 mg ibrutinib dose and completed 6 cycles of therapy. Two subjects 
had a dose reduction due to febrile neutropenia (dose reduced to 420 mg at Cycle 3 Day 1) and 
1 of these subjects had a further dose reduction due to onset of fever that required hospitalization 
(Cycle 4 Day 1), both subjects completed 6 cycles of therapy; supportive therapy (growth 
factors) was given prior to the event for 7 and 8 days, respectively. Lastly, 1 subject required 
2 dose reductions (Cycle 1 Day 8 and Cycle 2 Day 7) due to severe diarrhea that was controlled 
by anti-diarrheal therapy. The subject continued therapy at the reduced dose of 280 mg and is 
currently ongoing at Cycle 6.
For vincristine, dose reductions and discontinuations were reported in 11 of 33 subjects across all 
dose levels. With the exception of 1 subject who experienced sinus pain, neuropathy was the 
main reason for dose reduction of vincristine. Vincristine dose reductions occurred during 
Cycle 2 (n=1), Cycle 5 (n=4) and Cycle 6 (n=6). For prednisone, dose reductions were reported 
in 2 subjects treated at the recommended Phase 2 dose; the reported dose reduction was 
attributed to the local hospital administering 40 mg instead of 100 mg. For doxorubicin and 
cyclophosphamide, dose reductions were reported in 2 subjects enrolled at the highest dose level 
due to febrile neutropenia (both at Cycle 3 Day 1); both subjects completed 6 cycles of therapy.
1.3.4.3.
Treatment Discontinuations
Sixty-two of the 506 subjects (12%) in the monotherapy population and 9 of the 130 subjects
(7%) in the combination therapy population discontinued treatment due to an adverse event. The 
most frequently reported adverse events that led to treatment discontinuations were pneumonia 
(13 subjects), respiratory failure (4 subjects), and cardiac arrest and Richter’s Syndrome 
(3 subjects for each event).
1.3.5.
Background Therapy
R-CHOP, the currently accepted standard regimen for frontline treatment of patients with 
DLBCL worldwide, will be used as background therapy. For further information regarding 
rituximab, cyclophosphamide, doxorubicin, vincristine, or prednisone (or equivalent), refer to the
local prescribing information. 
1.4.
Overall Rationale for the Study
Diffuse large B-cell lymphoma is the most common type of NHL and constitutes 30% to 58% of 
all lymphomas.49 About half of patients diagnosed with DLBCL achieve long-term disease 
survival with a combination of rituximab and chemotherapy (R-CHOP).6 However, a substantial 
number of patients remain inadequately treated or relapse after response to initial treatment.13
Clinically, these patients appear to be older, present with high IPI scores, or may have bone 
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marrow involvement of the disease, characteristics that may in fact be surrogate markers of 
intrinsic molecular heterogeneity.45,31
It is increasingly appreciated that DLBCL is heterogeneous in terms of morphology, genetics, 
and biologic behavior. Immunohistochemistry and GEP are 2 of the assay platforms currently 
being used for determining cell of origin. Immunohistochemistry divides the population into 
2 categories: GCB and non-GCB. Gene expression profiling platforms assign specimens into 1 of 
3 diagnostic categories: GCB, ABC, or unclassified. Non-GCB comprises the categories of ABC 
and unclassified. Gene expression profiling identified GCB as the subtype with stronger 
predictive value for prognosis and response to R-CHOP.1 Subsequent IHC studies have 
demonstrated that these GCB and non-GCB variants can be accurately predicted using a panel of 
only 3 immunostains.19 The GCB subgroup, positive for CD10 and BCL-6, but negative for 
MUM1, has significantly better survival outcomes than the ABC group that is positive for 
MUM1.19,43 Additional subtypes, such as primary mediastinal B-cell lymphoma (PMBL), are 
less common but genetically and clinically distinct.43 Clinical studies with R-CHOP have shown 
the prognostic importance of subclassification of DLBCL, demonstrating that the GCB subgroup 
has a significantly better 3-year survival than the non-GCB subgroup (85% versus 69%; 
p=0.032).17 High concordance between GEP and IHC now established central IHC as a practical 
process for screening patients in the clinical setting.52
The gene expression profiles for ABC DLBCLs are also notable for the high expression of target
genes of the nuclear factor-kappa B (NF-B) transcription factor.9 The NF-B pathway is 
important for normal intracellular signaling during cellular differentiation and immune 
responses.9 However, the presence of high NF-B activity in B-cell receptor (BCR) signaling, as 
seen in the ABC subtype of DLBCL, has been suggested to contribute to poor prognosis.9,43
Conversely, the NF-B pathway is essentially silent in the GCB subtype of DLBCL, making this 
pathway a unique target for the non-GCB subtype of DLBCL.10 Targeted agents of the BCR 
pathway in non-GCB DLBCL may inhibit downstream activation of the NF-B pathway 
specifically in populations where this pathway is activated.
Bruton’s Tyrosine Kinase is a key component of the BCR-signaling cascade that can lead to 
activation of the NF-B pathway. In vitro data suggest that the BTK inhibitor ibrutinib can kill 
ABC DLBCL cell lines with constitutively activated BCR signaling, but have no effect on ABC 
and GCB DLBCL cell lines that do not rely on constitutive BCR signaling.10,47 These nonclinical 
data were corroborated by clinical results from the ABC-DLBCL cohort in PCYC-0475347 and 
the PCYC-1106-CA study of ibrutinib in relapsed/refractory DLBCL,55 suggesting that ibrutinib 
is active in subjects with DLBCL, with less activity in subjects with the GCB subtype. 
Interestingly, these data also suggest that ibrutinib shows superior activity among DLBCL
patients who are still chemosensitive. Together, these findings suggest a potentially important 
role for ibrutinib as front-line treatment in the non-GCB subtype. Early data from an ongoing 
Phase 1 combination study shows that ibrutinib can be safely combined with R-CHOP. This 
study will evaluate whether ibrutinib in combination with R-CHOP improves the outcome in 
newly diagnosed patients with the non-GCB subtype, ABC subtype, or both subtypes of DLBCL.
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At the time the study was designed and began enrolling in 2013, subjects with the non-GCB 
subtype of DLBCL were selected using the IHC method (not by GEP) because IHC was 
identified as a clinically viable and more widely available method. Immunohistochemistry, using 
various algorithms including the Hans algorithm, utilized commonly available FFPE tumor 
samples and was accepted worldwide as an approach to classify subjects into either the GCB and 
non-GCB subtype. In contrast, at that time GEP used freshly frozen tumor samples (there was no 
validated or reproducible GEP assay for DLBCL subtyping using commonly available FFPE 
tissue) and DNA microarrays, which made GEP an experimental approach with limited 
availability. Moreover, at that time GEP had a turnaround time of 2 to 3 weeks, which made the 
use of GEP challenging because many patients could not delay treatment until GEP results were 
available. Recently, however, standardized DLBCL cell-of-origin GEP assays 
 
that can be performed on FFPE specimens with shorter 
sample turnaround times have become available. This new approach will allow for retrospective 
analysis of available tumor samples by GEP from subjects who were screened and selected for 
this study using IHC. The analysis of the treatment benefit of subjects with the ABC subtype by 
GEP was included as a secondary endpoint when this study was initiated.
This study will evaluate whether ibrutinib in combination with R-CHOP improves the outcome 
in subjects with newly diagnosed non-GCB DLBCL selected by IHC or in subjects with newly 
diagnosed ABC DLBCL identified by GEP or both patient populations.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objectives
The primary objective is to evaluate if the addition of ibrutinib to rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone (R-CHOP) prolongs event-free survival (EFS)
compared with R-CHOP alone in subjects with newly diagnosed non-GCB subtype of DLBCL
selected by IHC or in subjects with newly diagnosed ABC subtype of DLBCL identified by GEP 
or both patient populations.
Secondary Objectives
The secondary objectives are to:

Evaluate PFS

Evaluate CR rate

Evaluate overall survival  

Evaluate patient-reported lymphoma symptoms and concerns as measured by the Lym 
subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)

Characterize the pharmacokinetics of ibrutinib and to explore the potential relationships 
between ibrutinib metrics of exposure with relevant clinical or biomarker information

Evaluate the safety of ibrutinib when combined with R-CHOP
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Exploratory Objectives
The exploratory objectives are to:

Evaluate patient-reported outcomes (PRO), related to well-being and general health status, 
utilizing the FACT-Lym and EuroQol questionnaire (EQ-5D-5L)

Explore the relationship between relevant biomarkers (eg, GEP, gene mutations) with 
clinical outcomes and mechanism of resistance
2.2.
Hypothesis
Ibrutinib in combination with R-CHOP will prolong EFS compared with R-CHOP alone in 
subjects with newly diagnosed non-GCB DLBCL selected by IHC or in subjects with newly 
diagnosed ABC DLBCL identified by GEP or in both patient populations.
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 R-CHOP versus R-CHOP alone in 
subjects 18 years and older with newly diagnosed non-GCB DLBCL.
Approximately 800 eligible subjects will be randomly assigned in this study, with 400 subjects 
planned per treatment arm. Eligible subjects will be stratified by Revised IPI (R-IPI; 1-2 vs. 3-5
[Attachment 1]), region (U.S./Western Europe vs. Rest of World), and number of pre-specified
treatment cycles per local practice (6 vs. 8 cycles) then randomized in a 1:1 ratio to receive either 
placebo+R-CHOP (Treatment Arm A) or 560 mg ibrutinib+R-CHOP (Treatment Arm B).
The study will include a Pretreatment (Screening) Phase, Active Treatment Phase, and a 
Posttreatment Follow-up Phase. Before any study related-procedure can be performed, all 
subjects must sign an informed consent form (ICF). Subjects will be evaluated for eligibility at 
Screening. Subjects must complete Screening procedures within 30 days before randomization, 
unless otherwise specified.
The Active Treatment Phase will extend from Day 1 Cycle 1 until study treatment
discontinuation due to disease progression, initiation of subsequent antilymphoma therapy, 
unacceptable toxicity, withdrawn, or completion of study treatment. All subjects will receive 
R-CHOP as background therapy for 6 or 8 cycles per site preference (21 days per cycle). Sites 
may choose to administer 6 or 8 cycles of treatment based on local practice. Once the number of 
cycles is selected by the site, all subjects at individual sites are intended to receive the 
prespecified number of treatment cycles (6 or 8); no individual subject adjustment is permitted
based on interim response. Study treatment administration begins on Cycle 1 Day 1 and ends on
Day 21 of the last cycle, unless if the subject experiences unacceptable toxicity or disease 
progression.
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After 4 cycles, an interim response assessment will be performed to evaluate progression for 
each subject. Subjects with progressive disease (PD) or relapsed disease after CR will be 
discontinued from study treatment. Subjects who discontinue any component of R-CHOP 
without disease progression, will continue study drug (placebo or ibrutinib) until 6 or 8 cycles
are completed (depending on the number of cycles pre-specified by each site), disease 
progression, or unacceptable toxicity, whichever occurs first. After completion of study 
treatment, subjects will undergo assessment of tumor response by computed tomography (CT) 
scan and positron emission tomography (PET) scan. Response criteria are based on the Revised 
Response Criteria for Malignant Lymphoma.5 Subjects with PET-positive or biopsy-proven
residual disease upon completion of at least 6 cycles of R-CHOP therapy are considered eligible 
to initiate subsequent antilymphoma therapy.
The Posttreatment Follow-up Phase will begin once a subject has completed study treatment. At 
the End-of-Treatment Visit, follow-up visits to assess for disease progression, will be required if 
study treatment is discontinued prior to PD and will be completed until PD, the clinical cutoff for 
the primary endpoint, or up to 5 years, whichever occurs first (see Time and Events Schedules; 
Table 1 and Table 3). After that, CT may be performed as clinically indicated (at the discretion 
of the investigator) per local standard of care. Subjects who discontinue study treatment for 
reasons other than disease progression must continue to have disease evaluations according to 
the Time and Events Schedule (Table 1). The Posttreatment Follow-up Phase will continue until 
death, loss to follow up, consent withdrawal, or study end, whichever occurs first. The end of 
study is defined as when 50% of the randomized subjects have died or 5 years after the last 
subject is randomized or the sponsor terminates the study, whichever comes first.
The investigator will evaluate sites of disease by radiological imaging, physical examination, or 
other procedures as necessary. At each site visit, subjects will undergo safety evaluations. Safety
evaluations will include adverse event monitoring, physical examinations, vital signs, 
concomitant medication usage, and clinical laboratory parameters. In a subset of subjects, blood 
samples will be drawn for assessment of pharmacokinetic parameters.
Three clinical cutoffs are planned (see Section 9.1.5); the primary efficacy analysis of EFS will 
be based on investigator assessment. Radiological and PET scans performed prior to the database 
lock for the final analysis of EFS must be transferred to the independent imaging laboratory for 
storage; the scans may be reviewed, if deemed necessary. Available tumor samples will be 
retrospectively analyzed to identify the ABC DLBCL population using GEP. An independent 
Data Monitoring Committee (DMC) will be commissioned for this study. Refer to Section 11.10,
Data Monitoring Committee, for details. A diagram of the study design is provided below in 
Figure 1.
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Figure 1:
Schematic Overview of the Study
3.2.
Study Design Rationale
This is a Phase 3, randomized, double-blind, controlled study evaluating the addition of ibrutinib 
to the standard of care in non-GCB DLBCL. The study will recruit patients globally and is 
adequately powered to demonstrate an improvement of the ibrutinib combination over the 
standard of care. This study design is widely employed to obtain global regulatory approval of 
new treatments.
Randomization will be used to minimize bias in the assignment of subjects to treatment arms, to 
increase the likelihood that known and unknown subject attributes (eg, demographic and baseline 
characteristics) are evenly balanced across treatment arms, and to enhance the validity of 
statistical comparisons across treatment arms. Blinded treatment will be used to reduce potential 
bias during data collection and evaluation of endpoints. Subjects will be stratified by R-IPI 
(1-2 vs. 3-5) score, a well-established prognostic index for patients with DLBCL; region; and 
number of pre-specified treatment cycles (6 vs. 8 cycles).
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3.2.1.
Study Population
The rationale for selecting the non-GCB DLBCL Intent-to-Treat (ITT) patient population in this
study is, in part, based on results from Studies PCYC-04753 and PCYC-1106-CA suggesting
that ibrutinib appears to be less active in subjects with GCB DLBCL (see Section 1.3.3). In 
addition, activity appears to be enhanced in the target population when subjects are 
chemosensitive.
3.2.2.
Study Treatments
The 560 mg daily dose of ibrutinib was selected as the recommended dose in combination with 
R-CHOP for this study based on nonclinical data and clinical data from Studies PCYC-04753 
and PCYC-1106-CA. See Section 1.3. The comparator in this study, R-CHOP, was selected as it 
is the standard of care (see Section 1.1.1).
The primary endpoint, EFS, has served as the basis for regulatory approval in DLBCL and 
represents a clinically meaningful improvement attributable to treatment in this subject 
population.42,29 The FACT-Lym questionnaire will provide an assessment of the subject’s own 
functional status, well-being, and lymphoma symptoms over time. The EQ-5D-5L assessment 
will provide estimates of utility to include in future cost effectiveness models.
The assessment of pharmacokinetics 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. 
3.2.3.
Biomarker Collection
Inhibition of BTK tyrosine phosphorylation by ibrutinib has been shown to abrogate downstream 
survival pathways (ERK1/2, PI3K, NF-B, MAPK). Inhibition by ibrutinib also interferes with 
activation of integrins and chemokine networks leading to interference with adhesion, migration,
and homing of malignant cells.21,38 It is anticipated that subjects with alterations in BCR 
signaling components or activation of alternative signaling pathways, may have a different 
response to treatment. The biomarker evaluations within this study will identify biomarkers
associated with response (and potentially resistance) to ibrutinib in subjects with non-GCB 
DLBCL.
4.
SUBJECT POPULATION
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor representative before enrolling a subject 
in the study. For a discussion of the statistical considerations of subject selection, refer to 
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Section 11.3, Sample Size Determination. The last assessment/evaluation or laboratory result 
obtained prior to randomization will be used to determine eligibility.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
Subject must be 18 years of age or older
2.
No prior treatment for DLBCL.
3.
Criterion modified per Amendment INT-1:
3.1 Histologically-confirmed non-GCB DLBCL
–
The verification of DLBCL will be based on central review of the local pathology report. 
–
Paraffin-embedded tumor tissue (block or slides) must be sent to the central laboratory 
for determination
of the non-GCB subtype by IHC prior to randomization
(Attachment 2).
4.
Stage II (not candidates for local X-ray therapy), III, or IV disease by the Ann Arbor 
Classification
5.
At least 1 measurable site of disease according to Revised Response Criteria for Malignant 
Lymphoma. The site of disease must be greater than 1.5 cm in the long axis regardless of 
short axis measurement or greater than 1.0 cm in the short axis regardless of long axis 
measurement, and clearly measurable in 2 perpendicular dimensions.
6.
R-IPI score of 1 (Attachment 1)
7.
Eastern Cooperative
Oncology Group performance status grade
of 0, 1, or 2
(Attachment 3)
8.
Criterion modified per amendment
8.1 Hematology values must be within the following limits prior to randomization and at 
baseline:
a.
Absolute neutrophil count (ANC) 1,000 cells/μL unless if bone marrow 
involvement
b.
Platelets 75,000 cells/μL unless if bone marrow involvement.
9.
Criterion modified per amendment
9.1 Biochemical values must be within the following limits prior to randomization and at 
baseline: 
a.
Alanine aminotransferase (ALT) 3 x upper limit of normal (ULN). Aspartate 
aminotransferase (AST) 3 x ULN.
b.
Total bilirubin ≤1.5 x ULN, unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin
c.
Serum creatinine ≤2 x ULN or estimated Glomerular Filtration Rate
≥40 mL/min/1.73m2
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10. LVEF within institutional normal limits, as determined by echocardiography or multiple 
uptake gated acquisition (MUGA) scan.
11. Women of childbearing potential and men who are sexually active must be practicing a 
highly effective method of birth control during and after the study consistent with local 
regulations regarding the use of birth control methods for subjects participating in clinical 
trials. Men must agree to not donate sperm during and after the study. For women, these 
restrictions apply for 12 months after the last dose of rituximab or 1 month after the last dose 
of study drug, whichever is later. For men, these restrictions apply for 12 months after the 
last dose of rituximab or 3 months after the last dose of study drug, whichever is later.
12. Women of childbearing potential must have a negative serum (beta-human chorionic 
gonadotropin [-hCG]) or urine pregnancy test at Screening. Women who are pregnant or 
breastfeeding are ineligible for this study.
13. Each subject (or their legally acceptable representative) must sign an informed consent form 
(ICF) indicating that he or she understands the purpose of and procedures required for the 
study and are willing to participate in the study.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
1.
Major surgery within 4 weeks of randomization
2.
Known central nervous system (CNS) lymphoma
3.
Known primary mediastinal lymphoma
4.
Prior history of indolent lymphoma
5.
Diagnosed or treated for malignancy other than DLBCL, 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
6.
History of stroke or intracranial hemorrhage within 6 months prior to randomization
7.
Requires 
anticoagulation 
with 
warfarin 
or 
equivalent 
vitamin 
K 
antagonists 
(eg, phenprocoumon)
8.
Criterion modified per Amendment INT-1:
8.1 Requires treatment with strong CYP3A inhibitors
9.
Prior anthracycline use 150 mg/m2
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
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11. Criterion modified per Amendment INT-1:
11.1 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 
intravenous (IV) antibiotics (see Section 9.5). Subjects with PCR-negative HBV are
permitted in the study.
12. 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
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's status changes (including laboratory results or receipt of additional medical records) 
after screening but before the first dose of study drug is given such that he or she no longer meets 
all eligibility criteria, then the subject should be excluded from participation in the study. 
Section 17.4, Source Documentation, describes the required documentation to support meeting 
the enrollment criteria.
4.3.
Prohibitions and Restrictions
Concurrent radiation with ibrutinib is prohibited. 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 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 intrathecal CNS 
prophylaxis, a short ibrutinib hold (up to 3 days) should be considered based on the clinical 
situation of the subject, including assessment of underlying lymphoma.

For emergency procedures, ibrutinib should be held after the procedure until the surgical site 
is reasonably healed, for at least 7 days after the urgent surgical procedure.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment arms 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 R-IPI score (1-2 vs. 3-5), region 
(U.S./Western Europe vs. Rest of World), and number of pre-specified treatment cycles
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(6 vs. 8 cycles), then randomized in a 1:1 ratio to either Treatment Arm A (placebo+R-CHOP) or 
Treatment Arm B (ibrutinib+R-CHOP). The interactive web response system (IWRS) will assign 
a unique treatment code, which will dictate the treatment assignment and matching study 
treatment kit for the subject. The requestor must use his or her own user identification and
personal identification number when contacting the IWRS, and will then give the relevant 
subject details to uniquely identify the subject.
Blinding
This is a double-blind study; 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. 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.

Personnel performing blood plasma concentration assays and analysis for pharmacokinetics.

Unblinded sponsor safety representative and Ethics Committee for serious adverse event
reporting.

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).
Data that may potentially unblind the treatment assignment (ie, study drug plasma 
concentrations) will be handled with special care to ensure that the integrity of the blind is 
maintained and the potential for bias is minimized. This 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 EFS. 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. 
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At the time of the interim analysis, the randomization codes and, if required, the translation of 
randomization codes into treatment and control arms will be disclosed to those authorized and 
only for those subjects included in the interim analysis.
6.
DOSAGE AND ADMINISTRATION
For the purposes of this study, ‘study drug’ refers to ibrutinib or placebo and ‘study treatment’ 
refers to ibrutinib/placebo, rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone (or equivalent). The dosages for the treatment combination are described below. All
dosing information must be recorded in the Dosage Administration page of the CRF. The 
ibrutinib treatment scheme is provided in Table 1.
6.1.
Study Treatment
All subjects will receive R-CHOP (rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, 
doxorubicin 50 mg/m2 IV, vincristine 1.4 mg/m2 IV [maximum total 2 mg], and prednisone 
[or equivalent] 100 mg orally) as the background therapy for 6 or 8 cycles per site preference
(21 days/cycle). Sites may choose to administer 6 or 8 cycles of treatment based on local 
practice; once the number of cycles is pre-specified by the site, all subjects at individual sites are 
intended to receive the same number of treatment cycles (6 or 8; no individual subject 
adjustment permitted based on interim response) (see Table 2).
Subjects will be randomized in a 1:1 ratio to Treatment Arm A (placebo, 4 capsules orally once 
daily continuously + R-CHOP) or Treatment Arm B (ibrutinib 560 mg (4 x 140-mg capsules 
orally once daily continuously + R-CHOP). Study treatment administration begins on Cycle 1 
Day 1 (within 72 hours of randomization) and ends on Day 21 of the last cycle (either 6 or 
8 cycles, as pre-specified by the site), unless if the subject experiences unacceptable toxicity or 
disease progression. Ibrutinib or placebo will be self-administered at home.
The amount (in mg) of all study treatment, except ibrutinib, to be administered will be
determined by body surface area (BSA; Attachment 4). If a subject experiences a >10% change 
in weight from the weight used in the previous BSA calculation, then BSA and dose should be 
recalculated.
6.1.1.
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 local practice at the dosages described above in
Section 6.1. Refer also to the study Investigational Product Procedures Manual.
6.1.2.
Ibrutinib or Placebo Administration
Subjects will be instructed to take 4 capsules of ibrutinib (for a dose of 560 mg) or placebo orally 
once daily, starting at Cycle 1, Day 1. 
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The capsules are to be taken around the same time each day with approximately 240 mL of water 
(ie, 8 ounces). The capsules should be swallowed whole and should not be opened, broken, or 
chewed.
Subjects should avoid consuming food and beverages containing grapefruit or Seville oranges for 
the duration of the study due to CYP3A inhibition. Subjects should refrain from taking the study 
drug on the morning of study visits designated for pharmacokinetic sampling until seen at the 
site (see Section 9.3.1).
If a dose of study drug is missed, it can be taken as soon as possible on the same day with a 
return to the normal schedule the following day. The subject should not take extra capsules to 
make up the missed dose.
Sufficient study drug required for treatment until the next visit will be dispensed. Unused study 
drug dispensed during previous visits must be returned and drug accountability records will be 
updated. Returned capsules must be discarded and may not be re-used in this study or outside the 
study. Study staff will instruct subjects on how to store study drug for at-home use as indicated 
for this protocol. Storage instructions are provided in the Site Investigational Product Procedures
Manual.
6.2.
Dose Modifications and Dose Delay
Below 
are 
recommendations 
for 
the 
management 
of 
toxicities 
with 
rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone (or equivalent). However, dose 
modifications should be done in accordance with the respective product labels in situations that 
differ from dose modification guidelines specified below. Refer to the product labels and 
institutional guidance for complete details on adverse events for each component of R-CHOP.
Treatment-emergent adverse events of R-CHOP combination therapy predominantly comprise 
hematoxicities 
(such 
as 
neutropenia, 
leucopenia, 
thrombocytopenia, 
and 
anemia). 
Nonhematologic disorders such as asthenia, sensory disturbance, mucositis, alopecia, sepsis, 
dyspnea, back pain, hyperglycemia, hypersensitivity, and cardiac disorders have all also been 
reported when treatment with R-CHOP has been administered. It is not always easy to assess the 
role of any 1 agent in these events, and therefore; it is at the investigators discretion to decide if 
1 or more agents are causal and take action as described in Sections 6.2.1 through 6.2.5.
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. If toxicity persists after a 2-week cycle delay that is related to 
1 specific drug (eg, vincristine, doxorubicin, etc.), the offending drug should continue to be 
withheld and the new cycle should be started with the remaining drugs. If R-CHOP 
chemotherapy is delayed, treatment with study drug should be continued during the delay phase. 
Subjects who discontinue any component of R-CHOP without disease progression will continue 
study drug (placebo or ibrutinib) until 6 or 8 cycles (depending on the number of cycles 
pre-specified by each site) are completed, disease progression, or unacceptable toxicity, 
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whichever occurs first. If study drug is delayed or withheld, any remaining study treatment
(ie, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [or equivalent] may 
be continued. If there is a delay in the start of a new cycle of more than 3 weeks due to 
insufficient recovery from toxicity (with all drugs withheld), subjects will be discontinued from
the study and have procedures performed as outlined in the End-of-Treatment Visit listed in the
Time and Events Schedule (Table 1). However, the start of a new cycle after more than a 3-week 
delay (with all drugs withheld) may occur if there is clear clinical benefit and only after approval 
by the sponsor.
The following parameters must be met on the first day of each cycle (other than Cycle 1):

Platelet count 75,000 cells/L (prior platelet transfusion is allowed)

Subjects with thrombocytopenia due to bone marrow infiltration from DLBCL 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)
6.2.1.
Rituximab
There will be no dose reductions for rituximab. Rituximab should be held for any Grade 4 
toxicity or for any rituximab-related, clinically significant, unmanageable Grade 3 adverse event. 
Rituximab should be held until the adverse event returns to baseline or resolves completely. 
Detailed dosing instructions for infusion reactions are provided in the product label.42
6.2.2.
Cyclophosphamide
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 must be delayed up to 3 weeks until the above values are documented on Day 1 of the
cycle. It is recommended that subjects who develop hematological toxicities thought to be 
causally related to cyclophosphamide have their dose adjusted on Day 1 of the subsequent cycle 
according to Table 6.
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Table 6:
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
Initiation of G-CSF for all 
subsequent cycles is recommended
<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 or ANCs are not required in subjects with thrombocytopenia or 
neutropenia due to bone marrow infiltration from DLBCL who entered the study with platelet counts <75,000/µL
or neutrophil counts <1,000 cells/μL.
6.2.3.
Doxorubicin
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 as an arrhythmia may occur directly after 
administration and electrocardiogram 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 7: 
Table 7:
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
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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. Recommended dose reductions due to 
hematological toxicities are indicated in Table 6.
6.2.4.
Vincristine
Dose adjustments for vincristine must follow the provided prescribing information. The 
vincristine dosage must be reduced if hepatic function is impaired according to Table 8:
Table 8:
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.
6.2.5.
Prednisone (or Equivalent)
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.
6.2.6.
Study Drug (Ibrutinib or Placebo)
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 21 consecutive 
days. Study drug should be discontinued permanently in the event of a toxicity lasting more than 
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21 days. No dose escalation of study drug (more than 4 capsules/day [ie, above 560 mg]) is 
allowed in this study. 
The actions in Table 9 below should be taken for the following drug-related toxicities. Changes
must be recorded in the Drug Accountability Forms and Dosage Administration page of the 
electronic CRF.

Grade 3 or greater neutropenia with infection or fever

Grade 4 neutropenia (ANC <0.5 x 109/L [ie, <500/mm3]) for >14 days

Grade 3 thrombocytopenia (platelets <50 x 109/L [ie, <50,000/mm3]) in the presence of 
significant bleeding (ie, Grade 2 bleeding)

Grade 4 thrombocytopenia (platelets <25 x 109/L [ie, <25,000/mm3])

Grade 3 or greater non-hematological toxicity
Table 9:
Ibrutinib/Placebo Dose Modifications
Occurrence of the Same 
Adverse Event
Action
First
Hold study drug until recovery to Grade ≤1 or baseline; may restart at original dose 
level
Second
Hold study drug until recovery to Grade ≤1 or baseline; restart at 1 dose level lower 
(3 capsules [ie, 420 mg daily])
Third
Hold study drug until recovery to Grade ≤1 or baseline; restart at 1 dose level lower 
(2 capsules [ie, 280 mg daily])
Fourth
Discontinue study drug
Refer to Section 8.2.4 for subjects requiring the initiation of anticoagulants while receiving study 
drug and for instructions on dose modifications or temporary hold during concomitant 
administration of CYP3A inhibitors or inducers. Refer to Section 4.3 for guidance on dose delays 
during the perioperative period for subjects who require surgical intervention or an invasive 
procedure while receiving study drug.
7.
TREATMENT COMPLIANCE
Upon termination of the study, or at the request of the sponsor or its designee, the pharmacist 
must return the study drug to the sponsor or its designee, after all drug supplies have been 
accounted for, unless it is destroyed at the site as agreed upon by both the sponsor and the site.
Instructions regarding accountability for study drug are provided in the Site Investigational 
Product Procedures Manual. 
7.1.
Ibrutinib or Placebo Compliance
The study drug (ibrutinib/placebo) is to be prescribed only by the principal investigator or a 
qualified physician listed as a sub-investigator on required forms. Records should be kept on the 
study drug accountability form provided by the sponsor or its designee. Dispensing of the study 
drug (ibrutinib/placebo) must be recorded in the subject’s source documents. The 
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ibrutinib/placebo may not be used for any purpose other than that outlined in this protocol, 
including other human studies, animal investigations, or in vitro testing. 
The IWRS will be used to assign centrally supplied study treatment kits for each subject. The 
investigator or the site pharmacist will maintain a log of all ibrutinib/placebo dispensed and 
returned. Drug supplies for each subject will be inventoried and accounted for throughout the 
study. Subjects will be provided with a diary card to record intake at home. Site personnel are to 
instruct the subject to bring the diary card and any unused ibrutinib/placebo to the site at the 
beginning of each treatment cycle to check ibrutinib/placebo dosing compliance.
Instructions for proper self-administration and ibrutinib/placebo storage conditions will be 
provided. Precautions associated with the use of ibrutinib/placebo and prohibited concomitant 
medications will be reviewed. Site staff will provide additional instruction to reeducate any 
subject who is not compliant with the ibrutinib/placebo schedule.
7.2.
R-CHOP Compliance
Background therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
(or equivalent) will be provided by qualified study-site personnel and each administration will be 
recorded in the CRF. The site pharmacist will maintain a log of all rituximab, cyclophosphamide, 
doxorubicin, and vincristine vials prepared for infusion and administration. Drug supplies, if 
provided by the sponsor, for each subject will be inventoried and accounted for throughout the
study. The infusion will be administered according to the approved prescribing information or 
approved institutional guidelines.
8.
PRESTUDY AND CONCOMITANT THERAPY
Systemic use of the following concomitant medications will be collected in the electronic CRF 
and recorded in the source documents beginning with signing of the ICF to 30 days after the last 
dose of the last study treatment: growth factors, transfusions, anti-infectives (antibacterials,
antivirals, and antimycotics), steroids, anti-arrhythmics and other cardiac supportive therapy, 
anti-epileptics, psychoanaleptics, and any anticancer therapy (including radiation). The sponsor 
must be notified in advance (or as soon as possible thereafter) of any instances in which 
prohibited therapies are administered. Concomitant therapies administered at the time of, and 
used in the treatment of a serious adverse event, should be recorded.
8.1.
Permitted Medications and Supportive Therapies
All concomitant medications for medical conditions other than DLBCL NHL are permitted other 
than those listed as CYP3A inhibitors, as clinically indicated. The use of growth factors is 
permitted in this study, but should be used according to institutional, provincial, or other 
guidelines (eg, American Society of Clinical Oncology) and according to the investigators site 
standard for use of growth factors during treatment of DLBCL with standard R-CHOP 
chemotherapy. All supportive therapies, other than anticancer treatment, needed for the 
management of subjects enrolled in this study are permitted.
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8.1.1.
Medications Permitted Prior to Study Treatment
8.1.1.1.
Pre-treatment Steroids
Steroids are permitted prior to randomization (up to 100 mg/day prednisone or equivalent) for a 
maximum of 10 days. If pre-treatment steroids exceed 10 days or 100 mg/day, please consult the 
medical monitor for approval. If steroids are administered, they should be given after the 
baseline imaging assessment, baseline laboratory assessments, baseline performance status 
assessment, and baseline R-IPI calculation. Steroids must be recorded on the electronic CRF.
8.1.2.
Medications Permitted During Treatment
The following are supportive therapies that are recommended:

Omeprazole 20 mg/day orally or equivalent therapy for peptic ulcer

5HT3 antagonists or equivalent anti-emetics

Premedication with acetaminophen (650 mg orally), diphenhydramine (50 to 100 mg IV or 
orally) and steroids, 30 to 60 minutes before starting each rituximab infusion, may attenuate 
infusion reactions

Loperamide for the treatment of diarrhea, starting at the time of the first watery stool. The 
loperamide dose regimen should be according to standard practice

Bowel care is recommended to prevent constipation and should be administered per standard 
practice

Platelet and RBC transfusions, and G-CSF are permitted, as necessary

Subjects who test positive for hepatitis B surface antigen or hepatitis B core antibody at 
screening must have hepatitis B DNA by PCR performed and confirmed as negative prior to 
randomization. Hepatitis B surface antigen positive subjects who are also hepatitis B DNA 
by PCR negative should receive prophylactic antiviral therapy (such as entecavir or 
tenofovir) and be treated according to local guidelines. Hepatitis B core antibody positive 
subjects who are also hepatitis B DNA by PCR negative should receive prophylactic 
antiviral therapy (such as entecavir or tenofovir) or undergo regular monitoring of hepatitis 
B virus DNA according to local guidelines. Carriers of hepatitis B should be closely 
monitored for clinical and laboratory signs of active hepatitis B virus infection and for signs 
of hepatitis during and following anti-B-cell treatment, according to local guidelines.
Consultation with a hepatitis specialist is also recommended.

Prophylactic treatment for pneumocystis carinii pneumonia is permitted according to local 
standards

Central nervous system prophylaxis is allowed and recommended in accordance with local 
guidelines. Subjects with 1) involvement of 2 extranodal sites and elevated LDH, 
or 2) lymphomatous involvement of the bone marrow, testis, or a para-meningeal site are 
considered to have a high risk of developing CNS disease and should receive CNS 
prophylaxis according to the standard local practice. CNS prophylaxis with IV methotrexate 
is not permitted in this study.
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8.1.2.1.
Uric Acid-lowering Agents
Subjects with more than 1 of the factors listed below are considered to be at increased risk of 
tumor lysis syndrome and should be considered for hydration and treatment with a uric 
acid-lowering agent as well as for frequent monitoring of tumor lysis associated signs and 
symptoms, including blood chemistry. Uric-acid lowering agents may include xanthine oxidase
inhibitor allopurinol or Uloric® [febuxostat] with or without rasburicase per the drug product 
package inserts. 

Serum creatinine ≥1.5 x ULN or calculated creatinine clearance <60 mL/min

Uric acid ≥450 µmol/L or 7.5 mg/dL

Bulky disease (eg, lymph node >10 cm or massive splenomegaly)

Elevated LDH >2 x ULN
8.2.
Prohibited Medications
The following medications and supportive therapies and procedures are prohibited during the 
treatment phase:

Any anticancer agent other than R-CHOP with the exception of medications that may have 
anticancer activity but are taken for other reasons, eg, megestrol (Megace), Cox-2 
inhibitors, and bisphosphonates

Anti-hormonal therapies are permitted, after discussion with the sponsor’s medical 
monitor

Chronic use of systemic corticosteroids above that given for R-CHOP chemotherapy. 
(Prednisone 20 mg/day or its equivalent is allowed for the treatment of adrenal 
insufficiency or other medical reason that is not cancer related)

Any experimental agents other than study drug
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
8.2.1.
Concomitant Use of Ibrutinib/Placebo and CYP3A Inhibitors or 
Inducers
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong or moderate 
CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. Co-administration 
of ketoconazole, a strong CYP3A inhibitor, in 18 healthy subjects increased dose normalized 
exposure, Cmax and AUC0-last, of ibrutinib by 29- and 24-fold, respectively. The maximal 
observed ibrutinib exposure (AUC) was ≤2-fold in 37 patients treated with mild and/or moderate 
CYP3A inhibitors when compared with the ibrutinib exposure in 76 patients not treated 
concomitantly with CYP3A inhibitors. Clinical safety data in 66 patients treated with moderate 
(n=47) or strong CYP3A inhibitors (n=19) did not reveal meaningful increases in toxicities. 
Strong inhibitors of CYP3A (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, and nefazadone) should be avoided. If a strong 
CYP3A inhibitor must be used, consider reducing the ibrutinib dose to 140 mg or withhold 
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treatment temporarily. Subjects should be monitored for signs of ibrutinib toxicity. If the benefit
outweighs the risk and a moderate CYP3A inhibitor must be used, monitor subject for toxicity 
and follow dose modification guidance as needed. Avoid grapefruit and Seville oranges during 
ibrutinib treatment, as these contain moderate inhibitors of CYP3A (see Section 6.2.6).
Co-administration of ibrutinib with strong inducers of CYP3A decreases ibrutinib plasma 
concentrations by approximately 10-fold. 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 5 and at 
http://www.pharmacologyweekly.com/content/pages/online-drug-therapy-tables.37
8.2.2.
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. 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.
8.2.3.
Concomitant Use of Ibrutinib/Placebo and QT Prolonging Agents
Any medications known to cause QT prolongation should be used with caution; periodic 
monitoring with electrocardiograms (ECG) and electrolytes should be considered and, if needed, 
the medical monitor may be contacted.
8.2.4.
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 withheld 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
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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.
8.2.5.
Radiation Therapy
Radiation therapy must not be given concurrently with study drug. Radiation is acceptable as 
consolidation as per local practice (eg, for patients with baseline bulky disease, defined as having 
a lymph node >10 cm in the longest diameter). Note: radiation therapy can only be administered 
after the end of treatment efficacy assessment.
8.3.
Subsequent Antilymphoma Therapies
Administration of subsequent antilymphoma therapy is not allowed until:

Confirmed residual disease after completion of at least 6 cycles of R-CHOP, 

PD (or relapse after CR) any time during treatment as established according to the
criteria described in Section 9.2.2.3, Criteria for Response Categories. 
Subjects without PD and who received subsequent therapy per confirmed PET-positive or biopsy 
proven residual disease upon completion of at least 6 cycles of R-CHOP therapy will continue to 
be followed until PD. For any subsequent antilymphoma therapy, the start date, end date, and
best response should be documented in the appropriate section of the electronic CRF.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The study is divided into 3 phases: a Pretreatment (Screening) Phase, an Active Treatment Phase, 
and a Posttreatment Follow-up Phase. The Time and Events Schedule summarizes the frequency 
and timing of efficacy, PRO, pharmacokinetic, biomarker, and safety measurements applicable 
to this study (Table 1).
9.1.2.
Pretreatment (Screening) Phase
All subjects must sign an ICF prior to the conduct of any study-related procedures. During this 
phase, eligibility criteria will be reviewed and a complete clinical evaluation performed as 
specified in the Time and Events Schedule (Table 1). The results of 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 start of study treatment 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 that assessments fulfill the study requirements and are performed within the 
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specified timeframe prior to randomization (Table 1). Echocardiography or multiple uptake gated 
acquisition (MUGA) scan is mandatory at Screening; echocardiography or MUGA may be 
repeated optionally at any time during the study (using same modality), as clinically indicated, 
either at an assessment visit or at unscheduled visit. The first FACT-Lym and EQ-5D-5L 
assessment will be administered prior to the first dose of study treatment. The study site staff 
should instruct the subject to carefully read the instructions and questions of the PRO
instrument(s) prior to marking responses, that there are no right or wrong answers, and that their 
responses to the questionnaire will not be used to determined their study eligibility.
Investigators are required to confirm that subjects who are 80 years old are eligible to receive 
R-CHOP according to the protocol, without preplanned dose reductions.
Verification of DLBCL Diagnosis and Determination of the non-GCB Subtype
Prior to randomization, subjects with DLBCL are required to submit local pathology reports to a 
central laboratory for verification of diagnosis. In addition, subjects are required to submit 
biopsy samples (tissue block or slides) to determine DLBCL subtype (ie, non-GCB or GCB
subtype) based on central IHC. One laboratory will be used to review local pathology reports for 
verification of DLBCL diagnosis and for determination of the non-GCB subtype based on central 
IHC. 
Diagnosis of DLBCL will be confirmed by a local pathology report. It is important that 
pathology reports contain the information listed below to allow verification of the DLBCL 
diagnosis. At a minimum, criteria (a), (b), (e), and (f) should be included within the pathology 
report. (In some cases, the information in the pathology report can be supplemented with 
information obtained by review of the hematoxylin and eosin [H&E] slide by a central 
pathologist.) A report from the local laboratory must be reviewed and approved by the central 
pathology laboratory to verify the below criteria prior to randomization.
a.
histologic documentation of entirely diffuse lymphoid architecture with no significant 
follicular or low grade component, 
b.
evidence of positive B-cell lineage, 
c.
presumptive evidence of monoclonality and/or aberrant neoplastic antigen expression 
and/or clonal immunoglobulin gene rearrangement and/or a clonal chromosomal 
abnormality,
d.
exclusion of misclassified DLBCL, 
e.
documentation of a sufficient large cell component and/or increased Ki67-defined 
proliferative rate, 
f.
no pathologic evidence that DLBCL represents transformation of a pre-existing B-NHL. 
A report from the local laboratory must be reviewed and approved by the central pathology 
laboratory to verify the above criteria prior to randomization.
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1) Diagnostic biopsy material (formalin fixed paraffin-embedded tumor tissue block or 
slides) will be sent to a sponsor approved central laboratory for determination of the 
non-GCB subtype by IHC prior to randomization. Results will be provided from the 
central laboratory within 4 to 7 working days from the shipment of the sample. Only 
subjects with central pathology laboratory IHC-confirmed non-GCB subtype of DLBCL 
and who fulfill all eligibility criteria will be considered eligible for participation in the 
study. If tissue blocks are sent, the remainder of the block will be returned after the 
DLBCL subtype has been confirmed.
9.1.3.
Active Treatment Phase
The Active Treatment Phase will begin at randomization and will continue until discontinuation 
of all study treatment (ie, ibrutinib/placebo, rituximab, cyclophosphamide, doxorubicin, 
vincristine, prednisone [or equivalent]) due to disease progression, initiation of subsequent 
antilymphoma therapy, unacceptable toxicity, withdrawn, or completion of study treatment. The 
last measurements taken on Cycle 1 Day 1 before administration of study treatment or at 
Screening (whichever value was last) will be defined as the baseline values for safety assessment 
and treatment decision. Laboratory values obtained prior to Cycle 1 Day 1 should be repeated if 
they were collected more than 5 days prior to the start of study treatment (ibrutinib or placebo).
These values should be consistent with the values in the inclusion and exclusion criteria 
(Sections 4.1 and 4.2, respectively) 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 exam (including lymphoma B-symptoms) will be 
conducted. 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).
All subjects will visit the study site on Day 1 of each cycle during the Active Treatment Phase. 
Clinical evaluations and laboratory studies may be repeated more frequently, if clinically 
indicated. When all evaluations have been completed, and it has been determined that the subject 
may continue treatment, 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. 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 PD is diagnosed, 
then the subject will discontinue study treatment, complete the End-of-Treatment Visit within 
30 days after the last dose of the last study treatment, and enter the Posttreatment Follow-up 
Phase.
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End-of-Treatment Visit
Subjects who discontinue the last study treatment due to progression, adverse event, or other 
reasons and enter the Posttreatment Follow-up Phase should have the End-of-Treatment Visit 
completed before starting any subsequent antilymphoma therapy. If a subject is unable to return 
to the site for the End-of-Treatment Visit, the subject should be contacted to collect adverse 
events that occur within 30 days after the last dose of the last study treatment. Additional 
information on reporting adverse events may be found in Section 12.
If the subject requires subsequent antilymphoma therapy in the interim period following the last 
dose of study treatment and the End-of-Treatment Visit, then this visit should be completed
earlier, ie, just prior to initiation of subsequent antilymphoma therapy. Refer to the Time and 
Events Schedule for a complete list of procedures to be performed (Table 1).
9.1.4.
Posttreatment Follow-up Phase
Assessments Up to the Primary Endpoint Analysis
After the completion of the End-of-Treatment procedures, all subjects will enter a Posttreatment 
Follow-up Phase in accordance with the Time and Events Schedule – up to Clinical Cutoff for 
Primary Endpoint Analysis; Table 1). Follow-up visits, to assess disease progression, will be 
required if treatment is discontinued prior to PD. The interval between follow-up visits should be
maintained at 16 or 24 weeks as required; if a visit occurs earlier or later than the scheduled visit 
date, then the next visit date should be rescheduled to maintain the required interval from the 
previous visit. At any visit, if there is clinical evidence or suspicion of PD, then a CT scan must 
be performed to document progression (See Section 9.2.2.1).
Survival follow up (physician visit or telephone contact) will be required for all subjects 
following PD until death, loss to follow up, consent withdrawal, or study end, whichever occurs 
first; and will be completed in accordance with the Time and Events Schedule – Up to Clinical 
Cutoff for Primary Endpoint Analysis (Table 1). The interval between Post-PD follow-up visits 
should be maintained at 16 weeks; if a visit occurs earlier or later than the scheduled visit date,
then the next visit date should be rescheduled to maintain the required interval from the previous 
visit.
At the time of disease progression or if residual disease is present upon completion of at least 
6 cycles, the subject is considered eligible to receive subsequent antilymphoma therapy. 
Subsequent antilymphoma therapy will be recorded in the electronic CRF. Subjects with residual 
disease who receive subsequent antilymphoma therapy will be followed until PD, clinical cutoff, 
or death (see the Time and Events Schedule – Up to Clinical Cutoff for Primary Endpoint 
Analysis, Table 1). Investigators should maintain adequate contact with the subject to obtain 
follow-up information on safety and survival status. Where allowed by local law, public records 
may be used to document death. Any new malignancy reported during the Posttreatment Follow-
up Phase will be recorded in the CRF (Section 12.3.4).
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The FACT-Lym will be performed until disease progression, death, or the clinical cutoff, 
whichever comes first. Refer to the Time and Events Schedule - Up to Clinical Cutoff for 
Primary Endpoint Analysis for the assessment schedule (Table 1). Following disease 
progression, sites should attempt to administer the EQ-5D-5L as specified in the Time and 
Events Schedule – Up to Clinical Cutoff for Primary Endpoint Analysis (Table 1), unless death 
or study end occurs first. Subjects who visit the site for the follow-up assessments should 
complete the EQ-5D-5L questionnaire at that time. If the EQ-5D-5L is conducted via a telephone 
call with the subject, then the subject’s questionnaire responses will be read over the telephone to 
the site staff who will record the data in the EQ-5D-5L. If the subject is unable to complete the 
EQ-5D-5L during the Posttreatment Follow-up Phase, the reason for not completing the 
questionnaire will be documented (ie, too ill, subject refused).
Assessments After the Primary Endpoint Analysis
Refer to Table 3 for the data to be collected every 24 weeks (physician visit or telephone 
contact). Radiologic disease evaluations may be performed as clinically indicated (at the 
discretion of the investigator) per local standard of care after the clinical cutoff for the primary 
endpoint analysis; available data may be entered into the eCRF.
9.1.5.
Clinical Cutoffs
Three clinical cutoffs are planned. The first clinical cutoff will occur when approximately 
270 EFS events have been observed. The second clinical cutoff will be for the final analysis of 
the primary endpoint EFS, and will occur approximately 30 months after the 800th subject is
randomized in the study. The interim analysis and final analysis of the primary endpoint EFS 
will take place at these 2 clinical cutoffs, respectively. The last clinical cutoff will occur at the 
end of the study, when 50% of the randomized subjects have died or 5 years after the last subject 
is randomized or the sponsor terminates the study, whichever occurs first. Investigators will be 
informed when the cutoffs have occurred.
Per the original study design, the number of events required for the interim analysis is 270 EFS
events. As of 12 July 2017, 230 EFS events have been reached. Due to this lower than expected 
EFS event rate (based on blinded data) and the short time expected between the interim and final 
analysis, the sponsor has omitted the first clinical cutoff for the interim analysis.
9.2.
Efficacy
9.2.1.
Evaluations
9.2.1.1.
CT/MRI/PET Scans
During the study, disease response will be assessed using CT scans of the neck, chest, abdomen, 
and pelvis with IV and oral contrast as indicated and as specified in the Time and Events 
Schedule - Up to Clinical Cutoff for Primary Endpoint Analysis (Table 1). Subjects who are 
intolerant of IV CT contrast agents will have CT scans performed with oral contrast and the 
reason for not using IV contrast will be specified in the electronic CRF. A separate CT scan is
preferred but, if the only available modality is combined/dual PET/CT scanner, then the CT 
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portion of a PET/CT may be submitted in lieu of a dedicated CT if it is of diagnostic quality. The 
CT scanning must be done according to the imaging requirements provided in the radiology 
manual to ensure that an optimized examination is done.
Evaluation of other sites of disease by radiological imaging, physical examination, or other 
procedures as necessary (to be performed throughout the study using the same method of 
assessment per subject) may also occur at the site level. Radiological and PET scans performed 
prior to the database lock for the final analysis of EFS must be transferred to the independent 
imaging laboratory for storage; the scans may be reviewed, if deemed necessary.
Magnetic resonance imaging (MRI) may be used to evaluate sites of disease that cannot be
adequately imaged using CT (in cases where MRI is desirable, a scan 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.
CT scans will be performed as specified in the Time and Events Schedule – Up to Clinical 
Cutoff for Primary Endpoint Analysis (Table 1). A whole body PET scan will also be done at the 
End-of-Treatment Visit, at least 3 weeks but preferably 6 to 8 weeks after the last dose of 
R-CHOP. A whole body PET scan at baseline is recommended but not mandatory. Follow-up 
visits will be required if treatment is discontinued prior to PD. Follow-up visits, including CT 
scans, will be completed every 16 weeks for the first 24 months, then every 24 weeks until PD,
the clinical cutoff for the primary endpoint, or up to 5 years, whichever occurs first. After that, 
CT may be performed as clinically indicated (at the discretion of the investigator) per local 
standard of care.
After disease progression, subjects will be monitored by physician visit or telephone contact to 
assess survival and collect subsequent antilymphoma therapy data for all subjects as specified in 
the Time and Events Schedules (Table 1 and Table 3). Monitoring will continue until the end of
the study.
Definition of a Positive PET Scan
Assessment of PET results is based on published criteria.26 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 [18F]-fluorodeoxyglucose 
(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.
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9.2.1.2.
Bone Marrow Assessment
Bone marrow evaluation (biopsy + aspirate) should be done before starting treatment. Subjects 
with bone marrow involvement must have a repeat bone marrow evaluation at the time of CR 
(preferably within 30 days of the initial documentation of CR). Adequate bone marrow 
evaluation is required. Bone marrow evaluation must include morphological examination and 
also IHC, if warranted, to confirm the presence or absence of lymphoma. If bone marrow 
involvement can be confirmed with morphology, then IHC is not necessary if not standard 
practice at the site.
9.2.1.3.
Fluid Aspiration at Other Sites of Disease
For sites of disease with fluid accumulation such as 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 before disease progression is diagnosed for a subject if the 
fluid accumulation is the only sign of disease progression.
9.2.1.4.
Physical Examination
During the Screening, Active Treatment, and Posttreatment Follow-up periods (see Time and
Events Schedule for procedures, Table 1), subjects should have a physical examination to
evaluate the presence of palpable lymph nodes, tumor masses, or spleen and liver enlargement. 
Symptom-directed questions will be asked to evaluate for the presence of B-symptoms.
9.2.1.5.
Patient-Reported Outcomes
Two PRO instruments, the FACT-Lym and EQ-5D-5L will be administered in this study. The 
FACT-Lym was originally developed to assess functional status and well-being of patients with 
NHL.11 Reliability and validity have been assessed in NHL53 and more recently construct 
validity has been supported in subjects with relapsed/refractory MCL.3 The FACT-Lym consists 
of the Functional Assessment of Chronic Illness Therapy-General (FACT-G) and a 
lymphoma-specific additional concerns subscale (Lym) (Attachment 6). Responses to all items 
are rated on a 5-point scale ranging from 0 “not at all” to 4 “very much”. The FACT-G consists 
of three 7-item subscales scored 0 to 28 (physical well-being, social well-being, and functional 
well-being) plus one 6-item subscale (emotional well-being) scored 0 to 24. The recall period is 
the past 7 days. The lymphoma scale includes 15 items and scores range from 0 to 60. Two 
summary scores may also be calculated: the FACT-Lym total score (FACT-G plus Lym) and the 
FACT-Lym trial outcome index score (physical well-being
+
functional well-being
+ lymphoma). Higher scores represent better functional status and well-being for all subscales 
and summary scales. The subscale of most interest in this study will be the Lym subscale. Carter 
et al (2008)3 and Cella et al (2005)4 reported a minimal important change score for the Lym 
subscale in a relapsed/refractory MCL population range from approximately 2.9 to 5.4. 
Therefore, a 5-point change in the Lym subscale was selected as a conservative estimate of 
clinically meaningful deterioration in lymphoma symptoms. Time to complete the FACT-Lym is 
approximately 7 to 12 minutes. 
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The EQ-5D-5L is a standardized instrument for use as a measure of health outcome
(Attachment 7).12 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.39 For purposes of this study, 
the EQ-5D-5L will be used to generate utility scores for use in cost effective analyses. The 
EQ-5D-5L is a 5-item questionnaire and a visual analogue scale ranging from 0 (worst 
imaginable health state) to 100 (best imaginable health state). 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. The UK weights will be used to generate 
patient utilities from the 5 dimensions of the EQ-5D-5L in this study. Data will be collected 
using electronic capture to enhance ease of collection, while flagging questions that may be 
missed accidently by the study subject.
After the clinical cutoff for the primary endpoint analysis, subjects will be treated according to 
the local standard care and available data will be entered into the eCRF. Patient-reported 
outcomes (EQ-5D-5L only) will be collected as specified in the Time and Events Schedule –
After Clinical Cutoff for Primary Endpoint Analysis (Table 3).
9.2.2.
Efficacy Criteria
9.2.2.1.
Assessment of Disease Response and Progressive Disease
Efficacy assessments for the purpose of the study result analyses will be performed by the 
investigators according to the Revised Response Criteria for Malignant Lymphoma.5 All efficacy 
assessments must continue until disease progression (even if subsequent antilymphoma therapy 
is started), withdrawal of consent from study participation, or clinical cutoff for the primary 
analysis. For all subjects with disease progression, a Study Event form accompanied with
documentation of disease progression should be sent to the sponsor medical monitor within 
24 hours.
9.2.2.2.
Definition of Measurable and Assessable Disease
Eligible subjects must have at least 1 measurable site of disease. Measurable sites of disease are 
defined as lymph nodes, lymph node masses, or extranodal sites of lymphoma.5 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.
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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, then these other sites of measurable disease may be included as 
assessable disease.
9.2.2.3.
Response Categories
The response categories being used to assess efficacy are based on the Revised Response Criteria 
for Malignant Lymphoma.5
Complete Response
For CR determination, all the following criteria must be met:
1.
Complete disappearance of all detectable evidence of disease and disease-related symptoms, 
if present before therapy.
2.
All lymph nodes and nodal masses must have regressed on CT to normal size (1.5 cm in 
the greatest transverse diameter [GTD] for nodes >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 1.0 cm in 
the short axis after treatment. All splenic and hepatic nodules and other extranodal disease 
must have disappeared.
3.
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.
4.
The spleen and/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.
5.
If the bone marrow was involved before treatment, the infiltrate must have cleared on 
repeated bone marrow biopsy. The biopsy sample on which this determination is made must 
be adequate (with a goal of >20 mm unilateral core). 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.).
6.
No new sites of disease are detected during assessment.
Partial Response
For PR determination, all the following criteria must be met:
1.
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.
2.
No increase should be observed in the size of other nodes, liver, or spleen, meeting the 
criteria for PD.
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3.
Splenic and hepatic nodules must regress by ≥50% in the SPD or, for single nodules, in the 
GTD.
4.
With the exception of splenic and hepatic nodules, other organs should not have any 
measurable disease.
5.
Bone marrow assessment is not required for PR determination.
6.
No new sites of disease should be observed.
7.
At least 1 PET-positive site of disease (required for the CT+PET assessment of PR).
Stable disease
Stable disease is defined as:
1.
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 PD.
2.
The PET should be positive at, at least 1 previously involved site of disease, with no new 
areas of lymphoma involvement on the Posttreatment CT or PET (for the combined 
CT+PET assessment of stable disease).
Progressive Disease or Relapsed Disease
Progressive disease or relapsed disease (after CR) is defined as:
Lymph nodes should be considered abnormal if the long axis is ≥1.6 cm, regardless of the short 
axis length. If a lymph node has a long axis from 1.1 cm to 1.5 cm, it should be considered 
abnormal only if its short axis is >1.0 cm. Lymph nodes ≤1.0 cm x ≤1.0 cm will not be 
considered abnormal for the assessment of PD/relapsed disease.
1.
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.
2.
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.
3.
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 PD, a lymph node with a diameter of the short axis of <1.0 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.
4.
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 PD, 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 
PD. Increased FDG uptake in a previously unaffected site should only be considered PD after 
confirmation with other modalities.
Cytology confirmation of DLBCL is required when there is an appearance on CT of a new lesion 
≥1.5 cm in its long axis and is PET-negative.
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For fluid collection (ascites, pleural, or pericardial effusions), cytology confirmation for presence 
of lymphoma is required.
9.2.3.
Endpoints
Primary Endpoint
The primary endpoint is EFS, defined as the duration from the date of randomization to the date 
of disease progression, relapse from CR as assessed by the investigator, initiation of subsequent 
systemic antilymphoma therapy for either PET-positive or biopsy-proven residual disease upon 
completion of at least 6 cycles of R-CHOP therapy, or death, whichever occurs first. Refer to the 
Statistical Analysis Plan for further details regarding censoring rules. 
Secondary Endpoint(s)
The secondary endpoints are defined as follows:

Progression-free survival is defined as the duration from the date of randomization to the 
date of progression, relapse from CR, or death, whichever occurs first.

CR rate is defined as the proportion of subjects with measurable disease who achieve CR.

Overall survival is defined as the duration from the date of randomization to the date of the 
subject’s death. If the subject is alive or the vital status is unknown, then the subject will be 
censored at the date the subject was last known to be alive.

Time to worsening 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.

Pharmacokinetic parameters (eg, oral plasma clearance [CL/F], oral volume of distribution 
at steady state [Vss/F]) or metrics of systemic exposure (eg, AUC, minimum observed 
plasma concentration [Cmin]) of ibrutinib after oral daily dosing in a subset of subjects. 
Parameters describing the potential relationships between ibrutinib metrics of exposure with 
relevant clinical, or biomarker information.

Safety parameters of ibrutinib when combined with R-CHOP.
Exploratory Endpoints

The mean change from baseline in EQ-5D-5L score for each postbaseline assessment.

Biomarkers associated with resistance to ibrutinib in subjects who progress on ibrutinib 
treatment compared to those that remain in CR.
9.3.
Pharmacokinetics
9.3.1.
Evaluations
Venous blood samples of approximately 2 mL will be collected from all subjects at selected sites 
for measurement of plasma concentrations of ibrutinib and the PCI-45227 metabolite (if possible 
and judged relevant) before dosing of study drug (ibrutinib or placebo capsules) on Day 1 of 
Cycles 1, 2, and 3, and postdose on Cycles 1 and 2 at 1 hour (window 45 to 75 minutes), 2 hours 
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(window 1.5 to 2.5 hours) and 4 hours (window 3.5 to 6 hours) after dosing of study drug 
(see Time and Events Schedule, Table 1). These sparse samples will be used for the development 
of a population-based pharmacokinetic model. It is estimated that 200 subjects on ibrutinib are 
needed to adequately assess this. Collection of pharmacokinetic samples will stop when this 
cutoff point has been reached (or earlier or later at the sponsor’s discretion).
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. 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 treatment and record the exact time of study treatment
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. If required, some 
plasma samples may be analyzed to document the presence of circulating metabolites using a 
qualified research method.
9.3.3.
Pharmacokinetic Parameters
Population pharmacokinetic analysis of plasma concentration-time data of ibrutinib and the 
metabolite PCI-45227 (if deemed relevant) will be performed using nonlinear mixed-effects
modeling (NONMEM), with the aim of providing estimates of pharmacokinetic parameters 
(eg, oral clearance) or metrics of systemic exposure (eg, AUC within the dosing interval). 
Model-derived plasma concentrations or metrics of exposure parameters (eg, Cmax or AUC) may 
be subjected to further analyses to explore pharmacokinetic correlations between exposure and 
relevant clinical or biomarker information.
9.4.
Companion Diagnostic and Biomarkers
9.4.1.
Companion Diagnostic
A companion diagnostic device will be developed in parallel to the clinical study for 
determination of DLBCL subtype. The DLBCL Classification IHC 
 assay used to
identify non-GCB and GCB subtypes is based on the Hans algorithm (2004) and utilizes a 
standardized IHC protocol. Subtyping will be accomplished by determination of the status of 
CD10, BCL6, and MUM 1. In addition, 
a GEP assay for identification of the 
ABC DLBCL subtype that will be retrospectively determined using available clinical study 
FFPE tissue specimens.
9.4.2.
Biomarkers
Variation in response to treatment in lymphoma may be attributable in part to disease 
heterogeneity. Recent studies in aggressive43 and indolent8 lymphoma highlight this molecular 
heterogeneity and identify tumor subtypes with distinct prognoses. Understanding the basic 
biological differences underlying disease subtypes may ultimately allow tailoring of drug 
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therapies for more effective treatment. Herein, we intend to identify the non-GCB subtype of 
DLBCL through IHC analysis of CD10, Bcl-6, and MUM1. Paraffin-embedded, formalin-fixed 
tumor tissue may also be analyzed for markers that may further define molecular characteristics 
of the non-GCB patient population or for other markers that may be implicated in drug efficacy 
(eg, MYD88, CARD11, NF-B, TP53, CD79B).
Paraffin-embedded, formalin-fixed tumor tissue or cells isolated from blood collections may also 
be subjected to RNA analysis (eg, GEP, quantitative reverse transcription [qRT]-PCR) or 
somatic mutational analysis (eg, MiSeq, ExomeSEQ) from all subjects entered within this study. 
Comparison of IHC results may be made to transcriptomic or genomic data from matching tumor 
or blood to correlate molecular subtype and mutational status. Gene expression profiling and 
mutational analysis may also be utilized to identify other signaling pathway markers that may 
correlate with response to treatment (eg, CD79B, TP53, MLL2, CARD11, MYD88)28 or other 
pathways/markers that may be up-regulated in the non-GCB subtype of DLBCL 
(eg, IL-6/STAT3).27 Similar analyses may be carried out in a fresh tissue biopsy (ie, collected at 
the time of progression, if feasible) or a blood sample from subjects progressing after ibrutinib 
treatment. Other prognostic markers that may be analyzed include BCL-2 expression and C-
MYC rearrangement.
Blood samples for biomarker evaluations will be collected from all subjects at timepoints as 
specified in the Time and Events Schedule (Table 1). These samples will be collected only at 
sites where local regulations and shipping logistics permit. Serum samples collected at the 
End-of-Treatment Visit and during the Posttreatment phase up to 24 months will be stored to 
allow for MRD assessments as necessary.
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the 
end of the study, it becomes clear that the analysis will not have sufficient scientific value for 
biomarker evaluation, or if there are not enough samples or responders to allow for adequate 
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy, 
completion of biomarker assessments will be based on justification and intended utility of the 
data.
If it is determined at any time before study completion that additional material is needed from a 
formalin-fixed paraffin-embedded 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. In this case, such analyses would be specific to research related to the 
study drug(s) or diseases being investigated.
9.5.
Safety Evaluations
All subjects who receive treatment will undergo safety evaluations. Any clinically significant
abnormalities persisting at the end of treatment will be followed by the investigator until 
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resolution or until a clinically stable endpoint is reached or until the end of the study. The study 
will be monitored by an independent DMC (details are provided in Section 11.10, Data 
Monitoring Committee).
The study will include the following evaluations of safety and tolerability according to the 
timepoints provided in the Time and Events Schedule (Table 1):
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 12, Adverse Event Reporting.
Adverse events will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE), Version 4.03.
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 treatment. Adverse events reported after 30 days 
following the last dose of study treatment should also be reported if considered related to study 
treatment. Progressive disease of DLBCL should not be reported as an adverse event, but 
instead, the clinical diagnosis that is associated with disease progression is to 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 of Special 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, Adverse Events of Special Interest,
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, then the investigator must submit to the sponsor 
laboratory certificates or accreditation and normal ranges for that facility as well. The local 
laboratory reports must be filed with the source documents.
Blood samples will be collected to assess the safety of study treatment. Required laboratory tests 
must be performed within 72 hours of the scheduled visit. For Day 1, Cycle 1 only, clinical 
laboratory tests do not need to be repeated if the Screening tests were performed within 5 days of 
the first dose of study treatment.
The investigator must review the local laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the adverse event section of the CRF.
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For example, laboratory abnormalities leading to an action regarding any study treatment
(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 laboratory section of the 
electronic 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 (Table 1):

Hematology Panel
-hemoglobin
-absolute lymphocyte count (ALC)
-platelet count 
-ANC
-white blood cell (WBC) count

Coagulation Studies
-activated partial thromboplastin time (aPTT)
-international normalized ratio (INR)/prothrombin time (PT)

Serum Chemistry Panel
-sodium
-total bilirubin
-potassium
-albumin
-creatinine
-uric acid
-AST
-LDH
-ALT
-alkaline phosphatase
-magnesiuma
a To be evaluated on Day 1 of Cycles 1 and 2, and as clinically indicated.

Screening for hepatitis B and C will include the following evaluations: hepatitis B surface 
antigen, hepatitis B core antibody, and hepatitis C antibody. Subjects who test positive for
hepatitis B surface antigen or hepatitis B core antibody must have hepatitis B DNA by PCR 
performed and confirmed as negative prior to randomization. Hepatitis B surface antigen 
positive subjects who are also hepatitis B DNA by PCR negative should receive 
prophylactic antiviral therapy (such as entecavir or tenofovir) and be treated according to 
local guidelines. Hepatitis B core antibody positive subjects who are also hepatitis B DNA 
by PCR negative should receive prophylactic antiviral therapy (such as entecavir or 
tenofovir) or undergo regular monitoring of hepatitis B virus DNA according to local 
guidelines. Carriers of hepatitis B should be closely monitored for clinical and laboratory 
signs of active hepatitis B virus infection and for signs of hepatitis during and following 
anti-B-cell treatment, according to local guidelines. Consultation with a hepatitis specialist is 
also recommended.

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.
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
Pregnancy test (serum -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. Heart rate and blood 
pressure will also be collected on Day 1 of each cycle and at the End-of-Treatment Visit. 
Abnormal vital signs considered to be clinically relevant by the investigator are to be
documented as adverse events.
Body Surface Area
Calculation of BSA at Cycle 1 Day 1 is required for cyclophosphamide, doxorubicin, vincristine 
(capped at 2 mg), and rituximab dosing. The BSA should be recalculated if a subject experiences 
a >10% change in weight from the weight used in the most recent BSA calculation. Weight will 
be collected as specified in the Time and Events Schedule.
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 Active 
Treatment phase, only a 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). An assessment of 
lymphoma B-symptoms (fever, night sweats and weight loss), change of status of lymph nodes, 
liver and spleen should also be done.
Echocardiogram or Multiple Uptake Gated Acquisition (MUGA) scans
An echocardiogram or MUGA scan is mandatory at Screening to confirm that the left ventricular 
ejection fraction is within institutional normal limits. The echocardiogram or MUGA may be 
repeated at any time during the study, as clinically indicated. When the exam is repeated, the 
same modality should be used.
Electrocardiogram
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).
9.6.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. Refer to the Time and Events Schedule for the timing and frequency of all 
sample collections (Table 1). Instructions for the collection, handling, storage, and shipment of 
samples are found in the laboratory manual that will be provided.
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10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost to follow up, or has not withdrawn consent before the end of study. 
10.2.
Discontinuation of Study Treatment
Subjects who discontinue any component of R-CHOP without disease progression will continue 
study drug (placebo or ibrutinib) until 6 or 8 cycles are completed (as pre-specified by each site), 
disease progression, or unacceptable toxicity, whichever occurs first. If study drug is 
discontinued, any remaining study treatment (ie, rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone [or equivalent]) may continue. Investigators are encouraged to keep a 
subject experiencing clinical benefit (ie, PR, CR, or stable disease) in the study unless significant
toxicity puts the subject at risk or routine noncompliance puts the study outcomes at risk. If a 
subject's study treatment must be discontinued, this will not result in automatic withdrawal of the 
subject from the study.
A subject's study treatment should be discontinued if:

The subject experiences overt disease progression or relapse

Unacceptable toxicity

The subject becomes pregnant

The subject refuses further treatment

A serious protocol violation has occurred, as determined by the principal investigator or the 
sponsor

The investigator believes that for safety reasons (eg, adverse event) it is in the best interest 
of the subject to discontinue study treatment
If a subject discontinues study treatment before the onset of disease progression, 
End-of-Treatment and posttreatment assessments should be obtained and follow up of scheduled 
assessments should be continued. Refer to Section 9.2.1 for instructions regarding posttreatment 
efficacy assessments and Section 9.2.2.1 for instructions on the Study Event form. The reason(s)
a subject discontinues treatment will be recorded on the CRF.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Withdrawal of consent

The sponsor discontinues the study

Lost to follow up
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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.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
All analyses will be performed based on data up to the timepoint of clinical cutoff. Long-term 
follow-up data will be summarized separately when the entire study has completed. Statistical 
inferences will be based on a 2-sided Type I rate of 0.05 unless indicated otherwise. In 
exploratory statistical models, main effects will be tested at the 2-sided 0.05 level, and 
interactions will be tested at the 0.10 level. 
11.1.
Analysis Populations
The analysis populations are defined as:
1.
Intent-to-Treat (ITT) population: defined as all randomized subjects, who are enrolled with 
the non-GCB DLBCL subtype by IHC. Subjects in this population will be analyzed 
according to the treatment to which they are randomized.
2.
ABC population: defined as all randomized subjects who are identified as having the ABC 
subtype as determined by GEP (retrospectively determined using available clinical study 
FFPE tissue specimens). Subjects in this population will be analyzed according to the 
treatment to which they are randomized.
3.
Per-protocol population: defined as all randomized subjects who undergo at least 1 adequate 
postbaseline disease assessment and do not have major protocol violations including, but not 
limited to, the following:
a.
Did not meet all inclusion and exclusion criteria
b.
Did not receive the treatment to which they were randomized
c.
Had <75% (the cutoff values are subject to change) of study drug compliance
4.
Biomarker population: defined as all randomized subjects with biomarker data collected.
5.
Pharmacokinetic-evaluable population: defined as all randomized subjects who received at 
least 1 dose of study drug and had at least 1 pharmacokinetic sample obtained posttreatment.
6.
Safety population: defined as all randomized subjects who received at least 1 dose of study 
drug. Safety data will be analyzed according to the actual treatment received.
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The ITT population will be used to summarize the study population and characteristics, efficacy, 
and PRO data; the safety population will be used to summarize the safety data, unless otherwise 
specified. The biomarker population will be used to summarize the exposure and biomarker data. 
The pharmacokinetic-evaluable population will be used to summarize the pharmacokinetic data.
11.2.
Subject Information
Analyses of disposition, demographic, baseline disease characteristics, and prior and 
concomitant therapy will be conducted on the ITT population. Analyses on treatment compliance 
and extent of exposure will be conducted on the Safety population. No statistical testing is 
planned. 
Unless otherwise specified, all continuous endpoints will be summarized using descriptive 
statistics, which will include the number of subjects with a valid measurement (n), mean, 
standard deviation, median, minimum, and maximum. All categorical endpoints will be 
summarized using frequencies and percentages. Percentages will be calculated by dividing the 
number of subjects with the characteristic of interest by the number of subjects in the analysis 
population and/or the evaluable population.
11.3.
Sample Size Determination
This study is designed to evaluate the effect of treatment on EFS and is powered for this 
endpoint. DLBCL is an aggressive but potentially curable disease with 30% to 55% of patients 
achieving durable cure.14 In consideration of durable cure patients in the estimation of study 
power and the study clinical cutoff date, the study population is differentiated as 2 subgroups 
based on potential curability with treatment, ie, those who could achieve durable cure (curable 
population; ie, those who achieve complete response and are not expected to relapse irrespective 
of follow-up time) and those who are not expected to achieve durable cure (non-curable 
population). The classic event-driven approach for obtaining a desired study power is not 
applicable to this study. Therefore, simulation studies were conducted in this combined 
population for estimation of study power with 1 planned interim analysis.

A 1:1 randomization ratio between 2 treatment arms

Approximately 800 subjects to be enrolled (about 400 subjects per treatment arm)

Assuming the cure rate for the control arm (placebo+R-CHOP) is 40%, and the targeted cure 
rate of improvement is 10% for the active treatment arm ibrutinib+R-CHOP (ie, the cure rate 
for ibrutinib+R-CHOP is 50%), the median EFS is assumed to be 15 years for cured subjects

Among those subjects not cured, a targeted hazard ratio (HR) of 0.75 is assumed. This 
corresponds to a 4-month increase in median EFS for the active treatment arm
(ibrutinib+R-CHOP) relative to the control arm (placebo+R-CHOP), assuming the median 
EFS for the control arm (placebo+R-CHOP) is 12 months

Dropout rate is 5%

One interim analysis will be performed, when approximately 270 EFS events are available 
for superiority testing at a significance level of 0.002 (1-sided)
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With approximately 800 subjects (about 400 subjects per treatment arm) to be randomized in 
approximately 27 months (30 subjects per month) and with a study follow-up period of
30 months after the 800th subject is randomized, it is anticipated that approximately 419 EFS
events will be observed and the study will have at least 90% power to show the statistical 
significance at the overall alpha level of 0.025 (1-sided). The interim analysis will occur when 
approximately 270 EFS events have been observed. The clinical cutoff for the final EFS analysis 
is 30 months after 800th subject randomized. The alpha level for the final analysis will be 
calculated using the cumulative alpha spending function of power family25 based on the actual 
number of events at the final analysis.
In this study, the primary endpoint analysis measures a combination of improvement in the cure 
rate and improvement in the EFS interval among those patients who are not cured. A statistically 
significant p-value indicates that the addition of ibrutinib to R-CHOP improves the clinical 
outcome of the experimental group when both parameters — difference in cure rate and 
difference in EFS of the non-cured population — are taken into account. A wide range of 
outcomes may result in a statistically significant difference between the groups. Table 10
presents a few examples of possible clinical outcomes and the corresponding probability that 
such outcomes will result in a statistically significant difference between the groups.
Table 10:
Examples of Possible Study Outcomes Based on Median EFS=12 Months for Non-cured 
Subjects
Cure rate
EFS HR for 
Non-cured 
Subpopulation
P (success) at IA 
(boundary
p-value = 0.002)
Cumulative P (success) at Final 
Analysis (either p-value <0.002 at IA or 
<0.024 at final analysis)
Control
Active 
Treated
40%
50%
0.70
0.74
0.96
0.75
0.61
0.92
0.80
0.47
0.88
40%
45%
0.70
0.49
0.82
0.75
0.33
0.70
0.80
0.20
0.57
EFS=Event-free Survival; HR=Hazard Ration; IA=Interim Analysis; P=Probability.
As addressed in Section 11.9, the interim analysis was omitted due to the lower than expected 
EFS event rate.
11.3.1.
Multiplicity Adjustment for ABC Subtype
The primary analysis of EFS will be performed with data from both the ITT population (by IHC) 
and the ABC population (by GEP) simultaneously using the method of Song and Chi (Song and 
Chi 2007)46,which utilizes a 2-stage testing procedure that maintains reasonable study power 
while strongly controlling the familywise Type I error rate. 
At Stage 1, if the p-value associated with the weighted statistic Z1 is less than 0.04, then proceed 
to Stage 2 for testing both the ITT population (based on log-rank test instead of weighted testing 
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statistic Z1) and the target subgroup (ABC population by GEP) at the alpha level of 0.05 
separately. If the p-value for the weighted statistics Z1 at Stage 1 is ≥0.04 and <0.2, then the 
ABC population will be tested at the corresponding significance level for the ABC population. 
The significance level for the ABC population is calculated to control the familywise error rate 
of 0.05 by incorporating the correlation between Z1 and Z2 (standardized test statistic for the 
ABC population by GEP). If significance is shown in the target subgroup (ABC population), 
then the ITT population can be re-tested at the significance level of 0.05 using a standard 
log-rank test. More details will be provided in the Statistical Analysis Plan.
11.4.
Efficacy Analyses
Descriptive statistics and subject listings will be used to summarize the data. For continuous 
variables, the number of observations, means, standard deviations, medians, and ranges will be 
used. For discrete variables, frequency will be provided. For time-to-event variables, 
Kaplan-Meier estimates will be provided.
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. The primary endpoint (EFS) will be tested 
using the method of Song and Chi46 as described in Section 11.3.1. All other tests will be 
conducted at a 2-sided alpha level of 0.05 and 95% CI will be provided, unless stated otherwise.
11.4.1.
Primary Endpoint
The primary endpoint is EFS, defined as the duration from the date of randomization to the date 
of disease progression, relapse from CR as assessed by the investigator, initiation of subsequent 
systemic antilymphoma therapy for either PET-positive or biopsy-proven residual disease upon 
completion of at least 6 cycles of R-CHOP therapy, or death, whichever occurs first. Event-free 
survival will be censored at the date of the last adequate disease assessment for subjects who do 
not have disease progression, subsequent systemic antilymphoma therapy, and are alive, as well 
as those subjects with unknown disease progression or unknown survival status at clinical cutoff. 
If there is no postbaseline tumor assessment and no death is observed for a subject, EFS will be 
censored on the date of randomization. The detailed EFS censoring rules are specified in 
Statistical Analysis Plan.
The stratified log rank test will be used to compare EFS distributions of the 2 treatment arms. 
The stratification factors to be used in the analysis are R-IPI score (1-2 vs. 3-5), region
(U.S./Western Europe vs. Rest of World), and number of treatment cycles (6 vs. 8 cycles). The 
HR for ibrutinib+R-CHOP relative to placebo+R-CHOP and its associated 95% CI will be 
calculated based on the stratified Cox proportional hazards model by the stratification factors. 
The EFS distribution and median EFS with a 95% CI will be estimated using the Kaplan-Meier 
product-limit method. In case there is strong evidence of crossing hazard, other test statistics 
such as Rényi statistics41 may be used. In addition, the proportional hazards cure model will be 
used to estimate the cure rate for each treatment arm.
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11.4.2.
Secondary Endpoints
11.4.2.1.
Progression-free Survival
Progression-free survival is defined as the duration from the date of randomization to the date of 
progression, relapse, or death, whichever occurs first. Progression-free survival will be analyzed 
in a similar fashion as EFS.
11.4.2.2.
Complete Response 
Complete response rate is defined as the proportion of subjects with measurable disease who 
achieve CR. All randomized subjects who have a valid baseline value will be included in this 
analysis. Subjects with missing post-randomization data are considered non-responders. 
Complete response rate will be summarized using descriptive statistics for categorical data by 
treatment arm.
The relative risk (ibrutinib+R-CHOP vs. placebo+R-CHOP) will be reported along with the 
associated 95% CI. Statistical inference will be evaluated using the Cochran-Mantel-Haenszel
Chi-square statistic, adjusted for the stratification factors. Logistic regression analysis will also 
be performed to estimate an odds ratio and its associated 95% CI between the 2 treatment arms,
adjusted for the stratification factors. 
11.4.2.3.
Overall Survival
Overall survival is defined as the duration from the date of randomization to the date of the 
subject’s death. Overall survival will be analyzed using the stratified log-rank test for treatment 
comparison. The overall survival distribution and median overall survival with its 95% CI will 
be estimated using the Kaplan-Meier product-limit method. The HR for ibrutinib+R-CHOP 
relative to placebo+R-CHOP and its associated 95% CI will be calculated based on the stratified 
Cox proportional hazards model by the stratification factors.
The same subgroup analysis of EFS may be performed for overall survival if the number of 
events within each subgroup is sufficient. In addition, the exploratory analysis, using the Cox 
proportional hazards model with and without the covariates, as well the exploratory analysis on 
the effect of subsequent antilymphoma therapy on overall survival will be performed as 
appropriate. 
11.4.2.4.
Time to Worsening on the Lym Subscale
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.
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11.4.3.
Other Exploratory Efficacy Endpoints
Additional exploratory efficacy endpoints are:

Evaluate the mean change from baseline in EQ-5D-5L score for each postbaseline 
assessment and/or the FACT-Lym score as appropriate.

Biomarkers associated with resistance to ibrutinib in subjects who progress on ibrutinib 
treatment compared to those who remain in CR.
Analyses for the exploratory efficacy endpoints will be performed using the methods specified in 
Section 11.4.
11.4.4.
Patient-Reported Outcomes
Patient-reported outcome measures listed in Section 9.2.1.5 will be analyzed using the methods 
specified in Section 11.4. For individual items and sub-scale scores within the PRO measures, 
descriptive statistics (mean, standard deviation, median, and range) will be calculated for each 
timepoint, for changes from baseline at each timepoint, as well as for changes from baseline to 
the last value. Other exploratory analyses will be performed as appropriate.
11.5.
Pharmacokinetic Analyses
Population pharmacokinetic analysis of ibrutinib plasma concentration-time data will be 
performed using nonlinear mixed-effects modeling. Data may be combined with data from other 
studies to support a relevant structural population-based pharmacokinetic model. Available 
subject characteristics (demographics, laboratory variables, genotypes, etc.) will be tested as 
potential covariates affecting pharmacokinetic parameters. Ibrutinib data will be listed for all 
subjects with available plasma concentrations. Subjects will be excluded from the 
pharmacokinetic analysis if their data do not allow for accurate assessment of the 
pharmacokinetics (eg, incomplete administration of the study drug; 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. 
A snapshot date for pharmacokinetic samples to be analyzed will be defined, if required. 
Samples collected before this date will be analyzed for ibrutinib and included in the population 
pharmacokinetic analysis. Samples collected after the snapshot date will be analyzed at a later 
date, and may be included in a population pharmacokinetic re-analysis when they become 
available after database lock.
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11.6.
Pharmacokinetic/Pharmacodynamic Analyses
Model-derived exposure parameters may be subjected to further analyses to explore 
pharmacokinetic/pharmacodynamic correlations between ibrutinib exposure and relevant clinical 
or biomarker information. Results will be presented in a separate report.
11.7.
Biomarker Analyses
Non-GCB DLBCL subjects, as assigned by IHC to exclude GCB, may be further characterized 
using transcriptomic (eg, GEP, qRT-PCR) and/or genomic (eg, MiSeq, ExomeSEQ) analysis. 
Hierarchical clustering algorithms (or similar analyses) will be utilized to evaluate gene 
signatures and genomic features that may affect subject response and/or effect biological 
characteristics of DLBCL. Genes that distinguish the DLBCL subgroup or influence drug target 
biology may also be compared. The effect of transcriptomic and genomic analysis on response 
endpoints will be tested using standard categorical tests or survival outcomes, as appropriate.
Analyses will be performed across treatment arms and stratified by clinical covariates or 
molecular subgroups using the appropriate statistical methods (parametric or non-parametric, 
univariate or multivariate; for example analysis of variance or survival analysis, depending on 
the endpoint). Results may be presented in a separate report.
11.8.
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
by treatment arms. Exposure to 
investigational product and reasons for discontinuation of study treatment will be tabulated.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events 
with onset during the Active Treatment Phase (ie, treatment-emergent adverse events and 
adverse events that have worsened since baseline) will be included in the analysis. For each 
adverse event, the percentage of subjects who experience at least 1 occurrence of the given event 
will be summarized by treatment arm. Treatment-emergent adverse events are adverse events 
that occur after the first dose of study treatment, and within 30 days following the last dose of 
study treatment; any adverse event that is considered study treatment-related regardless of the 
start date of the event; or any adverse event that is present at baseline but worsens in severity or 
is subsequently considered study treatment-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 severe or a serious adverse event.
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Clinical Laboratory Tests
Laboratory data of hematology, coagulation, and serum chemistry up to 30 days after last dose of 
study treatment or the End-of-Treatment 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, platelet count, total bilirubin, creatinine, alkaline phosphatase, and electrolytes (sodium, 
potassium). Shift tables for each cycle will be produced for selected laboratory parameters, to 
include hemoglobin, platelet count, WBC count, ALC, ANC, AST, ALT, LDH, total bilirubin, 
creatinine, alkaline phosphatase, albumin, uric acid, magnesium, and electrolytes (sodium, 
potassium). These 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 start to 30 days after the last dose of the 
last study treatment or the End-of-Treatment Visit date, whichever is later) will also be provided.
The worst toxicity grade during the study will be tabulated.
11.9.
Interim Analysis
An interim analysis was planned when approximately 270 EFS events have been observed.
However, as of 12 July 2017, 230 EFS events have been reached. Due to the lower than expected 
EFS event rate (based on blinded data) and the short time expected between the interim and final 
analysis (clinical cutoff for the primary analysis is 30 months after the 800th subject is 
randomized into the study anticipated first quarter 2018), the interim analysis will be omitted.
11.10. Data Monitoring Committee
An independent DMC will be established to monitor data on an ongoing basis to ensure the 
safety of the subjects enrolled in this study and to evaluate the efficacy of the treatment at the 
time of interim analysis. The committee will meet periodically to review interim data. After the 
review, the DMC will make recommendations regarding the conduct of the study. The details 
regarding DMC responsibilities, authorities, and procedures will be provided in a separate DMC 
charter.
At the interim analysis, the DMC may recommend stopping the study for efficacy, if the 
pre-specified stopping boundary is crossed. In addition to the planned interim analyses for 
efficacy, 4 safety review meetings are planned that will occur approximately 2 months after 50,
250, 450, and 650 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. Until the first safety 
analysis, all deaths, treatment discontinuations, and serious adverse events will be reviewed by 
the sponsor’s responsible physician on an ongoing basis to identify safety concerns, and the 
DMC will be informed of any new potential signals. 
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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*
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*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For ibrutinib, the expectedness of an adverse 
event will be determined by whether or not it is listed in the Investigator's Brochure.
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).
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).
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12.2.
Special Reporting Situations
Safety events of interest on a sponsor study treatment that may require expedited reporting 
and/or safety evaluation include, but are not limited to:

Overdose of a sponsor study drug or rituximab, cyclophosphamide, doxorubicin, vincristine 
or prednisone (or equivalent)

Suspected abuse/misuse of a sponsor study drug or rituximab, cyclophosphamide, 
doxorubicin, vincristine or prednisone (or equivalent)

Inadvertent or accidental exposure to a sponsor study drug or rituximab, cyclophosphamide, 
doxorubicin, vincristine or prednisone (or equivalent)

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion) or rituximab, cyclophosphamide, doxorubicin, 
vincristine or prednisone (or equivalent)
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 subjects who receive treatment will be considered evaluable for toxicity. 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 following the last dose of study treatment.
Adverse events reported after 30 days following the last dose of study treatment should also be 
reported if considered related to study treatment. Resolution information after 30 days should be 
provided. All Grade 3 or Grade 4 adverse events considered related to study treatment must be 
followed until recovery to baseline or Grade ≤1. Cardiac adverse events of Grade 2 or higher will 
be followed until improvement to baseline or Grade ≤1. The unresolved aforementioned events 
will be followed for a maximum of 6 months. All adverse events of special interest as defined in 
Section 12.3.3 related to bleeding or resulting in bleeding complications must be followed until 
recovery or until there is no further improvement. Serious adverse events, including those 
spontaneously reported to the investigator within 30 days after the last dose of the last study 
treatment, must be reported using the Serious Adverse Event Form. The sponsor will evaluate
any safety information that is spontaneously reported by an investigator beyond the time frame 
specified in the protocol.
Progressive disease should NOT be reported as an adverse event, but instead symptoms/clinical 
signs of disease progression may be reported. Otherwise, all events that meet the definition of a 
serious adverse event will be reported as serious adverse events, regardless of whether they are 
protocol-specific assessments.
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All adverse events, regardless of seriousness, severity, or presumed relationship to study 
treatment, must be recorded using medical terminology in the source document and the CRF. All 
records will need to capture the details of the duration and the severity of each episode, the 
action taken with respect to the study treatment, investigator’s evaluation of its relationship to 
the study treatment, and the subject outcome. Whenever possible, diagnoses should be given 
when signs and symptoms are due to a common etiology (eg, cough, runny nose, sneezing, sore 
throat, and head congestion should be reported as "upper respiratory infection"). Investigators 
must record in the CRF their opinion concerning the relationship of the adverse event to any 
study treatment. 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 treatment. The investigator (or sponsor where required) must report 
these events to the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) that approved the protocol unless otherwise required and documented by the 
IEC/IRB. 
For all studies with an outpatient phase, the subject must be provided with a "wallet (study) card" 
and instructed to carry this card with them for the duration of the study indicating the following:

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:
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
The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study treatment 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:
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to 
Section 12.1.1, Adverse Event Definitions and Classifications).

A standard procedure for protocol therapy administration will not be reported as a serious 
adverse event. Hospitalization or prolonged hospitalization for a complication of therapy 
administration will be reported as a serious adverse event.

The administration of blood or platelet transfusion. Hospitalization or prolonged 
hospitalization for a complication of such transfusion remains a reportable serious adverse 
event.

A procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling, pharmacokinetic or biomarker blood 
sampling). Hospitalization or prolonged hospitalization for a complication of such 
procedures remains a reportable serious adverse event.

Prolonged hospitalization for technical, practical, or social reasons in the absence of an 
adverse event

A procedure planned before entry into the study (must be documented in the CRF). 
Prolonged hospitalization for a complication considered to be at least possibly related to the 
study treatment remains a reportable serious adverse event.
12.3.3.
Adverse Events of 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.
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12.3.3.1.
Major Hemorrhage
Major hemorrhage is defined as:

Any treatment-emergent hemorrhagic adverse event of Grade 3 or higher.*

Any treatment-emergent serious adverse event of bleeding of any grade.

Any treatment-emergent central nervous system hemorrhage/hematoma of any grade.
*All hemorrhagic adverse events requiring a transfusion of red blood cells should be reported as 
a Grade 3 or higher adverse events per NCI CTCAE.
12.3.4.
Other Malignancies
In addition to all routine AE reporting, all new malignant tumors, including solid tumors, skin 
malignancies and hematologic malignancies, are to be reported for the duration of study 
treatment and during any protocol-specified follow-up periods including post-progression 
follow-up for overall survival.
12.3.5.
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form. Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, and congenital 
anomaly) are considered serious adverse events and must be reported using the Serious Adverse 
Event Form. Any subject who becomes pregnant during the study must discontinue further study 
treatment. Because the effect of the study drug on sperm is unknown, pregnancies in partners of 
male subjects included in the study will be reported by the study-site personnel within 24 hours of 
their knowledge of the event using the appropriate pregnancy notification form. Follow-up 
information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will 
be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
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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.
14.
STUDY DRUG INFORMATION
For the purposes of this study, ‘study drug’ refers to ibrutinib or placebo.
14.1.
Study Drug – Ibrutinib or Placebo
The ibrutinib supplied for this study will be manufactured and provided under the responsibility 
of the sponsor. Refer to the Investigator's Brochure for a list of excipients.
14.1.1.
Physical Description
Ibrutinib/placebo capsules are provided as a hard gelatin capsule. Ibrutinib capsules contain 
140 mg of ibrutinib. All formulation excipients are compendial and are commonly used in oral 
formulations. Refer to the ibrutinib Investigator's Brochure for a list of excipients. Placebo to 
match capsules will also be provided as a hard gelatin capsule.
14.1.2.
Packaging
To maintain the blind, the ibrutinib and matching placebo capsules will be packaged in opaque 
high-density polyethylene (HDPE) plastic bottles with labels bearing the appropriate label text as 
required by governing regulatory agencies. All study drug bottles will be dispensed in 
child-resistant packaging (bottle caps will be child-resistant).
14.1.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each 
bottle will contain a study specific label with a unique identification number. The investigational 
product (ibrutinib/placebo) will be blinded.
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14.1.4.
Preparation, Handling, and Storage
The recommended storage condition for ibrutinib/placebo capsules is controlled room 
temperature (15○C to 25○C). Current stability data indicate that the capsules will be stable for the 
duration of the clinical study under the labeled storage conditions. Study staff will instruct 
subjects on how to store medication for at-home use as indicated for this protocol. Refer to the Site 
Investigational Product Procedures Manual for additional guidance on ibrutinib/placebo handling 
and storage conditions.
14.2.
Background Therapy (R-CHOP)
Rituximab may be provided in 100 mg or 500 mg single use vials as a solution or as prescribed 
by the treating physician. Cyclophosphamide, doxorubicin, and vincristine may be provided 
by the sponsor as single use vials or as prescribed by the treating physician. Prednisone
(or equivalent) may be provided by the sponsor as tablets for oral dosing or as prescribed by the 
treating physician.
Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone labels will contain 
information to meet the applicable regulatory requirements. Rituximab, cyclophosphamide, 
doxorubicin, and vincristine must be prepared in an aseptic manner according to local standards for 
handling cytotoxic/cytostatic drugs. Refer to the rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone local prescribing information or the Site Investigational Product 
Procedures Manual for further instructions on preparation, handling, and storage.
14.3.
Drug Accountability
The investigator is responsible for ensuring that all study treatment received at the site is 
inventoried and accounted for throughout the study. The dispensing of study drug 
(ibrutinib/placebo) to the subject, and the return of study drug (ibrutinib/placebo) from the 
subject (if applicable), must be documented on the drug accountability form. The subject, or their 
legally acceptable representatives where applicable, must be instructed to return all original 
containers, whether empty or containing study drug (ibrutinib/placebo). The R-CHOP
administered to the subject must be documented on the drug accountability form, if provided by 
the sponsor. All study treatment will be stored and disposed of according to the sponsor's 
instructions. Site staff must not combine contents of any study treatment containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study drugs, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug (ibrutinib/placebo), or used returned study drug for 
destruction, will be documented on the drug return form. When the study site is an authorized 
destruction unit and any study treatment supplies are destroyed on-site, this must also be
documented on the drug return form. Potentially hazardous materials such as used ampules, 
needles, syringes and vials containing hazardous liquids, should be disposed of immediately in a 
safe manner and therefore will not be retained for drug accountability purposes.
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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 same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug (ibrutinib/placebo) from, nor store it at, any 
site other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Study protocol

Ibrutinib Investigator’s Brochure

Ibrutinib study drug diary

Revised Response Criteria for Malignant Lymphoma5

Site Investigational Product Procedures Manual

Imaging Manual

Laboratory manual and supplies

PRO questionnaires and user manuals: PRO questionnaires will include the FACT-Lym and 
EQ-5D-5L. The data collection format will be an electronic tablet. The format will be 
pre-programmed and subjects will make their responses directly on the tablet. Sample 
questionnaires are provided in Attachment 6 and Attachment 7.

IWRS Manual and supplies

Electronic data capture (eDC) Manual and electronic CRF Completion Guidelines

Diagnosis and subtyping report form

Subject information materials

Informed Consent

Study Event form (see Section 10.2)
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
This is a randomized, double blind, placebo-controlled study to compare the efficacy and safety 
of ibrutinib in combination with R-CHOP to R-CHOP alone in subjects with newly diagnosed 
DLBCL who are 18 years of age or older. All subjects will receive active treatment with 
R-CHOP as background therapy, which is recommended treatment by the National 
Comprehensive Cancer Network guidelines.32 The study is blinded to adequately test the 
hypotheses that the addition of ibrutinib will prolong EFS in this subject population and provide 
additional clinical benefit. 
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All participating subjects will receive full supportive care and will be followed closely for safety 
and efficacy throughout the study. Efficacy assessments will occur according to the 
internationally accepted Revised Response Criteria for Malignant Lymphoma.5
Safety 
assessments will occur through regular clinic visits including laboratory analyses.
An independent DMC will be established to review the safety and efficacy of the treatment 
combination and make recommendations as to the future conduct of the study. The sponsor will 
monitor blinded data on an ongoing basis to ensure the safety of the subjects enrolled in this 
study.
The total blood volume to be collected is estimated at 307 to 357 mL (Attachment 8), depending
on number of cycles of study drug given. The total volume of blood includes laboratory
assessments associated with Screening and treatment including pharmacokinetic and biomarker 
samples. The volume of blood to be drawn is considered to be normal and acceptable for subjects 
participating in a cancer clinical study and is deemed reasonable over the time frame of the 
study.
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.
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. 
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.
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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

New information that may adversely affect the safety of the subjects or the conduct of the 
study
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
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 for molecular 
subtyping may be obtained separately prior to the full study ICF. 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 additional safety evaluations, if needed, and subsequent 
disease-related treatments, or to obtain information about his or her survival status.
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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.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand ibrutinib, to 
understand DLBCL, to understand differences in response to drug, and to develop tests/assays
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related to ibrutinib and DLBCL. 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.
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study treatment to
the study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator
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
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 and date of birth (as allowed by local regulations). In 
cases where the subject is not randomized into the study, the date seen and date of birth (as 
allowed by local regulations) 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.
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17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study discussion 
and date of signed informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all adverse events and follow up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; any study treatment
administration information; and date of study completion and reason for early discontinuation of 
any study treatment or withdrawal from the study, if applicable. In addition, the author of an 
entry in the source documents should be identifiable. At a minimum, the type and level of detail
of source data available for a subject should be consistent with that commonly recorded at the 
study site as a basis for standard medical care. Specific details required as source data for the 
study will be reviewed with the investigator before the study and will be described in the 
monitoring guidelines (or other equivalent document). Subject-completed scales and assessments 
designated by the sponsor (PRO questionnaires) will be recorded directly into an electronic 
device and will be considered source data.
17.5.
Case Report Form Completion
Electronic Data Capture will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an electronic CRF, and transmitted in a 
secure manner to the sponsor within the timeframe agreed upon between the sponsor and the 
study site. The electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Study site personnel must complete the CRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit. The investigator 
must verify that all data entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or 
study-site personnel must adjust the CRF (if applicable) and complete the query.
If corrections to a CRF are needed after the initial entry into the CRF, this 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.
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17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review CRFs for accuracy and completeness during 
on-site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will use a combination of monitoring techniques: central, remote and on-site 
monitoring to monitor this study.
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 
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post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare data entered into the CRFs with the hospital or clinic records (source 
documents); a sample may be reviewed. 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.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last visit for the last subject participating in the 
study. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final subject visit at that study site, in the time frame specified in the Clinical Trial 
Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines
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
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. 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 for the study. 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 investigator as provided for below) shall be the property of the sponsor as 
author and owner of copyright in such work.
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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 18 months after the study end date, 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 
ICMJE Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical Journals, which state that the named authors must have made a significant 
contribution to the conception or design of the work; and drafted the work or revised it critically 
for important intellectual content; and given final approval of the version to be published; and 
agreed to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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REFERENCES
1.
Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene 
expression profiling. Nature. 2000;403(6769):503-511.
2.
Berglund M, Thunberg U, Amini RM, et al. Evaluation of immunophenotype in diffuse large B-cell lymphoma 
and its impact on prognosis. Mod Pathol. 2005;18(8):1113-1120.
3.
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.
4.
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.
5.
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 
2007;25(5):579-586.
6.
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in 
elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242.
7.
Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the 
first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a 
study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116(12):2040-2045.
8.
Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular features of
tumor-infiltrating immune cells. N Engl J Med. 2004;351(21):2159-2169.
9.
Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor B activity is required for survival 
of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001;194(12):1861-1874.
10.
Davis RE, Ngo VN, Lenz G, et al. Chronic active B cell receptor signaling in diffuse large B cell lymphoma. 
Nature. 2010;463(7277):88-92.
11.
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. 
12.
EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. Health Policy.
1990;16:199-208.
13.
Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly 
patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin 
Oncol. 2005;23(18):4117-4126. Epub 2005 May 2.
14.
Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive 
chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med. 1993;328(14):1002-1006.
15.
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: 30 Nov 2012. 
16.
Friedberg JW, Fisher RI. Diffuse large B-cell lymphoma. Hematol Oncol Clin N Am. 2008;22:941–952.
17.
Fu K, Weisenburger DD, Choi WWL, et al. Addition of rituximab to standard chemotherapy improves the 
survival of both the germinal center B-cell-like and non-germinal center B-cell-like subtypes of diffuse large 
B-cell lymphoma. J Clin Oncol. 2008;26(28):4587-4594.
18.
Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance 
rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(19):3121-3127.
19.
Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large 
B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-282.
20.
Herbrecht R, Cernohous P, Engert A, et al. Comparison of pixantrone-based regiment (CPOP R) with 
doxorubicin-based therapy (CHOP-R) for treatment of diffuse large b-cell lymphoma. Ann Oncol. 2013;00:1-6.
NCT01855750


JNJ-54179060 (ibrutinib)
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Approved, Date: 16 October 2017
21.
Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for 
treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood.
2011;117(23):6287-6296.
22.
Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell 
activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci.
2010;107:13075.
23.
Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 
Populations), National Cancer Institute. Bethesda, MD. Available at: 
http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the 
SEER web site, 2012. Accessed: 28 January 2013.
24.
Iqbal J, Neppalli VT, Wright G, et al. BCL2 expression is a prognostic marker for the activated B-cell-like type 
of diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(6):961-968.
25.
Jennison C, Turnbull BW. Group sequential methods with applications to clinical trials. Chapman & 
Hall/CRC.
26.
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.
27.
Lam LT, Wright G, Davis RE, et al. Cooperative signaling through the signal transducer and activator of 
transcription 3 and nuclear factor-B pathways in subtypes of diffuse large B-cell lymphoma. Blood.
2008;111(7):3701-3713.
28.
Lohr JG, Stojanov P, Lawrence MS, et al. Discovery and prioritization of somatic mutations in diffuse large 
B-cell lymphoma (DLBCL) by whole-exome sequencing. PNAS. 2012;109(10):3879-3884.
29.
MabThera(rituximab) SmPC 2013. Hertfordshire, UK. F. Roche Registration Limited. March 2013. 
Available at: http://www.medicines.org.uk/emc/medicine/2570. Accessed: 23 April 2013.
30.
MattsonJack CancerMPactdatabase. Available at: http://cancermpact.mattsonjack.com/Master/Login/
Login.aspx?ReturnUrl=%2fDefault.aspx. Accessed: 16 January 2013. 
31.
Mounier N, Briere J, Gisselbrecht C, et al. Rituximab plus CHOP (R-CHOP) overcomes bcl-2-associated 
resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood.
2003;101(11):4279-4284. Epub 2003 Feb 6.
32.
National Comprehensive Cancer Network guidelines Version 1.2013. Diffuse large B-cell lymphoma. 
18 December 2012. Available at: http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed: 
29 January 2013.
33.
Nyman H, Adde M, Karjalainen-Lindsberg ML, et al. Prognostic impact of immunohistochemically defined 
germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy. 
Blood. 2007;109(11):4930-4935.
34.
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.
35.
Pettengell R, Johnsen HE, Lugtenburg PJ, et al. Impact of febrile neutropenia on R-CHOP chemotherapy 
delivery and hospitalizations among patients with diffuse large B-cell lymphoma. Support Care Cancer.
2012;20(3):647-652.
36.
Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like 
chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised 
controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7(5):379-391.
37.
Pharmacology Weekly. Available at http://www.pharmacologyweekly.com/content/pages/online-drug-therapy-
tables. Accessed: 31 July 2013.
38.
Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic 
lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119(5):1182-1189. 
Epub 2011 Dec 16.
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39.
Rabin R, Oemar M, Oppe M, Janssen B, Herdman, M. EuroQol. EQ-5D-5L User Guide (Version 4.0). 
April 2011.
40.
Récher C, Coiffier B, Haioun C, et. al. Intensified chemotherapy with ACVBP plus rituximab versus standard 
CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label 
randomised phase 3 trial. Lancet. 2011;378:1858–1867.
41.
Rényi, A. On the theory of order statistics. Acta Mathematica Hungarica. 1953;4:191-231.
42.
Rituxan(rituximab) USPI [package insert] 2013. South San Francisco, CA. Genentech, Inc. October 2013. 
Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103705s5367s5388lbl.pdf. 
Accessed: 23 April 2013.
43.
Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy 
for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(25):1937-1947.
44.
Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy 
dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol.
2005;23(22):5027-5033.
45.
Shipp MA, Harrington DP, Anderson JR, et al. A predictive model for aggressive non-Hodgkin's lymphoma. 
The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med.
1993;329(14):987-994.
46.
Song Y, Chi GYH. A method for testing a prespecified subgroup in clinical trials. Statist. Med. 
2007;26:3535-3549. Published online 1 February 2007 in Wiley InterScience (www.interscience.wiley.com) 
DOI: 10.1002/sim.2825. Available at: http://onlinelibrary.wiley.com/doi/10.1002/sim.2825/pdf. Accessed: 
2 April 2017.
47.
Staudt LM, Dunleavy K, Buggy JJ, et al. The Bruton's tyrosine kinase (btk) inhibitor PCI-32765 modulates 
chronic active BCR signaling and induces tumor regression in relapsed/refractory ABC DLBCL. Blood. 
2011;118:Abstract 2716.
48.
Tilly H, Lepage E, Coiffier B, et al. Intensive conventional chemotherapy (ACVBP regimen) compared with 
standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood. 2003;102(13):4284-4289.
49.
Tilly H and Dreyling M. Diffuse large B-cell non-Hodgkin’s lymphoma: ESMO clinical practice guidelines for 
diagnosis, treatment and follow-up. Annals Oncol. 2010;21(Suppl 5):v172-v174.
50.
Uptodate. Available at: http://www.uptodate.com/contents/diffuse-large-b-cell-lymphoma-in-adults-beyond-
the-basics?source=related_link. Accessed: 30 April 2013.
51.
van Imhoff GW, Boerma EJG, van der Holt B, et al. Prognostic impact of germinal center-associated proteins
and chromosomal breakpoints in poor-risk diffuse large B-cell lymphoma. J Clin Oncol.
2006;24(25):4135-4142.
52.
Visco C, Xu-Monette A, Miranda RN. Comprehensive gene expression profiling and immunohistochemical 
studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse 
large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. 
Leukemia. 2012;26:2103-2113.
53.
Webster K, Cashy J, Cella D, et al. Measuring quality of life (QOL) in patients with non-Hodgkin’s 
Lymphoma (NHL): The Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym). Quality of Life 
Research. 2005;14(9):1650.
54.
Wilson WH, Dunleavy K, Pittaluga S, et al. Phase II study of dose-adjusted EPOCH and rituximab in untreated 
diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin 
Oncol. 2008;26(16):2717-2724.
55.
Wilson WH. The Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in 
the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a 
multicenter, open-label, phase 2 study. Blood (ASH Annual Meeting Abstracts) 2012;120:Abstract 686. 
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Attachment 1: Revised International Prognostic Index
The risk factors used in calculating the Revised International Prognostic Index are shown below. 
Give 1 point for each criterion met:
a)
Age >60 years
b)
Stage III or IV disease
c)
Serum LDH greater than upper limit of local normal range
d)
Eastern Cooperative Oncology Group performance status 2 (see Attachment 3)
e)
More than 1 extranodal site of disease
Source: Sehn LH, Berry B, Chhanabhai M, et al. The revised international prognostic index (R-IPI) is a better 
predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. 
Blood. 2007;109(5):1857-1861.
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Attachment 2: Decision Tree for Immunohistochemistry Classification of DLBCL
Source: Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large 
B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-282.
CD10
GCB
BCL6
MUM1
Non-GCB
Non-GCB
GCB
+
+
+
_
_
_
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Attachment 3: Eastern Cooperative Oncology Group Performance Status Scale
Grade 
Eastern Cooperative Oncology Group Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.
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Attachment 4: Body Surface Area Calculation
BSA should be calculated using a standard nomogram. An example nomogram follows:
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Attachment 5: 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.15,37
The 
list 
below 
reflects 
information obtained from the Indiana University, Division of Clinical Pharmacology, Indianapolis, IN website on 
July 2013. 
Inhibitors of CYP3A
Strong inhibitors:
All other inhibitors:
INDINAVIR
amiodarone
NELFINAVIR
NOT azithromycina
RITONAVIR
chloramphenicol
CLARITHROMYCIN
boceprevir
ITRACONAZOLE
ciprofloxacin
KETOCONAZOLE
delaviridine
NEFAZODONE
diethyl-dithiocarbamate
SAQUINAVIR
fluoxetine-metabolite norfluoxetine
TELITHROMYCIN
fluvoxamine
Moderate inhibitors:
gestodene
aprepitant
imatinib
erythromycin
mibefradil
diltiazem 
mifepristone
fluconazole
norfloxacin
grapefruit juice
norfluoxetine
Seville orange juice
star fruit
verapamil
telaprevir
Weak inhibitors:
troleandomycin
cimetidine
voriconazole
a
Azithromycin is unique in that it does not inhibit CYP3A.
Inducers of CYP3A
efavirenz
phenobarbital
nevirapine
phenytoin
barbiturates
pioglitazone
carbamazepine
rifabutin
glucocorticoids
rifampin
modafinil
St. John's wort
oxcarbazepine
troglitazone 
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Attachment 6: Sample FACT-Lym (Version 4)
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Attachment 7: Sample Health Questionnaire EQ–5D–5L
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Attachment 8: Estimated Blood Volumes for Laboratory Samples
The total blood volume for the study is approximately 307 to 357 mLs, depending on number of 
cycles (6 or 8) given (188 to 238 mL for safety, 18 mL for pharmacokinetics, 15 mL for serum 
immunoglobulin and beta2-microglobulin, 12 mL for biomarkers, 70 mLs for MRD, and 4 mL 
for pregnancy testing [women only]).
Estimated Volume of Blood to be Collected From Each Subject (6 cycles)
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Subject
Total Volume of 
Blood (mL)a
Safety (including Screening and posttreatment assessments)
- Hematology
5
20
100
- Coagulation (INR/PT and aPTT)
5
1
5
- Serum chemistryb
10
8
80
Serology (hepatitis)
3
1
3
Serum -hCG pregnancy tests
2
2
4
Pharmacokinetic samples
2
9
18
Serum IgG, IgM, IgA and beta2-microglobulin
5
3
15
Biomarkers 
6
2
12
Serum MRD
10
7
70
Approximate Total
48
53
307
aPTT=activated partial thromboplastin time; -hCG=beta-human chorionic gonadotropin; HIV=human 
immunodeficiency virus; Ig=immunoglobulin; INR=international normalized ratio; MRD=minimal residual disease; 
PT=prothrombin time
a
Calculated as number of samples multiplied by amount of blood per sample.
b
Serum chemistry includes serology (hepatitis) and serum -hCG pregnancy tests.
Note: An indwelling intravenous cannula may be used for blood sample collection.
Estimated Volume of Blood to be Collected From Each Subject (8 cycles)
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Subject
Total Volume of 
Blood (mL)a
Safety (including Screening and posttreatment assessments)
- Hematology
5
26
130
- Coagulation (INR/PT and aPTT)
5
1
5
- Serum chemistryb
10
10
100
Serology (hepatitis)
3
1
3
Serum -hCG pregnancy tests
2
2
4
Pharmacokinetic samples
2
9
18
Serum IgG, IgM, IgA and beta2-microglobulin
5
3
15
Biomarkers 
6
2
12
Serum MRD
10
7
70
Approximate Total
48
61
357
aPTT=activated partial thromboplastin time; -hCG=beta-human chorionic gonadotropin; HIV=human 
immunodeficiency virus; Ig=immunoglobulin; INR=international normalized ratio; MRD=minimal residual disease; 
PT=prothrombin time
a
Calculated as number of samples multiplied by amount of blood per sample.
b
Serum chemistry includes serology (hepatitis) and serum -hCG pregnancy tests.
Note: An indwelling intravenous cannula may be used for blood sample collection.
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Approved, Date: 16 October 2017
INVESTIGATOR AGREEMENT
NCT01855750

SAP_001.pdf: 
1
Status: Approved,  Date: 21 March 2018
Statistical Analysis Plan
A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine 
Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination with Rituximab, 
Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects With 
Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell 
Lymphoma
Protocol Number: PCI-32765DBL3001; Phase 3
JNJ-54179060 (ibrutinib)
Issue/Report Date:
21 March 2018
Document No.:
EDMS-ERI-57717339
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.
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Statistical Analysis Plan 
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Status: Approved,  Date: 21 March 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 4
ABBREVIATIONS ........................................................................................................................................ 5
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Study Objectives .............................................................................................................................. 6
1.2.
Study Design.................................................................................................................................... 7
1.2.1.
Revised International Prognostic Index........................................................................................ 7
1.2.2.
Study Phase ................................................................................................................................. 8
1.2.3.
Planned Clinical Cutoff ................................................................................................................. 9
1.2.4.
Disease Response Schedule and Method ................................................................................... 9
1.2.5.
Data Monitoring Committee.......................................................................................................... 9
1.3.
Statistical Hypotheses for Study Objectives .................................................................................. 10
1.4.
Sample Size Justification ............................................................................................................... 10
1.4.1.
Multiplicity Adjustment for Simultaneous Testing ....................................................................... 14
1.4.2.
Power of Hypothesis Testing Based on Simulation Studies....................................................... 16
1.5.
Randomization and Blinding .......................................................................................................... 17
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 18
2.1.
Analysis Sets.................................................................................................................................. 18
2.2.
Study Treatment and Study Medication......................................................................................... 18
2.3.
Baseline Definitions or Conventions .............................................................................................. 19
2.4.
Study Day and Visit Windows ........................................................................................................ 19
2.5.
Imputation of Missing Dates........................................................................................................... 19
2.6.
Definitions of Subgroups................................................................................................................ 21
2.7.
Other General Definitions............................................................................................................... 21
2.7.1.
Treatment-Emergent Adverse Events ........................................................................................ 22
2.7.2.
Year and Month .......................................................................................................................... 22
2.7.3.
Age.............................................................................................................................................. 22
2.7.4.
Time from Initial Diagnosis to Randomization ............................................................................ 22
2.7.5.
Date of Overall Response/Progressive Disease for Each Timepoint......................................... 22
2.7.6.
Date of Subsequent Systemic Antilymphoma Therapy Event.................................................... 22
2.7.7.
Date of Response/Best Response ............................................................................................. 23
2.7.8.
Date of Progression.................................................................................................................... 23
2.7.9.
Date of Subsequent Systemic Antilymphoma Therapy Event.................................................... 23
2.7.10.
Date of EFS Event...................................................................................................................... 23
2.7.11.
Date of PFS Event...................................................................................................................... 23
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 23
3.1.
Interim Analysis.............................................................................................................................. 23
3.2.
Data Monitoring Committee ........................................................................................................... 23
4.
SUBJECT INFORMATION................................................................................................................ 24
4.1.
Disposition Information................................................................................................................... 24
4.2.
Demographics and Baseline Characteristics ................................................................................. 24
4.3.
Extent of Exposure......................................................................................................................... 25
4.4.
Protocol Eligibility and Major Protocol Deviations.......................................................................... 25
4.5.
Prior and Concomitant Medications ............................................................................................... 26
4.6.
Medical History............................................................................................................................... 26
5.
EFFICACY ......................................................................................................................................... 26
5.1.
Analysis Specifications................................................................................................................... 26
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Status: Approved,  Date: 21 March 2018
5.1.1.
Level of Significance................................................................................................................... 26
5.1.2.
Data Handling Rules................................................................................................................... 26
5.1.3.
General Analysis Considerations ............................................................................................... 27
5.2.
Primary Efficacy Endpoint.............................................................................................................. 27
5.2.1.
Definition..................................................................................................................................... 27
5.2.2.
Primary Analysis of EFS............................................................................................................. 28
5.2.3.
Sensitivity Analysis of EFS ......................................................................................................... 29
5.2.3.1.
Imputing the Screen Failures due to GCB by IHC who are ABC by GEP............................... 29
5.2.3.2.
Imputing Missing GEP Test Results........................................................................................ 30
5.2.3.3.
Sensitivity Analysis .................................................................................................................. 31
5.2.3.4.
Additional Covariate-adjusted Analysis of EFS....................................................................... 32
5.2.3.5.
Subgroup Analysis of EFS....................................................................................................... 32
5.3.
Secondary Efficacy Endpoints ....................................................................................................... 33
5.3.1.
Progression-free Survival ........................................................................................................... 33
5.3.2.
Complete Response Rate........................................................................................................... 33
5.3.3.
Overall Survival........................................................................................................................... 34
5.3.3.1.
Time to Worsening on the Lym Subscale................................................................................ 34
5.3.4.
Related Exploratory Analyses .................................................................................................... 35
5.3.4.1.
Overall Response Rates.......................................................................................................... 35
5.3.4.2.
Duration of Response.............................................................................................................. 35
5.3.5.
Multiplicity Adjustment for Secondary Endpoints ....................................................................... 35
5.4.
Other Exploratory Efficacy Endpoints ............................................................................................ 35
6.
SAFETY............................................................................................................................................. 36
6.1.
Adverse Events .............................................................................................................................. 36
6.1.1.
All Adverse Events...................................................................................................................... 36
6.1.2.
Adverse Events of Special Interest............................................................................................. 37
6.2.
Deaths............................................................................................................................................ 37
6.3.
Clinical Laboratory Tests................................................................................................................ 37
6.3.1.
Creatinine Clearance.................................................................................................................. 38
6.3.2.
Analysis of Lymphocytosis.......................................................................................................... 38
6.4.
Electrocardiogram.......................................................................................................................... 38
6.5.
Vital Signs and Physical Examination Findings ............................................................................. 38
6.6.
Other Safety Parameters ............................................................................................................... 38
7.
PATIENT-REPORTED OUTCOMES................................................................................................. 38
REFERENCES............................................................................................................................................ 41
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Status: Approved,  Date: 21 March 2018
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
International Prognostic Index (IPI) and Revised IPI Categories ............................................... 7
Table 2: 
Calculated Nominal Significance Level at the Final Analysis ................................................... 12
Table 3: 
Simulation Results Based on Different Cure Rate Improvement and Different HR 
Assumptions for Non-curable Population ................................................................................. 13
Table 4: 
Examples of Possible Study Outcomes Based on Median EFS of 12 Months for Non-
cured Subjects .......................................................................................................................... 14
Table 5: 
Significance Alpha Level (2-sided) α1 for the ABC Population with Different EFS 
Events Proportion. .................................................................................................................... 16
Table 6: 
Concordance of IHC and GEP Data......................................................................................... 16
Table 7: 
Simulation Settings for Non-cured and Cured Population by GEP Subtype ............................ 16
Table 8: 
Simulation Results for Study Power ......................................................................................... 17
Table 9:
Visit Windows............................................................................................................................ 19
Table 10:
Subgroups................................................................................................................................. 21
Table 11:
Censoring Rules for Primary EFS Analysis .............................................................................. 28
FIGURES
Figure 1:
An Example of Song and Chi 2-Stage Testing Procedure ....................................................... 15
Figure 2:
Flow Chart for the Imputation of Missing GEP Sample ............................................................ 31
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Status: Approved,  Date: 21 March 2018
ABBREVIATIONS
ABC
activated B cell-like subtype of DLBCL
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
area under the curve
CI
confidence interval
CNS
central nervous system
CR
complete response
CRF
case report form
CT
computed tomography
DLBCL
diffuse large B-cell lymphoma
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EFS
event-free survival
EQ-5D-5L
EuroQol questionnaire
FACT-G
Functional Assessment of Chronic Illness Therapy-General
FACT-Lym
Functional Assessment of Cancer Therapy-Lymphoma
GEP
gene expression profiling
HR
hazard ratio
IHC
immunohistochemistry
IRC
Independent Review Committee
ITT
Intent-to-Treat population
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
non-GCB
non-germinal center B cell-like subtype of DLBCL
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PR
partial response
PRO
patient-reported outcome(s)
R-CHOP
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
R-IPI
Revised International Prognostic Index
ROC
receiver operating characteristic
SAE
serious adverse event
SD
stable disease
SF
screen failure
TEAE
treatment-emergent adverse event
TTW
time to worsening
U.S.
United States
WHO
World Health Organization
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1.
INTRODUCTION
This clinical study is a part of a comprehensive ibrutinib clinical development plan to evaluate 
the safety and efficacy of ibrutinib for subjects with B-cell malignancies. This randomized, 
double-blind, placebo-controlled, multicenter, Phase 3 study is designed to evaluate the efficacy 
and safety of ibrutinib in combination with rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone (R-CHOP). The study will evaluate if ibrutinib in combination with 
R-CHOP will prolong event-free survival (EFS) in subjects with newly diagnosed non-germinal 
center B cell-like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) selected by 
immunohistochemistry (IHC) or newly diagnosed subjects with activated B cell-like (ABC) 
subtype of DLBCL identified by gene expression profiling (GEP) or both populations.
The purpose of this Statistical Analysis Plan is to present key elements, including definitions and 
statistical methods, for the planned analyses for the primary, secondary, and safety endpoints. 
Details for derived variables and data handling conventions will be added to the Data Handling 
section and the Data Presentation Specifications (DPS).
1.1.
Study Objectives
The primary objective of this study is to evaluate if the addition of ibrutinib to R-CHOP prolongs 
EFS compared with R-CHOP alone in subjects with newly diagnosed non-GCB subtype of 
DLBCL or in subjects with newly diagnosed ABC subtype of DLBCL or in both populations.
The secondary objectives are to: 

Evaluate progression-free survival (PFS)

Evaluate the complete response (CR) rate

Evaluate overall survival (OS)

Evaluate patient-reported lymphoma symptoms and concerns as measured by the Lym 
subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)

Characterize the pharmacokinetics of ibrutinib and explore the potential relationships 
between ibrutinib metrics of exposure with relevant clinical or biomarker information

Evaluate the safety of ibrutinib when combined with R-CHOP
The exploratory objectives are to:

Evaluate patient-reported outcomes (PRO), related to well-being and general health 
status, utilizing the FACT-Lym and EuroQol (EQ-5D-5L)

Explore the relationship between relevant biomarkers (eg, GEP, gene mutations) with 
clinical outcomes and mechanism of resistance
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1.2.
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 R-CHOP versus R-CHOP alone in 
subjects with newly diagnosed non-GCB DLBCL or in subjects with newly diagnosed ABC 
subtype of DLBCL or in both populations.
Approximately 800 eligible subjects will be stratified by Revised International Prognostic Index 
(R-IPI; 1-2 vs. 3-5), region (United States [U.S.]/Western Europe vs. Rest of World), and 
number of pre-specified treatment cycles (6 cycles vs. 8 cycles), then randomized in a 1:1 ratio to 
receive either placebo+R-CHOP or 560 mg ibrutinib+R-CHOP. Prior to randomization, sites will 
pre-specify treatment of subjects with either 6 or 8 cycles. All subjects at individual sites must 
receive the same number of treatment cycles (6 or 8; no adjustment is permitted once 
pre-specified).
1.2.1.
Revised International Prognostic Index
The R-IPI is calculated based upon the following IPI risk factors (1 point for each factor present):

Age >60 years

Eastern Cooperative Oncology Group (ECOG) performance status ≥2

Elevated lactate dehydrogenase (LDH)

≥2 extranodal sites of disease 

DLBCL Stage III or IV
Table 1 lists the standard IPI and the R-IPI risk groups.
Table 1: 
International Prognostic Index (IPI) and Revised IPI Categories
Risk group
Number of IPI factors
Standard IPI
    Low
0, 1
    Low-intermediate
2
    High-intermediate
3
    High 4, 5
4, 5
Revised IPI
    Very gooda
0
    Good
1, 2
    Poor
3, 4, 5
IPI=international prognostic index
a The risk group of Very good (ie, R-IPI score of 0) does not meet the study eligibility 
criteria. 
In this study, the R-IPI risk group will be used as 1 of the randomization stratification factors
(ie, for eligible subjects with an R-IPI score ≥1). The stratification factors based upon R-IPI are 
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Statistical Analysis Plan 
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Status: Approved,  Date: 21 March 2018
the 2 higher risk groups: Good (High, R-IPI score of 1 to 2) and Poor (Low, R-IPI score of 3 to 
5).
1.2.2.
Study Phase
The study will include a Pretreatment (Screening) Phase prior to randomization; an Active 
Treatment Phase, which includes visits at the start of each cycle and an End-of-Treatment visit;
and a Posttreatment Follow-up Phase, which continues until death, loss to follow up, consent 
withdrawal, or study end, whichever occurs first.

The Screening Phase will extend up to 30 days prior to randomization, including the date of 
randomization unless otherwise specified. All subjects must sign an informed consent form 
prior to the conduct of any study-related procedures. 

The Active Treatment Phase will extend from Day 1 Cycle 1 until study treatment 
discontinuation due to disease progression, initiation of subsequent antilymphoma therapy, 
unacceptable toxicity, withdrawn, or completion of study treatment.

During the Active Treatment Phase, all subjects will receive R-CHOP as background 
therapy for 6 or 8 cycles as pre-specified (21 days per cycle). Subjects who discontinue 
R-CHOP without disease progression prior to completing 6 or 8 cycles will continue 
study drug until 6 or 8 cycles (depending on the number of cycles pre-specified by each 
site) are completed or the end of the Active Treatment Phase, whichever occurs first.

During the Active Treatment Phase, disease response assessment will be performed at 
both Cycle 4 (computed tomography [CT] only) and End-of-Treatment visit/early 
withdrawal (CT and PET). Whole body PET scan is recommended but not mandated at 
baseline. 

Disease response assessment criteria will be based on the Revised Response Criteria for 
Malignant Lymphoma (Cheson 2007). The progressive disease (PD) notification form
(Study Event form) were to be faxed to the medical monitors within 24 hours of the PD 
declaration.

At the end of treatment, all subjects are required to fill out the End-of-Treatment visit 
form within 30 days after the last dose of study drug. If a subject requires subsequent 
systemic antilymphoma therapy between the last dose of study drug and the expected 
date of the End-of-Treatment visit, then the End-of-Treatment visit should be completed 
before initiation of subsequent systemic antilymphoma therapy. 

The Posttreatment Follow-up Phase will start after subjects complete the End-of-Treatment 
procedures. Study end is defined as when 50% of the randomized subjects have died; 5 years 
after the last subject is randomized; or the sponsor terminates the study, whichever occurs 
first. The Posttreatment Follow-up Phase includes 2 parts, the pre-PD follow-up phase and 
the post-PD survival follow-up phase.
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1.2.3.
Planned Clinical Cutoff
Three clinical cutoffs were planned. The first clinical cutoff is an interim analysis, which will 
occur when approximately 270 EFS events are observed. The second clinical cutoff is the final 
analysis of EFS, which will occur at 30 months after the 800th subject is randomized. Treatment 
assignment will be unblinded to the study team at this clinical cutoff for the final analysis of EFS
and the analysis results will form the basis for the primary clinical study report. The last clinical 
cutoff will occur at the end of study. The main purpose of the last clinical cutoff is to update the 
long-term survival status. All available data prior to the time of a clinical cutoff will be included 
in each of the respective analyses. 
Per the original study design, the number of events required for the interim analysis is 270 EFS 
events. As of 12 July 2017, 230 EFS events have been reached. Due to this lower than expected 
EFS event rate and the short time expected between the interim and final analysis, the sponsor 
has omitted the first clinical cutoff for the interim analysis. Omission of the interim analysis is
documented in protocol Amendment INT-3 issued on 16 October 2017.
1.2.4.
Disease Response Schedule and Method
The primary efficacy analysis of EFS will be based on investigator’s assessment following the 
Cheson 2007 criteria (Cheson 2007). The investigator will evaluate sites of disease by CT scans 
of the neck, chest, abdomen, and pelvis with intravenous and oral contrast as indicated. Whole 
body PET scan is recommended but not mandated at baseline, but is required at the end of 
treatment. Magnetic resonance imaging may be used to evaluate sites of disease that cannot be 
adequately imaged using CT. Other sites of disease will be evaluated by radiological imaging, 
physical examination, or other procedures as necessary (to be performed throughout the study 
using the same method of assessment per subject).
An Independent Review Committee (IRC) will perform disease assessments for a random sample
of subjects. If the results of EFS, based on the IRC’s assessment, do not confirm the primary 
analysis results using the audit plan (Dodd method; Dodd 2011), then IRC will perform an 
independent assessment for all randomized subjects. The details are addressed in the IRC audit 
plan (Attachment 1). 
At each site visit, subjects will be evaluated for toxicity. Safety evaluations will include adverse 
event (AE) monitoring, physical examinations, concomitant medication usage, and clinical 
laboratory parameters. Blood samples will be drawn for assessment of pharmacokinetic 
parameters.
1.2.5.
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will be established to monitor data on an 
ongoing basis to ensure the safety of the subjects enrolled in this study and to evaluate the 
efficacy of the treatment at the time of interim analysis. The DMC is constituted according to 
regulatory agency guidelines. The DMC will meet periodically to review interim data. After the 
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review, the DMC will make recommendations regarding the conduct of the study. Further details 
regarding the responsibilities, authorities, and procedures will be provided in the DMC charter.
1.3.
Statistical Hypotheses for Study Objectives
The primary objective of this study is to evaluate if the addition of ibrutinib to R-CHOP prolongs 
EFS compared with R-CHOP alone in subjects with newly diagnosed non-GCB subtype of 
DLBCL (intent-to-treat [ITT] population), subjects with newly diagnosed ABC subtype of 
DLBCL (ABC population), or in both populations. The statistical hypotheses are described as 
follows: 
H0: Null hypothesis, the EFS distributions of the experimental treatment group, ST(t), and the 
placebo group, SP(t), are not different, at all timepoints t for both the ITT population and ABC 
population:
ST(t) = SP(t), for all t > 0
(1)
versus
H1: Alternative hypothesis, the EFS distributions of the experimental treatment group, ST(t), are
stochastically greater than that of the placebo group, SP(t), for the ITT population, and/or for the 
ABC population:
ST(t) SP(t), for all t ≥0, with strict inequality for some t
These hypotheses will be tested using a stratified log-rank test as detailed in Section 5.
The primary objective for the original design was to evaluate if the addition of ibrutinib to 
R-CHOP prolongs EFS compared with R-CHOP alone in subjects with newly diagnosed
non-GCB subtype of DLBCL only. The protocol was amended (protocol Amendment INT-3) to 
change the primary objective to “The addition of ibrutinib to R-CHOP prolongs EFS compared 
with R-CHOP alone in subjects with newly diagnosed non-GCB subtype of DLBCL selected by 
IHC, or subjects with newly diagnosed ABC subtype of DLBCL identified by GEP, or in both 
populations”.
1.4.
Sample Size Justification
This study is designed to evaluate the effect of treatment on EFS and is powered for this 
endpoint. DLBCL is an aggressive but potentially curable disease with 30% to 55% of patients 
achieving durable cure (Fisher 1993). For further insight into event estimation and the power 
calculation for this study, the study population was differentiated into 2 subgroups based on 
potential curability with treatment, ie, those who could achieve durable cure (curable population; 
those who achieve CR and are not expected to relapse irrespective of follow-up time) and those 
who are not expected to achieve durable cure (non-curable population). Simulation studies were 
conducted for estimating the event numbers, interim analysis timepoint, and power based on the 
following considerations:
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
A 1:1 randomization ratio between 2 treatment arms.

A total of 800 subjects to be enrolled (400 subjects per treatment arm).

Assuming the cure rate for the control arm (placebo+R-CHOP) is 40% and the targeted cure 
rate of improvement is 10% for the active treatment arm ibrutinib+R-CHOP (ie, the cure rate 
for ibrutinib+R-CHOP is 50%). The median EFS is assumed to be 15 years for cured 
subjects.

Among those subjects who are not cured, a targeted hazard ratio (HR) of 0.75 is assumed. 
This corresponds to a 4-month increase in median EFS for the active treatment arm 
(ibrutinib+R-CHOP) relative to the control arm (placebo+R-CHOP), assuming the median 
EFS for the control arm (placebo+R-CHOP) is 12 months.

One interim analysis to be performed after approximately 270 EFS events have been 
observed, for superiority testing at the nominal significance level of 0.002 (1-sided).
With approximately 800 subjects (about 400 subjects per treatment arm) to be randomized in 
approximately 27 months (30 subjects per month) and with a study follow-up period of 
30 months after the last subject is randomized, it is anticipated that approximately 419 EFS
events will be observed and the study will have at least 90% power to show statistical 
significance at an overall alpha level of 0.025 (1-sided).
The nominal alpha level for the final analysis will be calculated using the cumulative alpha 
spending function of the power family (Jennison and Turnbull 2000) based on the actual number 
of events at the final analysis. Table 2 shows the calculated nominal significance level at the 
final EFS analysis assuming the final observed EFS events range from 350 to 450. Based on the 
cumulative alpha spending function with an interim analysis of 270 EFS events and a nominal 
significance level of 0.002 (1-sided), if the final observed number of EFS events is 420, the final 
nominal significance level will be 0.02463 (1-sided) to maintain the overall alpha of 0.025 
(1-sided).
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Table 2: 
Calculated Nominal Significance Level at the Final Analysis
EFS Events
Information 
Fraction

Nominal Significance 
Level (1-sided)
350
0.771
9.66
0.02489
360
0.750
8.78
0.02485
370
0.730
8.02
0.02482
380
0.711
7.37
0.02478
390
0.692
6.80
0.02474
400
0.675
6.55
0.02472
410
0.659
6.08
0.02468
420
0.643
5.66
0.02463
430
0.628
5.47
0.02461
440
0.614
5.11
0.02456
450
0.600
4.94
0.02453
=index parameter for alpha spending function of the power family.
Simulation studies were also conducted based on the different assumptions of cure rate 
improvement and the risk reductions for those uncured subjects as detailed below:

The cure rate is 40% in the control arm (placebo+R-CHOP). 

A 5% or 10% improvement in cure rate with ibrutinib+R-CHOP treatment.

Median EFS is 15 years for both the control and active treatment arms in the curable 
population.

For the non-curable population in the control arm, the median EFS is assumed to be 12 or 
15 months.

For the non-curable population in the active treatment arm, the median EFS is based on the 
HRs of 0.70, 0.72, 0.75, and 0.80
for the ibrutinib+R-CHOP arm relative to 
placebo+R-CHOP arm.

Dropout rate is 5%.

The nominal statistical significance level of 0.002 (1-sided) is used at the interim analysis. 
For the final analysis, a nominal significance level of 0.024 (1-sided) will be used. This will 
result in an overall significance level of less than or equal to 0.025 (1-sided) given the 
anticipated total number of events at the final analysis.
Based on 10,000 simulation runs, the results listed in Table 3 indicate that the study power will 
be maintained at least 80% with a 10% improvement in cure rate. For a 5% (from 40% to 45%) 
improvement in cure rate, HRs of 0.7 or less are needed to maintain an 80% power.
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Table 3: 
Simulation Results Based on Different Cure Rate Improvement and Different HR Assumptions 
for Non-curable Population
Non-curable 
Control arm 
Median EFS
(months)
Non-curable 
TRT arm 
Median EFS
(months)
Non-curable 
Population 
HR
Timing of IA 
(months) 
(when 270 
events occur)
Number of 
Events at Final 
Analysis of 
EFS
Power (%) 
at Final 
Analysis
Cure rate 
Control, 40%;
TRT, 50%
12
17
0.70
32.8
415
96
12
16.7
0.72
32.6
417
95
12
16
0.75
32.3
419
92
12
15
0.80
31.9
423
88
15
21
0.70
36.3
389
96
15
20.8
0.72
36.1
391
95
15
20
0.75
35.8
394
93
15
18.8
0.80
35.3
398
87
Cure rate 
Control, 40%;
TRT, 45%
12
17
0.70
31.9
428
82
12
16.7
0.72
31.7
429
78
12
16
0.75
31.5
432
70
12
15
0.80
31.1
436
57
15
21
0.70
35.4
400
84
15
20.8
0.72
35.2
402
79
15
20
0.75
34.8
405
72
15
18.8
0.80
34.3
410
59
EFS=event-free survival; HR=hazard ratio; IA=interim analysis; TRT=active treatment.
In this study, the primary endpoint analysis measures a combination of improvement in the cure 
rate and improvement in the EFS interval among those subjects who are not cured. A statistically 
significant p-value for the log-rank test indicates that the addition of ibrutinib to R-CHOP 
improves the clinical outcome of the experimental group when both parameters, ie, difference in 
cure rate and difference in EFS of the non-cured population, are taken into account. A wide 
range of outcomes may result in a statistically significant difference between the groups. Table 4
presents a few examples of possible clinical outcomes and the corresponding probability that 
such outcomes will result in a statistically significant difference between the treatment arms.
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Table 4: 
Examples of Possible Study Outcomes Based on Median EFS of 12 Months for Non-cured 
Subjects
Cure Rate
EFS HR for
Non-cured 
Subpopulation 
P (success) at IA 
(boundary 
p-value = 0.002)
Cumulative P (success) at Final 
Analysis (either p-value < 0.002 at 
IA or <0.024 at final analysis) 
Control
Active 
Treated
40%
50%
0.70
0.74
0.96
0.75
0.61
0.92
0.80
0.47
0.88
40%
45%
0.70
0.49
0.82
0.75
0.33
0.70
0.80
0.20
0.57
EFS=Event-free Survival; HR=Hazard Ration; IA=Interim Analysis; P=Probability.
As addressed in Section 1.2.3, the interim analysis was omitted due to the lower than expected 
EFS event rate. The simulation study, to examine the original study power, discussed in the 
above section will be not applicable per protocol Amendment INT-3. An updated power 
calculation is described in Section 1.4.2. The significant alpha level for the final analysis will be 
overall 2-sided 0.05 instead of 0.048. The primary hypothesis was also changed into 
simultaneous testing for both ITT and ABC populations. The overall significance level will be 
based on a 2-sided alpha of 0.05 for multiplicity adjustment shared between the ITT and ABC 
populations. Multiplicity adjustment details will be discussed in Section 1.4.1. The power 
estimation for the ABC population will be provided in Section 1.4.2. The sample size for ABC 
will depend on the GEP test results.
1.4.1.
Multiplicity Adjustment for Simultaneous Testing
The primary analysis of EFS will be performed with data from both the ITT population and ABC 
population simultaneously using the method of Song and Chi (Song and Chi 2007), which 
utilizes a 2-stage testing procedure that maintains reasonable study power and also strongly 
controls the familywise Type I error rate. 
Song and Chi proposed a weighted test statistics Z1, which combines the target population of 
ABC, represented by Z2 and its complementary population, represented by 
. k is the proportion 
of events in ABC population among total events in ITT population.
(2)
Figure 1 illustrates the Song and Chi 2-stage testing procedure. At Stage I, if the p-value 
associated with the weighted statistic Z1 is less than 0.04, then proceed to Stage II for testing 
both the ITT (based on stratified log-rank test instead of weighted testing statistic Z1) and the 
target subgroup (ABC population) at the alpha level of 0.05 separately. If the p-value for the 
weighted statistics Z1 at Stage I is ≥0.04 and <0.2, then the ABC population will be tested at the 
corresponding significance level. The significance level for the ABC population is calculated to 
control the familywise error rate of 0.05 by incorporating the correlation between Z1 and Z2. If 
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significance is shown in the ABC population, then the ITT population can be re-tested at the 
significance level of 0.05 using a standard stratified log-rank test. 
Figure 1:
An Example of Song and Chi 2-Stage Testing Procedure
ABC=activated B cell-like DLBCL; ITT=intent-to-treat
*Actual significance level depends on the proportion of EFS events k, determined on blinded data before the signoff 
of this SAP. Please refer to Section 5.1.1 for the details.
Table 5 provides examples of calculated significance levels for the ABC population assuming 
different k - a proportion of EFS events in ABC population among total events in ITT 
population. For this study, we propose using a 2-sided alpha of 0.04 for the Stage I test (α1); the 
overall study population efficacy consistency control parameter assuming to be 2-sided alpha of 
0.2. The actual significance levels for the ABC population are shown in tables 5 with k ranges 
from 0.6 to 0.8. The true significance level for ABC population will be based on the observed 
EFS events in ABC population vs. ITT population.
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Table 5: 
Significance Alpha Level (2-sided) α1 for the ABC Population with Different EFS Events 
Proportion.
K
= 0.04
0.6
0.0255
0.7
0.0268
0.8
0.0300
: Significance level for weighted test statistic Z1; ABCactivated B cell-like DLBCL; EFS=event-free survival; 
k=proportion of EFS events in the ABC population among total events in ITT population.
The anticipated proportion of EFS events from the ABC subgroup is between 60% and 80%. 
This was based on the testing concordance (Table 6), using the 199 samples taken from Study 
DBL3001 (the selection scheme for those 199 subjects is in Attachment 2), the proportion of 
ABC is about 55% (57/104=54.8%). Subjects with the ABC subtype have an inferior efficacy 
profile than those with the GCB subtype (Lenz 2008). It is reasonable to assume more EFS 
events will come from patients with the ABC subtype than from those with the GCB or 
unclassified subtypes. Therefore, we assume that there will be at least 60% of the EFS events 
from the ABC population in our simulation studies.
Table 6: 
Concordance of IHC and GEP Data
Nanostring GEP
ABC
UNC
GCB
Sample Not 
Evaluable
Total
(N=199)
Evaluable Subjects 
(N=186)
IHCa
non-GCB
57
22
25
6
110
104
Randomized
45
18
21
5
89
84
GCB
7
7
68
7
89
82
ABC=activated B cell-like subtype; UNC=unclassified; GCB=germinal center B cell-like subtype; GEP=gene 
expression profiling; IHC=immunohistochemistry; non-GCB=non-germinal center B cell-like subtype 
a The data represents IHC results used for patient enrollment into Study DBL3001.
1.4.2.
Power of Hypothesis Testing Based on Simulation Studies
DLBCL is a curable disease with multiple subtypes. It is a mixed population with cured and 
non-cured populations. Within cured and non-cured populations, DLBCL is further classified as
ABC, GCB, and unclassified DLBCL subtypes by GEP. In the simulation setting that is used to
estimate the study power based on the Song and Chi method (Song and Chi 2007), we assume 
that there are different treatment outcomes for the cured or uncured by GEP subtypes of ABC 
and non-ABC (GCB, and unclassified). Table 7 shows the simulation settings.
Table 7: 
Simulation Settings for Non-cured and Cured Population by GEP Subtype
Treatment
Control
ABC
Cured
50%
40%
Non-cured
HR=0.75
Median=18 months
non-ABC
Cured
60%
60%
Non-cured
HR=0.8, 0.9, 1.0
Median=36 months
ABC=activated B cell-like DLBCL; HR=Hazard ratio 
Note: For the cured population, the median is 180 months/15 years. k=0.6, 0.7, 0.8 for the proportion of ABC among 
the 800 subjects in the study.
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Table 8 shows the simulation results on study power for both the ITT and ABC populations. An 
increased proportion of EFS events from the ABC subgroup is associated with increased study 
power. The reason to change the non-cured population median of 12 months to 18 and 36 months 
is due to the lower than expected EFS event accumulation.
Simulation results indicate that we will lose some power for the ITT population compared with 
the original design. However, we will have an opportunity to show statistical significance for the 
ABC subpopulation with reasonable probability. For example, with a proportion of events of 
k=0.6 and a HR of 0.8 for the non-cured and non-ABC population, the original study power for 
the ITT population is 0.702. After considering both the ITT and ABC populations based on Song 
and Chi method (Song and Chi 2007), the power is 0.693 for the ITT population and 0.722 for 
the ABC population. The overall study power, which is the probability that we will reach
statistical significance for either ITT or ABC population, is 0.771. 
Table 8: 
Simulation Results for Study Power
k (Prop of events 
in ABC)
HR (non-ABC, 
non-cured)
ABC
ITT
Either ITT or ABC
Original ITT
0.6
0.8
0.722
0.693
0.771
0.702
0.7
0.8
0.796
0.771
0.828
0.781
0.8
0.8
0.847
0.830
0.867
0.839
0.6
0.9
0.704
0.616
0.736
0.623
0.7
0.9
0.782
0.722
0.804
0.731
0.8
0.9
0.845
0.811
0.861
0.819
0.6
1.0
0.680
0.538
0.699
0.544
0.7
1.0
0.773
0.675
0.788
0.683
0.8
1.0
0.837
0.781
0.847
0.789
ABC=activated B cell-like DLBCL; HR=hazard ratio; ITT=intent-to-treat; k=proportion of EFS events in ABC vs. 
ITT population
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. Subjects will be randomly assigned in a 
1:1 ratio to 1 of the 2 treatment arms based on a computer-generated randomization schedule 
prepared before the study and under the supervision of the sponsor. The randomization will be 
balanced by using randomly permuted blocks, and stratified by R-IPI score (1-2 vs. 3-5), region 
(U.S./Western Europe vs. Rest of World), and number of pre-specified treatment cycles (6 cycles 
vs. 8 cycles), then randomized in a 1:1 ratio to either Treatment Arm A (placebo+R-CHOP) or 
Treatment Arm B (ibrutinib+R-CHOP).
This is a double-blind study. Subjects, investigators, the IRC, and the sponsor’s study team 
members will remain blinded to treatment assignment until the database has been locked for the
clinical study report. Personnel who may be unblinded during the study are:

The independent DMC, 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.
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
Personnel performing blood serum concentration assays and analysis for pharmacokinetics.

Unblinded sponsor safety representative and Ethics Committee for serious adverse event 
(SAE) reporting.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Analysis Sets
The analysis populations are defined as:
1.
Intent-to-Treat (ITT) population: all randomized subjects who are enrolled with the non-
GCB DLBCL subtype by IHC. Subjects in this population will be analyzed according to the 
treatment to which they are randomized.
2.
ABC population: ITT population who are identified as having the ABC subtype as 
determined by GEP (retrospectively determined using available clinical study formalin-fixed 
paraffin embedded tissue specimens). Subjects in this population will be analyzed according 
to the treatment to which they are randomized.
3.
Per-protocol (PP) Population: all randomized subjects who undergo at least 1 postbaseline 
disease assessment and do not have major protocol violations as described below:
a.
did not meet all inclusion and exclusion criteria
b. did not receive the treatment to which they were randomized
c.
had less than 75% of study treatment compliance
Subjects in this analysis set will be analyzed according to the treatment to which they are 
randomized. 
4.
Biomarker population: all randomized subjects with biomarker data collected.
5.
Pharmacokinetic-evaluable population: all randomized subjects who received at least 1 dose 
of study drug and had at least 1 pharmacokinetic sample obtained posttreatment.
6.
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 characteristics, efficacy, and PRO data and the 
safety population will be used to summarize the safety data, unless otherwise specified. The 
ABC population will be used to summarize the efficacy and/or other data as appropriate. The PP 
population will be used for sensitivity analysis of the primary endpoint EFS if there is a more 
than 10% difference between ITT and PP populations. The biomarker population will be used to 
summarize the biomarker data. Pharmacokinetic-evaluable population will be used to summarize 
the pharmacokinetic data.
2.2.
Study Treatment and Study Medication
For the purpose of analysis, the term “study treatment” refers to all drugs, ibrutinib/placebo in 
combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
(R-CHOP). The term “study medication or study drug” refers to ibrutinib/placebo.
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2.3.
Baseline Definitions or Conventions
Unless specified otherwise, the baseline value is defined as the last available (non-missing) value 
collected on or prior to the date of the first administration of study drugs.
2.4.
Study Day and Visit Windows 
The randomization day is considered to be Day 1. Study day is defined as the current date -
Day 1 + 1.
The study date and corresponding study visit/cycle will be captured on each case report form 
(CRF). Visit windows will be created around the study day of each scheduled visit. They will be 
used to aggregate data values that are to be summarized by visit. Table 9 lists an example of the 
visit windows and the targeted study day. Details about the visit window will be specified in the 
DPS.
Table 9:
Visit Windows
Scheduled Study Day 
Visit Window 
Scheduled Study Day 
Visit Window 
Cycle 1 Day 1a
1, 21
Cycle 5 Day 1 (Day 85) 
85, 105
Cycle 2 Day 1 (Day 22) 
22, 42 
Cycle 6 Day 1 (Day 106) 
106, 126
Cycle 3 Day 1 (Day 43) 
43, 63
Cycle 7 Day 1 (Day 127) 
127, 147
Cycle 4 Day 1 (Day 64) 
64, 84
Cycle 8 Day 1 (Day 148) 
148, 168
a Study Day 1 begins on the day of randomization. 
Each cycle consists of 21 days.
Baseline value is defined as the last available value collected on or prior to the randomization day.
When there is a cycle delay, subsequent cycles will be shifted based on the above windows accordingly.
2.5.
Imputation of Missing Dates
In general, imputation of missing dates will be made for AE onset date, AE resolution date, date 
of death, start and end dates of prior and concomitant and subsequent therapies, date of 
progression/relapse on the last prior therapy, date of second PD, and date of initial diagnosis 
according to the following rules. Start date will be imputed before the end date.

If the date is completely missing, no imputation will be made. 

If the year is missing, then no imputation will be made. 

If only the year is present but the month and day are missing, then June 30th will be used.

If only the day is missing but the year and month are available, then the 15th of the month 
will be used. 
The above imputations will be modified by the following rules:

If such imputed date for prior therapies or initial diagnosis is on or after the randomization 
date, then randomization date - 1 day will be used. If such imputed date for subsequent 
therapies is before date of last dose, then date of last dose +1 day will be used.
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
The imputed start date for subsequent therapies will be adjusted sequentially using the 
following steps:

If the imputed start date is before the treatment discontinuation date or (last dose date if 
no treatment discontinuation dates) but in the same year and month, then the treatment 
discontinuation date or last dose date if no treatment discontinuation date will be used. 

If subsequent therapy end date is not missing and is before the imputed subsequent 
therapy start date, then the subsequent therapy end date will be used as the start date.

If the imputed date is for a date of death and is before the last date that the subject is known 
to be alive, the latter date will be used.

The imputed AE start date will be adjusted sequentially using the following steps:

If the imputed date is in the same year and month but before the first dose date, then the 
first dose date will be 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 will be used. 

If AE end date is not missing and the imputed AE start date is after the AE end date, 
then the AE end date will be used.

If the imputed AE start date is after date of death, then date of death will be used.

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 will be used.

If the imputed date is for an AE end date and is after the death date, then the death date will 
be used, or if the imputed AE end date is before the AE start date, then the AE start date will 
be used.

The AE imputation rule will be used for concomitant medication.
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2.6.
Definitions of Subgroups
Table 10 provides definitions for each of the subgroups.
Table 10:
Subgroups
Subgroup
Definition of Group
Analysis Typea
Gender
Male, Female
E, S, D
Race
Caucasian, non-Caucasian
E, S, D
Region
U.S./Western Europe, Rest of World
E, S, D
Age
<65, ≥65 years
E, S, D
Baseline ECOG
0-1, 2
E, S, D
Baseline R-IPI score
Good [1-2] (Low),
Poor [3-5] (High)
E, D
Number of pre-specified treatment 
cycles
6 cycles, 8 cycles
E, D
Baseline DLBCL Stage of Disease
II, III-IV
E, D
Baseline lactate dehydrogenase level
≤ upper limit of local normal range, > upper 
limit of local normal range
E, D
Number of extranodal sites of disease
at baseline
≤ 1, >1 extranodal sites
E, D
Hepatic Impairment
Normal vs (Mild or Moderate)b
S, D
Concomitant use of CYP3A inhibitor 
Strength of CYP3A inhibitor (mild, 
moderate, strong, and other)
S
GEP subtype
GCB, ABC, Unclassified
E, D
a D=demographics; E=efficacy; S=safety. Analyses will be performed for each subgroup as appropriate.
ECOG=Eastern Cooperative Oncology Group
b National Cancer Institute Organ Dysfunction Working Group (NCI ODWG) Liver Function Classification.
2.7.
Other General Definitions 

Subsequent antilymphoma therapy is not allowed prior to PD/relapse from CR except for 
either PET-positive or biopsy-proven residual disease after completion of at least 6 cycles of 
R-CHOP therapy. The start date of the first subsequent antilymphoma therapy will be 
entered in the electronic CRF (eCRF). 

A PET scan is required at the end of treatment. It is recommended but not mandated at 
baseline. The end of treatment includes the completion of the scheduled 6 or 8 cycles of 
R-CHOP treatment or early withdrawal.

If an early withdrawal from treatment occurs after completion of 6 cycles of R-CHOP 
therapy, the initiation of subsequent antilymphoma therapy due to PET-positive or 
biopsy-proven residual disease will be counted as an EFS event. However, if the early 
withdrawal from treatment occurs before completion of 6 cycles of R-CHOP therapy, it will 
not be counted as an EFS event, even in the presence of PET-positive or biopsy-proven 
residual disease. Note that PET-positive residual disease is collected on an eCRF page. 

Regarding bone marrow biopsy, data reported on the ‘Bone Marrow Biopsy and Aspirate’ 
CRF will be used to derive bone marrow involvement. Subjects with a bone marrow aspirate 
or biopsy histology result of “positive” or histology negative but confirmed to be positive by 
IHC or flow cytometry is “yes”’ at baseline based on any method of assessment will be 
considered to have bone marrow involved at baseline. 
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Disease progression collection after the initiation of subsequent antilymphoma therapy: after the 
initiation of subsequent antilymphoma therapy, the patient will continue to be followed to assess 
disease progression every 16 weeks in the first 24 months, then every 24 weeks up to PD/relapse 
from CR, withdrawal, death, or clinical cutoff for the primary analysis, whichever occurs first.
2.7.1.
Treatment-Emergent Adverse Events
Treatment-emergent AEs are AEs that occur after the first dose of study treatment, and within 
30 days following the last dose of study treatment; any AE that is considered study 
treatment-related regardless of the start date of the event; or any AE that is present at baseline 
but worsens in severity within 30 days following the last dose of study treatment or is 
subsequently considered study treatment-related by the investigator. Adverse events occurring
after the initiation of the subsequent therapy will not be considered as the TEAE.
2.7.2.
Year and Month
1 year equals to 365.25 days and 1 month equals to 30.4375 days.
2.7.3.
Age
Age in years is collected on an eCRF page. 
2.7.4.
Time from Initial Diagnosis to Randomization
Time from initial diagnosis to randomization in days will be calculated as (date of randomization 
- date of initial diagnosis) and the result will be rounded to the integer. Partially missing initial 
diagnosis dates will be imputed based on the rules provided in Section 2.5 of the SAP. 
2.7.5.
Date of Overall Response/Progressive Disease for Each Timepoint
When multiple or repetitive assessments for the timepoint are performed on different dates, then:

For overall response:
The date is determined as the date of last assessment needed to document the response (CR, 
partial response [PR], or stable disease [SD])

For PD (PD/relapse from CR):
The date is determined as the date of the earliest assessment used to document PD or relapse 
from CR. The PD date is collected on the eCRF page.
2.7.6.
Date of Subsequent Systemic Antilymphoma Therapy Event
The subsequent systemic antilymphoma therapy event is defined as the initiation of systemic 
antilymphoma therapy for either PET-positive or biopsy-proven residual disease upon 
completion of at least 6 cycles of R-CHOP therapy. The date is determined as the date of the 
earliest disease assessment documenting the need for a subsequent systemic antilymphoma 
therapy event.
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2.7.7.
Date of Response/Best Response
Date of first observed response/best response (CR or PR).
2.7.8.
Date of Progression 
Date of first observed progression/relapse from CR.
2.7.9.
Date of Subsequent Systemic Antilymphoma Therapy Event 
Date of first subsequent systemic antilymphoma therapy event.
2.7.10.
Date of EFS Event 
Date of first observed EFS event: either progression, relapse from CR, subsequent systemic 
antilymphoma therapy event, or death.
2.7.11.
Date of PFS Event 
Date of first observed PFS event: either progression, relapse from CR, or death.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
3.1.
Interim Analysis
In the original study design, 1 interim analysis was planned for the primary endpoint EFS, when 
approximately 270 EFS events had been observed. However, the planned interim analysis was 
omitted in protocol Amendment INT-3 due to the lower than expected event accumulation. The 
final analysis of the primary endpoint of EFS is calendar driven, more specifically, the clinical 
cutoff is 30 months after the 800th subject is randomized into the study.
3.2.
Data Monitoring Committee
A DMC will be 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 will meet periodically to review interim data, assess the evidence of benefit or 
adverse effects of ibrutinib, and to monitor the conduct of the study. After the review, the DMC
will make recommendations regarding the conduct of the study. The details regarding the DMC
responsibilities, authorities, and procedures will be provided in a separate DMC charter.
At the interim analysis, the DMC could recommend stopping the study for efficacy, if the 
pre-specified stopping boundary was crossed. In addition to the planned interim analysis for 
efficacy, 4 safety review meetings were planned, which would occur approximately 1 month 
after 50, 250, 450, and 650 subjects have been randomized. The safety review was to focus on 
deaths, treatment discontinuations, SAEs, Grade ≥3 events, and AEs of special interest. Based on 
the results from these scheduled safety review meetings, the DMC chair requested an additional 
safety review meeting when the last subject was randomized. This additional meeting occurred 
on 29 January 2016. After reviewing the safety profiles for all 838 enrolled subjects, the DMC 
decided that there was no need to review any additional safety data. The next data review was 
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planned to occur at an interim analysis, when approximately 270 EFS events are observed. All 
deaths, treatment discontinuations, and SAEs will be reviewed by the sponsor’s responsible
physician on an ongoing basis to identify safety concerns and the DMC will be informed of any 
new potential signals. 
As indicated earlier, the original planned interim analysis was omitted in protocol 
Amendment INT-3 due to the lower than expected EFS event rate for blinded data. The interim 
analysis-related statements are no longer applicable. 
4.
SUBJECT INFORMATION
All statistical analyses will be performed using statistical analysis system (SAS®). Analyses of 
disposition, demographic, baseline disease characteristics, and prior and concomitant therapy 
will be conducted on the ITT population. Analyses of treatment compliance and extent of 
exposure will be conducted on the Safety population. Analyses of background therapy 
(R-CHOP) will be conducted on the Safety population. No statistical testing is planned.
Unless otherwise specified, all continuous endpoints will be summarized using descriptive 
statistics, which will include the number of subjects with a valid measurement (n), mean, 
standard deviation, median, minimum, and maximum. All categorical endpoints will be 
summarized using frequencies and percentages. Percentages will be calculated by dividing the 
number of subjects with the characteristic of interest by the number of subjects in the analysis 
population and/or evaluable population, as appropriate.
4.1.
Disposition Information
The number of subjects randomized, discontinuing and completing the study treatment will be 
reported for the ITT population. The reasons for discontinuation, as indicated by the 
investigators, will be summarized by the number of subjects reported. Those subjects who 
discontinue study treatment due to AEs will be further tabulated by relationship to study 
medication. The tabulation of the above information will be provided by treatment arms and 
combined. 
Descriptive statistics will be provided for time on study. Time on study is defined the same way 
as OS with reversed censoring, ie, subjects who die will be 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 demographic and baseline characteristics will be summarized for the ITT population.
Subject enrollment will be summarized by country and site. 
Summary of baseline demographics, vital signs, disease characteristics, and laboratory tests 
graded by National Cancer Institute Common Terminology Criteria for Adverse Events 
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(NCI-CTCAE; the most recent version will be used), and stratification factors will be 
summarized by treatment arm and combined.
Two panels of baseline clinical laboratory tests will be summarized by frequency: hematology, 
and serum chemistry. Frequencies of NCI-CTCAE grade are to be provided for the following 
laboratory tests at baseline: 
Hematology: hemoglobin, white blood cell, absolute neutrophil count (ANC), absolute 
lymphocyte count (ALC), and platelets.
Chemistry: sodium, potassium, creatinine, creatinine clearance, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase, LDH, total bilirubin, albumin, and 
magnesium.
Note: Magnesium is to be evaluated on Day 1 of Cycles 1 and 2, and as clinically indicated.
4.3.
Extent of Exposure
All extent-of-exposure summaries are to be presented for the safety population. The frequency of 
subjects who receive at least 1 postbaseline treatment cycle will be tabulated by the number of 
cycles. The number of treatment cycles will be summarized, along with time on study treatment 
and dose intensity for each study drug.
Summaries will be provided for total dose of each study drug administered by cycle and total 
cumulative dose. The number and percentage of subjects on treatment, and number and 
percentage of subjects with cycle delays will also be presented based on the CRF data collection. 
For each study drug, the following summaries are to be reported: number of subjects dosed and 
number of subjects with cycle delay, dose reduced, and dose discontinued.
The reasons for dose modification will be summarized for each of the following categories: cycle 
delay, dose reduction, and dose discontinuation. 
For each type of dose modification mentioned above, AEs leading to change in dose will be 
summarized for each of the study drugs by treatment arms. 
4.4.
Protocol Eligibility and Major Protocol Deviations
Subjects with major protocol deviations will be listed by treatment arm. Protocol deviations will 
be based on clinical review, including, but not limited to the following: eligibility criteria, 
treatment compliance, subject safety, efficacy assessment deviations, and other(s) which might 
significantly impact safety/efficacy assessment. Protocol deviations will be closely monitored 
during the execution of the study and the final set of protocol deviation criteria will be finalized 
before database lock. The major protocol deviations will be reviewed and/or classified based on 
clinical review of the protocol deviations.
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4.5.
Prior and Concomitant Medications
For summarization purposes, medications will be coded to a generic term based on the World 
Health Organization (WHO) drug dictionary. Medications administered prior to the first dose of 
study medication will be considered prior medications. Concomitant therapies include those 
taken on or after first dose date of study treatment through 30 days after the last dose of study 
treatment. However, for CYP3A inhibitors or inducers, concomitant use is defined as 
administration on or after the first dose of study treatment through the last dose of study 
treatment.
The incidence of prior and concomitant medications will be summarized by Anatomical 
Therapeutic Chemical (ATC) class and drug generic term. 
4.6.
Medical History
Abnormal medical history findings reported by investigator will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA; the most recent version will be used) and 
summarized by system organ class and preferred term.
5.
EFFICACY
5.1.
Analysis Specifications
5.1.1.
Level of Significance
In general, all tests will be performed at a 1-sided significance level of 0.025, unless otherwise 
specified. All interval estimations will be reported using 2-sided 95% confidence intervals (CIs).
Multiplicity adjustment for the primary endpoint EFS for both ITT population and ABC 
population is described in Section 1.4.1 using the Song and Chi method (Song and Chi 2007). 
Following Figure 1, if the weighted test statistics p-value at Stage I is <0.04 (2-sided), then the 
significance level will be 0.05 (2-sided) for both the ITT and ABC populations. If the p-value 
corresponding to the weighted test statistic at Stage I is ≥0.04 but <0.2 (2-sided), then the 
significance level for ABC population will be 0.02709, based on the actual proportion 
(176/247=0.7126) of the ABC EFS events among the total events in the ITT population. If the 
observed p-value for ABC population is < 0.02709, then the null hypothesis for ABC population 
will be rejected and we can re-test the ITT population using 0.05 (2-sided) significance level.
The level of significance for secondary endpoints is specified in Section 5.3.5.
5.1.2.
Data Handling Rules
The data handling rules will be outlined in the DPS.
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5.1.3.
General Analysis Considerations
Descriptive statistics and subject listings will be used to summarize the data. For continuous 
variables, the number of observations, means, standard deviations, medians, and ranges will be 
used. For discrete variables, frequency and percentage will be presented. For time-to-event 
variables, Kaplan-Meier estimates will be provided. 
Disease progression and response will be based on investigator assessment, using the Revised 
Response Criteria for Malignant Lymphoma (Cheson 2007). Detailed criteria for response 
categories can be found in the protocol. An IRC will perform an independent disease assessment 
for selected random samples based on the audit plan to determine disease progression and 
response, which will be evaluated as confirmation of the investigator tumor evaluation. The 
details will be described in audit plan (Attachment 1).
Key efficacy analysis will be performed based on both the ITT and the ABC populations as 
described in Section 2.1. The subgroup analyses (see the list of subgroups in Section 2.6) will be 
performed for both the primary endpoint EFS and the key secondary endpoints including PFS
and OS.
5.2.
Primary Efficacy Endpoint
5.2.1.
Definition
The primary endpoint is EFS, which is defined as the duration from the date of randomization to
the date of disease progression, relapse from CR as assessed by the investigator, initiation of 
systemic antilymphoma therapy for either PET-positive or biopsy-proven residual disease upon 
completion of at least 6 cycles of R-CHOP therapy, or death, whichever occurs first. 
Subjects who have withdrawn from the study or who are lost to follow up will have EFS
censored at the date of their last adequate disease assessment on or before the withdrawal date. 
For subjects who do not have an EFS event (ie, subjects who do not have PD/relapse from CR, a 
subsequent systemic antilymphoma therapy event, and are alive), as well as for those subjects 
with unknown EFS status or unknown survival status, as of the data cutoff date, EFS will be 
censored at the date of the subject’s last adequate disease assessment. If there are no baseline or 
postbaseline disease assessments (and no death is observed), for a subject, EFS will be censored 
on the date of randomization. All subjects will continue to be followed until either confirmation 
of PD/relapse from CR, death, or clinical cutoff for the primary endpoint, whichever occurs first,
for the final EFS analysis. The details of the censoring rules are listed in Table 11.
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Table 11:
Censoring Rules for Primary EFS Analysis
Situation
Outcome
Date
Event 
Description/ 
Censoring 
Reason
Progression/Relapse from CRa
documented at a scheduled visit or 
between scheduled visits 
EFS eventb
PD datea
PD
Death before first documented PD
EFS event
Date of death 
Death
PD or death, documented after clinical 
cutoff but prior to the database lock
EFS event
PD date or death date
PD or Death
Initiation of subsequent systemic 
antilymphoma therapy event due to 
residual diseasec at a scheduled visit or 
between scheduled visits 
EFS event
Earliest date of disease assessment 
documenting need for subsequent 
systemic antilymphoma therapy 
eventc
New 
antilymphoma 
therapy due to 
residual diseasec
No baseline tumor assessments
Censored 
Date of randomization
No baseline 
disease 
assessment
No on-study tumor assessments, no 
death, and no withdrawal
Censored
Date of randomization
No death or 
on-study disease 
assessment
Withdrawal of consent to study 
participation or investigator/sponsor 
terminatione before PD or death
Censored 
Date of last adequate disease 
assessmentd
Withdrew 
consent
Lost to follow up before documented 
PD or death 
Censored 
Date of last adequate disease 
assessmentd
Lost to follow up
CR=complete response; EFS=event-free survival; PD=progressive disease; PET=positron emission tomography
a PD will indicate progression/relapse from CR; PD date is the earliest date of disease assessment documenting 
progression/relapse from CR.
b If more than 1 EFS event occurs for a subject, the event occurring first will be the subject’s EFS event, and this 
date will determine the subject’s time to EFS event.
c The initiation of subsequent systemic antilymphoma therapy event is a special case of initiation of subsequent 
systemic antilymphoma therapy, and is defined as the initiation of systemic antilymphoma therapy for either 
PET-positive or biopsy-proven residual disease upon completion of at least 6 cycles of R-CHOP therapy.
d Adequate disease assessment is defined as an assessment having sufficient evidence to correctly indicate that 
progression has or has not occurred. The Screening visit, the visit occurring at the end-of-treatment Cycle 4, the 
End-of-Treatment visit, and Pre-PD Posttreatment visits were designed to provide adequate disease assessment.
e Discontinuations/withdrawals mentioned in this table refer to those that apply to the entire study and not to those 
that solely apply to treatment.
5.2.2.
Primary Analysis of EFS
The primary analysis will be based on the ITT and ABC populations following the Song and 
Chi method (Song and Chi 2007) discussed in Section 1.4.1. At Stage I, the stratified log-rank 
test will be used for both the ITT and ABC populations; the weight parameter of k will be the 
proportion of the number of EFS events observed in the ABC population (0.02709 based on data 
after CCO). The weighted test statistic Z1 will be estimated using equation (2) in Section 1.4.1, 
which considers both the ABC and complementary ABC population (GCB, unclassified and 
unknown/missing). If the corresponding p-value (p1) to the weighted test statistic Z1 is less than 
0.04 (2-sides), then test both the ITT and ABC populations using the significance level of 0.05 
(2-sided) based on the stratified log-rank test. The stratification factors to be used in the analysis 
are R-IPI (1-2 vs. 3-5), region (U.S./Western Europe vs. Rest of World), and number of 
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pre-specified treatment cycles (6 cycles vs. 8 cycles). If p1 is greater than or equal to 0.04 but less 
than 0.2, then test the ABC population using the significance level of 0.02709. If the ABC 
population is significant, then re-test the ITT population using the significance level of 0.05.
(2-sided). The HR for ibrutinib+R-CHOP relative to placebo+R-CHOP and its associated 95% 
CI will be calculated based on the stratified Cox proportional hazards model, stratified by the 
stratification factors. The EFS distribution and median EFS with a 95% CI will be estimated 
using the Kaplan-Meier product-limit method for the ITT population.
In case there is strong evidence of crossing hazard, other test statistics such as Rényi statistics
(Rényi 1953) may be used instead of log-rank test. In addition, the proportional hazards cure 
model will be used to estimate the cure rate for each treatment arm.
5.2.3.
Sensitivity Analysis of EFS
Sensitivity analyses will be performed to evaluate the robustness of the analyses. Per protocol 
Amendment INT-3, the retrospective GEP test for all study screened subjects will be performed. 
Some of the screen failure patients due to GCB by IHC were proven to be ABC by GEP and 
should have been enrolled in the study. Imputation of the clinical data for those subjects who are 
GCB by IHC but ABC by GEP will be made to assess whether the results are consistent if the 
GEP test had been used for subject selection instead of IHC. In addition, approximately 10% of 
patients in the study may not have sufficient or unqualified samples for GEP testing. Sensitivity 
analyses will be performed after imputing the missing GEP results. 
5.2.3.1.
Imputing the Screen Failures due to GCB by IHC who are ABC by 
GEP
The original study design is to enroll subjects with the non-GCB subtype based on IHC. It is 
increasingly appreciated that DLBCL is heterogeneous in terms of morphology, genetics, and 
biologic behavior. Gene expression profiling and IHC are 2 of the assay platforms currently 
being used for determining cell of origin. Gene expression profiling platforms assign specimens 
into 1 of 3 diagnostic categories: GCB, ABC, or unclassified. Immunohistochemistry divides the 
population into 2 categories: GCB and non-GCB. The study protocol was amended to perform 
retrospective GEP testing for all screened study subjects. The sensitivity analysis will be 
performed by imputing the subjects with the ABC subtype that were classified as GCB by IHC. 
The hot deck imputation method will be used to impute the missing data.
For example, the missing A subjects (GCB by IHC and ABC by GEP and meeting all eligibility 
criteria) are allocated to the ibrutinib group and placebo group using a 1:1 randomization ratio.
Randomly assign A x 50% subjects to ibrutinib group (A1), and A x 50% subjects to placebo 
group (A2).

Given a percentage p, for each of the A1 x p subjects assigned to the ibrutinib group, sample 
the subjects based on the bootstrapping method with replacement from the ibrutinib group in 
the sampling pool. For each of the A x (1-p) subjects assigned to the ibrutinib group, sample 
the subjects with replacement from the placebo group in the sampling pool. 
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
For each of the A2 subjects assigned to the placebo group, sample the subjects with 
replacement from the placebo group in the sampling pool. 

Repeat above steps 1,000 times. Efficacy result will be estimated based on multiple 
imputation method through SAS MIANALYZE procedure.
The percentage p can be chosen as 100%, 75%, and 50%, respectively. The lower percentage of 
p is the lower estimated ibrutinib effect and favors the control arm.
5.2.3.2.
Imputing Missing GEP Test Results
The GEP test will be retrospectively performed for all screened study subjects. It is expected that 
not every subject will have sufficient samples for the GEP test or will not be amenable to testing 
and so the GEP subtype will be undetermined. However, the missing GEP test results (~10%) 
can be reasonably assumed to be random. Therefore, the missing GEP results will be statistically 
imputed.  A sensitivity analysis will be performed based on the imputed missing GEP results. 
The imputation method will follow the procedures illustrated in Figure 2. First, the complete 
dataset including subjects with known IHC results, GEP results, and other pretreatment or 
baseline information if available will be randomly split into 2 subsets: two thirds for the training 
set and one third for the independent testing set. The training set will be used to fit 
2 classification models - logistics regression model and decision tree. Least absolute shrinkage 
and selection operator (lasso) and/or elastic net regularization method may be applied in variable 
selection in logistic regression should a great number of baseline covariates are available. 
Second, the predictive accuracy of the fitted models using the training set will be assessed using 
the testing set data. The predictive accuracy will be measured by the area under the receiver 
operating characteristic (ROC) curve. Generally, the model or GEP classifier with greatest area 
under the curve (AUC) estimated from testing dataset will be the final classifier. However, if the 
AUC of logistic regression model is close to but not the greatest, the consideration will be given 
to this model because it can be easily fitted, verified and interpreted.  Missing GEP results will 
be imputed using the final classifier. The cutoff of the predicted probability of GEP ABC for the 
final classifier will be determined to maximize ABC concordance or sensitivity while Non-ABC 
concordance or specificity will be equal to or greater than 80%. This relatively high specificity 
will ensure reasonably high ABC predictive value, or positive predictive value (PPV).
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Figure 2:
Flow Chart for the Imputation of Missing GEP Sample
For the imputed ABC subjects, some of them may be already randomized in the study and some 
of them may be screen failures (SFs) due to the IHC GCB result. These SF cases do not have 
clinical data information because they were not enrolled in the study. Therefore, the hot deck 
method discussed in Section 5.2.3.1 will used to impute the postbaseline information for these 
SFs. 
5.2.3.3.
Sensitivity Analysis
Sensitivity analyses will include:
1) Stratified Wilcoxon test for the ITT population
2) Restricted Mean EFS Time difference (Uno 2014)
3) Subjects with EFS events observed after missing ≥2 consecutive scheduled disease 
assessment visits will be censored at the last adequate disease assessment before the 
2 consecutive missing assessment visits
4) Censoring subjects who receive subsequent antilymphoma therapy and who did not meet the 
criteria for a subsequent antilymphoma therapy event at the date of last adequate disease 
assessment on or before subsequent antilymphoma therapy
5) Sensitivity analysis based on the final validated assay for the non-GCB subtype of DLBCL
6) Sensitivity analysis based on the imputed results for subjects who are ABC by GEP, but GCB 
by IHC will be performed as appropriate (data imputation will be based on Section 5.2.3.1)
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7) Sensitivity analysis will be performed as appropriate for subjects who have a missing GEP 
sample, based on the imputed ABC subtype results (imputation is described in 
Section 5.2.3.2).  
8) Sensitivity analysis based on the per-protocol population. If 90% or more subjects from ITT 
analysis set are included in PP analysis set then no analysis will be performed on PP analysis 
set.
5.2.3.4.
Additional Covariate-adjusted Analysis of EFS
Additional exploratory analyses on EFS will be performed using a selected set of potential 
prognostic variables (obtained at or before baseline) as covariates in Cox regression models.
Potential prognostic factors are as follows: 

Age (<65 vs. ≥65 years)

Gender

Race: (Caucasian vs. non-Caucasian)

Revised International Prognostic Index (1-2 vs. 3-5)

Region (U.S./Western Europe vs. Rest of World)

Number of pre-specified treatment cycles (6 vs. 8 cycles)

Baseline ECOG performance status (0-1 vs. 2)

Baseline DLBCL stage of disease (II vs. III-IV)

Baseline LDH level (≤ upper limit of local normal range vs. > upper limit of local normal 
range)

Number of extranodal sites of disease at baseline (≤ 1 vs. >1 extranodal sites)

GEP subtype, GCB vs. ABC vs. unclassified
Each factor will be assessed individually for prognostic values (1-sided p-value <0.05) using a 
univariate Cox model. Factors that are deemed to have prognostic value will be included as 
covariates in a multivariate Cox model to assess their significance in the presence of other 
factors. Selection methods (such as stepwise selection) will be used to identify the final set of 
prognostic factors (exit 1-sided p-value set to be 0.05). Treatment will then be added to this final 
model to assess the effect of treatment when adjusted for these prognostic factors.
5.2.3.5.
Subgroup Analysis of EFS
Descriptive subgroup analysis will be performed for the selected potential prognostic variables
(Section 5.2.3.4) to assess the internal consistency of the treatment benefit using a Forest plot. 
Hazard ratios between the 2 treatment arms within the subgroups and their 95% CIs will be 
calculated.
Additionally, exploratory subgroup analyses will be performed on EFS to determine the possible 
interaction of the subgroups with treatment using the Cox Proportional Hazard Model. If an 
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interaction results in statistical significance (1-sided p <0.10), then the nature of treatment 
comparisons within each subgroup stratum will be examined. 
5.3.
Secondary Efficacy Endpoints 
The secondary endpoints, along with corresponding analysis methods, are defined in the 
following 
subsections.
The 
treatment 
effect 
of 
ibrutinib+R-CHOP 
compared 
to 
placebo+R-CHOP will be tested with the corresponding statistics test. For the time to events 
endpoint, log-rank test will be used; for binary endpoint, the Cochran-Mantel-Haenszel Chi-
square statistic will be used under the hierarchical test procedure, the comparison will be subject 
to the significance of the superiority test of ibrutinib over placebo.
5.3.1.
Progression-free Survival 
Progression-free survival is defined as the duration from the date of randomization to the date of 
progression, relapse from CR, or death, whichever occurs first.
Progression-free survival will be analyzed in a similar fashion as EFS. However, in contrast to 
EFS, the censoring rules for PFS will not be influenced by initiation of subsequent 
antilymphoma therapy, either as an event or otherwise. Sensitivity analysis, subgroup analysis, 
and the covariate-adjusted analysis will be performed as appropriate in a similar fashion as the 
primary endpoint EFS, except for the censoring rule; ie, PFS is not censored for subjects who 
received subsequent antilymphoma therapy.
The treatment effect of ibrutinib+R-CHOP compared to placebo+R-CHOP based on PFS will be 
tested with a stratified log-rank test adjusted for the randomization stratification factors.
The HR for ibrutinib+R-CHOP relative to placebo+R-CHOP and its associated 95% CI will be 
calculated based on the stratified Cox proportional hazards model, stratified by the stratification 
factors.
The PFS analysis will be performed for both the ITT and ABC populations.
5.3.2.
Complete Response Rate
Complete response rate is defined as the proportion of subjects who have measurable disease at 
baseline and achieve a CR prior to the initiation of subsequent antilymphoma therapy.
All randomized subjects who have a valid baseline value will be included in this analysis. 
Subjects with missing post-randomization data are considered non-responders. Complete 
response rate will be summarized using descriptive statistics for categorical data by treatment 
arm.
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The relative risk (ibrutinib+R-CHOP vs. placebo+R-CHOP) of CR will be reported along with 
the 
associated 
95% CI. 
Statistical 
inference 
will 
be 
evaluated 
using 
the 
Cochran-Mantel-Haenszel Chi-square statistic, adjusted for the stratification factors R-IPI score, 
region, and number of pre-specified treatment cycles. Logistic regression analysis will also be 
performed to estimate an odds ratio and its associated 95% CI between the 2 treatment arms,
adjusted for the stratification factors. 
The CR analysis will be performed for both the ITT and ABC populations.
5.3.3.
Overall Survival
Overall survival is defined as the duration 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.
Overall survival will be analyzed using the stratified log-rank test for treatment comparison. The 
OS distribution and median OS with its 95% CI will be estimated using the Kaplan-Meier 
product-limit method. The HR for ibrutinib+R-CHOP relative to placebo+R-CHOP and its 
associated 95% CI will be calculated based on the stratified Cox proportional hazards model, 
incorporating the stratification factors.
The same subgroup analysis planned for EFS may be performed for OS if the number of events 
within each subgroup is sufficient. 
The OS analysis will be performed for both the ITT and ABC populations.
In addition, exploratory analyses, using the Cox proportional hazards model with and without the 
covariates specified in Section 5.2.3.4, will be performed.
5.3.3.1.
Time to Worsening on the Lym Subscale
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 
2 criteria; a 3-point decrease and a 5-point decrease from baseline in patient symptoms (see 
Section 7). Time to worsening will be analyzed using the log-rank test. 
The treatment effect of ibrutinib+R-CHOP compared to placebo+R-CHOP based on TTW will 
be tested with a stratified log-rank test adjusted for the randomization stratification factors. The 
HR for ibrutinib+R-CHOP relative to placebo+R-CHOP and its associated 95% CI will be 
calculated based on the stratified Cox proportional hazards model, stratified by the stratification 
factors.
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5.3.4.
Related Exploratory Analyses
5.3.4.1.
Overall Response Rates
Overall response rate is defined as the proportion of subjects who achieve either a CR or PR as 
their best overall response as assessed by investigator. All responses of CR and PR after 
subsequent antilymphoma therapy will be excluded.
All randomized subjects with a measurable disease at baseline will be included in this analysis. 
Subjects with missing post-randomization data are considered non-responders. 
The order of overall response categories is: CR> PR> SD> PD> NE. The highest category of 
overall response is the best overall response.
Overall response rate will be estimated in the same manner as CR rate.
5.3.4.2.
Duration of Response
Duration of response will be analyzed for subjects with a CR or PR according to the investigator 
and is defined as the interval between the date of initial documentation of a response and the date 
of first documented evidence of PD or death. The censoring rule for duration of response is the 
same as PFS.
Only subjects who achieve a CR or PR will be included in the analysis of duration of response. 
Duration of response will be summarized descriptively using the Kaplan-Meier method. 
5.3.5.
Multiplicity Adjustment for Secondary Endpoints
Inferential hypothesis testing for secondary endpoints will be conducted only if the primary 
analysis of EFS achieves statistical significance.
A sequential gate-keeping procedure will be used to test other secondary endpoints if the primary 
endpoint of EFS achieves statistical significance for both the ITT and ABC populations. Formal 
hypothesis testing will be made for the ITT population only in hierarchical order. More 
specifically, if PFS achieves statistical significance, then CR will be tested, If CR achieves 
statistical significance, then OS will be tested, followed by TTW in the Lym subscale of the 
FACT Lym. All statistical significance levels are defined at a 1-sided alpha of 0.025.
5.4.
Other Exploratory Efficacy Endpoints 
Additional exploratory efficacy endpoints:

Evaluate the mean change from baseline in EQ-5D-5L score for each postbaseline 
assessment and/or the FACT-Lym score, as appropriate.

Evaluate biomarkers associated with resistance to ibrutinib in subjects who progress on 
ibrutinib treatment compared to those who remain in CR.
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6.
SAFETY
All safety analyses will be based on the safety population. The baseline value for safety 
assessment is defined as the value collected at the time closest to, but prior to, the start of study 
drug administration.
Safety parameters to be evaluated are the incidence, intensity, and type of AEs, clinically 
significant changes in the subject’s physical examination findings, vital signs measurements, and 
clinical laboratory results by treatment arm. 
Safety analyses will be performed by the treatment actually received. 
6.1.
Adverse Events
6.1.1.
All Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
MedDRA (the latest version will be used). All reported AEs with onset date on or after the first 
dose of study drug up through 30 days after the last dose (ie, TEAEs) will be included in the 
analysis. For each AE, the percentage of subjects who experience at least 1 occurrence of the 
given event will be summarized by treatment arm. 
Treatment-emergent AEs are AEs that occur after the first dose of study drug, through the Active 
Treatment Phase, and for 30 days following the last dose of study drug; any AE that is 
considered study drug-related regardless of the start date of the event; or any event that is present 
at baseline but worsens in severity or is subsequently considered study drug-related by the 
investigator. 
Analysis of TEAEs includes:

Incidence of AEs and SAEs by system organ class and preferred term

Incidence of AEs and SAEs by severity

Incidence of AEs and SAEs by relationship to study drug

Incidence of AEs by subgroup (eg, age, sex, race, region, baseline ECOG, baseline hepatic 
impairment, and concomitant use of CYP3A inhibitor)
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 (highest to lowest incidence
within ibrutinib+R-CHOP arm). The same summary will be provided for study drug-related AEs
(study drug-related includes possible, probable, or very likely related to study drug), SAEs, and 
drug-related SAEs, as well as AEs leading to treatment discontinuation and death.
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6.1.2.
Adverse Events of Special Interest 
Major hemorrhage is an AE of special interest and is a subset of hemorrhagic events that are 
Grade ≥3, serious, or belonging to central nervous system (CNS) hemorrhage/hematoma. 
Other safety observations include cytopenia, lymphocytosis, atrial fibrillation and atrial flutter, 
infections, 
other 
malignancies, 
hypertension,
Leukostasis, 
Tumor 
lysis 
syndrome, 
Hypersensitivity, Eye disorders, Hepatic disorders, SCAR (severe cutaneous adverse reactions),
interstitial lung disease, Cardiac Arrhythmias (excluding Atrial Fibrillation) and rituximab-
related infusion reaction. Where applicable, the currently agreed-upon grouping criteria for 
ibrutinib TEAEs will be applied. Treatment-emergent AEs of special interest will be summarized 
similarly to TEAEs.
6.2.
Deaths
The incidence of deaths within 30 days after last dose are to be reported, as well as all deaths for 
all subjects treated. Cause of death will be summarized as well in this table. In particular, 
frequencies of deaths due to study-treatment-related AEs will be reported.
6.3.
Clinical Laboratory Tests
Laboratory data of hematology, coagulation, and serum chemistry up to 30 days after last dose or 
the End-of-Treatment visit date, whichever is later, will be reported in SI units. Coagulation 
parameters are
activated partial thromboplastin time and international normalized 
ratio/prothrombin time.
Summary statistics (mean, standard deviation, median, and range) will be calculated for all 
numerical laboratory results in SI units, including change from baseline at each timepoint of 
assessment and change from baseline to the last value. 
Graphical displays of over-time summaries will be presented for the following key laboratory 
parameters: ANC, ALC, hemoglobin, white blood cell count, platelet count, total bilirubin, 
creatinine, creatinine clearance, alkaline phosphatase, and electrolytes (sodium, potassium).
Shift tables from baseline to worst value on study (from treatment start to 30 days after the last 
dose or the End-of-Treatment visit date, whichever is later) will be produced for selected 
laboratory parameters, to include hemoglobin, white blood cell count, platelet count, ANC, ALC, 
AST, ALT, LDH, total bilirubin, creatinine, creatinine clearance, alkaline phosphatase, albumin, 
magnesium, and electrolytes (sodium, potassium). The worst toxicity grade during treatment will 
be tabulated.
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6.3.1.
Creatinine Clearance
Creatinine clearance (CrCl) is calculated using the Cockroft-Gault formula:
            
For males, the factor is 1 instead of 0.85.
6.3.2.
Analysis of Lymphocytosis 
A descriptive summary of ALCs with and without lymphocytosis, time to lymphocytosis, and 
duration of lymphocytosis will be provided by treatment. Lymphocytosis is defined as ALCs
increasing ≥50% from baseline and achieving level ≥5x109/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 <5x109/L, whichever occurs first. Time to 
lymphocytosis is defined as the interval between the date of first dose and the first date that 
subject had lymphocytosis, presented in weeks. Duration of lymphocytosis will be derived from 
the first date that a subject had lymphocytosis until the event recovered for the first time,
presented in weeks. Subjects who have not recovered will be censored at the last laboratory
assessment. 
6.4.
Electrocardiogram
Abnormal electrocardiogram findings will be summarized.
6.5.
Vital Signs and Physical Examination Findings
Abnormal physical examination findings will be tabulated by body system.
6.6.
Other Safety Parameters
Frequencies of ECOG score will be reported over time. Descriptive statistics of change in ECOG 
scores from baseline will also be provided. 
7.
PATIENT-REPORTED OUTCOMES 
Two PRO instruments, the FACT-Lym and EQ-5D-5L will be administered in this study. The 
following section describes PRO analyses that assess subject-perceived disease burden and 
symptoms. These will be assessed throughout the study. Patient-reported outcome assessments 
using the FACT-Lym and EQ-5D-5L will be analyzed to examine if the subjects’ perspective of 
response to treatment are accompanied by measurable changes in disease symptoms and health 
status. 
FACT-Lym consists of the Functional Assessment of Chronic Illness Therapy-General 
(FACT-G) and a lymphoma-specific additional concerns subscale (Lym) (Protocol 
Attachment 6). Responses to all items are rated on a 5-point scale ranging from 0 “not at all” to 
4 “very much”. The FACT-G consists of three 7-item subscales scored 0 to 28 (physical 
well-being, social well-being, and functional well-being) plus one 6-item subscale (emotional 
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well-being) scored 0 to 24. The recall period is the past 7 days. The lymphoma scale includes 
15 items and scores range from 0 to 60. Two summary scores may also be calculated: the 
FACT-Lym total score (FACT-G plus Lym) and the FACT-Lym trial outcome index score 
(physical well-being + functional well-being + lymphoma). Higher scores represent better 
functional status and well-being for all subscales and summary scales. The subscale of most 
interest in this study will be the Lym subscale. 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. For the 
purpose 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)
(Protocol Attachment 7). 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. The United Kingdom weights will be used to generate patient utilities 
from the 5 dimensions of the EQ-5D-5L in this study. Data will be collected using electronic 
capture to enhance ease of collection, while flagging questions that may be missed accidently by 
the study subject.
PROs will be collected before any other visit procedure according to the protocol Time and 
Events schedule. The FACT-Lym will be performed until disease progression, death, or the 
clinical cutoff, whichever comes first. The EQ-5D-5L will be performed until death or study end. 
Following disease progression, sites should attempt to administer the EQ-5D-5L every 16 weeks 
for 2 times, unless death or study end occurs first. Specifically, the FACT-Lym and EQ-5D-5L 
questionnaires will be administered on Day 1 of every cycle during the Active Treatment Phase 
and at the End-of-Treatment visit. During the pre-PD follow-up period, they will be administered 
every 16 weeks during the first 2 years, and, after the first 2 years, every 24 weeks, until PD, 
clinical cutoff, or 5 years. During the Post-PD follow-up period, the EQ-5D-5L will be 
performed every 16 weeks until death, study end, or 32 weeks, whichever occurs first. During 
the first 6 cycles, if a PRO assessment was conducted but the cycle was subsequently delayed, 
the PRO assessment should be repeated on Day 1 of the cycle when the treatment is resumed. 
For each of the PRO scales, descriptive statistics (number of observations, mean, standard 
deviation, median, minimum, maximum) of scores at baseline and postbaseline assessments will 
be reported by treatment group. Specifically, for both instruments, descriptive statistics will be 
calculated for the raw data and the change from baseline at each timepoint of assessment as well 
as for the changes from previous assessment. Time to worsening analysis is specified in the 
secondary endpoints analysis Section 5.3.3.1. Time to worsening will be analyzed using the 
log-rank test. 
For the FACT-Lym, the primary interest is the Lymphoma subscale, however other FACT 
subscales will also be examined, including:

The 4 individual domain scores of the FACT-G (Physical Well-being, Family/Social 
Well-being, Emotional Well-being, Functional Well-being) 
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
The Trial Outcome Index score: Physical and Functional domains of the FACT-G items plus 
the Lym Subscale score)

The FACT-Lym total score (FACT-G plus FACT-Lym)
In the event of missing item(s) in a FACT-Lym assessment, the subscale scores will be computed 
according 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 lymphoma subscale of the 
FACT-Lym is defined as the interval from the date of randomization to the start date of the 
worsening and improvement, respectively. Worsening and improvement is defined by 2 criteria; 
3-point or greater and 5-point or greater reduction and increase from baseline in the 
Lym lymphoma subscale (Carter 2008; Cella 2005). Death and missing data due to very ill as 
noted on the CRF will also be considered as worsening. Subjects who did not have a baseline 
and/or postbaseline assessment, or who did not meet the worsening/improvement criterion prior 
to PD are censored at the clinical cutoff date. Other subjects without worsening/improvement are 
censored at the last known date without events. Time to worsening and time to improvement in 
the lymphoma subscale 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, Trial Outcome Index, and total score from baseline to 
postbaseline may be explored using a waterfall plot. Exploratory analyses may be conducted to 
examine time to worsening or improvement according to clinical response status (ie, responder 
vs. non-responder) or by subject baseline characteristics of interest (ie, ECOG performance 
status).
For the FACT-Lym and EQ-5D-5L scores, a mixed effects model with repeated measures 
analysis will be conducted to estimate change from baseline at each timepoint between the 
2 treatments. Subjects in the ITT population who have a baseline value and at least 
1 post-randomization value will be 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 weeks as a continuous variable, treatment-by-time interaction, and stratification 
factors as fixed effects.
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REFERENCES
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.
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.
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 
2007;25(5):579-586. Epub 2007 Jan 22.
Dodd LE, Korn EL, Freidlin B, Gray R, Bhattacharya S. An audit strategy for progression free survival. 
Biometrics. 2011;67:1092-1099.
Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive 
chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993;328(14):1002-1006.
Jennison C, Turnbull B. W. Group sequential methods with applications to clinical trials. Chapman & Hall/CRC.
Lenz G, Wright G, Dave SS, et al. Stromal Gene Signatures in Large-B-Cell Lymphomas. N Engl J Med. 
2008;359:2313-2123.
Rényi, Alfréd. On the theory of order statistics. Acta Mathematica Hungarica. 1953;4:91-231.
Song Y, Chi GYH. A method for testing a prespecified subgroup in clinical trials. Statist Med. 2007;26:3535-3549.
Uno, H, Claggett, B, Tian, L, et al. Moving beyond the hazard ratio in quantifying the between-group difference in 
survival analysis. J Clin Oncol. 2014;32(22):2380-2385.
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