Clinical trial NCT01611090
Conditions: Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Keywords: Chronic lymphocytic leukemia Small lymphocytic lymphoma Relapsed or refractory chronic lymphocytic leukemia Relapsed or refractory small lymphocytic lymphoma Ibrutinib PCI-32765 JNJ-54179060 Bruton's tyrosine kinase inhibitor Bendamustine Rituximab
Sponsor: Janssen Research & Development, LLC
Start date: 2012-09-19; Completion date: 2019-01-23
Enrollment: 578 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine the safety and efficacy of Ibrutinib administered in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Detailed description:
This is a randomized (patients will be assigned by chance to study treatments), double-blind (patients 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 determine the benefits and risks of combining ibrutinib with bendamustine and rituximab (BR) in patients with relapsed or refractory CLL/SLL following at least 1 line of prior systemic therapy. Approximately 580 patients will be randomized in a 1:1 ratio to either treatment arm A (placebo) or treatment arm B (ibrutinib 420 mg).

Study medication will be administered orally once daily on a continuous schedule. All patients will receive BR as the background therapy plus either ibrutinib or placebo for a maximum of 6 cycles, after which treatment with ibrutinib or placebo will continue until disease progression or unacceptable toxicity.

A treatment cycle will be defined as 28 days. The study will include a screening phase, a treatment phase, and a follow-up phase. Study end is defined as when either 80% of the patients have died or 5 years after the last patient is randomized into the study, whichever occurs first.

Patients in treatment arm A (placebo) who complete the treatment phase, with disease progression or (after interim analysis) meet International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for treatment, may crossover to ibrutinib treatment (as in treatment arm B), at the investigators discretion. This open-label, next-line treatment with ibrutinib will continue until disease progression, unacceptable toxicity, withdrawal from study, or until the study end, whichever occurs earlier. One interim analysis is planned for the study. Efficacy evaluations will include computed tomography scans, laboratory testing, focused physical examinations, bone marrow biopsy and aspirate, and assessment of patient-reported outcomes. In both treatment arms, samples for the development of a population-based pharmacokinetic (PK; study of what the body does to a drug) approach will be collected. Safety will be assessed throughout the study.

Arms: arm 1: Ibrutinib 420 mg will be administered orally once daily on a continuous schedule. All subjects will receive background therapy with bendamustine and rituximab (BR) for a maximum of 6 cycles (a cycle is defined as 28 days, with the exception of Cycle 1, which will be 29 days to allow for rituximab dosing prior to bendamustine and study medication). arm 2: Matching placebo will be administered orally once daily on a continuous schedule. All subjects will receive background therapy with BR for a maximum of 6 cycles (a cycle is defined as 28 days, with the exception of Cycle 1, which will be 29 days to allow for rituximab dosing prior to bendamustine and study medication).
Interventions: intervention 1: Ibrutinib intervention 2: Bendamustine hydrochloride intervention 3: Rituximab intervention 4: Placebo
Intervention descriptions: intervention 1: Type=exact number, unit=mg, number=420 , form=capsule, route=oral use. Capsule is taken once daily continuously. intervention 2: Type=exact number, unit=mg, number=70 mg/m2, route=intravenous use. Administered intravenously on Cycle 1, Days 2-3 and Cycles 2-6, Days 1-2. intervention 3: Type=exact number, unit=mg, number=375 mg/m2 and 500 mg/m2, route=intravenous use. Administered intravenously on Cycle 1, Day 1, and Cycles 2-6, Day 1, respectively. intervention 4: Form=capsule, route=oral use. Capsule is taken once daily continuously.

Protocol documents:
Prot_000.pdf: 
1
Approved, Date: 21 August 2017
Janssen Research & Development*
Clinical Protocol
Randomized, Double-blind, Placebo-controlled Phase 3 Study of Ibrutinib, a Bruton's 
Tyrosine Kinase (BTK) Inhibitor, in Combination with Bendamustine and Rituximab (BR) 
in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small 
Lymphocytic Lymphoma
Protocol PCI-32765CLL3001; Phase 3
Amendment INT-7
JNJ-54179060 (ibrutinib)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious Diseases BVBA; Janssen 
R&D Ireland; 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, Phase 2, and Phase 3 clinical studies.
This study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER:  2012-000600-15
UTN NUMBER: U1111-1135-3745
Status:
Approved
Date:
21 August 2017
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-36178368, 10.0
Compliance: This study will be conducted in compliance with this protocol, 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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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 22
TIME AND EVENTS SCHEDULE .............................................................................................................. 25
TIME AND EVENTS SCHEDULE — AFTER INTERIM ANALYSIS: APPLIES TO SUBJECTS 
CONTINUING IBRUTINIB OR SUBJECTS IN FOLLOW-UP........................................................... 28
TIME AND EVENTS SCHEDULE — CROSSOVER TO IBRUTINIB ........................................................ 30
ABBREVIATIONS AND DEFINITIONS OF TERMS.................................................................................. 32
1.
INTRODUCTION................................................................................................................................ 34
1.1.
Chronic Lymphocytic Leukemia..................................................................................................... 34
1.2.
Ibrutinib........................................................................................................................................... 35
1.2.1.
Nonclinical Studies ..................................................................................................................... 35
1.2.2.
Clinical Studies ........................................................................................................................... 35
1.2.2.1.
Human Pharmacokinetics........................................................................................................ 35
1.2.2.2.
Clinical Efficacy Studies in Chronic Lymphocytic Leukemia and Small Lymphocytic 
Lymphoma............................................................................................................................... 36
1.2.2.2.1.
Study PCYC-04753.............................................................................................................. 36
1.2.2.2.2.
Study PCYC-1102-CA.......................................................................................................... 37
1.2.2.2.3.
Study PCYC-1108-CA.......................................................................................................... 37
1.2.2.2.4.
Study PCYC-1109-CA.......................................................................................................... 38
1.2.2.2.5.
Summary of Efficacy of Ibrutinib in CLL............................................................................... 38
1.2.2.3.
Treatment-related Lymphocytosis ........................................................................................... 38
1.2.2.4.
Overview of Clinical Safety...................................................................................................... 40
1.3.
Overall Rationale for the Study...................................................................................................... 41
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 42
2.1.
Objectives ...................................................................................................................................... 42
2.2.
Hypothesis ..................................................................................................................................... 42
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 43
3.1.
Overview of Study Design.............................................................................................................. 43
3.1.1.
Treatment With Ibrutinib After Interim Analysis .......................................................................... 47
3.2.
Study Design Rationale.................................................................................................................. 47
4.
SUBJECT SELECTION..................................................................................................................... 48
4.1.
Inclusion Criteria ............................................................................................................................ 48
4.2.
Exclusion Criteria ........................................................................................................................... 50
4.3.
Prohibitions and Restrictions ......................................................................................................... 52
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 52
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 53
6.1.
Bendamustine and Rituximab Administration ................................................................................ 54
6.2.
Study Drug Administration ............................................................................................................. 54
6.3.
Dose Modification........................................................................................................................... 55
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7.
TREATMENT COMPLIANCE............................................................................................................ 57
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 57
8.1.
Permitted Medications.................................................................................................................... 58
8.2.
Prohibited Medications................................................................................................................... 58
8.3.
Precautions with Concomitant Medications ................................................................................... 59
8.4.
Subsequent Therapies................................................................................................................... 60
9.
STUDY EVALUATIONS .................................................................................................................... 60
9.1.
Study Procedures........................................................................................................................... 60
9.1.1.
Overview..................................................................................................................................... 60
9.1.2.
Screening Phase ........................................................................................................................ 61
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 62
9.1.4.
Follow-up Phase......................................................................................................................... 62
9.1.5.
Crossover to Ibrutinib Treatment................................................................................................ 63
9.2.
Efficacy........................................................................................................................................... 64
9.2.1.
Evaluations ................................................................................................................................. 65
9.2.1.1.
Radiographic Imaging Assessments ....................................................................................... 65
9.2.1.2.
Definition of Measurable and Assessable Disease ................................................................. 65
9.2.1.3.
Bone Marrow Assessment....................................................................................................... 66
9.2.1.4.
Response Categories .............................................................................................................. 66
9.2.1.5.
Patient-Reported Outcomes.................................................................................................... 69
9.3.
Pharmacokinetics........................................................................................................................... 71
9.3.1.
Evaluations ................................................................................................................................. 71
9.3.2.
Analytical Procedures................................................................................................................. 71
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 71
9.4.
Biomarkers ..................................................................................................................................... 72
9.4.1.
Circulating B-lymphocytes From Blood ...................................................................................... 72
9.5.
Safety Evaluations ......................................................................................................................... 72
9.6.
Sample Collection and Handling.................................................................................................... 76
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 76
10.1.
Completion ..................................................................................................................................... 76
10.2.
Discontinuation of Treatment ......................................................................................................... 76
10.3.
Withdrawal From the Study............................................................................................................ 76
11.
STATISTICAL METHODS................................................................................................................. 77
11.1.
Analysis Sets.................................................................................................................................. 77
11.2.
Sample Size Determination ........................................................................................................... 77
11.3.
Subject Information ........................................................................................................................ 78
11.4.
Efficacy Analyses ........................................................................................................................... 78
11.4.1.
Primary Efficacy Endpoint........................................................................................................... 78
11.4.2.
Secondary Efficacy Endpoints.................................................................................................... 78
11.4.3.
Analysis Methods........................................................................................................................ 79
11.5.
Pharmacokinetic Analyses............................................................................................................. 79
11.6.
Biomarker Analyses ....................................................................................................................... 80
11.7.
Safety Analyses ............................................................................................................................. 80
11.8.
Interim Analysis.............................................................................................................................. 81
11.9.
Data Monitoring Committee ........................................................................................................... 82
12.
ADVERSE EVENT REPORTING ...................................................................................................... 82
12.1.
Definitions ...................................................................................................................................... 82
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 82
12.1.2.
Attribution Definitions.................................................................................................................. 83
12.1.3.
Severity Criteria .......................................................................................................................... 84
12.2.
Special Reporting Situations.......................................................................................................... 85
12.3.
Procedures..................................................................................................................................... 85
12.3.1.
All Adverse Events...................................................................................................................... 85
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12.3.2.
Serious Adverse Events ............................................................................................................. 87
12.3.3.
Adverse Events of Interest.......................................................................................................... 88
12.3.3.1.
Major Hemorrhage................................................................................................................... 88
12.3.4.
Pregnancy................................................................................................................................... 88
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 88
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 89
13.1.
Procedures..................................................................................................................................... 89
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 89
14.
STUDY DRUG INFORMATION......................................................................................................... 89
14.1.
Physical Description of Study Drug(s) ........................................................................................... 89
14.2.
Packaging ...................................................................................................................................... 89
14.3.
Labeling.......................................................................................................................................... 90
14.4.
Preparation, Handling, and Storage............................................................................................... 90
14.5.
Drug Accountability ........................................................................................................................ 90
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 91
16.
ETHICAL ASPECTS ......................................................................................................................... 91
16.1.
Study-Specific Design Considerations........................................................................................... 91
16.2.
Regulatory Ethics Compliance....................................................................................................... 92
16.2.1.
Investigator Responsibilities ....................................................................................................... 92
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 92
16.2.3.
Informed Consent ....................................................................................................................... 93
16.2.4.
Privacy of Personal Data ............................................................................................................ 94
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 95
16.2.6.
Country Selection ....................................................................................................................... 95
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 95
17.1.
Protocol Amendments.................................................................................................................... 95
17.2.
Regulatory Documentation ............................................................................................................ 96
17.2.1.
Regulatory Approval/Notification ................................................................................................ 96
17.2.2.
Required Prestudy Documentation............................................................................................. 96
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 97
17.4.
Source Documentation................................................................................................................... 97
17.5.
Case Report Form Completion ...................................................................................................... 97
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 98
17.7.
Record Retention ........................................................................................................................... 98
17.8.
Monitoring ...................................................................................................................................... 99
17.9.
Study Completion/Termination....................................................................................................... 99
17.9.1.
Study Completion ....................................................................................................................... 99
17.9.2.
Study Termination..................................................................................................................... 100
17.10.
On-Site Audits .............................................................................................................................. 100
17.11.
Use of Information and Publication.............................................................................................. 100
REFERENCES.......................................................................................................................................... 102
INVESTIGATOR AGREEMENT ............................................................................................................... 119
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LIST OF ATTACHMENTS
Attachment 1:
Eastern Cooperative Oncology Group Performance Status Scale .......................... 105
Attachment 2:
CLL and SLL Staging Criteria................................................................................... 106
Attachment 3:
Inhibitors and inducers of CYP3A4/5 ....................................................................... 108
Attachment 4:
Maximum Blood Volumes During the Study............................................................. 109
Attachment 5:
Response-related Definitions ................................................................................... 110
Attachment 6:
EORTC QLQ-C30..................................................................................................... 111
Attachment 7:
EORTC QLQ-CLL 16................................................................................................ 113
Attachment 8:
EQ-5D-5L.................................................................................................................. 114
Attachment 9:
FACIT-Fatigue Scale................................................................................................ 117
Attachment 10:
International Workshop on Chronic Lymphocytic Leukemia Criteria for 
Treatment ................................................................................................................. 118
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1
Criteria for Response Categories ............................................................................................. 68
Table 2  
Hematologic Adverse Event Grading Table.............................................................................. 85
FIGURES
Figure 1
Pattern of Response – Ibrutinib + BR versus Single-Agent Ibrutinib: Blood 
Lymphocytes versus Lymph Nodes Sum of Products of Diameters: Studies PCYC-
1102-CA and PCYC-1108-CA .................................................................................................. 39
Figure 2
Study Design Schematic – Prior to Interim Analysis ................................................................ 45
Figure 3
Study Design Schematic – Post- Interim Analysis.................................................................... 46
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PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
9 May 2012
Amendment INT-1
5 December 2012
Amendment INT-2
13 September 2013
Amendment INT-3
30 January 2014
Amendment INT-4
13 April 2015
Amendment INT-5
29 April 2016
Amendment INT-6
28 September 2016
Amendment INT-7
21 August 2017
Amendments are listed beginning with the most recent amendment.
Amendment INT-7 (21 August 2017)
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is to provide an end date for
minimal residual disease (MRD) assessment collection (to be discontinued as of 31 July 2017).
Applicable Sections
Description of Changes
Rationale: The study objective to evaluate the rate of MRD-negative remission has been met and sufficient MRD 
data have been collected to determine change in depth of response over time with a median follow-up of over 
3 years.
Time and Events 
Schedule – After 
Interim Analysis; 
Time and Events 
Schedule -  Crossover 
to Ibrutinib; 
9.2.1.3. Bone Marrow 
Assessment
Footnote (h) added to T&E Schedule-After Interim Analysis and Footnote (l) added to 
T&E Schedule-Crossover to Ibrutinib: 
The last date for MRD collection is 31 July 2017; no further MRD data will be collected 
after that date.
The following footnote was added to the Section 9.2.1.3 heading:
With the implementation of Amendment INT-7, collection of all MRD data is
discontinued. The last date for MRD collection is 31 July 2017, which corresponds to
approximately 5 years after the first subject entered the study; no further MRD data will 
be collected after that date.
Amendment INT-6 (28 September 2016)
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment:  To provide an end date for electronically-collected patient-reported 
outcome (ePRO) data.
Applicable Section(s)
Description of Change(s)
Rationale: To provide an end date (18 September 2016 [4 years after the first subject entered the study]) for 
collection of ePRO data since pre-specified study objectives to evaluate subjects’ quality of life have been met and 
sufficient ePRO data have been collected.
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Applicable Section(s)
Description of Change(s)
Synopsis Efficacy 
Evaluations/Endpoints; 
Time and Events 
Schedule-After Interim 
Analysis: Applies to 
Subjects Continuing 
Ibrutinib or Subjects in 
Follow-up; 
Time and Events 
Schedule-Crossover to 
Ibrutinib;
9.2.1.5 Patient-
Reported Outcomes
Following text added to Synopsis: 
With Amendment INT-6, collection of all ePRO data is discontinued. The last date for 
ePRO collection is 18 September 2016, which corresponds to 4 years after the first subject 
entered the study; no further ePRO data will be collected after that date.
Footnote (g) added to T&E Schedule-After Interim Analysis and Footnote (k) added to 
T&E Schedule-Crossover to Ibrutinib: 
The last date for ePRO collection is 18 September 2016, which corresponds to 4 years 
after the first subject entered the study; no further ePRO data will be collected after that 
date.
Following text added to Section 9.2.1.5: 
With the implementation of Amendment INT-6, collection of all ePRO data is
discontinued. The last date for ePRO collection is 18 September 2016, which corresponds 
to 4 years after the first subject entered the study; no further ePRO data will be collected 
after that date.
Rationale: Inactive website link to examples of CYP3A4/5 inhibitors/inducers removed and replaced with working 
link.
8.3 Precautions with 
Concomitant 
Medications;
Attachment 3
The following link deleted (http://www.pharmacologyweekly.com/content/pages/online-
drug-therapy-tables), as well as corresponding reference, and replaced with working link 
from Attachment 3. 
Inactive link, as well as corresponding reference, deleted from Attachment 3.
Amendment INT-5 (29 April 2016)
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment:  To provide clarity surrounding MRD evaluations in subjects with CR, 
response assessments following Amendment INT-4, and criteria for disease progression for subjects with new onset 
of lymphocytosis.
Applicable Section(s)
Description of Change(s)
Rationale: To align the MRD evaluations with other ibrutinib CLL studies.
Time and Events
Schedule-After 
Interim Analysis: 
Applies to Subjects 
Continuing Ibrutinib 
or Subjects in 
Follow-up;
Time and Events 
Schedule-Crossover 
to Ibrutinib;
9.2 Efficacy;
9.2.1.3 Bone Marrow 
Assessment
For subjects with suspected CR, in addition to a bone marrow aspirate sample, a 
concurrent peripheral blood sample will be sent for MRD analysis.
Rationale: To address questions from investigators.
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Applicable Section(s)
Description of Change(s)
9.2.1.1 Radiographic;
Imaging Assessment; 
9.2.1.4 Response 
Categories
Clarified the timing and scope of efficacy evaluations following Amendment INT-4. 
Clarified how to assess a response at a visit that does not include a radiographic 
assessment.
Rationale: To clarify when the new onset of lymphocytosis meets the criteria for disease progression and to align 
the definition with other CLL studies in the ibrutinib program.
Table 1 Criteria for 
Response Categories
Text added: “or a ≥50% increase from the nadir count confirmed on ≥2 serial assessments 
if the ALC is ≥30,000/µL and lymphocyte doubling time is rapid, unless considered 
treatment-related lymphocytosis.”
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.
11.7 Safety Analyses;
12.3.3.1 Major 
Hemorrhage;
12.3.3.2 Intracranial 
Hemorrhage (section 
deleted)
Intracranial hemorrhage is no longer mentioned separately from major hemorrhage; rather, 
it is subsumed within the new definition for major hemorrhage.
Rationale: To align the protocol with the latest safety information on drug-drug interactions of ibrutinib.
8.3 Precautions with 
Concomitant 
Medications
Text regarding use of CYP3A4/5 inhibitors was revised to the following: “If a moderate 
CYP3A inhibitor must be used, reduce ibrutinib treatment to 140 mg for the duration of 
the inhibitor use. For subjects who are already on a moderate CYP3A inhibitor 
concomitantly with ibrutinib without significant toxicity, the investigator may consider 
the overall risk-benefit to determine if a dose reduction of ibrutinib is appropriate.”
Rationale: Minor clarification in the Time and Events Schedule-After Interim Analysis: Applies to Subjects 
Continuing Ibrutinib or Subjects in Follow-up.
Time and Events 
Schedule-After 
Interim Analysis: 
Applies to Subjects 
Continuing Ibrutinib 
or Subjects in 
Follow-up
Added window of 7 days.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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Amendment INT-4 (13 April 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: Following positive interim analysis and pursuant to the independent Data 
Monitoring Committee (DMC) recommendations on 10 March 2015, the study is unblinded and placebo subjects
will be offered treatment with ibrutinib. Subjects continuing on ibrutinib will have a reduced schedule of 
assessments. 
Applicable Section(s)
Description of Change(s)
Rationale: To provide access to ibrutinib within this study for subjects who received placebo. IRC-confirmed 
disease progression is no longer a requirement for crossing over to receive ibrutinib.
Synopsis Overview of 
Study Design,
Synopsis Dosage and 
Administration;
Time and Events 
Schedule; 
2. Objectives;
3.1 Overview of 
Study Design; 
3.1.1 Treatment With 
Ibrutinib After 
Interim Analysis; 
4 Subject Selection;
5 Treatment 
Allocation and 
Blinding;
9.1.5 Crossover to 
Ibrutinib Treatment; 
9.5 Safety 
Evaluations; 
Attachment 10
Access to ibrutinib for subjects on placebo may be provided at the discretion of the 
investigator at the time the subject has progression or meets IWCLL criteria for treatment. 
Broader eligibility criteria for crossover to ibrutinib.
Reduced schedule of assessments and number of laboratory evaluations.
Rationale: To address the FDA request to follow subjects receiving ibrutinib until the median progression-free 
survival (PFS) is reached. 
Synopsis Overview of 
Study Design; 
3.1 Overview of 
Study Design;
17.9.1 Study 
Completion
End of study definition was revised to change the length of time from last patient in study 
from 4 years to 5 years so that median PFS can be reached. 
Rationale: Studies have been conducted to evaluate the effect of food on the absorption of ibrutinib. Population 
pharmacokinetics analysis showed that mean systemic exposure (area under the plasma concentration-time curve 
[AUC]) in 16 subjects with CLL taking ibrutinib in the fed condition was not significantly higher than the mean
AUC in the complete pharmacokinetic population instructed to take the drug at least 30 minutes before or 2 hours 
after a meal.  Instructions specific to ibrutinib administration have been revised to remove the restriction of 
“approximately 30 minutes before eating or approximately 2 hours after a meal”. 
6.2 Administration
Deleted text: Each dose of study medication should be taken at least 30 minutes before 
eating or approximately 2 hours after a meal, at approximately the same time each day.
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Applicable Section(s)
Description of Change(s)
Rationale: At the time of Protocol Amendment INT-4, the last dose of BR given to any subject was more than 
9 months ago. The study is unblinded for primary analysis and considered completed in regards to evaluation of BR.
The study will continue for the purpose of evaluating long-term efficacy and safety of ibrutinib.
16.2.2 Independent 
Ethics Committee or 
Institutional review 
Board 
As of Amendment INT-4, reports of adverse events that are serious, unlisted/unexpected, 
and associated with bendamustine or rituximab will no longer be provided for reporting to 
IEC/IRB. 
Rationale: To describe the planned PFS and overall survival assessments to be done after the interim analysis.
11.4.1 Primary 
Efficacy Endpoint
Text added: After interim analysis, PFS and overall survival will be updated in subsequent 
analysis.
Rationale: Ibrutinib has been approved for the treatment of mantle cell lymphoma and chronic lymphocytic 
leukemia since this protocol was first issued. 
1 Introduction
Text regarding the approval status of ibrutinib was revised to include updated information 
regarding approvals for MCL and CLL.
Rationale: Correction of numeric symbol associated with GFR calculation and broadening eligibility criteria for 
crossover to ibrutinib.
9.1.5 Crossover to 
Ibrutinib Treatment
The criterion for estimated GFR (Cockcroft-Gault) was updated to ≥30 mL/min.
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Approved, Date: 21 August 2017
Amendment INT-3 (30 January 2014)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To provide access to next-line treatment with ibrutinib within this study 
for subjects initially assigned to placebo who have independent review committee (IRC)-confirmed disease 
progression (ie, each subject has met the primary endpoint), at investigator’s discretion and with medical monitor 
approval. The aim is to protect the primary endpoint by mitigating potential early dropout and also to provide an 
opportunity of access to ibrutinib for subjects who previously received placebo. This crossover is triggered by (a.)
the recently released positive interim results of Study PCYC-1112-CA, which demonstrated significant benefit in 
progression-free survival and overall survival for subjects with relapsed/refractory CLL treated with ibrutinib 
compared to ofatumumab, and (b.) anticipated increasing access to ibrutinib through commercial, named-patient 
program or other access programs. Crossover has been discussed and agreed with the DMC for Study 
PCI-32765CLL3001.
Applicable Section(s)
Description of Change(s)
Rationale: To provide access to ibrutinib within this study for subjects who received placebo and have 
IRC-confirmed disease progression and meet the IWCLL criteria for requiring subsequent anti-CLL therapy.
Synopsis; Time and
Events Schedule; 
Time and Events 
Schedule for Subjects 
with IRC-confirmed 
Progression Who are 
Eligible to Receive 
Next-line Ibrutinib;
3.1 Overview of 
Study Design
(Figure 2); 
3.1.1 Unblinded 
Next-Line Treatment 
With Ibrutinib (new 
section); 4.1 Inclusion 
Criteria; 5 Treatment 
Allocation and 
Blinding; 9.1.5 Next-
line Ibrutinib 
Treatment 
(new section); 9.2.1.5 
Patient-Reported 
Outcomes; 
9.4 Biomarkers; 
9.5 Safety 
Evaluations;
Attachment 4
At investigators request, subjects who have IRC-confirmed disease progression and meet 
the IWCLL criteria for requiring subsequent anti-CLL therapy and other eligibility criteria 
may be considered for next-line ibrutinib treatment. If upon unblinding by a medical 
monitor separate from the study team it is determined that the subject was randomized to 
placebo, the subject will be permitted to cross over to receive ibrutinib 420 mg orally, 
daily. Open-label next-line treatment with ibrutinib will continue until disease progression, 
unacceptable toxicity, withdrawal from study, or until the study end, whichever occurs 
earlier.
Text describing eligibility criteria for subjects who crossover from placebo to ibrutinib
treatment, as well as a new Time and Events Schedule (Time and Events Schedule for 
Subjects with IRC-confirmed Progression Who are Eligible to Receive Next-line Ibrutinib) 
have been added.
Operational details for the crossover treatment period have been added.
Safety evaluations for the crossover treatment period have been added.
Rationale: Additional new safety information (rashes, and infection) based on studies conducted with ibrutinib has 
been added. 
Abbreviations; 1.2.2.4 
Overview of Clinical 
Safety
Added language on severe rash, including Stevens-Johnson Syndrome (SJS) and 
infections.
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Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
Applicable Section(s)
Description of Change(s)
Rationale: Clarification to IWCLL criteria for partial response was published in November 2013. 
9.2.1.4 Response 
Categories (Table 1); 
References
Note added to Table 1 to align with recently published clarification to IWCLL response 
criteria.
Reference by Hallek et al (2013) providing clarification of IWCLL criteria for a partial 
response has been added to list of references.
Rationale: On November 13, 2013 the FDA approved ibrutinib for the treatment of adult patients with MCL who 
have received at least one prior therapy. Therefore, the statement below indicating ibrutinib has not been approved 
has been deleted.
1.2 Ibrutinib
The following text has been deleted: “Ibrutinib is an 
investigational product that has not been approved for 
marketing in any country.”
Text regarding the US approval has been added.
Rationale: Safety data, since the time the original protocol was finalized, have been updated. These data included 
information from the 2013 Investigator’s Brochure. 
1.2.2.4 Overview of 
Clinical Safety
At the time of the original protocol (09 May 2012), safety data for 312 subjects were 
available. Safety data as of 06 Apr 2013 for the 506 subjects treated with ibrutinib 
monotherapy and 130 subjects treated with ibrutinib in combination with chemotherapy 
have been added.
The following text has been deleted: Slight corneal dystrophy and opacity were observed 
in dogs treated at the highest dose (ie, 150 mg/kg/day) in nonclinical toxicology studies. 
Grade 1 or 2 ocular findings (ie, blurred vision, dry eye, eye pain, visual impairment, and 
increased lacrimation) have been reported in clinical studies. The events were considered 
unrelated to ibrutinib treatment.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment INT-2 (13 September 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: The overall reason for the amendment is to update the protocol for 
consistency with updated safety information in the new Investigator’s Brochure (IB; version 7) and to implement a 
recommendation from the Data Monitoring Committee (DMC).
Applicable Section(s)
Description of Change(s)
Rationale: To clarify the mechanism of action of ibrutinib.
Synopsis; 
1.2 Introduction
Based on current information, the description of the mechanism of action of ibrutinib as a 
potent, orally-administered, covalent small molecule inhibitor of Bruton’s tyrosine kinase 
(BTK) has been updated in the protocol.
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JNJ-54179060 (ibrutinib) 
Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
Applicable Section(s)
Description of Change(s)
Rationale: To clarify cycle duration and other scheduling guidance.
Time & Events 
Schedule
Added cycle length to footnote “a” as follows: A standard cycle should be no less than 26 
days and no more than 30 days.
Changed footnote “l” as follows: Must be done within 7 days prior to randomization in 
order to meet inclusion criteria.
4.1 Inclusion Criteria 
Incl. #7 and #8
Deleted “within 7 days prior to randomization” for hematology and chemistry from entry 
criteria. Retained it as a mandatory requirement in Time & Events schedule.
9.1.3 Double-blind 
Treatment Phase and 
End of Treatment
Added that the End-of-Treatment Visit shall have a 30 day +7-day window to be consistent 
with the collection of adverse events that occur within 30 days after the last dose of study 
treatment.
Rationale: To align with the most recent protocol template update (29 March 2013)
4.2 Exclusion Criteria
Updated note to exclusion criteria that if a subject’s health status changes such that he or 
she no longer meets eligibility criteria, he or she may not participate in the study.
12.3.1 All Adverse 
Events
Updated that all subjects will be instructed to carry the study card with them for the 
duration of the study.
13.1 Procedures
Updated that all product quality complaints (PQCs) should be reported to the sponsor 
within 24 hours.
Rationale: To align with the annual IB update.
1.2.2.1 Human 
Pharmacokinetics
Updated the following with final results from Study PCI-32765CLL1002: Results 
demonstrated a 24-fold increase in ibrutinib area under the plasma concentration-time 
curve (AUC0-last) and a 29-fold increase in Cmax following co-administration with 
ketoconazole.
1.2.2.3 Treatment-
related 
Lymphocytosis
Updated background information on the potential for observed transient lymphocytosis in 
some patients treated with ibrutinib.
1.2.2.4 Overview of 
Clinical Safety
Updated the paragraph describing hemorrhagic events and added paragraph on other 
malignancies.
12.3.1 All Adverse 
Events
Added instructions on appropriate reporting interval for all new malignancies.
8.1 Permitted 
Medications
Added background information describing the risk of leukostasis in subjects treated with 
ibrutinib and provided supportive care and management guidelines for subjects considered 
at risk. 
11.7 Safety Analyses
Added information on the reporting of adverse events of special interest with ibrutinib, 
major hemorrhage and intracranial hemorrhage.
Rationale: To provide further clarifications of existing text.
3.1 Overview of 
Study Design; 
Definitions of Terms; 
Throughout the 
document
Added text defining the use of the terms study treatment (bendamustine hydrochloride, 
rituximab, and ibrutinib/placebo) and study drug (ibrutinib/placebo) within this protocol. 
Clarified that the End-of-Treatment Visit should be scheduled within 30 days of the last 
dose of study treatment (ie, bendamustine, rituximab, or oral study drug) and not 
exclusively the study drug. Clarified that the Follow-up Phase will begin once a subject 
discontinues study medication treatment.
8.1 Permitted 
Medications
Clarified that pre-medication is permitted not only for rituximab but also for bendamustine 
infusions per the respective package inserts.
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Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
Applicable Section(s)
Description of Change(s)
6.3 Dose 
Modification 
(Bendamustine)
Modified the following statement: If bendamustine hydrochloride is discontinued for 
toxicity, then treatment with rituximab may be continued. for up to 6 cycles.
6.3 Dose 
Modification 
(Study Medication)
Clarified that for Grade 3 thrombocytopenia (platelets <50 x 109/L [ie, <50,000/L]) dose 
modifications of oral study medication should be done only if this toxicity is accompanied 
by significant bleeding.
4.2 Exclusion Criteria
Excl. #5
Clarified that subjects will be excluded if they were previously treated with a 
bendamustine-containing regimen who did not achieve a response or who relapsed and 
required treatment within 24 months of treatment with that regimen.
6.3 Dose 
Modification 
(Rituximab)
Added that if rituximab is discontinued for toxicity, then treatment with bendamustine 
hydrochloride may be continued.
6.3 Dose 
Modification 
(Study Medication)
Added that if ibrutinib or placebo is discontinued for toxicity, then treatment with 
bendamustine hydrochloride and rituximab may be continued.
9.1.3 Double-blind 
Treatment Phase
Clarified that rituximab administration must begin after randomization:
Subjects must start rituximab within 72 hours of after randomization.
Rationale: Further clarified the requirements regarding Cyclin D 1 or BCL-1 testing for diagnostic purposes.
4.1 Inclusion Criteria
Incl. # 2c
Added a clarification statement explaining that these tests are required only when the 
diagnosis of CLL/SLL is not otherwise clear.
Rationale: Clarified that subjects who have had their study treatment assignment unblinded due to an emergency 
may continue study treatment with the approval of the sponsor.
5 Treatment 
Allocation and 
Blinding
Modified wording to: “Subjects who have had their treatment assignment unblinded should 
continue to return for scheduled evaluations and with sponsor approval may continue 
study treatment.”
Rationale: To ensure continuous administration of the oral study medication.
6.2 Study Drug 
Administration
Removed the requirement to skip a dose of ibrutinib/placebo when a dose was not taken 
within the 6-hour window of the scheduled time stipulated in the protocol.
Rationale: For further safety precautions
Section 6, Dosage and 
Administration
Provided guidance regarding bendamustine dosing in the event of rituximab-related 
toxicity (eg, infusion reactions).
Rationale: Bendamustine is a more bone marrow suppressive drug than ibrutinib; however, the hematologic criteria 
for re-initiating ibrutinib are more stringent than those of bendamustine. The purpose of this change is to eliminate 
inconsistencies between the hematologic criteria used for re-initiation of ibrutinib and bendamustine
6.3 Dose 
Modification 
(ibrutinib/placebo 
table)
Aligned the instructions for re-initiation of oral study medication following severe 
hematologic toxicity with those of bendamustine by adding a footnote to the table.
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Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
Applicable Section(s)
Description of Change(s)
Rationale: Levact®/Ribomustin® package insert does not require withholding the drug for mild or moderate hepatic 
impairment whereas TREANDA® insert recommends discontinuations for mild and moderate hepatic impairment. 
Some of the sites follow TREANDA package insert, others use Levact/Ribomustin package insert. This change will 
align the protocol guidance with both package inserts.
6.3 Dose 
Modification 
(Bendamustine
hydrochloride)
Clarified the wording regarding administration of bendamustine in the event of elevated 
transaminases or elevated bilirubin as follows:
Withholding of bendamustine hydrochloride should be considered discontinued in the 
event of AST or ALT value >2.5 X ULN or total bilirubin value >1.5 X ULN.
Rationale: To implement Data Monitoring Committee recommendation
8.1 Permitted 
Medications
Added wording that “Use of anti-microbial prophylaxis (eg, pneumocystis pneumonia 
prophylaxis with sulfamethoxazole and trimethoprim or equivalent) according to the 
institution’s guidelines is strongly recommended.”
Rationale: To clarify that certain medications are prohibited only during the Treatment Phase and not during the 
Follow-up Phase. 
8.2 Prohibited 
Medications
Modified wording to “The following medications are prohibited during the treatment 
phase of the study: any chemotherapy (other than BR), anticancer immunotherapy, 
corticosteroids (at dosages equivalent to prednisone >20 mg/day), experimental therapy, 
and radiotherapy.”
Rationale: To update the guidelines for use of concomitant medication with ibrutinib based on the results of clinical 
studies.
8.3 Precautions with 
Concomitant 
Medications; 
Attachment 3
Clarified the concomitant use of ibrutinib with CYP3A4/5 inhibitors/inducers, QT 
prolonging agents, and antiplatelet agents and anticoagulants during the study; added 
section on drugs that have their plasma concentrations altered by ibrutinib.
Rationale: Conventional cytogenetics is not commonly used to characterize CLL in countries around the world and 
therefore, is being removed from the protocol as a mandatory technique.
Time & Events 
Schedule, 9.1.2 
Screening Phase, 
9.2.1.3 Bone Marrow 
Assessment
Changed conventional cytogenetics (ie, karyotyping) to an optional procedure. Added that, 
for subjects with SLL, a lymph node biopsy may be used for immunophenotyping, 
morphology, and FISH testing to confirm the diagnosis.
Rationale: For consistency with other CLL protocols in the program
9.1.4 Follow-up phase
Added that any data related to the occurrence of other malignancies or transformation to a
more aggressive histology (Richter’s transformation) during the Follow-up phase needs to 
be collected.
Rationale: To align the Patient-Reported Outcomes (PRO) collection with the clinical schedules
9.1.1 Overview;
9.2.1.5 Patient-
Reported Outcomes
All visit-specific PRO assessments during a visit should preferably be conducted before 
any tests…
The PRO questionnaires will be collected preferably at the beginning of the clinic visits 
prior to any procedures or physician interactions according to the schedule described in the 
Time and Events Schedule.
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Approved, Date: 21 August 2017
Applicable Section(s)
Description of Change(s)
Rationale: To align with Pharmacyclics, Inc. protocols and also with the IRC charter
Time & Events 
Schedule; 9.2.1.3 
Bone Marrow 
Assessment
Clarified that after the completion of BR, a bone marrow or aspirate should be collected in 
the event of a new onset of cytopenia to determine the underlying cause.
Added this information to footnote “j” in the Time & Events Schedule.
Rationale: Total bilirubin is composed of direct and indirect; therefore, if total bilirubin is within normal range, 
then direct bilirubin is not expected to be elevated and is usually not measured in those circumstances.
9.5. Safety 
Evaluations (Clinical 
Laboratory Tests)
Changed direct bilirubin sampling to an optional procedure when total bilirubin is within 
normal limits.
Rationale: To provide further clarification in line with the latest published guidelines and also to be aligned with 
the protocols across the ibrutinib program
9.5. Safety 
Evaluations (Clinical 
Laboratory Tests)
Added that monitoring of Hepatitis B polymerase chain reaction (PCR) and liver enzymes 
and prophylactic antiviral medication should be considered per published guidelines for at 
least 12 months following the last dose of rituximab.
Rationale: To clarify how body surface area (BSA) calculations are performed by the interactive web response 
system (IWRS) at each visit.
9.5 Safety 
Evaluations (Body 
Surface Area)
Clarified that the initial BSA is recalculated only if a subject experiences a >10% change 
in weight in subsequent cycles.
Rationale: To further clarify the hematologic adverse event grading for subjects with advanced CLL/SLL
12.1.3 Severity 
Criteria
Modified Table 2 to further align with the IWCLL criteria for evaluation of hematologic 
toxicity.
Rationale: For completeness
Attachment 2
Added Ann Arbor staging system for SLL subjects.
Rationale: To allow sufficient amount of peripheral blood to be collected to confirm and characterize the diagnosis 
of CLL by immunophenotyping and FISH analysis.
9.1.1 Overview; 16.1 
Study Specific Design 
Considerations; 
Attachment 4
Increased the volume of peripheral blood sample for diagnosis of CLL in the blood volume 
table; added a footnote to the table indicating that the blood volume required for CLL 
diagnosis may vary by country or site, therefore, additional blood may be drawn to be sent 
to a separate local laboratory; updated the total blood volume estimated to be collected in 
the first year will normally not exceed 335 mL in the corresponding sections of the text.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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Approved, Date: 21 August 2017
Amendment INT-1 (5 December 2012)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to clarify management of study 
medication with concomitant CYP3A4/5 inhibitors/inducers and warfarin or other anticoagulants, to clarify 
management of study medication during the perioperative periods, and to incorporate feedback from investigators, 
health authorities, and the study Steering Committee. 
Applicable Section(s)
Description of Change(s)
Rationale: Prohibited equivalent vitamin K antagonists (in addition to warfarin) as a precautionary safety measure.
4.2. Exclusion 
Criteria
Modified criterion #13 to exclude subjects requiring anticoagulation with equivalent 
vitamin K antagonists (eg, phenprocoumon), in addition to warfarin. 
Rationale: Updated the guidelines for concomitant use of anticoagulants as a precautionary safety measure.
6.3. Dose 
Modification
Removed detailed text on concomitant administration of study medication and 
anticoagulant treatment and referred to section 8.3.
8.3. Precautions with 
Concomitant 
Medications
Updated the text for the management of study medication with anticoagulants during the 
study, to reflect updated standard language and ensure consistency across ibrutinib 
protocols. Clarified that the concomitant use of warfarin or equivalent vitamin K 
antagonists (eg, phenprocoumon) with study medication is prohibited during the study. 
Removed the need for a PK sample in the case of a bleeding event. 
Rationale: Updated the guidelines for concomitant use of CYP-inhibiting/inducing drugs based on the results of 
clinical pharmacology studies. 
4.2. Exclusion 
Criteria; 
Attachment 3
Removed the eligibility restriction for subjects requiring treatment with strong CYP2D6 
inhibitors in the exclusion criteria. Removed the list of CYP2D6 inhibitors from 
Attachment 3.
8.3. Precautions with 
Concomitant 
Medications
Updated the text for the management of ibrutinib with CYP3A4/5 inhibitors/inducers 
during the study, to reflect updated standard language and ensure consistency across 
ibrutinib protocols.
Rationale: Platelet cutoff is being changed for consistency with the Phase 1b/2 Study PCYC-1108-CA evaluating 
bendamustine, rituximab, and ibrutinib. 
4.1. Inclusion 
Criteria; 6.3. Dose 
Modification
Modified inclusion criterion and requirement for bendamustine reinstatement following 
hematologic events to platelet count of 50 x 109/L (ie, 50,000/L) instead of 75 x 
109/L (ie, 75,000/L). 
Rationale: For further safety precautions. 
4.3. Prohibitions and 
Restrictions
Added guidelines for subjects who require surgical intervention while receiving study 
medication and referred to this section in Section 6.3. 
6.3. Dose 
Modification
Modified dose modification criteria of study medication for Grade 4 neutropenia.
8.1. Permitted 
Medications 
Added statement that the rituximab dose may be split over 2 days during Cycle 1 for 
subjects with an increased risk of TLS. 
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JNJ-54179060 (ibrutinib) 
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Approved, Date: 21 August 2017
Applicable Section(s)
Description of Change(s)
Rationale: To provide further instructions about bone marrow aspirate and biopsy sampling. 
Time & Events 
Schedule; 9.1.2. 
Screening Phase; 
9.2.1.3. Bone Marrow 
Assessment; 9.5. 
Safety Evaluations; 
Attachment 4
Clarified the timing, methodology, and purpose of the bone marrow biopsy and aspirate (or 
peripheral blood) samples at screening and during the study. Modified the wording of the 
cytogenetics row and footnote in the Time & Events schedule for clarity. Included the 
peripheral blood sample for diagnosis of CLL in the blood volume table in Attachment 4.
Rationale: To provide clarity surrounding MRD evaluations. 
Time & Events 
Schedule; 9.2.1.3. 
Bone Marrow 
Assessment
Further defined the timing and methodology of MRD assessments during the study.
Rationale: To delete unnecessary screening procedures and to increase safety measures at the time of adverse 
events. 
Time & Events 
Schedule; 
Attachment 4
Deleted row for Coombs test in the Time & Events Schedule and the blood volumes table. 
9.5. Safety 
Evaluations
Removed reticulocytes and Coombs from screening requirements. Added that local 
laboratories may be used for reticulocyte count and Coombs test for adverse events.
Rationale: To eliminate inconsistency between definition of refractory and exclusion criterion #5.
3.1. Overview of 
Study Design
Deleted the following statement: Refractory is defined as either failure to achieve at least a 
PR to therapy or relapse within 12 months of combination CIT or purine analog systemic 
therapy.
Rationale: To expand evaluations that will be collected during the follow-up phase, consistent with health 
technology agency advice.
3.1. Overview of 
Study Design, 
Figure 2; 9.1.4. 
Follow-up Phase
Added that during the follow-up phase, the IWCLL criteria that were met during 
subsequent therapy will be collected, as well as response to subsequent therapy. 
Rationale: To further specify diagnosis to ensure enrolled subjects have CLL (and not MCL).
4.1. Inclusion Criteria
Expanded CLL/SLL diagnosis criteria to include criterion “c.”
Rationale: For consistency with bendamustine package insert.
4.1. Inclusion Criteria
The length of time required for practicing highly effective birth control methods after the 
last dose of bendamustine was made consistent for men and women (ie, 6 months) in 
criterion #9.
6.3. Dose 
Modification
Clarified existing dose modification criteria for bendamustine, and added criteria for 
bendamustine discontinuation due to hepatotoxicity. 
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Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
Applicable Section(s)
Description of Change(s)
Rationale: For consistency with the package insert for rituximab.
6.3. Dose 
Modification
Modified the statement that describes when the rituximab dose should be held.  
Rationale: To align with the IRC charter. 
9.2.1.4. Response 
Categories and 
Table 1
Expanded on lymph nodes, liver, and spleen criteria for disease response (PR and PD), and 
expanded the definition of PD. 
Rationale: Validation of the CLL-16 has not been completed by EORTC. The scoring and measurement properties 
of the CLL-16 may be evaluated as part of this study.
9.2.1.5. Patient-Report 
Outcomes
Added statements explaining that alternate scoring approaches for the CLL-16 may be 
considered and that psychometric validation of the CLL-16 may be conducted using 
blinded treatment group data prior to database lock.
Rationale: To describe what multiplicity adjustment will be done for secondary PRO endpoints.
11.4.3. Analysis 
Methods
Clarified that details of multiplicity adjustment for secondary PRO endpoints to control 
alpha will be specified in the SAP. 
Rationale: To prevent the need for future protocol amendments in the event of changes in capsule size or color.  
14.1. Physical 
Description of Study 
Drugs
Removed reference to “gray” color and “size 0” of capsules. 
Rationale: Updated attachment for compliance with privacy requirements.
Attachments
In Attachment 6, subject’s initials and date of birth have been deleted to protect subject’s 
identity.
Rationale: For consistency with the CRF and clinical practice in case of adverse events. 
9.5. Safety 
Evaluations
Added that additional laboratory parameters may be obtained at unscheduled visits. 
Rationale: To aid with clinical trial registry procedures. 
Title page; synopsis
Added the Universal Trial Number (UTN).
Rationale: For consistency with other ibrutinib protocols.
1.2.2.1. Human 
Pharmacokinetics
Added paragraph regarding preliminary results from Study PCI-32765CLL1002. 
1.2.2.4. Overview of 
Clinical Safety 
Provided additional detail in the paragraph describing hemorrhagic AEs. Added text 
regarding mitigation of bleeding risk. Deleted paragraph regarding atrial fibrillation. 
4.2. Exclusion 
Criteria
Moved exclusion criterion for subjects requiring treatment with CYP3A4/5 inhibitors to a 
separate criterion from the exclusion criterion for subjects requiring anticoagulation with 
warfarin or equivalent vitamin K antagonists.
6.2. Study Drug 
Administration
Added statement to clarify the timing of study medication dosing on the days of PK 
sampling. 
6.3. Dose 
Modification
Clarified that study medication may be held for a maximum of 28 consecutive days, unless 
reviewed and approved by the sponsor.
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JNJ-54179060 (ibrutinib) 
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Approved, Date: 21 August 2017
Applicable Section(s)
Description of Change(s)
8.2. Prohibited 
Medications
Clarified that short courses (<14 days) of corticosteroids for non-cancer related medical 
reasons are permitted at doses not to exceed 100 mg/day of prednisone or equivalent.
8.3. Precautions with 
Concomitant 
Medications
Updated the guidelines for use of ibrutinib and QT prolonging agents. 
9.5. Safety 
Evaluations
Added ocular-related symptoms.
Attachment 3
Updated the list of CYP3A4/5 inhibitors, included the appropriate website, and added a 
statement that the website should be checked for the latest information. 
Rationale: Provided further clarification of existing text.
Time & Events 
Schedule
Moved “(within 72 hours of randomization)” to the row for rituximab 375 mg/m2.
3.1. Overview of 
Study Design
Added more detail for stratification factors by further defining failure to respond and
separate lines of therapy. 
3.1. Overview of 
Study Design; 9.5.
Safety Evaluations
Deleted “all” when referring to CBC tests are performed at the central laboratory. 
4.1. Inclusion Criteria
Added “or SLL” to inclusion criterion #5.
4.2. Exclusion 
Criteria
Clarified that subjects with active infection with Hepatitis C will be excluded.  
7. Treatment 
Compliance; 14.4. 
Preparation, 
Handling, and 
Storage; 15. Study-
Specific Materials
Corrected the name of the pharmacy manual to “Site Investigational Product Procedures.”
8.1. Permitted 
Medications 
Added that neutrophil growth factors are permitted per the ASCO guidelines or according 
to the institution’s guidelines.
9.1.3. Treatment 
Phase
Provided additional details regarding the timing of laboratory values and the requirements 
for meeting eligibility criteria.
9.2. Efficacy 
Evaluations
Clarified text in MRD bullet that evidence of CR is by clinical parameters (not all response 
parameters)
9.2.1.1. Radiographic 
Imaging Assessments
Added additional details regarding imaging assessments.
9.2.1.4. Response 
Categories; Reference 
Section
Added reference to IWCLL e-letter by Hallek.
9.2.1.2. Definition of 
Measureable and 
Assessable Disease 
Added that subjects must have 1 measurable lymph node >1.5 cm to be eligible. Made 
minor editorial changes in second paragraph regarding additional lesions. 
9.4. Biomarkers
Made minor editorial changes for clarity. 
15. Study-Specific 
Materials
Updated the list of supplies provided to investigators. 
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JNJ-54179060 (ibrutinib) 
Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
Applicable Section(s)
Description of Change(s)
Rationale: To correct typographical errors.
3.1. Overview of 
Study Design, 
Figure 2; 9.1.3. 
Double-Blind 
Treatment Phase
Clarified that rituximab (and not the study medication) is to be administered within 
72 hours of randomization.
9.1.2. Screening 
Phase
Changed last sentence to “Results will be collected in the CRF and subjects with 20% of 
cells with del (17p) will not be eligible to participate in the study.”
Rationale: For consistency with latest company protocol template. 
10.3 Withdrawal 
From the Study 
Paragraph added on withdrawal from the use of samples in future research.  
12.1.1. Adverse Event 
Definitions and 
Classifications
Added text regarding EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use.
12.3.1. Adverse 
Events
Removed subject’s date of birth from the study card information. Added text about 
reporting unlisted and associated SAEs to the head of the investigational institute where 
required. 
16.2.5. Long-Term 
Retention of Samples 
for Additional Future 
Research
Added section.
17.11. Use of 
Information and 
Publication
Clarified when the company and the investigator are permitted to publish data from the 
study. 
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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JNJ-54179060 (ibrutinib) 
Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
SYNOPSIS
Randomized, Double-blind, Placebo-controlled Phase 3 Study of Ibrutinib, a Bruton's Tyrosine Kinase 
(BTK) Inhibitor, in Combination with Bendamustine and Rituximab (BR) in Subjects With Relapsed or 
Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
EudraCT NUMBER:  2012-000600-15
UTN NUMBER: U1111-1135-3745
Chronic lymphocytic leukemia (CLL) is incurable except for the minority of patients who have successful 
stem 
cell transplantation.
Ibrutinib 
(PCI-32765; JNJ-54179060)
is 
a 
first-in-class 
potent, 
orally-administered, covalently binding small molecule inhibitor of Bruton’s tyrosine kinase (BTK). As a 
single agent in previously-treated patients with CLL, an overall response rate (ORR) of 67% was 
observed. 
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective is to determine whether the addition of ibrutinib to BR significantly improves 
progression-free survival (PFS) compared with BR in subjects with relapsed or refractory CLL/SLL.
Secondary Objectives
The secondary objectives are to evaluate the following: safety; ORR; overall survival (OS); rate of 
minimal residual disease (MRD)-negative remissions;
improvement in hematologic parameters 
(hemoglobin, neutrophil count, platelet count); improvement in disease-related symptoms (fatigue, night 
sweats, weight loss, fever, and abdominal discomfort due to splenomegaly); and patient-reported 
symptoms, functional status, and well-being as measured by European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ) C30, EORTC QLQ CLL 16, 
EQ-5D-5L, and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale. Other 
secondary objectives are to characterize the PK of ibrutinib and explore its potential effect on 
bendamustine and rituximab PK, the potential relationships between ibrutinib metrics of exposure with 
relevant clinical or biomarker information, and to examine biomarkers related to BCR and compensatory 
signaling pathways and explore their association with resistance to ibrutinib treatment.
Hypothesis
The primary hypothesis of this study is that the addition of ibrutinib to BR compared with BR alone will 
significantly improve PFS in subjects with relapsed or refractory CLL/SLL.
OVERVIEW OF STUDY DESIGN
This is a randomized (1:1), double-blind, placebo-controlled, multicenter, Phase 3 study of approximately 
580 subjects to determine the benefits and risks of combining ibrutinib and BR in subjects with relapsed 
or refractory CLL/SLL following at least 1 line of prior systemic therapy. Randomization will be 
stratified by whether refractory to purine analog therapy (yes or no) and number of prior lines of therapy 
(1 or >1). All subjects will receive BR as the background therapy plus either ibrutinib or placebo for a
maximum of 6 cycles, after which treatment with ibrutinib or placebo will continue until disease 
progression or unacceptable toxicity. The study will include a Screening Phase, a Treatment Phase, and a 
Follow-up Phase. Study end is defined as when either 80% of the subjects have died or 5 years after the 
last subject is randomized into the study, whichever occurs first. 
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Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
Following the positive outcome of an interim analysis and pursuant to the independent Data Monitoring 
Committee (DMC) recommendations on 10 March 2015, the study is unblinded. Subjects in the placebo 
arm will be offered access to ibrutinib at the discretion of the investigator, at determination of disease 
progression or when the subject meets IWCLL criteria for treatment, as outlined in Section 9.1.5. Such 
subjects will be treated and assessed according to a separate Time & Events schedule.
SUBJECT SELECTION
Key eligibility criteria include the following: subjects who are 18 years of age; have relapsed or
refractory CLL or SLL following at least 1 prior line of systemic therapy; have active disease status per 
the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria with measurable nodal 
disease by computed tomography (CT); and have an Eastern Cooperative Oncology Group (ECOG)
Performance Status score of 0 or 1.
DOSAGE AND ADMINISTRATION
Bendamustine hydrochloride 70 mg/m2 will be administered via IV infusion over 30 minutes on Cycle 1, 
Days 2 and 3, and on Cycles 2-6, Days 1 and 2 for up to 6 cycles. Rituximab will be administered at a 
dose of 375 mg/m2 on Cycle 1, Day 1, and 500 mg/m2 in Cycles 2-6, Day 1. A cycle will be defined as 
28 days, with the exception of Cycle 1, which will be 29 days to allow for rituximab dosing prior to 
bendamustine and study medication. Subjects randomized to Treatment Arm A will receive placebo 
(3 capsules) administered orally once daily continuously. Subjects randomized to Treatment Arm B will 
receive ibrutinib 420 mg (3 x 140-mg capsules) administered orally once daily continuously. Treatment 
with study medication (placebo or ibrutinib) will continue from Cycle 1 until disease progression or 
unacceptable toxicity.
As of Amendment INT-4, access to ibrutinib for subjects on Treatment Arm A (placebo) may be provided
at determination of disease progression or when subject meets IWCLL criteria for treatment.
EFFICACY EVALUATIONS/ENDPOINTS
Efficacy evaluations will include CT scans, laboratory testing, focused physical examinations, bone 
marrow biopsy and aspirate, and assessment of PROs.a Subjects will have disease evaluations every 
12 weeks until disease progression. 
PHARMACOKINETIC EVALUATIONS
In both treatment arms, sparse samples for the development of a population-based pharmacokinetic (PK)
approach will be collected from all subjects and evaluated for ibrutinib and potentially for PCI-45227. In 
addition, for a subset of subjects at selected sites, sparse sampling will be performed in both treatment 
arms to explore a potential effect of ibrutinib on the PK of bendamustine and rituximab.
BIOMARKER EVALUATIONS
Blood samples will be collected and analyzed to better understand the mechanism of action of ibrutinib 
with an aim to develop predictors of resistance. 
SAFETY EVALUATIONS
Safety will be assessed by adverse events (AEs), physical examinations, laboratory tests, and concomitant 
medication usage. Specific timing is provided in the Time and Events Schedule. 
                                                
a With Amendment INT-6, collection of all ePRO data is discontinued. The last date for ePRO collection is 
18 September 2016, which corresponds to 4 years after the first subject entered the study; no further ePRO data 
will be collected after that date.
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JNJ-54179060 (ibrutinib) 
Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
STATISTICAL METHODS
The primary efficacy endpoint of PFS will be determined by an Independent Review Committee (IRC). 
The study is designed to detect a hazard ratio of 0.7 for the ibrutinib + BR group relative to placebo + BR 
group (corresponding to an improvement of 43% in median PFS, eg, from 15 months to 21.5 months) 
with 90% power at a 1-sided significance level of 0.025, using a group sequential testing design. Two 
analyses are planned: an interim analysis using an O’Brien & Fleming boundary after approximately 
171 (50%) PFS events (progressive disease [PD] or death) have occurred, and a final analysis after 
342 PFS events have occurred. An independent Data Monitoring Committee (DMC) will review safety 
data periodically and data from the interim analysis.
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JNJ-54179060 (ibrutinib) 
Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
TIME AND EVENTS SCHEDULE
NOTE: As of Amendment INT-4: After the interim analysis, subjects will no longer follow this Time and Events Schedule. Subjects will be 
treated and assessed according to separate T&E Schedules, following this table.
Screening
(within 
30 days 
prior to 
random-
ization)
Treatment Phase (1 Cycle = 28 days)a
Post-Treatment 
Follow-up Phase
Cycle 1a
Day
Cycle 2-6
Day
Cycle 7-12
Day
Cycle 
13, 16, 
etc. 
(every 
3 cycles)
Disease 
Evaluations
Every 
12 weeks
(7 days) 
(Starting 
on C1, D1)
End of 
Treatment 
Visit
Prior to 
Disease 
Progression 
(Every 
12 weeks
7 days)
Following 
Disease 
Progression 
(Every 
16 weeks)
1
2
3
8
15
1
2
15
1
Day 1
Drug Administration 
Rituximab 375 mg/m2 (within 
72 hours of randomization)
X
Rituximab 500 mg/m2
X
Bendamustine hydrochloride 
70 mg/m2
X
X
X
X
Study medication (ibrutinib 
420 mg or matching placebo)
------------------------------------------------Continuous-----------------------------------
Dispense study medication and 
check drug accountability
X
X
X
X
Ongoing Subject Review
Concomitant medicationb
X
------------------------------------------------Continuous--------------------------------------------------------
Adverse eventsb
X
------------------------------------------------Continuous--------------------------------------------------------
Procedures
Informed consent
X
Medical and disease history
X
Height, vital signs, and ECOG 
Performance Status Score
X
Body surface area (BSA)
X
Electrocardiogramc
X
X
X
Weight
X
X
X
Disease-related symptoms and 
physical examinationd
X
X
X
X
X
X
X
X
Patient-reported outcomes 
(EORTC QLQ-C30 and 
EQ-5D-5L questionnaires)
X
Xe
Xe
X
X
X
Xf
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JNJ-54179060 (ibrutinib) 
Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
Screening
(within 
30 days 
prior to 
random-
ization)
Treatment Phase (1 Cycle = 28 days)a
Post-Treatment 
Follow-up Phase
Cycle 1a
Day
Cycle 2-6
Day
Cycle 7-12
Day
Cycle 
13, 16, 
etc. 
(every 
3 cycles)
Disease 
Evaluations
Every 
12 weeks
(7 days) 
(Starting 
on C1, D1)
End of 
Treatment 
Visit
Prior to 
Disease 
Progression 
(Every 
12 weeks
7 days)
Following 
Disease 
Progression 
(Every 
16 weeks)
1
2
3
8
15
1
2
15
1
Day 1
Patient-reported outcomes 
(EORTC QLQ-CLL 16 and 
FACIT-Fatigue Scale 
questionnaires)
X
Xg
Xg
X
X
X
Disease Evaluations
CT neck, chest, abdomen, and 
pelvish
X
Xh
X
Xh
Bone marrow aspirate and biopsy
Xi
(X)j
Xj
Minimal residual disease
Xj
Xj
Survival status and subsequent 
antineoplastic therapies
X
X
Laboratory Assessmentsk
Complete blood count
Xl
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
Xl
X
X
X
X
X
X
X
X
Hepatitis serologies
X
Urine or serum pregnancy test
X
aPTT, INR
X
Serum immunoglobulin and 
β2 microglobulin
X
X
X
X
Cytogenetics (karyotyping and 
FISH)m
X
Biomarker blood samplesn
Xn
X
X
PK sample (study medication)
Xo
Xo
PK sample (bendamustine)p
Xq
Xq
PK sample (rituximab)p
Xr
Xr
Xr
Xr
a
For Cycle 1 only, the duration will be 29 days to allow for rituximab dosing prior to bendamustine and study medication. A standard cycle should be no less than 
26 days or more than 30 days.
b
Adverse events and concomitant medications should be recorded from the time of written informed consent up until 30 days after the last dose of study treatment
c
To be conducted for all subjects at screening. For a subset of subjects at selected sites, additional ECGs will be performed on Day 2 of Cycles 1 and 2 prior to study 
medication administration, immediately before the 2-hr PK sample for study medication, and immediately before the 4-hr PK sample for study treatment. 
d
The screening physical examination must be a full examination. Follow-up examinations must document presence or absence, or increase or decrease or no change 
of hepatomegaly, splenomegaly, and lymphadenopathy. Subjects should be questioned regarding changes in ocular status and referred to an ophthalmologist for any 
Grade 2 symptoms.
e
During Cycles 1-12, the EORTC QLQ-C30 and EQ-5D-5L questionnaires will be performed at the beginning of Cycles 1, 3, 5, 7, and 10. 
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Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
f
For the first 3 follow-up assessments, the EQ-5D-5L questionnaire only will be completed by the subject, including subjects who receive next-line ibrutinib therapy. 
Data will be collected in person (preferred) or via telephone with the subject. 
g
During Cycles 1-12, the EORTC QLQ-CLL 16 and FACIT-Fatigue Scale questionnaires will be performed at the beginning of Cycles 1, 2, 4, 6, 8, and 10.  
h
To be performed every 12 weeks for the first 2 years and then every 6 months until disease progression or death.
i
A unilateral bone marrow biopsy and bone marrow aspirate or peripheral blood sample must be obtained during screening or up to 90 days before randomization for 
evaluations described in Section 9.2.1.3. 
j
For subjects with suspected CR, a confirmatory bone marrow aspirate and biopsy must be obtained and an MRD evaluation of bone marrow aspirate must be 
performed. This should occur no earlier than 2 months following the completion of BR. Subsequent MRD evaluations (peripheral blood) in subjects with CR will 
occur every 12 weeks with disease evaluations. For subjects with suspected PD based on new onset of cytopenia after the completion of BR, a bone marrow aspirate 
or biopsy should be performed to determine the underlying cause.
k
Additional details regarding laboratory testing will be included in the Laboratory Manual. 
l
Must be done within 7 days prior to randomization. 
m
This should be performed on a peripheral blood sample or a bone marrow aspirate. Conventional karyotype evaluations are optional; FISH is required. For subjects 
with SLL, a lymph node biopsy may be used for immunophenotyping, morphology, and FISH testing to confirm the diagnosis.
n
Blood samples for biomarker analysis will be collected predose at Day 1 and Day 15 of Cycle 1 and at the end of treatment or at disease progression. 
o
To be obtained at Day 2 of Cycles 1 and 2, at predose, and at 1 hr (window 45-75 min), 2 hrs (window 1.5-2.5 hrs), and 4 hrs (window 3.5-6 hrs) following dosing of 
study medication.
p
To be obtained only for a subset of subjects at selected sites. For subjects at the selected sites, participation is mandatory.
q
To be obtained at Day 2 of Cycles 1 and 2, prior to the start of bendamustine infusion, immediately prior to the end of bendamustine infusion, and at 1 hr 
(window 45-75 min), 2 hrs (window 1.5-2.5 hrs), and 4 hrs (window 3.5-6 hrs) following dosing of oral study medication administration. 
r
To be obtained at Days 1 and 15 of Cycle 1, Day 1 of Cycles 2-6 prior to starting rituximab infusion, and on Day 1 of Cycles 7-9.
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JNJ-54179060 (ibrutinib) 
Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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TIME AND EVENTS SCHEDULE — AFTER INTERIM ANALYSIS: APPLIES TO SUBJECTS CONTINUING IBRUTINIB OR 
SUBJECTS IN FOLLOW-UP
Treatment Phase 
Post-Treatment
Follow-up Phase
Disease Evaluations
Every 12 weeks
(7 days) 
End of 
Treatment 
Visit
Prior to Disease 
Progression (Every 
12 weeks
7 days)
Following Disease 
Progression (Every 
16 weeks 7 days)
Drug Administration
Ibrutinib 420 mg
------------------------------Continuous-------------------------
Xa
Dispense ibrutinib and 
check drug accountability
X
Ongoing Subject Review
Concomitant medication
------------------------------Continuous------------------------------------------------------
Adverse events
------------------------------Continuous------------------------------------------------------
Procedures
Patient-reported outcomes 
(EORTC QLQ-C30, 
EQ-5D-5L, EORTC QLQ-
CLL 16 and FACIT-
Fatigue Scale 
questionnaires)g
X
X
X
Xb
Disease Evaluations
Physical Examination and 
Disease-related symptoms
X
X
X
CT neck, chest, abdomen, 
and pelvis
Xc
Xd
Bone marrow aspirate and 
biopsy
Xe
Minimal residual diseasee,f, 
h
X
Survival status and 
subsequent antineoplastic 
therapies
X
X
Laboratory Assessments
Complete blood count
(local labs only)
X
X
X
Serum chemistry
X
Biomarker blood samples
X
a
Subjects who were on placebo will have an EOT visit. If they do not require immediate treatment, they will continue in follow up until investigator-determined PD.
b
For the first 3 follow-up assessments, only the EQ-5D-5L questionnaire will be completed by subjects.
c
To be performed every 24 weeks until disease progression in subjects treated with ibrutinib. No IRC assessments will be required. 
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JNJ-54179060 (ibrutinib) 
Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
d
Subjects who were previously on ibrutinib who are in Pre-PD follow-up phase will have CT scan performed every 24 weeks until disease progression. Subjects who 
were previously on placebo who are in Pre-PD follow-up phase will have CT scan performed as per standard of care.
e
For subjects with suspected CR only, a confirmatory bone marrow aspirate and biopsy must be obtained. A concurrent MRD evaluation of bone marrow aspirate and 
peripheral blood sample should be performed. 
f
Peripheral blood MRD assessment for all responding subjects
g
The last date for ePRO collection is 18 September 2016, which corresponds to 4 years after the first subject entered the study; no further ePRO data will be collected 
after that date.
h
The last date for MRD collection is 31 July 2017; no further MRD data will be collected after that date.
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JNJ-54179060 (ibrutinib) 
Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
TIME AND EVENTS SCHEDULE — CROSSOVER TO IBRUTINIB
Treatment Phase
Follow-up Phase
Assessment of
Eligibility for 
Ibrutinib 
Therapy
Day 1 and every 4 weeks 
until week 12
Every 12 weeks (±7 days) 
from week 12 until PD
End-of-Treatment Visit
Follow-up (every 
16 weeks ±7 days)
Procedures
Confirmed disease progression or meets 
IWCLL criteria for treatmenta
X
Medical monitor review
X
Medical historyb
X
Informed consent
X
Drug Administration
Ibrutinib 420 mg 
--------------------------Continuous--------------------------
Dispense ibrutinib and check drug 
accountability
X
X
Ongoing Subject Review
Concomitant medicationc
----------------------------------------------Continuous-----------------------------------------------------------
Adverse eventsc
----------------------------------------------Continuous-----------------------------------------------------------
Laboratory Assessments
Complete blood count (local labs only)
X
Xe
X
X
Serum chemistryd
X
Biomarkers 
Xf
Disease Evaluations
Investigator assessment of response
Xg
Minimal residual diseaseh,i, l
X
Survival status and subsequent 
antineoplastic therapies
X
Patient-reported outcomes (EQ-5D-5L)k
X j
a
For Amendment INT-3: IRC-confirmed PD; for Amendment INT-4, investigator determined PD.
b
Only required if crossover occurs >30 days after last dose of blinded study treatment.
c
All AEs and concomitant medications from the time a signed and dated informed consent form for crossover is obtained until 30 days following the last dose of 
study drug will be reported.
d
See Section 9.5 for parameters to be collected.
e
Additional CBC to be taken at Week 2.
f
Blood samples for biomarkers will be collected at Week 12 Day 1 and at disease progression. 
g
Investigator assessment of response to be performed every 12 weeks for the first year, and then every 24 weeks thereafter until disease progression. Evaluations are 
to be performed per standard of care. 
h
For subjects with suspected CR only, a confirmatory bone marrow aspirate and biopsy should be obtained. A concurrent MRD evaluation of bone marrow aspirate
and peripheral blood sample should be performed.
i
Peripheral blood MRD assessment for all responding subjects.
j
This also applies to subjects with PD who crossover to receive ibrutinib therapy. They will still be required to complete 3 post-PD follow-up EQ-5D-5L assessments 
every 16 weeks.
k
The last date for ePRO collection is 18 September 2016, which corresponds to 4 years after the first subject entered the study; no further ePRO data will be collected 
after that date.
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JNJ-54179060 (ibrutinib) 
Clinical Protocol PCI-32765CLL3001 Amendment INT-7
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Approved, Date: 21 August 2017
l
The last date for MRD collection is 31 July 2017; no further MRD data will be collected after that date.
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JNJ-54179060 (ibrutinib) 
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ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviations
AE
adverse event
AIHA
autoimmune hemolytic anemia
ALC
absolute lymphocyte counts
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC0-last
area under the curve from time 0 to the last observation
-hCG
beta-human chorionic gonadotropin
BCR
B cell receptor
BR
bendamustine and rituximab
BSA
body surface area
BTK
Bruton’s tyrosine kinase
CBC
complete blood count
CI
confidence interval
CIT
chemoimmunotherapy
CLL
chronic lymphocytic leukemia
CNS
central nervous system
CR
complete response
CRF
case report form
CRi
complete response with incomplete marrow recovery
CT
computed tomography
CTCAE
common terminology criteria for adverse events
CYP
cytochrome P450
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EORTC
European Organization for Research and Treatment of Cancer
ESMO
European Society for Medical Oncology
FACIT
Functional Assessment of Chronic Illness Therapy
FACS
fluorescence activated cell sorting
FCR
fludarabine, cyclophosphamide, and rituximab
FISH
fluorescent in situ hybridization
GEP
gene expression profile
GFR
glomerular filtration rate
HIV
human immunodeficiency virus
ICF
informed consent form
IEC
independent ethics committee
IgVH
immunoglobulin variable heavy gene
IL
interleukin
INR
international normalized ratio
IRB
institutional review board
IRC
independent review committee
ITP
autoimmune thrombocytopenia
ITT
intent to treat
IV
intravenous(ly)
IWCLL
International Workshop on Chronic Lymphocytic Leukemia
IWRS
interactive web response system
JRD
Janssen Research & Development, LLC
LDH
lactic acid dehydrogenase
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LDT
lymphocyte doubling time
MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimal residual disease
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network 
NCI
National Cancer Institute
NHL
Non-Hodgkin’s lymphoma
NONMEM
nonlinear mixed-effects modeling
nPR
nodular partial response
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PCYC
Pharmacyclics, Inc. 
PD
progressive disease
PFS
progression-free survival
P-gp
p-glycoprotein
PK
pharmacokinetic(s)
PLL
prolymphocytic leukemia
PR
partial response
PRO
patient-reported outcomes
QLQ
quality of life questionnaire
RT
Richter’s transformation
SAE
serious adverse event
SJS
Stevens-Johnson Syndrome
SLL
small lymphocytic lymphoma
SMA
somatic mutation analysis
TLS
tumor lysis syndrome
ULN
upper limit of normal
USPI
United States Package Insert
UTI
urinary tract infection
WBC
white blood cell
WHO
World Health Organization
Definitions of Terms
Study medication or 
study drug
Ibrutinib/placebo
Study treatment
Bendamustine hydrochloride, rituximab, and ibrutinib/placebo
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1.
INTRODUCTION
1.1.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the 
developed world. It is characterized by an accumulation of monoclonal mature B cells 
(CD5+CD23+) in the blood, bone marrow, and secondary lymph organs. These cells are 
constantly being stimulated by their B-cell receptors (BCRs) as well as their interaction with 
their microenvironment.8 According to the World Health Organization (WHO), small 
lymphocytic lymphoma (SLL), a disease which presents with similar pathological findings but 
without the lymphocytosis, is considered to be a manifestation of the same underlying disorder 
as CLL.4
Once diagnosed, patients may have a variable course, some not requiring treatment for decades 
and others requiring more urgent treatment, particularly those with clinically symptomatic 
disease.20 According to the International Workshop on Chronic Lymphocytic Leukemia 
(IWCLL) guidelines, the following features are indications for therapy: progressive marrow 
failure (manifested by anemia or thrombocytopenia), massive or progressive splenomegaly 
(at least 6 cm or greater), massive lymph nodes (at least 10 cm in the longest diameter), 
progressive lymphocytosis with a rapid lymphocyte doubling time (LDT) occurring in less than 
6 months, worsening autoimmune cytopenias resistant to corticosteroids or other standard 
treatment, and constitutional symptoms.22
Historically, the main frontline treatment for CLL was chlorambucil. Over the past 2 decades, 
however, new agents and combinations of chemotherapy have been shown to be superior to 
chlorambucil. Fludarabine and bendamustine were shown to have improved efficacy compared 
with chlorambucil in randomized studies.7,26,39 The addition of cyclophosphamide to fludarabine 
further improved response rates and progression-free survival (PFS) compared with fludarabine 
alone.11,16,17,31 The addition of rituximab to fludarabine and cyclophosphamide (FCR) in the 
frontline setting resulted in significant improvement in PFS and overall survival (OS) compared 
with fludarabine and cyclophosphamide alone.21
A recent Phase 2 study evaluated the combination of bendamustine and rituximab (BR) in 
patients with relapsed or refractory disease. The median number of prior therapies for CLL was
2 (range 1 to 5). The complete response (CR) rate was 9% and overall response rate (ORR) was
59%. Median PFS was 15 months and median OS was 34 months.15 However, in the high-risk 
group of subjects with del (17p), the response was poor, with only 1 (7.1%) of 14 subjects 
responding with a CR. The median PFS for all 14 subjects was 6.8 months. 
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1.2.
Ibrutinib
Ibrutinib 
(PCI-32765; 
JNJ-54179060)
is a 
first-in-class 
potent, 
orally-administered, 
covalently-binding small molecule inhibitor of Bruton’s tyrosine kinase (BTK) currently under 
development for the treatment of B-cell malignancies. Ibrutinib is being co-developed by 
Pharmacyclics, Inc. and Janssen Research & Development, LLC (JRD). 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.
The investigational drug product is an oral formulation in a hard gelatin capsule form containing 
micronized ibrutinib. The initial approval of ibrutinib by the United States (US) FDA for the 
treatment of adult patients with MCL who have received at least one prior therapy was received 
on 13 November 2013. This indication is based on overall response rate. An improvement in 
survival or disease-related symptoms has not been established. Subsequently it received approval
in the US for the treatment of patients with CLL who have received at least one prior therapy, 
and for the treatment of CLL patients with 17p deletion. It is also approved in the EU for the 
treatment of adult patients with CLL who have received at least one prior therapy, or in first line 
in the presence of 17p deletion or TP53 mutation in patients unsuitable for 
chemo-immunotherapy. Approvals have also been obtained in a number of other countries 
worldwide. 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. 
1.2.1.
Nonclinical Studies
The generation and maintenance of normal and malignant B cells is controlled by biochemical 
signals transmitted by the BCR. Bruton’s tyrosine kinase is an enzyme required for BCR 
signaling. Selective BTK inhibition is a novel approach to target diseases driven by BCR 
activation, such as CLL/SLL. 
In vitro studies have shown that ibrutinib binds covalently to a cysteine residue 481 in the BTK
active site, leading to potent and irreversible inhibition of BTK enzymatic activity. In cellular 
signal transduction assays with a B-cell lymphoma cell line, ibrutinib
inhibited 
autophosphorylation of BTK, and phosphorylation of further downstream kinases. 
1.2.2.
Clinical Studies
1.2.2.1.
Human Pharmacokinetics
Extensive pharmacokinetic (PK) sampling has been performed on approximately 186 subjects 
across 
4
studies
(Studies 
PCYC-04753, 
PCYC-1102-CA, 
PCYC-1104-CA, 
and 
PCYC-1109-CA). Results show that plasma concentrations of ibrutinib generally increased with 
increasing dosages from 1.25 to 12.5 mg/kg/day. An increase in ibrutinib AUC was 
approximately proportional to dose. The coefficient of variation for the AUC ranged from 60% 
to 107% across all studies. The mean apparent terminal half-life of ibrutinib ranged from 4.3 to 
8.9 hours, with median Tmax of 2 hours. There was no apparent accumulation of ibrutinib 
exposure after repeated daily dosing.
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In Study PCYC-1102-CA, ibrutinib was administered as a fixed dosage of 420 mg/day to 
subjects with relapsed/refractory CLL/SLL. Approximately 95% of subjects had steady-state 
ibrutinib AUC values 160 ng∙h/mL, indicating that the 420-mg/day dose is adequate to achieve 
exposures yielding full BTK active-site occupancy. 
Study PCI-32765CLL1002 was an open-label drug-drug interaction study of 18 men, in which 
ibrutinib was administered alone at a 120-mg dose or in combination with ketoconazole at a 
40-mg dose. Results demonstrated a 24-fold increase in ibrutinib area under the plasma 
concentration-time curve (AUC0-last) and a 29-fold increase in Cmax following co-administration 
with ketoconazole. Terminal half-life was not increased.
Ibrutinib single-dose administration was well tolerated. No drug-related adverse events were
reported. No Grade 3 or 4 toxicities or serious adverse events were reported.
1.2.2.2.
Clinical Efficacy Studies in Chronic Lymphocytic Leukemia and Small 
Lymphocytic Lymphoma
As of the end of 2011, more than 300 patients with various B-cell malignancies have received 
ibrutinib across 7 clinical studies, 4 of which included patients with CLL/SLL. Patients with 
CLL or SLL have received single-agent ibrutinib across 2 clinical studies: Study PCYC-04753, a 
Phase 
1 
dose-finding 
study 
in 
patients 
with 
recurrent 
B-cell 
lymphoma, 
and 
Study PCYC-1102-CA, a Phase 1b/2 study in patients with CLL/SLL. Two additional 
Phase 1b/2 studies are ongoing to evaluate the safety and efficacy of ibrutinib in combination 
with chemoimmunotherapy (CIT) or CD20 monoclonal antibody therapy in patients with 
relapsed or refractory CLL/SLL, specifically with BR or FCR in Study PCYC-1108-CA, and 
with ofatumumab in Study PCYC-1109-CA.
1.2.2.2.1.
Study PCYC-04753
This was a Phase 1, multicenter, dose-escalation study of ibrutinib in subjects with surface 
immunoglobulin positive B-cell Non-Hodgkin’s Lymphoma (NHL). Subjects were observed for 
dose-limiting toxicities (DLTs) and other adverse events (AEs) as well as for laboratory and 
physical examination changes. Fifty subjects were evaluable for efficacy. The ORR was 60%, 
with 7 CRs and 23 PRs. Safety data are available for 65 subjects. The most common AEs were 
diarrhea (41.5%), fatigue (38.5%), cough (27.7%), nausea (26.2%), headache (21.5%), and 
pyrexia (20.0%). The most common Grade 3 AE was anemia (7.7%). Adverse events led to 
discontinuation for 15.4% of subjects. Five subjects died within 30 days of the last dose, 4 from 
disease progression and 1 from respiratory depression. The maximum tolerated dose (MTD) of 
ibrutinib was not reached.
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1.2.2.2.2.
Study PCYC-1102-CA
Study PCYC-1102-CA is a Phase 1b/2, open-label, multicenter study. One hundred seventeen 
subjects with CLL/SLL were enrolled into 1 of 5 treatment groups, each receiving 1 of 2 fixed 
dose levels (420 mg/day or 840 mg/day) of ibrutinib.32 Of the 61 subjects in Groups 1 
(relapsed/refractory; 420 mg) and 3 (relapsed/refractory; 840 mg) with relapsed or refractory 
disease had received a median of 4 (range: 1 to 12) prior therapies, with all subjects receiving 
nucleoside analogs. The median age for subjects in Groups 1 and 3 was 64 years. Thirty-nine 
percent of subjects had an ECOG performance score of 0 and 61% had a score of 1 or 2.
Molecular, clinical, and prior treatment characteristics reflected a poor-risk population. 
Twenty-eight (46%) subjects from Groups 1 and 3 were considered refractory to purine analog 
therapy (ie, <12-month treatment-free interval following purine analog regimen). Fifty-four 
percent had bulky disease (defined as single lymph nodes measuring 5 cm). Seventy-nine 
percent of subjects had at least 1 molecular poor-risk feature (immunoglobulin variable heavy 
gene [IgVH] unmutated, del [17p], del [11q], or β2 microglobulin >3 mg/L), with 36% of 
subjects having del (17p).
The ORR was 67% with 2% CRs. An additional 23% of subjects had >50% shrinkage of 
lymphadenopathy (nodal response) and 3% had stable disease. The 840-mg cohort was stopped 
after comparable efficacy and safety between 420 mg and 840 mg was shown. The 12-month 
PFS estimate for Group 1 was 88% and for Group 3 was 82%.
Safety data are available for 114 subjects across all 5 treatment groups. The most common AEs 
were diarrhea (53.5%), fatigue (28.1%), nausea (24.6%), upper respiratory tract infection 
(22.8%), cough (22.8%), and arthralgia (21.1%). The most common Grade 3 AEs were anemia 
(8.8%), neutropenia (7.0%), and thrombocytopenia (7.0%). Four subjects died within 30 days of 
last dose, 2 from sepsis and 2 from pneumonia.
1.2.2.2.3.
Study PCYC-1108-CA
Study PCYC-1108-CA is an ongoing combination CIT Phase 1b/2 study which has completed 
enrollment. Among 33 subjects with relapsed and refractory CLL/SLL enrolled, 30 have 
received BR and ibrutinib and 3 have received FCR and ibrutinib. The FCR cohort enrollment 
was suspended due to slow enrollment related to the lack of subjects at participating sites with 
relapsed CLL in whom the FCR regimen was considered appropriate. For subjects receiving the 
BR combination, bendamustine 70 mg/m2 was administered on Day 1 and Day 2, combined with 
rituximab at 375 mg/m2 on Day 1 of Cycle 1 and 500 mg/m2 on Day 1 for all subsequent courses 
for a maximum of 6 cycles. Ibrutinib was administered as a continuous daily oral dose of 
420 mg. The median number of prior therapies was 2 (range 1 to 4). There were 37% and 13% of 
subjects, respectively, who were considered either refractory to a purine analog-containing 
regimen or to BR (treatment-free interval prior to enrollment was <12 months). Bulky disease 
was present in 52% of subjects. 
At a median follow-up of 4.9 months (range 2.7 to 8.3 months), the ORR was 90% (CR 10%, 
partial response [PR] 80%). Two additional subjects achieved a nodal response with residual 
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lymphocytosis. Responses appear to be independent of high-risk clinical or genomic features. 
Ninety percent of subjects currently remain on study. Three subjects have discontinued, 2 for 
progressive disease (PD) and 1 in pursuit of a stem cell transplant.
For the 30 subjects who received the combination of ibrutinib and BR, the most common AEs 
were diarrhea (70%), nausea (57%), fatigue (37%), thrombocytopenia, headache, and 
neutropenia (27% each). The most commonly reported Grade 3 AEs were neutropenia (23%), 
fatigue, rash, thrombocytopenia, and tumor lysis syndrome (TLS) (7% each). Serious adverse 
events (SAEs) (regardless of attribution) were reported for 10% of subjects and included 
cellulitis, TLS, and febrile neutropenia. There have been no discontinuations due to AEs and no 
deaths on study. 
1.2.2.2.4.
Study PCYC-1109-CA
Study PCYC-1109-CA is an ongoing Phase 1b/2 study combining ibrutinib with ofatumumab.
Based 
on 
preliminary 
data 
from 
27 
subjects 
with 
relapsed 
or 
refractory 
CLL/SLL/prolymphocytic leukemia (PLL) (n=24) or Richter’s transformation (RT, n=3), all
subjects achieved a PR (100% ORR). Safety data are available for 47 subjects. The most 
common AEs have been contusion (42.6%), diarrhea (31.9%), peripheral sensory neuropathy 
(25.5%), and stomatitis (21.3%). The most common AE of Grade 3 was anemia (10.6%). Three 
subjects died within 30 days of last dose, 1 from pneumonia and myocardial infarction, 1 from 
subdural hematoma, and 1 from pneumonia. The median follow-up is 6.5 months (range: 5.3 to 
10.2 months). 
1.2.2.2.5.
Summary of Efficacy of Ibrutinib in CLL
Efficacy results from Studies
PCYC-04753, PCYC-1102-CA, PCYC-1108-CA, and 
PCYC-1109-CA demonstrate that ibrutinib has robust activity in CLL both as a single agent and 
in combination. All studies included patients with relapsed and refractory disease. Response rates 
for the 4 studies were independent of high-risk factors or genomic features. The predictable and 
characteristic pattern of response, with rapid reduction in lymphadenopathy, frequent and early 
hematologic improvement, and transient lymphocytosis, is consistent with the established 
anti-homing, anti-adhesion, pro-apoptotic, and anti-proliferative effects of BTK inhibition in 
CLL cells. Of particular note, high response rates have been demonstrated with continuing 
therapy in Studies PCYC-1102-CA, PCYC-1108-CA, and PCYC-1109-CA. 
1.2.2.3.
Treatment-related Lymphocytosis
Similar to other agents targeting B-cell receptor signaling, transient lymphocytosis is a 
pharmacodynamic effect of ibrutinib, in which the inhibition of BTK-mediated cellular homing 
and adhesion results in a mobilization of tumor cells to the peripheral blood.45
Upon initiation of treatment, a transient phase of increase in lymphocyte counts (ie, 50% 
increase from baseline and above absolute count 5000/μL), often associated with reduction of 
lymphadenopathy, has been observed in most patients (75%) with relapsed/refractory CLL/SLL 
treated with ibrutinib. This effect has also been observed in some patients (33%) with 
relapsed/refractory MCL treated with ibrutinib. This observed transient lymphocytosis is usually 
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not associated with an adverse event 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 resolves within a median of 
7.1 weeks in the MCL and 18.7 weeks in the CLL patients.
A substantial increase in the number of circulating lymphocytes has been observed in a subset of 
patients. There have been isolated cases of leukostasis reported in these patients while treated 
with ibrutinib.
A high number of circulating lymphocytes (>400,000/μL) may confer increased risk; these 
subjects should be closely monitored. Administer supportive care such as hydration and/or 
leukapheresis as indicated. Ibrutinib may be temporarily held, and the medical monitor should be 
contacted.
In Study PCYC-1108-CA, treatment-related lymphocytosis was observed, although it was not as 
pronounced in subjects treated with ibrutinib in combination with BR compared with ibrutinib 
alone. Approximately one-third of the subjects have developed transient treatment-related 
lymphocytosis with a peak absolute lymphocyte count (ALC) greater than 50% above baseline 
value. In 5 (17%) of 30 subjects, the peak ALC was greater than 200% above baseline counts. 
The pattern of response is depicted in the following figures. 
Figure 1
Pattern of Response – Ibrutinib + BR versus Single-Agent Ibrutinib: Blood Lymphocytes versus 
Lymph Nodes Sum of Products of Diameters: Studies PCYC-1102-CA and PCYC-1108-CA
1
Mean Percent Change From Baseline
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
-110
Cycles
Cycles
700
600
500
400
300
200
100
0
-100
-200
Screen
Cycle 2
Cycle 4
Cycle 5
Cycle 6
Cycle 8
Cycle 9
Cycle 11
Cycle 12
Cycle 14
ALC—Ibrutinib single agent
ALC—ibrutinib + BR
SPD—Ibrutinib single agent
SPD—ibrutinib + BR
Screen
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle 7
Cycle 8
Cycle 9
Cycle 10
Cycle 11
Cycle 12
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An increase in the number of circulating lymphocytes in the peripheral blood in the setting of 
unequivocal improvement in at least 1 other disease-related parameter, including lymph node 
size, spleen size, hematologic parameters (hemoglobin and platelet count), or disease-related 
symptoms was not considered an indicator of PD by the investigators. This is consistent with the 
recommendation of the current National Comprehensive Cancer Network (NCCN) guideline 
(2012).28
1.2.2.4.
Overview of Clinical Safety
The integrated safety profile of ibrutinib administered as monotherapy to 506 patients across 
8 clinical studies (PCYC-04753, PCYC-1102-CA, PCYC-1104-CA, and PCYC-1106-CA, 
PCI32765MCL2001, PCYC-1111-CA, PCYC-1117-CA, and PCI-32765-JPN-101) has been 
evaluated. The most common treatment-emergent adverse events as of 06 April 2013 were 
diarrhea (42.1%), fatigue (33.8%), nausea (26.1%), cough (20.2%), and peripheral edema 
(18.6%). Grade 3 or higher adverse events were experienced by 60.7% of patients, the most 
common (> 2%) of which were hematologic in nature: neutropenia (9.7%), thrombocytopenia 
(6.5%), and anemia (4.9%). Pneumonia (7.7%) was the most frequent nonhematologic Grade 3 
or higher adverse event. Serious adverse events were experienced by 46.4% of treated patients. 
The only serious events occurring in more than 2% of patients were pneumonia (7.9%), atrial 
fibrillation (3.2%), and febrile neutropenia (2.8%).
The safety of ibrutinib administered as combination therapy to 130 subjects was evaluated in 
3 clinical 
studies: 
PCYC-1108-CA, 
PCYC-1109-CA, 
and 
PCI-32765DBL1002 
(ibrutinib administered 
in 
combination 
with 
standard 
R-CHOP 
(rituximab 
with 
cyclophosphamide, doxorubicin, vincristine, and prednisone). 
As of 06 April 2013, 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 Grades 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).  
There are reports of hemorrhagic events in subjects treated with ibrutinib in both monotherapy 
and combination clinical studies. The majority of these hemorrhagic adverse events were of 
Grade 1 or 2 in severity; those included contusion, epistaxis, and petechiae. Hemorrhagic events 
of Grade 3 or higher, including central nervous system (CNS) hemorrhage of any grade severity, 
occurred in 3.4% (17/506) of subjects treated in monotherapy studies and in 3.1% (4/130) of 
subjects treated in combination therapy studies; none were reported in the healthy volunteer 
studies (N=100). In the extension study, PCYC-1103-CA, 2 additional Grade 3 events associated 
with bleeding were reported (‘gastrointestinal haemorrhage’ and ‘haematotympanum’). Details 
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of these events are provided in the Investigator’s Brochure.
It is not clear whether or not these events are attributable to ibrutinib. However, it is possible that 
treatment with ibrutinib could increase the risk of bruising or bleeding. Subjects in the current 
study will be monitored closely for hemorrhagic adverse events. Guidance on use of antiplatelet 
agents and anticoagulants is provided in Section 8.3.
Other malignant diseases have been observed in subjects who have been treated with ibrutinib, 
including skin cancers, adenocarcinomas, and other hematologic malignancies. It is not clear 
whether or not these events are attributable to ibrutinib. Subjects in the current study will be 
monitored for other malignancies. 
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; 37.6%). 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.
1.3.
Overall Rationale for the Study
Although there have been impressive gains in treatment and in the understanding of the biology 
of CLL, the disease is incurable using chemotherapy or CIT. Stem cell transplant may be 
curative, but few patients are able to undergo this treatment.20 The more relapses patients incur, 
the more resistant patients become to therapy.24,27 Therefore, there is a need for further 
development of therapies for CLL. 
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2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective is to determine whether the addition of ibrutinib to BR significantly 
improves PFS compared with BR in subjects with relapsed or refractory CLL/SLL.
Secondary Objectives
The secondary objectives are:

To evaluate the safety of ibrutinib in combination with BR

To evaluate the ORR (CR + complete response with incomplete marrow recovery (CRi) + 
PR + nodular partial response [nPR])

To evaluate the OS

To evaluate the rate of minimal residual disease (MRD)-negative remissions

To evaluate improvement in hematologic parameters (hemoglobin, neutrophil count, platelet 
count)

To evaluate improvement of disease-related symptoms (fatigue, night sweats, weight loss, 
fever, and abdominal discomfort due to splenomegaly)

To evaluate patient-reported symptoms, functional status, and well-being as measured by 
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
(EORTC-QLQ)-C30, EORTC QLQ-CLL 16, EQ-5D-5L, and Functional Assessment of 
Chronic Illness Therapy (FACIT)-Fatigue Scale

To characterize the PK of ibrutinib and explore its potential effect on bendamustine and 
rituximab PK, the potential relationships between ibrutinib metrics of exposure with relevant 
clinical or biomarker information

To examine biomarkers related to BCR and compensatory signaling pathways and explore 
their association with resistance to ibrutinib treatment
2.2.
Hypothesis
The primary hypothesis of this study is that the addition of ibrutinib to BR compared with BR 
alone will significantly improve PFS in subjects with relapsed or refractory CLL/SLL.
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3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study to determine 
the benefits and risks of combining ibrutinib and BR in subjects with relapsed or refractory 
CLL/SLL following at least 1 line of prior systemic therapy. 
All subjects will receive background therapy with BR for a maximum of 6 cycles as described in 
Section 6. A cycle will be defined as 28 days, with the exception of Cycle 1, which will be 
29 days to allow for rituximab dosing prior to bendamustine and study medication. For the 
purposes of this protocol, study treatment is defined as bendamustine hydrochloride, rituximab, 
and ibrutinib/placebo; study drug is defined as ibrutinib/placebo. Approximately 580 subjects 
will be randomized in a 1:1 ratio to either Treatment Arm A (placebo) or Treatment Arm B
(ibrutinib 420 mg). Study medication will be administered orally once daily on a continuous 
schedule.
Stratification factors will include whether refractory to purine analog therapy (yes or no) and 
number of prior lines of therapy (1 or >1). For stratification, refractory is defined specifically as 
a failure to respond (ie, progressive disease [PD] or stable disease [SD]) to a purine analog or a 
recurrence of disease within 12 months of the last dose of purine analog therapy. Separate lines 
of therapy are defined as single or combination therapy regimens that are either separated by 
disease progression or refractory disease or by a treatment-free interval of 6 months or greater. In 
addition, a change of regimen due to insufficient response may be considered a separate line of 
therapy.
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. 
The Screening Phase will be up to 30 days prior to randomization. The Treatment Phase will 
extend 
from 
randomization 
until 
study 
treatment 
(bendamustine, 
rituximab, 
and 
ibrutinib/placebo) discontinuation. Subjects will receive both BR and study medication (ibrutinib 
or placebo) for the first 6 cycles, and thereafter will receive study medication until disease 
progression or unacceptable toxicity. For subjects who discontinue BR prior to completing 
6 cycles, treatment with study medication will continue. The Follow-up Phase will begin once a 
subject discontinues study treatment. Subjects who discontinue for reasons other than disease 
progression will continue to have disease evaluations according to the Time and Events 
Schedule. The Follow-up Phase will continue until death, loss to follow up, consent withdrawal, 
or study end, whichever occurs first. Study end is defined as when either 80% of the subjects 
have died or 5 years after the last subject is randomized into the study, whichever occurs first. 
Assessment of tumor response and progression will be conducted in accordance with the 
IWCLL 2008 Guidelines.22 The investigator will evaluate sites of disease by radiological 
imaging, physical examination, or other procedures as necessary, and review of hematology and 
clinical chemistry results. A central laboratory will perform complete blood count (CBC) testing. 
The primary efficacy analysis of PFS will be based on assessment by an Independent Review 
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Committee (IRC). Patient-reported symptoms, functional status, and well-being will also be 
measured. 
During the study, safety evaluations will include AE monitoring, physical examinations,
concomitant medication usage, and clinical laboratory parameters (hematology, chemistry, 
coagulation). At each site visit, subjects will be evaluated for toxicity. Blood samples will be 
drawn for assessment of PK and biomarker parameters. All study evaluations will be conducted 
according to the Time and Events Schedule. 
An independent Data Monitoring Committee (DMC) will be formed and constituted according to 
regulatory agency guidelines (see Section 11.9). One interim analysis is planned for the study 
(see Section 11.8). 
A diagram of the study design for the double-blind phase of the study is provided in Figure 2,
and the study design after interim analysis is provided in Figure 3.
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Figure 2
Study Design Schematic – Prior to Interim Analysis
a
A cycle will be defined as 28 days, except for Cycle 1, which will be 29 days.
Screening Phase
(within 30 days before randomization)
Assess Eligibility Criteria
Randomization
Subjects must start rituximab within 72 hours after randomization
Treatment Arm Aa
Background Therapy: 
Bendamustine 70 mg/m2 IV on Cycle 1, Days 2-3 and 
Cycles 2-6, Days 1-2;
Rituximab 375 mg/m2 Cycle 1, Day 1, and 
500 mg/m2 Cycles 2-6, Day 1;
Study Medication: 
Placebo oral once daily continuously
starting on Cycle 1, Day 2 until disease progression or 
unacceptable toxicity
Treatment Arm Ba
Background Therapy: 
Bendamustine 70 mg/m2 IV on Cycle 1, Days 2-3 and 
Cycles 2-6, Days 1-2;
Rituximab 375 mg/m2 Cycle 1, Day 1, and 
500 mg/m2 Cycles 2-6, Day 1;
Study Medication: 
Ibrutinib 420 mg oral once daily continuously 
starting on Cycle 1, Day 2 until disease progression 
or unacceptable toxicity
Treatment Discontinuation
Complete End-of-Treatment Visit
Follow-up Phase
Prior to Disease Progression (if applicable): 
Continue disease evaluations
Follow-up for survival status, subsequent 
antineoplastic therapies, IWCLL criteria met for 
subsequent therapy, and response to subsequent 
therapy
Following Disease Progression: 
Follow-up for survival status, subsequent 
antineoplastic therapies, IWCLL criteria met for 
subsequent therapy, and response to subsequent 
therapy
Double-Blind Treatment Phase
Next Line Ibrutinib Treatment 
IRC-confirmed disease progression; confirm eligibility; request medical 
monitor approval. Crossover to ibrutinib 420 mg oral once daily (until 
disease progression, unacceptable toxicity, or study end), may be 
permitted for subjects randomized to placebo.
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Figure 3
Study Design Schematic – Post- Interim Analysis
Treatment Phase Post-IA
Treatment Arm A 
Placebo
Treatment Arm B 
Ibrutinib
Non-PD/Treatment not 
indicated
Complete End-of-
Treatment Visit and enter 
Pre-PD Follow-up
Investigator-determined 
PD/Treatment indicated
Complete End-of-Treatment 
Visit
Crossover to Ibrutinib
Ibrutinib 420 mg oral once daily continuously

Disease evaluations as per standard of care
Continue disease evaluations 
until PD
Continue disease evaluations 
until PD
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3.1.1.
Treatment With Ibrutinib After Interim Analysis
At investigator’s discretion, subjects who have received placebo in the blinded phase of the study 
and have disease progression or meet the IWCLL criteria for requiring subsequent anti-CLL 
therapy and other eligibility criteria may be offered ibrutinib treatment. These subjects will 
follow the Time and Events Schedule titled, “Crossover to Ibrutinib”. Subjects who have 
received ibrutinib in the blinded phase of the study will follow the Time and Events Schedule 
titled “After Interim Analysis: Applies To Subjects Continuing Ibrutinib or Subjects in 
Follow-Up”. Treatment with ibrutinib will continue until disease progression, unacceptable 
toxicity, withdrawal from study, or until the study end, whichever occurs earlier.
3.2.
Study Design Rationale
Rationale for Background Therapy, Study Medication Dose, Randomization
Background treatment with BR will be at the dose and schedule considered standard for patients 
with relapsed or refractory CLL, which were based on the findings of a Phase 1b study and a 
subsequent Phase 2 study.1,15 Both NCCN (Version 2012) and ESMO treatment guidelines 
(Version 2011) list BR as one of the recommended treatment options for patients with relapsed 
or refractory disease, except for patients with del (17p).28,10
The dose of ibrutinib for this study is based on Study PCYC-1108-CA, in which subjects were 
treated with ibrutinib 420 mg/day in combination with the standard 6-cycle regimen of BR. The 
study demonstrated promising efficacy and acceptable tolerability for this combination. 
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. Blinded treatment will be used to reduce 
potential bias during data collection and evaluation of endpoints. 
Rationale for Efficacy Endpoints, Patient-Reported Outcomes (PROs), Biomarkers
The primary endpoint of PFS has served as the basis for regulatory approvals in CLL. The 
secondary endpoints of ORR and OS are recommended endpoints for the clinical study
evaluation of new treatments for CLL.22 Advances in detection technologies have determined 
that some patients who achieve CRs have MRD as shown by the continued presence of small 
numbers of CLL cells. Therefore, the absence of MRD is included as a secondary endpoint.
Patient-reported outcome data are included to complement data collected by other methods. This 
type of data may contribute to enhanced communication of results to patients, clinicians, 
regulators and payers. Frequency of data collection is varied to reduce respondent burden with 
symptom data being collected more frequently than data related to functional status and 
well-being. 
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Inhibition of BTK tyrosine phosphorylation by ibrutinib has been shown to abrogate downstream 
survival pathways (eg, ERK1/2, PI3K, NF-kB, and MAPK). Inhibition by ibrutinib also 
interferes with activation of integrins and chemokine networks leading to interference with 
adhesion, migration, and homing of malignant cells.23,38 It is anticipated that subjects with 
alterations in BCR signaling components or activation of alternative signaling pathways may 
have differential response to treatment. The biomarker evaluations within this study will identify 
biomarker classifiers associated with resistance to ibrutinib in subjects with CLL. The results 
may assist in the development of this drug in these and other indications.
4.
SUBJECT SELECTION
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, 
then the investigator should consult with the appropriate sponsor representative before enrolling 
a subject in the study. For a discussion of the statistical considerations of subject selection, refer 
to Section 11.2, Sample Size Determination.
Entry criteria for subjects in Treatment Arm A (placebo) who have disease progression and may 
be eligible to crossover to receive treatment with ibrutinib are provided in Section 9.1.5.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
18 years of age or older;
2.
Criterion modified per amendment 
2.1.
Criterion modified per amendment
2.2.
Diagnosis of CLL or SLL that meets published diagnostic criteria:22
a.
Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally 
co-expressing at least one B-cell marker (CD19, CD20, or CD23) and CD5. 
b. The diagnosis of CLL requires a history of lymphocytosis with a B-lymphocyte count 
5,000/L while SLL patients are characterized by the same criteria with a circulating 
B-lymphocyte count <5,000/L. Prolymphocytes may comprise no more than 55% of 
blood lymphocytes. 
c.
There is no evidence of cyclin D1 rearrangement or BCL-1 overexpression. This 
evidence is required only when the diagnosis of CLL/SLL is not otherwise clear.
3.
Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring 
treatment: 
a.
Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia or thrombocytopenia;
b.
Massive (ie, at least 6 cm below the left costal margin), progressive, or symptomatic 
splenomegaly;
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c.
Massive nodes (ie, at least 10 cm in longest diameter), progressive, or symptomatic 
lymphadenopathy;
d.
Progressive lymphocytosis with an increase of more than 50% over a 2-month period or 
a lymphocyte doubling time (LDT) of less than 6 months (which may be extrapolated). 
Lymphocyte doubling time can be obtained by linear regression extrapolation of ALCs 
obtained at intervals of 2 weeks over an observation period of 2 to 3 months. For 
patients with initial blood lymphocyte counts of less than 30 x 109/L (30,000/L), LDT 
should not be used as a single parameter to define indication for treatment. In addition, 
factors contributing to lymphocytosis or lymphadenopathy other than CLL 
(eg, infections) should be excluded;
e.
Constitutional symptoms, defined as 1 or more of the following disease-related 
symptoms or signs:
1)
Unintentional weight loss >10% within the previous 6 months prior to screening;
2)
Significant fatigue (inability to work or perform usual activities);
3)
Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without evidence of 
infection; or
4)
Night sweats for more than 1 month without evidence of infection.
4.
Measurable nodal disease by computed tomography (CT). Measurable nodal disease is 
defined as at least one lymph node >1.5 cm in longest diameter in a site that has not been 
previously irradiated. An irradiated lesion may be assessed for measurable disease only if 
there has been documented progression in that lesion since radiotherapy has ended; 
5.
Criterion modified per amendment
5.1.
Relapsed or refractory CLL or SLL following at least 1 prior line of systemic therapy, 
consisting of at least 2 cycles of a chemotherapy-containing regimen;
6.
ECOG Performance Status score of 0 or 1 (Attachment 1); 
7.
Criterion modified per amendment.
7.1.
Criterion modified per amendment.
7.2.
Hematology values within the following limits:
a.
Absolute neutrophil count (ANC) 1 x 109/L (ie, 1000/L).
b.
Platelets 50 x 109/L (ie, 50,000/L) and more than 7 days since last 
transfusion.
8.
Criterion modified per amendment.
8.1.
Biochemical values within the following limits:
a.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 x 
upper limit of normal (ULN).
b.
Total bilirubin 1.5 x ULN (unless due to Gilbert’s syndrome).
c.
Creatinine 2 x ULN and estimated glomerular filtration rate (GFR 
[Cockcroft-Gault]) 40 mL/min. 
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9.
Criterion modified per amendment
9.1.
Women of childbearing potential and men who are sexually active with a woman of 
childbearing potential 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 studies. Men must agree to not 
donate sperm during and after the study. For females, these restrictions apply for 
6 months after last dose of bendamustine, 12 months after the last dose of rituximab 
or 1 month after the last dose of study medication, whichever is later. For males, 
these restrictions apply for 6 months after the last dose of bendamustine, 12 months 
after the last dose of rituximab, or 3 months after the last dose of study medication, 
whichever is later.
10. Women of childbearing potential must have a negative serum (-human chorionic 
gonadotropin [-hCG]) or urine pregnancy test at screening.
11. Must sign (or their legally-acceptable representatives must sign) an informed consent 
document indicating that they understand the purpose of and procedures required for the 
study and are willing to participate in the study.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Recent therapeutic interventions including: 
a.
Prior nitrosoureas within 6 weeks prior to randomization.
b.
Therapeutic anticancer antibodies within 4 weeks prior to randomization.
c.
Radio- or toxin-immunoconjugates or immunotherapy within 10 weeks prior to 
randomization.
d.
All other chemotherapy, radiation therapy within 3 weeks prior to randomization.
e.
Major surgery within 4 weeks prior to randomization.
2.
Prior treatment with ibrutinib or other BTK inhibitors or prior randomization in any other 
clinical study evaluating ibrutinib.
3.
Concurrent enrollment in another therapeutic investigational clinical study.
4.
The presence of deletion of the short arm of chromosome 17, ie, del (17p13.1), as defined by 
del (17p) in 20% of cells examined on any pretreatment fluorescence in situ hybridization 
(FISH) or cytogenetics evaluation. Cytogenetic status results must be documented in patient 
records prior to randomization.
5.
Criterion modified per amendment.
5.1.
Patients previously treated with a bendamustine-containing regimen who did not 
achieve a response or who relapsed and required treatment within 24 months of 
treatment with that regimen.
6.
Subjects for whom the goal of therapy is tumor debulking prior to stem cell transplant.
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7.
Received a hematopoietic stem cell transplant. 
8.
Known central nervous system (CNS) leukemia/lymphoma or Richter’s transformation.
9.
Patients with uncontrolled autoimmune hemolytic anemia (AIHA) or autoimmune 
thrombocytopenia (ITP) (Coombs positivity in absence of hemolysis is not an exclusion).
10. Chronic use of corticosteroids in excess of prednisone 20 mg/day or its equivalent.
11. History of prior malignancy, except:
a.
Malignancy treated with curative intent and with no known active disease present for 
3 years before randomization.
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease.
c.
Adequately treated cervical carcinoma in situ without evidence of disease.
12. History of stroke or intracranial hemorrhage within 6 months prior to randomization; or 
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.
13. Criterion modified per amendment
13.1.
Requires anticoagulation with warfarin or equivalent vitamin K antagonists 
(eg, phenprocoumon).
14. Known history of Human Immunodeficiency Virus (HIV) or Hepatitis C, or active infection 
with Hepatitis B or Hepatitis C. 
15. Any uncontrolled active systemic infection or 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.
16. A woman who is pregnant or breast feeding, or a man who plans to father a child while 
enrolled in this study or within 3 months after the last dose of study drug.
17. Requires treatment with strong CYP3A4/5 inhibitors (Attachment 3).
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 randomization such that they 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.
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4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation. Subjects should avoid 
use of foods or beverages containing grapefruit or Seville oranges, as these contain certain 
ingredients that inhibit CYP3A4/5. Prohibited medications and precautions with concomitant 
medications are detailed in Sections 8.2 and 8.3, respectively.
The following guidance should be applied during the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving study medication
(ibrutinib/placebo):

For any surgery or invasive procedure requiring sutures or staples for closure, study 
medication should be held at least 7 days prior to the intervention and should be held at least 
7 days after the procedure, and restarted at the discretion of the investigator when the 
surgical site is reasonably healed without serosanguineous drainage or the need for drainage 
tubes.  

For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis), study medication 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 study medication, it is not necessary to hold study 
medication for these procedures.

For emergency procedures, study medication should be held after the procedure until the 
surgical site is reasonably healed, for at least 7 days after the urgent surgical procedure.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups in a 1:1 ratio 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 purine analog refractory 
status (yes vs. no) and number of prior lines of therapy (1 or >1). The interactive web response 
system (IWRS) will assign a unique treatment code, which will dictate the treatment assignment 
and matching study drug kit for the subject. The requestor must use his or her own user 
identification and personal identification number when contacting the IWRS, and will then enter
the relevant subject details to uniquely identify the subject. 
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Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the 
subject. In such cases, the investigator may in an emergency determine the identity of the 
treatment by contacting the IWRS. It is recommended that the investigator contact the sponsor or 
its designee if possible to discuss the particular situation, before breaking the blind. Telephone 
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In 
the event the blind is broken, the sponsor must be informed as soon as possible. The date, time, 
and reason for the unblinding must be documented by the IWRS, in the appropriate section of the 
case report form (CRF), and in the source document. The documentation received from the 
IWRS indicating the code break must be retained with the subject's source documents in a secure 
manner. Subjects who have had their treatment assignment unblinded should continue to return 
for scheduled evaluations and with sponsor approval may continue study treatment.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. However, a subject with IRC-confirmed disease progression who 
meets the eligibility criteria for next-line ibrutinib therapy may be unblinded by a medical 
monitor separate from the study team. If the subject is found to be randomized to placebo
(Treatment Arm A), the investigator will be informed of the subject’s eligibility and the subject 
will be allowed to start treatment with next-line ibrutinib, 420 mg daily. After positive interim 
analysis, the study is unblinded and investigators informed of subject treatment allocation. 
Subjects receiving placebo may be eligible for ibrutinib treatment, according to the criteria in 
Section 9.1.5.  
6.
DOSAGE AND ADMINISTRATION
All subjects will receive BR as the background therapy for a maximum of 6 cycles, as shown 
below. A cycle will be defined as 28 days, with the exception of Cycle 1, which will be 29 days 
to allow for rituximab dosing prior to bendamustine and study medication.

Bendamustine hydrochloride: 70 mg/m2 infused IV over 30 minutes on Cycle 1, Days 2 and 
3, and on Cycles 2-6, Days 1 and 2 for up to 6 cycles, unless progression of disease or 
unacceptable toxicity is encountered prior to Cycle 6.

Rituximab, 375 mg/m2 in the first cycle, Day 1, and 500 mg/m2 in Cycles 2 through 6, 
Day 1.
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If a rituximab infusion is interrupted on Day 1 due to toxicity and has to be split over a 2-day 
period in Cycle 1, bendamustine may be administered on Days 3 and 4 or immediately after the 
subject’s recovery from toxicity (if recovery occurs later). The administration of study 
medication should start on the same day as bendamustine. A similar approach to dosing may be 
used for subsequent cycles.
Subjects will be randomized 1:1 to receive either treatment arm A or B. Treatment will continue 
until disease progression or unacceptable toxicity. Ibrutinib or placebo will be self administered 
at home.
Treatment Arm A: 
Placebo (3 capsules) will be administered orally once daily continuously.
Treatment Arm B: 
Ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily continuously.
6.1.
Bendamustine and Rituximab Administration
Investigators should refer to the package inserts for the storage and handling, and detailed 
instructions 
on 
the 
administration 
of 
bendamustine 
hydrochloride 
and 
rituximab, 
respectively.40,41 BR is administered IV, per institutional standards, at the dosages described 
above. BR treatment will be administered for a maximum of 6 cycles in absence of disease 
progression or treatment-limiting toxicity.
6.2.
Study Drug Administration
Subjects will be instructed to take 3 capsules of ibrutinib (for a dose of 420 mg) or placebo orally 
once daily. 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 intact and subjects should not 
attempt to open capsules or dissolve them in water. On the days subjects receive both study 
medication and BR, placebo or ibrutinib will be administered after the CIT infusions. Subjects 
should refrain from taking study medication on the morning of study visits designated for 
pharmacokinetic sampling until instructed to do so at the site.
If a dose 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.
At any given visit, sufficient study medication required for treatment until the next visit should 
be dispensed. Unused study medication dispensed during previous visits must be returned and 
drug accountability records will be updated. Returned capsules cannot be re-used in this study or 
outside the study. Study staff will instruct subjects on how to store medication for at-home use as 
indicated for this protocol. 
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6.3.
Dose Modification
Doses of bendamustine hydrochloride and rituximab should be reduced or held in accordance 
with the dose modification guidelines in the respective product labels, as described below.40,41
Bendamustine hydrochloride
Bendamustine hydrochloride administration should be delayed in the event of Grade 4 
hematologic toxicity or clinically significant Grade 2 non-hematologic toxicity. Once 
non-hematologic toxicity has recovered to Grade 1, bendamustine hydrochloride can be 
reinitiated at the discretion of the investigator. For hematologic events, bendamustine 
hydrochloride can be reinitiated after blood counts have improved (ANC 1 x 109/L 
[1,000/L], platelets 50 x 109/L [50,000/L]), at the discretion of the investigator.
In addition, dose reduction may be warranted as follows:

Dose modifications for hematologic toxicity: for Grade 3 toxicity, the dose may be reduced 
to 50 mg/m2 on Days 1 and 2 of each cycle. If Grade 3 toxicity recurs, the dose may be 
reduced to 25 mg/m2 on Days 1 and 2 of each cycle.

Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 
toxicity, the dose may be reduced to 50 mg/m2 on Days 1 and 2 of each cycle.
Dose re-escalation in subsequent cycles may be considered at the discretion of the investigator. 
Withholding of bendamustine hydrochloride administration should be considered in the event of 
AST or ALT value >2.5 X ULN or total bilirubin value >1.5 X ULN.
If bendamustine hydrochloride is discontinued for toxicity, then treatment with rituximab may be 
continued.
Rituximab
There will be no dose reductions for rituximab. Rituximab should be held for any Grade 4 
toxicity or other clinically significant events, as detailed in the product label. Particular attention 
should be paid to the Warnings and Precautions sections. Detailed dosing instructions for 
infusion reactions are provided in the product label.41
If rituximab is discontinued for toxicity, then treatment with bendamustine hydrochloride may be 
continued.
Study Medication (Ibrutinib or placebo)
Treatment with study medication (ibrutinib/placebo) should be held for any unmanageable, 
potentially study drug-related toxicity that is Grade 3 in severity. Study medication may be held 
for a maximum of 28 consecutive days, unless reviewed and approved by the sponsor. Study 
medication should be discontinued permanently in the event of a toxicity lasting more than 
28 days. No dose escalation of study medication (above 420 mg) is allowed in this study. The 
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actions in the table below should be taken for the following drug-related toxicities. Changes must 
be recorded in the Dosage Administration CRF: 

Grade 4 neutropenia (ANC <0.5 x 109/L [ie, <500/L]): If receiving study medication 
only, actions in the table below should be taken immediately. If receiving concurrent BR
and study medication, action should be taken if the Grade 4 neutropenia persists for 
>14 days. Neutrophil growth factors are permitted per American Society of Clinical 
Oncology (ASCO) guidelines or according to the institution’s guidelines and use must be 
recorded in CRF.

Grade 3 thrombocytopenia (platelets <50 x 109/L [ie, <50,000/L]) in the presence of 
significant bleeding; or in subjects with baseline thrombocytopenia a platelet decrease of 
50% to 74% from baseline in the presence of significant bleeding.

Grade 4 thrombocytopenia (platelets <25 x 109/L [ie, <25,000/L]); or in subjects with 
baseline thrombocytopenia a decrease of >75% from baseline or <20 x 109/L 
(ie, <20,000/L), whichever is higher. 

Grade 3 or 4 nausea, vomiting, or diarrhea (if persistent despite optimal antiemetic or 
anti-diarrheal therapy) or any other Grade 4 toxicity or any unmanageable Grade 3 
toxicity.
Occurrence 
Action
1st
Hold study medication until recovery to Grade ≤1 or baseline; may restart at 
original dose level
2nd
Hold study medication until recovery to Grade ≤1 or baseline; restart at 1 
dose level lower (280 mg daily)
3rd
Hold study medication until recovery to Grade ≤1 or baseline; restart at 1 
dose level lower (140 mg daily)
4th
Discontinue study medication
Note: For hematologic events that occurred while the subject was receiving concurrent BR and study medication, 
study medication may be re-initiated when BR is initiated after the counts have improved (ie, ANC 1,000/L 
and platelets 50,000/L).
If ibrutinib/placebo is discontinued for toxicity, then treatment with bendamustine hydrochloride 
and rituximab may be continued.
Refer to Section 8.3 for subjects requiring the initiation of anticoagulants while receiving study 
medication, and for instructions on dose modifications or dose holds during concomitant 
administration of CYP3A4/5 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 medication. 
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7.
TREATMENT COMPLIANCE
The investigator or designated study personnel will maintain a log of all study drug dispensed 
and returned. Drug supplies for each subject will be inventoried and accounted for throughout 
the study. On pharmacokinetic sampling days for study medication only, the timing of meals in 
relation to the drug intake will also be recorded. 
The study drug is to be prescribed only by the principal investigator or a qualified physician 
listed as a subinvestigator on required forms (eg, FDA Form 1572). Records should be kept on 
the study drug accountability form provided by the sponsor or its designee (any alternative forms 
must be preapproved by the sponsor). Further instructions regarding accountability for study 
drug are provided in the Site Investigational Product Procedures Manual. Administration of the 
study drug must be recorded in the subject’s source documentation. The study drug may not be 
used for any purpose other than that outlined in this protocol, including other human studies, 
animal investigations, or in vitro testing.  
8.
PRESTUDY AND CONCOMITANT THERAPY
All prestudy antineoplastic therapies, including those since diagnosis of CLL/SLL, must be 
recorded at screening.
Concomitant therapies must be recorded throughout the study beginning with the time of written 
informed consent to 30 days after the last dose of study treatment (ie, bendamustine, rituximab, 
and ibrutinib/placebo).
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
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8.1.
Permitted Medications
Antiemetics are permitted if clinically indicated. Standard supportive care medications are 
permitted, including pre-medication for rituximab and bendamustine infusions per the rituximab 
and bendamustine package inserts, respectively. Use of neutrophil growth factors (filgrastim and 
pegfilgrastim) is permitted per the ASCO guidelines or according to the institution’s 
guidelines.34 Use of anti-microbial prophylaxis (eg, pneumocyctis pneumonia prophylaxis with 
sulfamethoxazole and trimethoprim or equivalent), according to the institution’s guidelines, is 
strongly recommended.
For subjects considered at risk for tumor lysis syndrome (TLS):
Subjects with more than 1 of the factors listed below are considered to be at increased risk of 
TLS and should be considered for hydration and treatment with a uric acid-lowering agent as 
well as for frequent monitoring of tumor lysis associated signs and symptoms. Uric-acid 
lowering agents may include xanthine oxidase inhibitor allopurinol or Uloric [febuxostat] with or 
without rasburicase per the drug product package inserts. 

Serum creatinine 1.5 x ULN or calculated creatinine clearance <60 mL/min

White blood cell (WBC) 50,000/L

Uric acid 450 mol/L or 7.5 mg/dL

Bulky disease (eg, lymph node >10 cm or massive splenomegaly)

Elevated LDH >2 x ULN
For subjects with an increased risk of TLS, rituximab may be split over a 2-day period in 
Cycle 1.
For subjects considered at risk for leukostasis:
A high number of circulating lymphocytes (>400,000/μL) may confer increased risk; these 
patients should be closely monitored. Administer supportive care such as hydration and/or 
leukapheresis as indicated. Ibrutinib may be temporarily held, and medical monitor should be 
contacted.
8.2.
Prohibited Medications
The following medications are prohibited during the treatment phase of the study: any 
chemotherapy (other than BR), anticancer immunotherapy, corticosteroids (at dosages equivalent 
to prednisone >20 mg/day), experimental therapy, and radiotherapy. Corticosteroids are 
permitted as premedication for administration of rituximab or for the management of 
hypersensitivity as per institutional policy.
In addition, short courses (<14 days) of 
corticosteroids for non-cancer related medical reasons (eg, treatment for autoimmune cytopenias) 
are permitted at doses not exceeding 100 mg/day of prednisone or equivalent.
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8.3.
Precautions with Concomitant Medications
Concomitant Use of Ibrutinib/Placebo and CYP3A4/5 Inhibitor/Inducers
Ibrutinib is metabolized primarily by CYP3A4/5. Co-administration of ibrutinib with strong 
CYP3A4/5 inducers (such as carbamazepine and rifampin) can decrease ibrutinib plasma 
concentrations and should be avoided. Co-administration of ketoconazole, a strong CYP3A4/5 
inhibitor, in 18 healthy subjects, increased dose normalized exposure for Cmax and AUC0-last of 
ibrutinib by 29- and 24-fold, respectively. However, in 38 subjects treated with mild and/or 
moderate CYP3A4/5 inhibitors the ibrutinib exposure (AUC) was 2-fold the upper limit of the 
range of 76 subjects not treated concomitantly with CYP3A4/5 inhibitors. Clinical safety data in 
subjects treated with weak, moderate, or strong CYP3A4/5 inhibitors did not reveal meaningful 
increases in toxicities. Since no exposure data are available in patients treated concomitantly 
with strong inhibitors of CYP3A4/5 (eg, ketoconazole, indinavir, nelfinavir, ritonavir, 
saquinavir, clarithromycin, telithromycin, itraconazole, and nefazadone), these inhibitors should 
be avoided. If ibrutinib must be administered with a strong inhibitor, the sponsor's Medical 
monitor should be consulted before use, and a dose reduction of ibrutinib to 140 mg daily or a 
temporary hold of ibrutinib should be considered. Subjects should be monitored for signs of 
ibrutinib toxicity. If a moderate CYP3A inhibitor must be used, reduce ibrutinib treatment to 
140 mg for the duration of the inhibitor use. For subjects who are already on a moderate CYP3A 
inhibitor concomitantly with ibrutinib without significant toxicity, the investigator may consider 
the overall risk-benefit to determine if a dose reduction of ibrutinib is appropriate. Avoid 
grapefruit and Seville oranges during ibrutinib treatment, as these contain moderate inhibitors of 
CYP3A4/5 (see Section 6.3).
Examples of inhibitors, inducers, and substrates can be found in Attachment 3 and at 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx.43
Drugs That Have Their Plasma Concentrations Altered by Ibrutinib
In vitro studies indicated that ibrutinib is a weak inhibitor of CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, and CYP3A4/5. The dihydrodiol metabolite of ibrutinib is a weak inhibitor 
of CYP2B6, CYP2C8, CYP2C9, and CYP2D6. Both ibrutinib and the dihydrodiol metabolite are 
at most weak inducers of CYP450 isoenzymes in vitro. Therefore, it is unlikely that ibrutinib has 
any clinically relevant drug-drug interactions with drugs that may be metabolized by the 
CYP450 enzymes. 
In vitro studies indicated that ibrutinib is not a substrate of p-glycoprotein (P-gp), but is a mild 
inhibitor. Ibrutinib is not expected to have systemic drug-drug interactions with P-gp substrates. 
However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp after a therapeutic 
dose. There is no clinical data available; therefore, co-administration of narrow therapeutic index 
P-gp substrates (eg, digoxin) with ibrutinib may increase their blood concentration and should be 
used with caution and monitored closely for toxicity.
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Concomitant Use of Ibrutinib/Placebo and QT Prolonging Agents
Any medications known to cause QT prolongation should be used with caution; periodic 
monitoring with ECGs and electrolytes should be considered and, if needed, the medical monitor 
should be contacted.
Concomitant Use of Ibrutinib/Placebo and Antiplatelet Agents and Anticoagulants
Warfarin or other vitamin K antagonists (eg, phenprocoumon) should not be administered 
concomitantly with ibrutinib. Supplements such as fish oil and vitamin E preparation 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 held at least 3 to 7 days pre- and post-surgery depending upon the type of 
surgery and the risk of bleeding (see Section 4.3).
Subjects requiring the initiation of therapeutic anticoagulation therapy (other than warfarin or a 
vitamin K antagonist) during the course of the study should have treatment with study 
medication held, the sponsor’s medical monitor should be contacted, and study medication 
should not be restarted until the subject is clinically stable and the re-initiation of study 
medication is approved by the sponsor’s medical monitor. Subjects should be observed closely 
for signs and symptoms of bleeding. No dose reduction is required when study medication is 
restarted.
8.4.
Subsequent Therapies
Administration of other therapies for CLL after study treatment should not be initiated until 
progressive disease has been established according to the criteria described in Section 9.2.1.4. If 
clinically appropriate, new anticancer therapy should be withheld until confirmation of 
progressive disease by the IRC. Any subsequent therapy for CLL (including start and end date 
and best response) should be documented in the CRF.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The study is divided into a Screening Phase, a Double-blind Treatment Phase, and a 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.
All visit-specific PRO assessments during a visit should preferably be conducted before any 
tests, procedures, or other consultations for that visit to prevent influencing subject perceptions.
PRO assessments will be captured electronically and preprogrammed in the appropriate 
sequence. Adverse event information will be collected using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. A separate 
toxicity scale will be used for grading hematologic adverse events (see Section 12.1.3). 
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Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
For each subject, the maximum amount of blood drawn will not normally exceed 335 mL within 
the first year. For a subset of subjects at selected sites, an additional 40 mL of blood will be 
drawn in the first year to explore the potential effect of ibrutinib on bendamustine and rituximab 
PK. Following the first year, the maximum amount of blood drawn will not exceed 25 mL every 
12 weeks, and is estimated at 32 mL for the end-of-treatment visit. Repeat or unscheduled 
samples may be taken for safety reasons. Detailed information is provided in Attachment 4.
9.1.2.
Screening Phase
Screening procedures will be performed up to 30 days before randomization. All subjects must 
sign an informed consent form prior to the conduct of any study-related procedures. During the 
Screening Phase, eligibility criteria will be reviewed and a complete clinical evaluation will be 
performed as specified in the Time and Event Schedule. This evaluation will include a complete 
medical history, including confirmation of CLL/SLL diagnosis, staging at study entry
(Attachment 2), key features of disease, and all prior cancer therapy. A sponsor review of prior 
therapy and active disease status per ICWLL criteria must occur before randomization is 
approved. Details of the approval process will be provided to sites as a separate document.
Concomitant medication and AEs will be recorded starting with the signing of the study 
informed consent. For women of childbearing potential, a urine or serum beta-hCG pregnancy 
test will be performed. Clinical assessments performed as part of the subject’s routine clinical 
evaluation and not specifically for this study need not be repeated after signed informed consent 
has been obtained provided the assessments fulfill the study requirements and are performed 
within the specified timeframe prior to randomization. 
A CBC, full physical examination, and CT will occur as part of the disease evaluation. Results of 
radiologic assessments obtained prior to signing the informed consent as part of the subject's 
standard of care may be used for this study if performed within 30 days before randomization. 
Subsequent assessments performed throughout the study must use the same method of 
assessment per subject. A bone marrow biopsy, and an aspirate or peripheral blood sample are
required, preferably within 30 days of randomization; however, results within 90 days of 
randomization are acceptable. Bone marrow biopsies should be evaluated locally for 
morphology. All subjects will have a bone marrow aspiration or peripheral blood draw 
performed locally to assess the cytogenetic profile using the standard CLL FISH probes to detect 
abnormalities in chromosomes 13q, 12, 11q, and 17p. In addition, immunophenotyping should 
be performed on the aspirate or blood sample. Conventional karyotype evaluations are optional; 
FISH is required. Results will be collected in the CRF and subjects with 20% of cells with 
del (17p) will not be eligible to participate in the study. For subjects with SLL, a lymph node 
biopsy may be used for immunophenotyping, morphology, and FISH testing to confirm the 
diagnosis.
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9.1.3.
Double-Blind Treatment Phase
The double-blind Treatment Phase will begin at randomization and will continue until disease 
progression, unacceptable toxicity, or other reasons as described in Section 10. Subjects must 
start rituximab within 72 hours after randomization. The latest measurements taken on Day 1 of 
Cycle 1 before administration of study treatment or at screening will be defined as the baseline 
values. Central laboratory values that are obtained prior to Cycle 1, Day 1 should be repeated in 
the event that they are >48 hours old. An additional local laboratory sample should be taken to 
ensure the eligibility criteria are still met for hematology and chemistry values within 48 hours 
prior to dosing. 
The subject will report to the study site on Day 1 of each cycle for study-related procedures 
outlined in the Time and Events Schedule. 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 can continue treatment, sufficient treatment will be 
dispensed. Instructions for proper self-administration of study drug and storage conditions will 
be reviewed. If a subject shows signs of progression on physical examination or laboratory 
assessment, the subject may continue study treatment until progression is confirmed by CT scan. 
If progressive disease is diagnosed, then the subject will discontinue study treatment, complete 
the End-of-Treatment Visit 30 days (+7-day window) after the last dose of study treatment, and 
enter the Follow-up Phase.
End of Treatment
An End-of-Treatment Visit will be scheduled 30 days (+7-day window) after the last dose of 
study treatment for all subjects, including those discontinuing treatment for any reason, except 
for lost to follow up, death, or withdrawal of consent for study participation. Subjects who 
discontinue treatment and enter the Follow-up Phase should have the End-of-Treatment Visit 
completed before starting any subsequent treatment for CLL. If a subject is unable to return to 
the site for the End-of-Treatment Visit, then the subject should be contacted to collect AEs that 
occur within 30 days after the last dose of study treatment. Additional information on reporting 
of AEs can be found in Section 12. Refer to the Time and Events Schedule for a complete list of 
procedures to be performed at the End-of-Treatment Visit.
9.1.4.
Follow-up Phase
The Follow-up Phase will begin once a subject discontinues treatment. Subjects who discontinue 
treatment for reasons other than disease progression will continue to have disease evaluations 
every 12 weeks and will be followed for survival status, recording subsequent antineoplastic
therapy, the IWCLL criteria which were met requiring subsequent therapy, and response to 
subsequent therapy. 
Following disease progression, contact will be made every 16 weeks until study end to 
determine:
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
IWCLL criteria which were met requiring subsequent therapy and response to subsequent 
therapy;

Subsequent antineoplastic therapy;

Occurrence of any other malignancy; 

Occurrence of transformation to a more aggressive histology (Richter’s transformation); and

Survival status.
The EQ-5D-5L questionnaire will be administered as shown in the Time and Events Schedule. If 
the subject is at the site for the follow-up assessment, then the subject should complete the 
questionnaire. If the follow-up assessment 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 them in the PRO instrument. 
The Follow-up Phase will continue until death, loss to follow up, consent withdrawal, or study 
end, whichever occurs first. It is important that survival status be assessed and that the date of 
death is documented for each subject randomized to treatment, regardless of whether or not the 
subject received treatment. If the information on survival status and subsequent therapy is 
obtained via telephone contact, then written documentation of the communication must be 
available for review in the source documents. If the subject has died, then the date and cause of 
death will be collected and documented on the CRF.
9.1.5.
Crossover to Ibrutinib Treatment
Subjects who satisfy all eligibility criteria listed below will be permitted to receive ibrutinib 
treatment at investigator’s discretion.
Eligibility Criteria for Crossover to Ibrutinib Treatment
1.
Criterion modified per amendment
1.1
Investigator-determined disease progression OR active disease requiring treatment as 
per the IWCLL 2008 criteria (refer to inclusion criterion in Attachment 10)
2.
Criterion deleted per amendment
3.
Criterion deleted per amendment
4.
Criterion modified per amendment
4.1
Platelet count 30,000/μL 
5.
Criterion modified per amendment
5.1
Biochemical values within the following limits:
a.
Adequate liver function indicated by total bilirubin ≤1.5 x ULN (unless due to Gilbert's 
syndrome) or up to 3 x ULN in the absence of other indications of liver disease.
b.
Creatinine ≤2 x ULN and estimated GFR (Cockcroft-Gault) 30 mL/min.
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6.
No uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as 
exhibiting ongoing signs/symptoms related to the infection and without improvement, 
despite appropriate antibiotics or other treatment) or ongoing intravenous anti-infective 
treatment
7.
No currently active clinically significant cardiovascular disease such as uncontrolled 
arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the New 
York Heart Association Functional Classification, or history of myocardial infarction within 
6 months prior to first dose with study drug
8.
No history of stroke or intracranial hemorrhage within 6 months
9.
Recovered from acute toxicities due to chemotherapy or other anti-CLL treatment. 
Nonhematologic toxicities have resolved to NCI CTCAE (v 4.03) Grade ≤2
10. Criterion deleted per amendment
11. Criterion modified per amendment
11.1
No known Richter’s transformation
12. Does not require or receive anticoagulation with warfarin or equivalent vitamin K 
antagonists (eg, phenprocoumon)
13. Criterion modified per amendment
13.1
Women of childbearing potential and men who are sexually active with a woman of 
childbearing potential 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 studies. Men must agree to not 
donate sperm during and after the study. For subjects receiving ibrutinib treatment 
within 12 months of stopping BR treatment, criterion 9.1 in Section 4.1 should be 
followed to ensure subject’s compliance.
14. Must sign (or their legally-acceptable representatives must sign) an informed consent 
document indicating that they understand the purpose of and procedures required for the 
study and are willing to participate in the study.
9.2.
Efficacy
Efficacy evaluations will be conducted as specified in the Time and Events Schedule and will 
include the following: 

Disease-related symptoms and physical examination: For disease-related symptoms, subjects 
will be asked about the presence or absence and severity of fatigue, night sweats, fevers, 
weight loss, and abdominal discomfort. All post-screening physical examinations will focus 
on examination of lymph nodes, liver, and spleen. 

CBC with measurement of parameters including ALC by a central laboratory. 

CT scan of the neck, chest, abdomen, and pelvis. 

MRD: peripheral blood and bone marrow aspirate/biopsy with flow cytometry assessment(s) 
for MRD should be done if there is evidence of CR by clinical parameters. MRD is 
determined by flow cytometry (MRD negative defined as <1 CLL cell per 
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10,000 leukocytes). Subsequent MRD samples will continue to be obtained from peripheral 
blood at disease evaluation visits.

Patient-reported symptoms, functional status, and well-being will be measured by 
EORTC-QLQ-C30, EORTC QLQ-CLL 16, EQ-5D-5L, and FACIT-Fatigue Scale.
For timing and scope of the efficacy evaluations following the implementation of the 
Amendment INT-4, refer to the Time and Events Schedule titled: “After Interim Analysis: 
Applies to Subjects Continuing Ibrutinib or Subjects in Follow-Up.”
9.2.1.
Evaluations
9.2.1.1.
Radiographic Imaging Assessmentsb
During the study, disease response will be assessed using CT scans with IV contrast of the neck
(full neck views starting from the base of the skull must be obtained), chest, abdomen, and 
pelvis. The size of liver, lymph nodes, and spleen will be evaluated. All imaging should be 
performed according to the Image Acquisition Guidelines. Subjects who are intolerant of IV CT 
contrast agents may have CT scans performed with oral contrast. In the event disease progression 
is suspected due to physical examination or laboratory tests, a CT scan must be performed for 
further disease status evaluation. The subject may continue study treatment until disease 
progression is confirmed by CT scan. CT scans should be performed according to the Time and 
Events Schedule until disease progression is confirmed by the IRC, regardless of whether or not 
the subject remains on study treatment.
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, the MRI must be obtained at 
baseline and at all subsequent disease 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.
9.2.1.2.
Definition of Measurable and Assessable Disease
Subjects must have at least 1 measurable lymph node >1.5 cm detected by CT scan in order to 
participate in this study.22 Measurable sites of disease are defined as lymph nodes, lymph node 
masses, or extranodal sites of lymphoma/leukemia. Each measurable site of disease must be 
greater than 1.5 cm in longest diameter. Measurement must be determined by imaging 
evaluation. All other sites of disease are considered assessable, but not measurable.
Up to 6 measurable lymph nodes (target lesions), 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. In addition, the selection of target lesions 
                                                
b Following positive interim analysis, review of CT scans by the IRC is no longer required. In the event disease 
progression is suspected, the confirmation of disease progression will be done by the study responsible medical 
monitor based on the data entered in the eCRF. Subjects may continue ibrutinib treatment until disease 
progression or meeting the IWCLL criteria for requiring subsequent anti-CLL therapy. For subjects continuing 
ibrutinib treatment in the main study phase, CT scans should be performed as specified in the Time and Events 
Schedule titled “After Interim Analysis: Applies to Subjects Continuing Ibrutinib or Subjects in Follow-Up.”
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should be from as disparate regions of the body as possible. Additional lesions that are present 
but are not included in the target lesion assessment should be added as non-target lesions and
followed throughout the study. The longest diameter of the spleen and liver will be assessed at 
screening and at all subsequent disease evaluations. 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 including 
peripheral blood counts.
9.2.1.3.
Bone Marrow Assessmentc
A unilateral bone marrow biopsy must be obtained during screening or up to 90 days before 
randomization to confirm the diagnosis of CLL or SLL and for morphological evaluation. A 
bone marrow aspirate or peripheral blood sample should also be obtained within the same 
timeframe for immunophenotyping (IHC or flow cytometry) and cytogenetics (FISH) to confirm 
and characterize the diagnosis of CLL or SLL. Conventional karyotype evaluations are optional; 
FISH is required. For subjects with SLL, a lymph node biopsy may be used for 
immunophenotyping, morphology, and FISH testing to confirm the diagnosis.
For subjects who have suspected CR based on the most recent physical examination, CT scans, 
and CBC results, a confirmatory bone marrow aspirate and biopsy must be obtained. This should 
occur when the subject shows clinical signs of having CR, and should occur no earlier than 
2 months following the completion of BR. The bone marrow aspirate and biopsy should be sent 
to a local laboratory for evaluation of morphology and immunophenotyping. An additional bone 
marrow aspirate and a concurrent peripheral blood sample will be sent to the central laboratory 
for MRD analysis. Subsequent follow up for MRD by peripheral blood evaluation will continue 
every 12 weeks for subjects who obtain a bone marrow evaluation, regardless of the bone 
marrow biopsy results. As of Amendment INT-4, all responding subjects will be required to have 
peripheral blood MRD evaluations performed as specified in the Time and Events Schedule 
“After Interim Analysis: Applies to Subjects Continuing Ibrutinib or Subjects in Follow-Up.”
After the completion of BR, if there is a new onset of cytopenia, a bone marrow aspirate or
biopsy should be performed to determine the underlying cause, ie, autoimmune cytopenias, drug-
related cytopenias, or disease progression.
9.2.1.4.
Response Categoriesd
Assessment of response should include physical examination, radiographic imaging, and 
evaluation of blood and bone marrow (if applicable). The definition of response will be 
                                                
c With the implementation of Amendment INT-7, collection of all MRD data is discontinued. The last date for MRD
collection is 31 July 2017, which corresponds to approximately 5 years after the first subject entered the study; 
no further MRD data will be collected after that date.
d Following Amendment INT-4, radiographic imaging (ie, CT scans) should be done every 24 weeks, as specified in 
the Time and Events schedule. Assessment of response should continue to occur every 12 weeks and should 
include physical examination, and evaluation of blood (local laboratory values) and bone marrow (if applicable).
At the visits which do not include a CT scan, radiographic assessments of CLL should be considered together 
with the evidence of disease status based on physical examinations, evaluations of blood and bone marrow (if 
applicable).
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evaluated by the criteria listed in Table 1 and the text immediately following. Any response must 
be confirmed by CT and central laboratory values and must last for at least 2 months to be 
considered confirmed. For response-related definitions, see Attachment 5. 
Disease evaluations, for the purpose of the study result analyses, will be performed by an IRC 
blinded to study treatment information and independent of investigators and personnel who are 
involved in conduct of the study. As part of the central review, radiographic evaluations will be 
assessed by an independent radiologist and relevant clinical data will be assessed by an 
independent oncologist. Detailed procedures will be described in a separate charter.
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Table 1
Criteria for Response Categories
Parameter
CR
PR
PD
Group A
Lymphadenopathya
None >1.5cm
Decrease ≥50%b
increase ≥50% or 
appearance of new 
lesions >1.5 cm
Hepatomegaly
None
Decrease ≥50%
increase ≥50% or 
appearance of new 
hepatomegaly
Splenomegaly
None
Decrease ≥50%
increase ≥50% or 
appearance of new 
splenomegaly
Blood lymphocytes
<4000/µL
Decrease ≥50% from 
baseline
increase ≥50% over 
baselined
Marrowc
Normocellular, <30% 
lymphocytes, no B lymphoid 
nodules. Hypocellular marrow 
defines CRi
50% reduction in marrow 
infiltrates or B lymphoid 
nodules
Group B
Platelet count
>100,000/µL
>100,000/µL or increase 
≥50% over baseline
Decrease of ≥50% from 
baseline secondary to 
CLL
Hemoglobin
>11 g/dL
>11g/dL or increase 
≥50% over baseline
Decrease of >2g/dL from 
baseline secondary to 
CLL
Neutrophilsc
>1500/µL
>1500/µL or increase 
≥50% over baseline
a Sum of the products of multiple lymph nodes (as evaluated by CT scans)
b Defined as a decrease in lymph nodes of ≥50% either in the sum products of the diameter of up to 6 lymph nodes, or in the 
largest diameter of the enlarged lymph node detected prior to the therapy, as well as no increase in any lymph node and no new 
enlarged lymph nodes. Note: in small lymph nodes <2 cm, an increase of <25% is not considered to be significant.
c This parameter is not relevant for the PD category.
d Subjects with treatment-related lymphocytosis should remain on study treatment in the absence of other criteria for progressive 
disease.
Note: Group A defines the tumor load and Group B defines the function of the hematopoietic system
CR: all of the criteria need to be met and patients have to lack disease related constitutional symptoms. Bone marrow aspirate at 
least 2 months following the last dose of bendamustine and rituximab is required to confirm CR.
PR: At least 2 criteria from Group A plus 1 of the criteria from Group B must be met. In all cases, in order for a response to be
termed a PR, the blood lymphocyte count should be normalized or decreased >50% from baseline (if elevated at baseline). 
NOTE: If only 1 measurable Group A criterion is present at baseline (eg, enlarged lymph nodes but no other abnormality), per 
recent clarification of the IWCLL criteria46 these subjects are still considered evaluable for PR if the given parameter improves 
by at least 50% for a minimum of 2 months. Subjects are also required to have 1 Group B parameter, which can either be 
improvement in a previously abnormal finding or the persistence of a normal value for at least 2 months as a result of therapy.
PD: at least 1 of the above criteria from Group A or B are met; or transformation to more aggressive histology (eg, Richter’s 
transformation); or a ≥50% increase from the nadir count confirmed on ≥2 serial assessments if the ALC is ≥30,000/µL and 
lymphocyte doubling time is rapid, unless considered treatment-related lymphocytosis. A new organ infiltrate, bone lesion, 
ascites, or pleural effusion confirmed due to CLL would also be considered PD.
Reference:  modified from 2008 IWCLL criteria22,42,46
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Complete Response with an Incomplete Marrow Recovery (CRi)
CRi is defined as a complete response with an incomplete recovery of the subject’s bone 
marrow. Subjects who have a CRi fulfill the criteria for a CR, but continue to have persistent 
anemia, thrombocytopenia, or neutropenia, and a hypocellular bone marrow. These cytopenias 
are due to drug toxicity in the bone marrow and are not due to any evidence of CLL. 
Nodular Partial Response (nPR)
nPR is a response where subjects meet the criteria for a CR, but the bone marrow biopsy shows 
that there are still B-lymphoid nodules present. These nodules are residual disease and therefore 
the subject is termed an nPR. 
Partial Response (PR) with Lymphocytosis
PR with lymphocytosis is a response where subjects meet the criteria for a PR and have 
persistent lymphocytosis.
Stable Disease
Not meeting criteria for CR, CRi, nPR, PR, or PD. 
Treatment-related Lymphocytosis
Treatment-related lymphocytosis is defined as an elevation in blood lymphocyte count of 50% 
compared with baseline that occurs in the setting of unequivocal improvement in at least 1 other 
disease-related parameter, including lymph node size, spleen size, hematologic parameters 
(hemoglobin and platelet count), or disease-related symptoms. Treatment-related lymphocytosis 
is isolated lymphocytosis occurring when no other criteria for progressive disease are met. In this 
particular setting, it will not be considered PD. This is supported by the most recent version of 
the NCCN guidelines and the IWCLL clarification letter.28,42
9.2.1.5.
Patient-Reported Outcomese
Patient-reported outcomes will be measured by 4 questionnaires. The EORTC QLQ-C30 is a 
general cancer assessment, the EORTC QLQ-CLL 16 is specific to symptoms or problems 
associated with CLL, and the FACIT-Fatigue Scale specifically assesses aspects of fatigue. 
Samples of the PRO scales are provided in Attachments 6, 7, 8, and 9. The PRO questionnaires 
will be collected preferably at the beginning of the clinic visits prior to any procedures or 
physician interactions according to the schedule described in the Time and Events Schedules. 
Data will be collected using electronic data capture to enhance ease of collection and quality of 
data (fewer missing values and extraneous marks).35
                                                
e With the implementation of Amendment INT-6, collection of all ePRO data is discontinued. The last date for 
ePRO collection is 18 September 2016, which corresponds to 4 years after the first subject entered the study; no 
further ePRO data will be collected after that date.
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The EORTC QLQ-C30 includes 30 separate items resulting in 5 functional scales (physical 
functioning, role functioning, emotional functioning, cognitive functioning, and social 
functioning), 1 Global Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and 
pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties).14 The recall period is 1 week (the past week). The EORTC QLQ-C30 has been 
widely used among cancer patients in general and specifically in CLL patients.5,9,25 Scale scores 
range from 0 to 100. A change of 10 points is considered clinically meaningful for the 
functioning scales. Administration time is approximately 11 minutes. 
The EORTC QLQ-CLL 16 is a 16-item disease specific module that comprises 5 domains of 
patient-reported health status important in CLL.12 There are three multi-item scales that include
fatigue (2 items), treatment side effects and disease symptoms (8 items), and infection (4 items), 
and 2 single-item scales on social activities and future health worries. Responses are measured 
on a 4-point scale ranging from 1 (not at all) to 4 (very much). These scores are transformed to 
give a rating from 0 (no symptoms or problems) to 100 (severe symptoms or problems). This is a 
new instrument developed specifically to assess health status of patients with CLL. Item 
development followed best practices, but the instrument has not been completely validated. Data 
from this study would contribute to understanding the measurement characteristics and scoring 
of the instrument in the target population. In addition to scoring the EORTC QLQ-CLL 16 as 
hypothesized by the instrument developer, other scoring approaches of the instrument may be 
evaluated. For example, expanding the Disease Effects Scale to include additional items that 
relate to B-cell or lymphoma symptoms may increase the sensitivity of this domain. The scoring 
and psychometric validation of the EORTC QLQ-CLL 16 will be examined using blinded 
treatment group data prior to database lock.
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome.13 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 “thermometer” visual analog 
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 
United Kingdom weights will be used to generate patient utilities from the 5 dimensions of the 
EQ-5D-5L in this study.
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FACIT-Fatigue is an instrument for use as a measure of the effect of fatigue in patients with 
cancer and other chronic diseases (http://www.facit.org). Responses to the 13-item 
FACIT-Fatigue Scale are reported on a 5-point categorical response scale ranging from 0 (not at 
all) to 4 (very much). Higher scores indicate poorer health status. The FACIT-Fatigue Scale has 
been validated in the general population (http://www.ncbi.nlm.nih.gov/pubmed/11900238) as 
well as for patients with cancer and rheumatoid arthritis. 
9.3.
Pharmacokinetics
9.3.1.
Evaluations
In both treatment arms, blood samples will be collected from all subjects for determination of 
plasma concentrations of ibrutinib and the PCI-45227 metabolite (if possible and judged 
relevant) according to the Time and Events Schedule. These sparse samples will be used for the 
development of a population-based PK model. 
In addition, in a subset of subjects at selected sites, sparse sampling will be performed in both 
treatment arms according to the Time and Events Schedule to explore a potential effect of 
ibrutinib on the PK of bendamustine and rituximab. For subjects at the selected sites, 
participation is mandatory.
9.3.2.
Analytical Procedures
Plasma samples will be analyzed to determine either concentrations of ibrutinib and the 
metabolite PCI-45227 or bendamustine, using a validated, specific, and sensitive LC-MS/MS 
method by or under the supervision of the sponsor. Serum samples will be analyzed to determine 
concentrations of rituximab using a validated, specific, and sensitive immune-assay.
9.3.3.
Pharmacokinetic Parameters
Population pharmacokinetic analysis of plasma concentration-time data of ibrutinib will be 
performed using nonlinear mixed-effects modeling (NONMEM), with the aim of providing 
estimates of PK parameters (eg, oral clearance) or metrics of systemic exposure (eg, area under 
the plasma concentration-time curve within the dosing interval). Model-derived plasma 
concentrations or metrics of exposure parameters (eg, Cmax or AUC) may be subjected to 
further analyses to explore PK correlation between exposure and relevant clinical or biomarker 
information.
In a subset of subjects at selected sites, population PK of bendamustine and rituximab will also 
be explored in both arms of the study using NONMEM, with the aim of exploring whether 
ibrutinib coadministration had an effect on bendamustine and rituximab PK parameters.
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9.4.
Biomarkers
B-cell receptor signaling is critically involved in the progression of several B-cell malignancies, 
including CLL/SLL. Bruton’s tyrosine kinase is a central regulator of BCR signaling and BCR 
stimulation leads to its phosphorylation and subsequent activation. Ibrutinib, an irreversible 
inhibitor of BTK, induces apoptosis and inhibits cellular migration and adhesion in malignant 
B cells. 
To better understand the mechanism of action of ibrutinib with an aim to develop predictors of 
resistance, blood samples will be collected as specified in the Time and Events Schedules and 
analyzed. Results will be used to inform development in other B-cell indications.
Plasma protein analysis may evaluate potential serum protein biomarkers that may contribute to 
BTK resistance or sensitivity. Isolated peripheral B-lymphocytes may also be evaluated for 
1) protein expression of ZAP-70, CD38, 2) RNA/DNA status for IgVH (mut/non-mut), and 
3) other RNA/DNA signatures that may predict acquired resistance.
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the 
end of the study, it becomes clear that the analysis will not have sufficient scientific value for 
biomarker evaluation, or if there are not enough samples or responders to allow for adequate 
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy, 
completion of biomarker assessments is based on justification and intended utility of the data. 
9.4.1.
Circulating B-lymphocytes From Blood
B-lymphocytes may be isolated from collected samples and may be characterized for gene 
expression profiling (GEP) somatic mutation analysis (SMA) and protein expression of ZAP-70, 
CD38 as well as other potential biomarkers that may contribute to resistance to BTK inhibition 
in CLL. Absolute lymphocyte counts will be determined for each subject at each collection 
timepoint, and samples will be subjected to designated analyses. Plasma protein analysis may 
include evaluation of interleukin (IL)-4, IL-6, and CXCL-12, as well as other potential serum 
protein biomarkers that may contribute to BTK resistance or sensitivity.
9.5.
Safety Evaluations
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedules. Any clinically significant abnormalities 
persisting at the end of treatment will be followed by the investigator until resolution or until a 
clinically stable endpoint is reached or until the end of the study.
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Adverse Events
All AEs, with the exception of progression of CLL/SLL, will be reported from the time a signed 
and dated informed consent form is obtained until 30 days following the last dose of study 
treatment or until the start of a subsequent systemic antineoplastic therapy, if earlier. Adverse 
events reported after 30 days following the last dose of study treatment should also be reported if 
considered related to study treatment. The sponsor will evaluate any safety information that is 
spontaneously reported by an investigator beyond the time frame specified in the protocol. 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally-acceptable representative) for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 12, Adverse Event Reporting. 
Non-hematologic AEs and hematologic AEs events will be graded according to specifications 
listed in Section 12.1.3. 
For subjects who crossover to next-line ibrutinib treatment, all AEs from the time a signed and 
dated informed consent form for crossover is obtained until 30 days following the last dose of 
study drug will be reported.
Clinical Laboratory Tests
CBCs obtained as per the Time and Events Schedule will be sent to a central laboratory to 
perform the assay. Other tests should be performed at the laboratory facilities associated with the 
investigational site, except where noted below. 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.
Blood samples to assess the safety of study treatment will be collected as specified in the Time 
and Events Schedule. The investigator must review the laboratory report, document this review, 
and record any clinically relevant changes occurring during the study in the adverse event section 
of the CRF. For example, laboratory abnormalities leading to an action regarding study 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 AE, the 
following laboratory values should be reported in the laboratory section of the CRF: the value 
indicative of the onset of each toxicity grade, the most abnormal value observed during the AE, 
and the value supporting recovery to Grade 1 or to baseline values. 
Refer to Section 8.1 for risk factors and management of subjects considered to be at risk of TLS.
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The following tests will be performed:

Hematology Panel (central laboratory)
-hemoglobin
-ANC
-WBC count
-ALC
-platelet count

Serum Chemistry Panel (local laboratory)
-lactic acid dehydrogenase (LDH)
-ALT
-creatinine
-total bilirubin
-potassium
-direct bilirubin (optional when total 
bilirubin is within normal limits)
-alkaline phosphatase
-albumin
-AST
-uric acid
-phosphate
-sodium
-magnesium

Coagulation (local laboratory)
-activated partial thromboplastin time (aPTT)
-INR

Hepatitis B Screening (local laboratory)
-Hepatitis B surface antigen
-Hepatitis B core antibody
Hepatitis B DNA needs to be performed if Hepatitis B Core Antibody is positive. DNA PCR 
needs to be confirmed negative prior to randomization in subjects who are Hepatitis B core Ab 
positive. During study treatment and for at least 12 months following the last dose of rituximab, 
regular monitoring of Hepatitis B PCR and liver enzymes and prophylactic antiviral medication 
should be considered per published guidelines.44

Hepatitis C Screening (local laboratory)
-Hepatitis C antibody

Urine or serum -hCG pregnancy testing for women of childbearing potential only (local 
laboratory)

Beta2-microglobulin and serum immunoglobulin levels (IgG, IgM, IgA) (local laboratory)

If additional laboratory parameters (eg, absolute reticulocyte counts, Coombs tests, blood 
urea nitrogen, calcium, glucose, total protein, chloride, creatine phosphokinase, haptoglobin) 
are obtained because of an adverse event, they should be documented at an unscheduled visit 
(local laboratory).
After interim analysis, the following clinical laboratory tests will be performed by the local 
laboratory, as specified in the Time and Events schedule:
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
Hematology Panel
-hemoglobin
-ANC
-WBC count
-ALC
-platelet count

Serum Chemistry Panel
-potassium
-AST
-creatinine
-ALT
-total bilirubin
-alkaline phosphatase
Vital Signs
Temperature, heart rate, and blood pressure will be recorded at screening. Blood pressure and 
heart rate measurements should be preceded by at least 5 minutes of rest in a quiet setting 
without distractions (eg, television, cell phones).
Body Surface Area
Calculation of body surface area (BSA) at Cycle 1, Day 1 is required for bendamustine 
hydrochloride and rituximab dosing. The IWRS will collect the height and weight of the subject 
at randomization and calculate the BSA. The IWRS will collect the weight at each subsequent 
cycle. If there is a >10% change in weight from the weight used in the most recent BSA 
calculation, the IWRS will re-calculate the BSA and adjust the dose accordingly. Weight will be 
collected as specified in the Time and Events Schedule.
Physical Examination
A complete physical examination will be conducted at screening. During treatment cycles, a 
limited focused physical examination must be must be performed to document the presence or 
absence, increase or decrease or no change in the status of lymph nodes, liver, and spleen. 
During the examination, review of symptoms should include inquiry of ocular symptoms (eg, dry 
eye, watering eye/abnormal discharge, eye pain, blurred vision/double vision, decreased visual 
acuity, photophobia/sensitivity to light, floaters, flashing lights, and eye irritation). Subjects 
should be referred to an ophthalmologist for a formal examination if any Grade ≥2 symptoms are 
reported. 
Electrocardiograms
An ECG will be performed at screening for all subjects. For a subset of subjects at selected sites, 
additional ECGs will be performed according to the Time and Events Schedule. The subject 
should be in a quiet setting without distractions (eg, television, cell phones). Subjects should rest 
in a supine position for at least 5 minutes before ECG collection and should refrain from talking 
or moving arms or legs. Abnormalities noted at screening should be included in the medical 
history.
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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. Instructions for the collection, handling, and shipment of samples are found 
in the laboratory manual that will be provided for sample collection and handling.
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 Treatment
If a subject's study treatment must be discontinued, then this will not result in automatic 
withdrawal of the subject from the study. Subjects who discontinue study treatment should 
continue to have assessments performed as specified in the Time and Events Schedule. A 
subject's study treatment should be discontinued if any of the following occurs:

The subject experiences disease progression or relapse

The subject experiences unacceptable toxicity

The subject becomes pregnant

The subject refuses further treatment with the study treatment

The investigator believes that for safety reasons (eg, adverse event) it is in the best interest 
of the subject to stop treatment 
The investigator must notify the sponsor within 24 hours if a subject has been determined to have 
disease progression and provide documentation of disease progression for review by the 
sponsor’s Medical Monitor. If a subject shows signs of disease progression on physical 
examination or laboratory assessment, the subject may continue study treatment until disease 
progression is confirmed by CT scan.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

The sponsor discontinues the study
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If a subject is lost to follow-up, then 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.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, Long-
Term Retention of Samples for Additional Future Research). In such a case, samples will be 
destroyed after they are no longer needed for the clinical study. Details of the sample retention 
for research are presented in the main Informed Consent Form (ICF).
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
11.1.
Analysis Sets
The intent-to-treat (ITT) population is defined as all subjects randomized into the study and will 
be classified according to assigned treatment group, regardless of the actual treatment received. 
This population will be used for primary efficacy analyses including PFS and OS, and all 
analyses of disposition, demographic, and baseline disease characteristics.
The safety population is defined as all randomized subjects who receive at least 1 dose of study 
treatment. This population will be used for all safety analyses and all analyses of treatment 
compliance and exposure. All data will be analyzed according to the treatment subjects actually 
received. The PK evaluable population will include all subjects who receive at least 1 dose of 
study medication and have at least 1 post-treatment PK sample. 
11.2.
Sample Size Determination
A recent Phase 2 study reported a median PFS of 15 months in patients with relapsed or 
refractory CLL treated with combination of BR.15 It is assumed that the PFS follows an 
exponential distribution with a constant hazard ratio.
Approximately 580 subjects (290 per treatment group) will be randomized to observe 342 PFS 
events. The study is designed to detect a hazard ratio of 0.7 for the ibrutinib + BR group relative 
to placebo + BR group (corresponding to an improvement of 43% in median PFS, eg, from 
15 months to 21.5 months) with 90% power at a 1-sided significance level of 0.025, using a 
group sequential testing design. Assuming the enrollment rate is on average 32 subjects per 
month, the total study duration is expected to be approximately 33 months with 18 months of 
enrollment and 15 months of follow up in order to observe 342 PFS events. 
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11.3.
Subject Information
The distribution of subjects by treatment group for each of the analysis populations will be 
provided. The number of subjects enrolled, dosed, and discontinued will be summarized. 
Treatment discontinuation will be summarized according to the reasons for discontinuation and 
by treatment group.
Demographic and baseline vital sign variables will include age, sex, race, ethnicity, height, 
weight, blood pressure, and BSA. Baseline disease characteristics (documented in the source 
documents and CRF) will include time from initial diagnosis to randomization, histological
diagnosis (CLL, SLL), stage of disease, treatment history (relapsed, refractory), and ECOG 
Performance Score (0, 1).
11.4.
Efficacy Analyses
11.4.1.
Primary Efficacy Endpoint
The primary efficacy endpoint, PFS, is defined as the interval between the date of randomization 
and the date of disease progression or death, whichever is first reported. Disease progression will 
be based on assessments from an IRC, using 2008 IWCLL Guidelines as defined in 
Section 9.2.1.4. The process and conventions of the IRC will be detailed in a separate IRC 
charter.
All subjects, including those who discontinued study treatment or started new antineoplastic
therapy, will be followed for PFS until a PFS event occurs (disease progression or death) or until 
the data cutoff. For subjects who receive subsequent antineoplastic therapy without documented 
progression, data will be censored at the date of the last disease evaluation before the start of 
such therapy. For subjects who have not progressed and are still alive at the cutoff date for the 
final analysis or who withdraw from the study (withdrawal of consent or lost to follow up), data 
will be censored at the date of the last disease evaluation. 
After interim analysis, PFS and overall survival will be updated at subsequent analyses.
11.4.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:

ORR, defined as the proportion of subjects with measurable disease achieving a best overall 
response of either CR, CRi, PR, or nPR, as evaluated by the IRC

OS, defined as the interval between the date of randomization and the date of death from any 
cause. Survival time of living subjects will be censored on the last date a subject is known to 
be alive or lost to follow-up.

Rate of MRD-negative remissions, defined as the proportion of subjects who reach 
MRD-negative disease status (<1 CLL cell per 10,000 leukocytes)
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
Improvement in disease-related symptoms (fatigue, night sweats, weight loss, fever, and 
abdominal discomfort due to splenomegaly)

Hematologic improvement in the subset of subjects with cytopenia(s) at baseline 
(hemoglobin <11 g/dL, platelets <100 x 109/L [ie, <100,000/μL], or ANC <1.5 x 109/L 
[ie, <1500/μL]), with sustained improvement defined as improvement in cytopenias by 
≥50%, or hemoglobin ≥11 g/dL, ANC ≥1.5 x 109/L (ie, ≥1500/μL), platelets ≥100 x 109/L 
(ie, ≥100,000/μL), with the duration of improvement lasting for ≥60 days without blood 
transfusion or growth factors.

Improvement in patient-reported symptoms, functional status, and well-being as measured 
by:

The FACIT-Fatigue Scale summary score

The EORTC QLQ-C30 Physical Functioning Score

The EORTC QLQ-CLL 16 domain scores
11.4.3.
Analysis Methods
The primary efficacy analysis will be based on the PFS determined by the IRC and will be 
performed on the ITT population, which is defined as all randomized subjects. The 
Kaplan-Meier method will be used to estimate the distribution of PFS for each treatment group. 
The stratified log-rank test will be used to compare the PFS between the 2 treatment groups. The 
median PFS will be provided for each treatment group and the hazard ratio for ibrutinib + BR 
relative to placebo + BR and its associated 95% confidence interval (CI) will be calculated based 
on 
the 
Cox 
proportional 
hazards 
model 
stratified 
by 
the 
stratification 
factors. 
Investigator-determined PFS will be analyzed as a sensitivity analysis of primary efficacy 
analysis.
For the secondary efficacy endpoints, OS will be compared using the stratified log-rank test. The 
Kaplan-Meier method will be used to estimate the distribution of OS for each treatment group. 
The ORR and the rate of MRD-negative remissions will be obtained and comparison of the rates 
will be performed between the 2 treatment groups using the Cochran-Mantel-Haenszel 
chi-square test. Disease-related symptom improvement and hematologic improvement data will 
be summarized as appropriate. Scores from EORTC QLQ-C30, EORTC QLQ-CLL 16, 
EQ-5D-5L, and the FACIT-Fatigue will be descriptively summarized by treatment group. 
Longitudinal analysis with repeated measures may be used as appropriate. Multiplicity 
adjustment will be made for analyses of selected secondary efficacy endpoints to control the 
overall type 1 error. Details will be specified in the statistical analysis plan.
11.5.
Pharmacokinetic Analyses
The plasma concentration data for ibrutinib and, if possible and judged relevant, PCI-45227 at 
each timepoint will be summarized using descriptive statistics. 
Population PK analysis of ibrutinib plasma concentration-time data will be performed using 
NONMEM. Data may be combined with data from other studies to support a relevant structural 
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population-based PK model. Available subject characteristics (demographics, laboratory 
variables, genotypes, etc.) will be tested as potential covariates affecting PK parameters. 
Ibrutinib data will be listed for all subjects with available plasma concentrations per treatment
group. Subjects will be excluded from the PK analysis if their data do not allow for accurate 
assessment of the PK (eg, incomplete administration of the study agent; concentration data not 
sufficient for PK parameter calculation due to missing PK 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 PK 
parameters. All subjects and samples excluded from the analysis will be clearly documented in 
the study report.
Model-derived exposure parameters may be subjected to further explore PK/pharmacodynamic 
correlation between exposure with relevant clinical or biomarker information.
The plasma concentration data for bendamustine and rituximab at each timepoint will be 
summarized using descriptive statistics. Population PK analysis of plasma concentration-time 
data will be performed using NONMEM. Pharmacokinetic parameters will be obtained from 
population PK models reported in the literature with the aim of exploring whether ibrutinib 
coadministration had an effect on bendamustine and rituximab PK parameters.29,35
Details of the analyses will be given in a population PK analysis plan and the results of the 
population PK analyses will be presented in a separate report.
11.6.
Biomarker Analyses
Biomarker studies are designed to identify markers predictive of resistance to ibrutinib. Analyses 
will be performed within each treatment group in total and stratified by clinical covariates or 
molecular subgroups. The associations of biomarkers with clinical response or time-to-event 
endpoints will be assessed using the appropriate statistical methods (analysis of variance 
[ANOVA], categorical, or survival model), depending on the endpoint. Results may be presented 
in a separate report.
11.7.
Safety Analyses
Analysis of safety data will be conducted on the safety population, which includes subjects 
randomized who receive any study treatment. All data will be analyzed according to the 
treatment actually received.
The safety variables to be analyzed include AEs, clinical laboratory tests (hematology and
chemistry), physical examination results, ECGs, and deaths. Safety variables are to be tabulated 
by descriptive statistics (n, mean, median, standard deviation, minimum, and maximum; or n and 
percent). No formal statistical testing is planned. 
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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 AEs with onset 
during the treatment phase (ie, treatment-emergent AEs, and AEs that have worsened since 
baseline) 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 group.
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 or is subsequently considered treatment-related by the investigator. Adverse events of 
special interest with ibrutinib are the events of major hemorrhage. Subjects with adverse events 
of special interest may be counted or listed. Adverse events of special interest will be 
summarized similarly to treatment-emergent adverse events.
Clinical Laboratory Tests
Laboratory tests will be summarized by hematology and serum chemistry, separately. Selected 
hematologic and chemistry laboratory parameters are detailed in Section 9.5. Descriptive 
statistics will be provided for the values of selected clinical laboratory tests at each scheduled 
on-treatment evaluation including the final value by treatment group. Percent change from 
baseline to each scheduled on-treatment evaluation and to the final value will also be 
summarized. For selected variables, the mean value and mean percent change over time will be 
presented graphically.
A summary of the shifts in selected laboratory hematology and serum chemistry parameters from 
baseline to the worst toxicity grade during the study will be provided. The worst toxicity grade 
during the study will be tabulated.
11.8.
Interim Analysis
An interim analysis using classical O’Brien & Fleming boundary for both efficacy and futility 
will be conducted after observing approximately 50% (171) PFS events (PD or death).29 The 
stopping boundaries were implemented by Lan-Demets spending function using East® software 
v5.3 to control the 1-sided Type I error of 0.025 and Type II error of 0.10 for the comparison on 
PFS endpoint. This method ensures that the type I error is not inflated. The 1-sided cumulative 
alpha spent will be 0.0015 at the interim and 0.025 at the final analysis. Assuming the enrollment 
rate is 32 subjects per month, the interim analysis will take place after approximately 19 months
after the first subject has been randomized. The exact timing of the interim analysis will be 
determined according to the PFS events required.
The DMC may make recommendations regarding study continuation if the pre-specified 
boundary is crossed for efficacy or futility.
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11.9.
Data Monitoring Committee
An independent DMC will be formed to monitor data on a regular basis to ensure the safety of 
the subjects in this study, assess the evidence of benefit or adverse effects of ibrutinib, and to 
monitor the conduct of the study. The DMC is comprised of experts in CLL/SLL, medical safety, 
and biostatistical aspects of clinical studies. Details regarding DMC roles, responsibilities, and 
activities will be provided in a separate DMC Charter. 
At the interim analysis, the DMC may make recommendations regarding study continuation if 
the pre-specified stopping boundary is crossed for efficacy or futility. In addition to the planned 
interim analysis, the DMC will meet periodically to review the cumulative safety data throughout 
the study. There will be 2 planned safety review meetings. The first safety review meeting will 
be held after approximately 120 subjects (~20% of the expected enrollment) have been 
randomized, and the second will be after approximately 300 subjects have been randomized. The 
DMC safety review will focus on deaths, treatment discontinuations, SAEs, and Grade 3/4 AEs
and AEs of special interest, to identify any potential added toxicity when ibrutinib is combined 
with BR. Based on the results from these scheduled safety review meetings, the DMC chair may 
request additional safety analyses and more frequent monitoring. Until the first safety review, 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.
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])
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This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the informed consent form 
(refer to Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For an investigational product, the expectedness 
of an adverse event will be determined by whether or not it is listed in the Investigator's 
Brochure. For a non-sponsor investigational medicinal product (eg, a comparator product) with a 
marketing authorization, the expectedness of an adverse event will be determined by whether or 
not it is listed in the Treanda USPI40 or the Rituxan USPI41.
Adverse Event Associated With the Use of the Study Treatment
An adverse event is considered associated with the use of the treatment 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 treatment.
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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 treatment. 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 treatment. 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
Adverse event severity is a clinical determination of the intensity of an adverse event. The 
severity assessment for a non-hematologic adverse event or serious adverse event should be 
completed using the NCI CTCAE Version 4.03. Any non-hematologic adverse event or serious 
adverse event not listed in the NCI CTCAE Version 4.03 will be graded according to investigator 
clinical judgment by using the standard grades as follows: 
Grade 1: Mild AE
Grade 2: Moderate AE
Grade 3: Severe AE
Grade 4: Life-threatening or disabling AE
Grade 5: Death related to the AE
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
Hematological adverse events
An evaluation of hematologic toxicity in subjects with advanced CLL/SLL must consider the 
high frequency of marrow involvement and previous exposure to chemotherapy with consequent 
medullary compromise at the initiation of therapy. The standard hematologic grading system for 
solid tumors cannot, therefore, be directly applied. A substantial proportion of subjects would be 
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considered to have Grade 2 to 4 hematologic toxicity before any therapy is given. Therefore, the 
following modified schema will be used to quantitate hematologic deterioration, in accordance 
with the IWCLL recommendations.22
Table 2
Hematologic Adverse Event Grading Table
Decrease in Platelets or Hgb (nadir) from 
Pre-treatment Value, %
ANC/μL (nadir)c
Toxicity Grade
0-10%a
≥2000
0
11-24%a,b
≥1500 and <2000
1
25-49%a,b
≥1000 and <1500
2
50-74%a,b
≥500 and <1000
3
>75%a,b
<500
4
a
Platelet counts must be below normal levels for Grades 1 to 4: If, at any level of decrease, the platelet count is 
<20 x 109/L (20,000/μL), this will be considered Grade 4 toxicity, unless a severe or life-threatening decrease in 
the initial platelet count (eg, <20 x 109/L [20,000/μL]) was present pretreatment, in which case the patient is not 
evaluable for toxicity referable to platelet counts.
b
Hemoglobin levels must be below normal levels for Grades 1 to 4. Baseline and subsequent hemoglobin
determinations must be performed before any given transfusions. 
c
If the ANC reaches <1 x 109/L (1,000/μL), it should be a Grade 3 toxicity. If the ANC was <1 x 109/L (1,000/μL) 
before therapy, the patient is not evaluable for toxicity referable to the ANC.
Reference: Hallek 200822
12.2.
Special Reporting Situations
Safety events of interest on a sponsor medicinal product that may require expedited reporting or 
safety evaluation include, but are not limited to:

Overdose of a sponsor medicinal product

Suspected abuse/misuse of a sponsor medicinal product

Inadvertent or accidental exposure to a sponsor medicinal product

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor medicinal product, eg, name confusion)
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All subjects who receive treatment will be considered evaluable for toxicity. All adverse events 
(with the exception of progression of CLL) and special reporting situations, whether serious or 
non-serious, will be reported from the time a signed and dated informed consent form is obtained 
until 30 days following the last dose of study treatment or until the start of a subsequent systemic 
antineoplastic therapy, if earlier. 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 AEs considered related to 
study drug must be followed until recovery to Grade ≤1. The unresolved aforementioned events 
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will be followed for a maximum of 6 months. All AEs related to bleeding or resulting in bleeding 
complications must be followed until recovery to Grade ≤1. 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.
Serious adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study treatment, must be reported using the Serious Adverse Event Form. 
The sponsor will evaluate any safety information that is spontaneously reported by an 
investigator beyond the time frame specified in the protocol. Progressive disease of CLL 
(for which there are protocol-specific assessments), should NOT be reported as an AE, but 
instead symptoms/clinical signs of unexpected disease progression are to be reported. Otherwise, 
all events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments.
All adverse events, regardless of seriousness, severity, or presumed relationship to study therapy, 
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 study therapy. All 
measures required for adverse event management must be recorded in the source document and 
reported according to sponsor instructions. The intensity (severity) of non-hematological AEs 
will be assessed using NCI CTCAE Version 4.03. Hematological AEs will be assessed using the 
IWCLL criteria.
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 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. 
Subjects (or their designees, if appropriate) must be provided with a "study card" and instructed 
to carry this card with them for the duration of the study indicating the following:

Subject's name

Subject number

Study site number

Investigator's name and 24-hour contact information

Local sponsor's name and 24-hour contact information
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
Statement that the subject is participating in a clinical study.
12.3.2.
Serious Adverse Events
All serious adverse events occurring during clinical studies must be reported to the appropriate 
sponsor contact person by investigational staff 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 member of the investigational 
staff, 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) or may be made by telephone report in 
exceptional circumstances.
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a clinical study must be reported as a 
serious adverse event, except hospitalizations for the following:

A standard procedure for protocol therapy administration, including administration of 
background therapy (BR), will not be reported as a SAE. Hospitalization or prolonged 
hospitalization for a complication of therapy administration will be reported as a SAE.

The administration of blood or platelet transfusion. Hospitalization or prolonged 
hospitalization for a complication of such transfusion remains a reportable SAE.

A procedure for protocol/disease-related investigations (eg, scans, 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 SAE.

Prolonged hospitalization for technical, practical, or social reasons in the absence of an 
adverse event
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
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 SAE.
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 (see Section 12.1.1, 
Adverse Event Definitions and Classifications).
12.3.3.
Adverse Events of Interest
Specific AEs, or groups of AEs, 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, even if non serious) following the procedure described above for 
SAEs and will require enhanced data collection.  
12.3.3.1.
Major Hemorrhage
Major hemorrhage is defined as: 

Any treatment-emergent hemorrhagic adverse event of Grade 3 or higher. All 
hemorrhagic events requiring a transfusion of red blood cells should be reported as 
Grade 3 or higher adverse events per NCI CTCAE. 

Any treatment-emergent serious adverse event of bleeding of any grade.

Any treatment-emergent central nervous system hemorrhage/hematoma of any grade. 
12.3.4.
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the investigational staff 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.
The effect of the study drug on sperm is unknown. Therefore, pregnancies in partners of male 
subjects included in the study will be reported by the investigational staff 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.
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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. PQCs may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC 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 procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all clinical studies conducted by the sponsor or its 
affiliates will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the investigational staff within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, then the investigational staff 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
14.1.
Physical Description of Study Drug(s)
Ibrutinib capsules are provided as a hard gelatin capsule containing 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. 
Bendamustine hydrochloride may be provided in 100-mg single-use vials as a lyophilized 
powder or prescribed by the investigator. Rituximab may be provided in 100-mg or 500-mg 
single use vials as a solution or prescribed by the treating physician. 
14.2.
Packaging
To maintain the blind, the ibrutinib capsules and placebo to match capsules are packaged in opaque 
high-density polyethylene (HDPE) plastic bottles with labels bearing the appropriate label text as 
required by governing regulatory agencies. All bottles will utilize child resistant packaging 
(caps will be child resistant).
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14.3.
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.
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
The recommended storage condition for ibrutinib capsules is room temperature (15 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. Refer to the Site Investigational Product Procedures Manual 
for additional guidance on study drug preparation and handling.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects must be instructed to return all original containers, whether empty 
or containing study drug. All study drug will be stored and disposed of according to the sponsor's 
instructions. Site staff must not combine contents of the study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the drug return form. When the site is an authorized destruction unit and study 
drug supplies are destroyed on site, this must also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the investigational staff, 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 from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
Details of the background therapy (BR) dispensed must be recorded on a drug accountability 
form. Handling and disposal of BR must be performed according to the appropriate labeling 
instructions and institution guidelines.
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15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Study Protocol

Subject study tools (appointment card, emergency ID card etc, as applicable per country)

Investigator study tools and quick reference cards

Ibrutinib Investigator’s Brochure

Package inserts for bendamustine hydrochloride and rituximab

Trial Center File, and corresponding site specific documentation

Site Investigational Product Procedures manual and Site IP Binder

Laboratory manual and laboratory kits

Notification procedure for subject disease progression

Imaging Site Operations Manual and Image Acquisition Guidelines

NCI-CTCAE Version 4.03

PRO questionnaires and user manuals: PRO questionnaires will include the EORTC 
QLQ-C30, EQ-5D-5L, EORTC QLQ-CLL 16, and the FACIT-Fatigue Scale. 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 Attachments 6, 7, 8, and 9, but should not be used for collection of subject data. 

IWRS Manual and codes

eDC Manual and electronic CRF Completion Guidelines
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
In addition to receiving either ibrutinib or placebo, all subjects will receive active treatment with 
BR as background therapy, which is recommended treatment by NCCN and ESMO for the 
patient population in this study. 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 response criteria from the 2008 IWCLL 
Guidelines. Safety assessments will occur through regular clinic visits including laboratory 
analyses.
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. 
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The total blood volume to be collected is estimated at 335 mL for the first year, 25 mL every 
12 weeks following the first year, and 32 mL at the end-of-treatment visit. For a subset of 
subjects at selected sites, an additional 40 mL of blood will be drawn in the first year to explore 
the potential effect of ibrutinib on bendamustine and rituximab PK. This includes laboratory
assessments associated with treatment and includes 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.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical 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 clinical study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents:

Final protocol and, if applicable, amendments

Sponsor-approved informed consent form (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), the informed consent form, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
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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

Revision(s) to informed consent form 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 
investigational drug. From Amendment INT-4, these will no longer be provided for 
bendamustine or rituximab.

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable informed 
consent form 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 clinical 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 must give written consent according to local requirements after the nature of the 
study has been fully explained. The consent form must be signed before performance of any 
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study-related activity. The consent form that is 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 investigational 
staff must explain to potential subjects 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 staff without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the informed consent form the subject is authorizing such access, and agrees to allow his 
or her study physician to recontact the subject for the purpose of obtaining consent for additional 
safety evaluations, if needed, and subsequent disease-related treatments, or to obtain information 
about his or her survival status.
The subject will be given sufficient time to read the informed consent form 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 personally dated signature. After having 
obtained the consent, a copy of the informed consent form must be given to the subject.
If the subject is unable to read or write, then 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 informed consent form after the oral consent of the subject 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 study subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator to allow direct access to his or her original medical records 
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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.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 2 years (or according to local regulations) 
for additional research. Samples will only be used to understand ibrutinib, to understand 
CLL/SLL, to understand differential drug responders, and to develop tests/assays related to 
ibrutinib and CLL/SLL. The research may begin at any time during the study or the post-study 
storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Study). 
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 or its designee. 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 
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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 drug to the 
investigational site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed, written IEC/IRB approval of the protocol, amendments, 
informed consent form, any recruiting materials, and if applicable, subject compensation 
programs. This approval must clearly identify the specific protocol by title and number and 
must be signed by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, then a general statement may be substituted for this list. If an investigator 
or a member of the investigational staff is a member of the IEC/IRB, then 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)

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 clinical 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
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
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 
number and date of birth. In cases where the subject is not randomized into the study, the date 
seen and date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study discussion 
and date of informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all adverse events and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; study drug administration 
information; and date of study completion and reason for early discontinuation of study drug or 
withdrawal from the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a study subject should be 
consistent with that commonly recorded at the 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
Case report forms are provided for each subject in electronic format. 
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study 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 site. The 
electronic file will be considered to be the CRF.
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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. Designated 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 confirm that all data entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or 
an authorized member of the investigational staff must adjust the CRF (if applicable) and 
complete the query.
If corrections to a CRF are needed after the initial entry into the CRF, then this can be done in 
3 different ways:

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)

Site manager can generate a query for resolution by the investigational staff

Clinical data manager can generate a query for resolution by the investigational staff 
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 
associated personnel before the study, and periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's database. 
Written instructions will be provided for collection, preparation, and shipment of samples. 
Guidelines for CRF completion will be provided and reviewed with study 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 clinical 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.
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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, then 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, then the investigator must permit access to such reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the CRFs with the hospital or clinic records (source 
documents). The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the CRF are known to the sponsor and 
investigational staff and are accessible for verification by the sponsor site contact. If electronic 
records are maintained at the investigational site, then the method of verification must be 
discussed with the investigational staff. 
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 investigational staff. 
The sponsor expects that, during monitoring visits, the relevant investigational staff will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed when 80% of the subjects have died or 5 years after the last 
subject is randomized into the study, whichever occurs first. The sponsor will ensure that 
subjects benefiting from treatment with ibrutinib will be able to continue treatment after the end 
of the study. The final data from the investigational site will be sent to the sponsor (or designee) 
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after completion of the final subject assessment at that site, in the time frame specified in the 
Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the investigational site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Investigational sites will be closed upon 
study completion. An investigational site is considered closed when all required documents and 
study supplies have been collected and a site closure visit has been performed.
The investigator may initiate 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 an investigational site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the 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 staff are responsible for being present and 
available for consultation during routinely scheduled 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/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 exploratory 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.
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The investigator understands that the information developed in the clinical study will be used by 
the sponsor in connection with the continued development of ibrutinib, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain CRF data from all investigational sites that participated in the study, and direct 
transmission of clinical laboratory data from a central laboratory, and electronic PRO data into 
the sponsor's data base. Recruitment performance or specific expertise related to the nature and 
the key assessment parameters of the study will be used to determine a coordinating investigator. 
Results of biomarker analyses performed after the Clinical Study Report has been issued will be 
reported in a separate report and will not require a revision of the Clinical Study Report. Study 
subject identifiers will not be used in publication of biomarker 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.
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, then 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 site until the combined results from the completed study have 
been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register or disclose the existence of and the results of clinical studies as 
required by law.
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Attachment 1: 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, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair33
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Attachment 2: CLL and SLL Staging Criteria
Rai Staging System
Stage 0
Stage 0 CLL is characterized by absolute lymphocytosis (>15,000/mm3) without adenopathy, 
hepatosplenomegaly, anemia, or thrombocytopenia.
Stage I
Stage I CLL is characterized by absolute lymphocytosis with lymphadenopathy without 
hepatosplenomegaly, anemia, or thrombocytopenia.
Stage II
Stage II CLL is characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with 
or without lymphadenopathy.
Stage III
Stage III CLL is characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or 
without lymphadenopathy, hepatomegaly, or splenomegaly.
Stage IV
Stage IV CLL is characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or 
without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.
Binet Classification 
Clinical stage A*
Clinical stage A CLL is characterized by no anemia or thrombocytopenia and fewer than three areas of 
lymphoid involvement (Rai stages 0, I, and II).
Clinical stage B*
Clinical stage B CLL is characterized by no anemia or thrombocytopenia with three or more areas of
lymphoid involvement (Rai stages I and II).
Clinical stage C
Clinical stage C CLL is characterized by anemia and/or thrombocytopenia regardless of the number of 
areas of lymphoid enlargement (Rai stages III and IV).
*[Note: Lymphoid areas include cervical, axillary, inguinal, and spleen.]
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The Ann Arbor SLL Staging System with Cotswold’s Modifications
Stage I: Involvement of a single lymph node region (eg, cervical, axillary, inguinal, 
mediastinal) or lymphoid structure such as the spleen, thymus, or Waldeyer's ring.
Stage II: Involvement of two or more lymph node regions or lymph node structures on the same 
side of the diaphragm. Hilar nodes should be considered to be "lateralized" and when involved 
on both sides, constitute Stage II disease. For the purpose of defining the number of anatomic 
regions, all nodal disease within the mediastinum is considered to be a single lymph node 
region, and hilar involvement constitutes an additional site of involvement. The number of 
anatomic regions should be indicated by a subscript (eg, II-3).
Stage III: Involvement of lymph node regions or lymphoid structures on both sides of the 
diaphragm. This may be subdivided stage III-1 or III-2: stage III-1 is used for patients with 
involvement of the spleen or splenic hilar, celiac, or portal nodes; and stage III-2 is used for 
patients with involvement of the para-aortic, iliac, inguinal, or mesenteric nodes.
Stage IV: Diffuse or disseminated involvement of one or more extranodal organs or tissue 
beyond that designated E, with or without associated lymph node involvement.
Additional notes: 

All cases are subclassified to indicate the absence (A) or presence (B) of the systemic 
symptoms of significant unexplained fever, night sweats, or unexplained weight loss 
exceeding 10% of body weight during the 6 months prior to diagnosis.

The designation "E" refers to extranodal contiguous extension (ie, proximal or 
contiguous extranodal disease) that can be encompassed within an irradiation field 
appropriate for nodal disease of the same anatomic extent. More extensive extranodal 
disease is designated stage IV.

The subscript "X" is used if bulky disease is present. This is defined as a mediastinal 
mass with a maximum width that is equal to or greater than one-third of the internal 
transverse diameter of the thorax at the level of T5/6 interspace or >10 cm maximum 
dimension of a nodal mass. No subscripts are used in the absence of bulk.

Subjects can be clinically or pathologically staged. Splenectomy, liver biopsy, lymph 
node biopsy, and bone marrow biopsy are mandatory for the establishment of 
pathological stage. The pathologic stage at a given site is denoted by a subscript 
(eg, M=bone marrow, H=liver, L=lung, O=bone, P=pleura, and D=skin).
Source: The Ann Arbor staging system with Cotswolds modifications. Data from Lister TA, Crowther D, Sutcliffe SB, et al., 
J Clin Oncol 1989; 7:1630.
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Attachment 3: Inhibitors and inducers of CYP3A4/5
Examples 
of 
inhibitors 
and 
inducers 
of 
CYP3A4/5 
can 
be 
found 
at 
the 
following 
website:
http://medicine.iupui.edu/clinpharm/ddis/table.aspx.43 The list below reflects information obtained from the Indiana 
University, Division of Clinical Pharmacology, Indianapolis, IN website on July 2013.

A strong inhibitor is one that causes a >5-fold increase in plasma AUC values or >80% decrease in clearance. 
Strong inhibitors are capitalized in the list below. 

A moderate inhibitor is one that causes a >2-fold increase in plasma AUC values or 50-80% decrease in 
clearance.

A weak inhibitor is one that causes a >1.25-fold but <2-fold increase in plasma AUC values or 20-50% 
decrease in clearance.
Inhibitors of CYP3A4/5
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
TELTHROMYCIN
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 CYP3A4.
Inducers of CYP3A4/5
efavirenz
phenobarbital
nevirapine
phenytoin
barbiturates
pioglitazone
carbamazepine
rifabutin
glucocorticoids
rifampin
modafinil
St. John's wort
oxcarbazepine
troglitazone 
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Attachment 4: Maximum Blood Volumes During the Study
Maximum Volume of Blood to be Collected From Each Subject
Type of Sample
Volume 
per 
Sample 
(mL)
No. of 
Samples 
per 
Subject 
(First 
Year)
Total 
Volume 
of Blood 
(mL)a  
(First 
Year)
No. of 
Samples 
(q 12 
weeks
after First 
Year)
Total 
Volume of 
Blood 
(mL)a
(q 12 
weeks
after First 
Year
No. of 
Samples 
End-of 
Treatment 
Visit
Total Volume 
of Blood (mL)a  
End-of 
Treatment Visit
Serum chemistryc
5
16
80
1
5
1
5
Serum -hCG 
pregnancy test
2
1
2
0
0
0
0
Serology 
(Hepatitis)
5
1
5
0
0
0
0
Coagulation
2
1
2
0
0
0
0
Hematologyc
5
21
105
2b
10b
1
5
CLL diagnosis 
20
1
20
0
0
0
0
Pharmacokinetic 
samples
2
8
16
0
0
0
0
Serum 
immunoglobulin
5
5
25
1
5
1
5
Minimum residual 
disease
10
2
20
1
10
0
0
Biomarkersc
17
3
51
0
0
1
17
Biomarker 
analyses (ZAP-70, 
CD38, IgVH)
9
1
9
0
0
0
0
TOTAL
335
25
32
Additional PK 
samples (subset of 
subjects only)
2
20
40
0
0
0
0
a. Calculated as number of samples multiplied by amount of blood per sample. Blood volume for CLL diagnosis 
may vary by country or site, where additional blood may be drawn to be sent to a separate local laboratory.
b. Only 1 sample (5 mL) would be taken if the every-12-week disease assessment occurs at the same time as the 
every-3-cycle assessment.
c. For subjects receiving ibrutinib treatment: Only 1 sample (5 mL) will be taken at screening for serum chemistry 
evaluations; and 2 samples (17 mL each) will be taken for biomarker samples. Blood samples for CBC 
evaluations will be collected at screening, on Day 1 of Treatment Phase and at weeks 2, 4, 8, and 12 and then 
every 12 weeks thereafter until progression, and at the end of treatment visit. Each CBC sample is 5 mL.
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Attachment 5: Response-related Definitions
Minimal Residual Disease
MRD is determined by flow cytometry. MRD negative is defined as <1 CLL cell per 
10,000 leukocytes.2 This should be performed on the bone marrow aspirate when available. 
Peripheral blood MRD testing can also be performed by flow cytometry in those subjects that 
achieve a CR.
Sustained Hematologic Improvement
In the subset of patients with cytopenia(s) at baseline (hemoglobin <11 g/dL, platelets <100 x 
109/L [ie, <100,000/μL], or ANC <1.5 x 109/L [ie, <1500/μL]), a sustained improvement is 
defined as an improvement in cytopenias by >50% from baseline, or hemoglobin 11 g/dL, ANC 
≥1.5 x 109/L (ie, 1500/L), platelets ≥100 x 109/L (ie, 100,000/L) with the duration of 
improvement lasting for ≥60 days without blood transfusion or growth factors. 
Richter’s Transformation
Richter’s transformation is characterized by the development of high-grade NHL or Hodgkin’s 
disease. This can include new or progressive lymphadenopathy or organomegaly, fever, loss of 
weight and muscle mass, and other health problems. Confirmation of Richter’s transformation is 
made with a biopsy (eg, lymph node) demonstrating the histologic transformation. 
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Attachment 6: EORTC QLQ-C30
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Attachment 7: EORTC QLQ-CLL 16
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Attachment 8: EQ-5D-5L
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Attachment 9: FACIT-Fatigue Scale
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Attachment 10:
International Workshop on Chronic Lymphocytic Leukemia Criteria for 
Treatment
Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring treatment22:
a.
Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia or thrombocytopenia;
b.
Massive (ie, at least 6 cm below the left costal margin), progressive, or symptomatic 
splenomegaly;
c.
Massive nodes (ie, at least 10 cm in longest diameter), progressive, or symptomatic 
lymphadenopathy;
d.
Progressive lymphocytosis with an increase of more than 50% over a 2-month period or 
a lymphocyte doubling time (LDT) of less than 6 months (which may be extrapolated). 
Lymphocyte doubling time can be obtained by linear regression extrapolation of ALCs 
obtained at intervals of 2 weeks over an observation period of 2 to 3 months. For 
patients with initial blood lymphocyte counts of less than 30 x 109/L (30,000/L), LDT 
should not be used as a single parameter to define indication for treatment. In addition, 
factors contributing to lymphocytosis or
lymphadenopathy other than CLL 
(eg, infections) should be excluded;
e.
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
corticosteroids or other standard therapy;
f.
Constitutional symptoms, defined as 1 or more of the following disease-related 
symptoms or signs:
1)
Unintentional weight loss >10% within the previous 6 months prior to screening;
2)
Significant fatigue (inability to work or perform usual activities);
3)
Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without evidence of 
infection; or
4)
Night sweats for more than 1 month without evidence of infection.
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INVESTIGATOR AGREEMENT
NCT01611090

SAP_001.pdf: 
1
Janssen Research & Development 
Statistical Analysis Plan
Randomized, Double-blind, Placebo-controlled Phase 3 Study of Ibrutinib, a Bruton's
Tyrosine Kinase (BTK) Inhibitor, in Combination with Bendamustine and Rituximab (BR)
in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small 
Lymphocytic Lymphoma
Protocol PCI-32765CLL3001; Phase 3
JNJ 54179060  (Ibrutinib)
Date:
9 February 2015 
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-99931663
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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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 4
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Trial Objectives ................................................................................................................................ 6
1.1.1
Primary Objective ......................................................................................................................... 6
1.1.2
Secondary Objectives................................................................................................................... 6
1.2.
Trial Design ...................................................................................................................................... 7
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 8
1.4.
Sample Size Justification ................................................................................................................. 9
1.5.
Randomization ................................................................................................................................. 9
1.6.
Blinding Procedures....................................................................................................................... 10
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 10
2.1.
Study Medication............................................................................................................................ 10
2.2.
Analysis Sets.................................................................................................................................. 10
2.3.
Baseline Definitions........................................................................................................................ 11
2.4.
Cycles............................................................................................................................................. 11
2.5.
Visit Windows................................................................................................................................. 11
2.6.
Study Day and Cycle Day .............................................................................................................. 12
2.7.
Missing and Partial Dates .............................................................................................................. 12
2.8.
Treatment-Emergent Period .......................................................................................................... 14
2.9.
Definition of Subgroups.................................................................................................................. 14
2.10.
Exposure Related Definitions......................................................................................................... 15
3.
INTERIM ANALYSIS AND DATA REVIEW COMMITTEE ............................................................... 16
3.1.
Data Monitoring Committee........................................................................................................ 16
3.2.
Interim Analysis .......................................................................................................................... 16
4.
SUBJECT AND TREATMENT INFORMATION................................................................................ 16
4.1.
Subject Disposition......................................................................................................................... 17
4.2.
Demographics and Baseline Characteristics ................................................................................. 17
4.3.
Prior and Concomitant Medications ............................................................................................... 18
4.4.
Protocol Deviations ........................................................................................................................ 18
4.5.
Extent of Exposure......................................................................................................................... 18
5.
EFFICACY ......................................................................................................................................... 18
5.1.
Analysis Specifications................................................................................................................... 20
5.1.1.
Level of Significance................................................................................................................... 20
5.1.2.
Data Handling Rules................................................................................................................... 21
5.1.3.
General Analysis Considerations ............................................................................................... 21
5.2.
Primary Efficacy Endpoint.............................................................................................................. 21
5.2.1.
Progression Free Survival (PFS) based on IRC......................................................................... 21
5.2.2.
Primary Analysis Methods for PFS............................................................................................. 21
5.2.3.
Sensitivity Analysis of PFS ......................................................................................................... 22
5.2.4.
Subgroup Analysis of PFS.......................................................................................................... 22
5.3.
Secondary Endpoints..................................................................................................................... 22
5.3.1.
Overall Survival........................................................................................................................... 22
5.3.2.
Sensitivity Analysis of Overall Survival....................................................................................... 23
5.3.3.
Overall Response Rate............................................................................................................... 23
5.3.4.
Rate of Minimal Residual Disease-Negative Response............................................................. 23
5.3.5.
Sustained Hematologic Improvement......................................................................................... 24
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5.3.6.
24
5.3.7.
Disease-Related Symptom Improvement................................................................................... 24
5.4.
Other Efficacy Endpoints ............................................................................................................ 24
6.
SAFETY............................................................................................................................................. 25
6.1.
Adverse Events .............................................................................................................................. 25
6.1.1.
All Adverse Events...................................................................................................................... 26
6.2.
Adverse Events of Clinical Interest and other safety observations ............................................ 27
6.3.
Deaths......................................................................................................................................... 27
6.4.
Exposure-Adjusted Incidence Rates.............................................................................................. 27
6.4.1.
Restriction on the First Event ..................................................................................................... 27
6.4.2.
Duration of Exposure: Censored & Non-censored ..................................................................... 28
6.4.3.
Incidence Rate per Subject ........................................................................................................ 28
6.4.4.
Average EAIR per Preferred Term ............................................................................................. 28
6.4.5.
Average EAIR per SOC.............................................................................................................. 28
6.4.6.
Average EAIR on a Global Level................................................................................................ 29
6.5.
Clinical Laboratory Tests................................................................................................................ 29
6.5.1.
Creatinine Clearance.................................................................................................................. 30
6.5.2.
Analysis of Lymphocytosis.......................................................................................................... 30
6.6.
Electrocardiogram.......................................................................................................................... 30
7.
PATIENT-REPORTED OUTCOMES................................................................................................. 31
7.1.1.
EORTC QLQ-C30....................................................................................................................... 31
7.1.2.
EORTC QLQ-CLL 16.................................................................................................................. 31
7.1.3.
EQ-5D-5L.................................................................................................................................... 31
7.1.4.
FACIT-Fatigue ............................................................................................................................ 32
7.1.5.
Exploratory analyses with Patient-reported outcome Questionnaires........................................ 32
7.1.6.
Analysis Methods........................................................................................................................ 32
Time to Improvement and Deterioration Analysis............................................................................................. 33
8.
PHARMACOKINETICS AND PHARMACODYNAMICS ANALYSIS ............................................... 34
9.
BIOMARKER ANALYSIS.................................................................................................................. 34
10.
CHANGES TO PROTOCOL SPECIFIED ANALYSES..................................................................... 34
11.
REFERENCES................................................................................................................................... 34
12.
APPENDIX 1: ADDITIONAL EXPLORATORY ANALYSIS TO SUPPORT HEMAR ...................... 35
12.1.
Subgroup Definition........................................................................................................................ 35
12.2.
Further endpoints for analyses (OR, RR, RD) ............................................................................... 36
12.2.1.
Subgroups for further endpoints from market access analysis .................................................. 36
12.3.
Cross-over correction for the Overall Survival Endpoint................................................................ 37
Database and variables .............................................................................................................................. 37
Tables delivered.......................................................................................................................................... 38
IPCW APPROACH AND MODIFICATION................................................................................................. 38
CONCLUSIONS & RECOMMENDATIONS ............................................................................................... 39
Possibility of overcompensation by weights................................................................................................ 39
Modification of IPCW approach by parametric analysis ............................................................................. 39
Final Statement ........................................................................................................................................... 40
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AMENDMENT HISTORY
ABBREVIATIONS
AE(s)
adverse event (s)
AESI
adverse events of special interest
ALT
alanine aminotransferase
ALC
absolute lymphocyte counts
ANC
absolute neutrophil count 
ANCOVA
analysis of covariance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BR
bendamustine and rituximab
BSA
body surface area
BTK
Bruton’s tyrosine kinase 
CBC
complete blood count
CI
confidence interval 
CIT
chemoimmunotherapy
CLL
chronic lymphocytic leukemia
CR
complete response
CRF
case report form 
CRi
complete response with an incomplete marrow recovery
CT
computed tomography (scan)
CYP
cytochrome P450
DBP
diastolic blood pressure
DOL
duration of lymphocytosis
DOR
duration of response
DMC
Data Monitoring Committee
EAIR
exposure-adjusted incidence rate
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of
Life Questionnaires Core 30
EQ-5D
EuroQoL Five-Dimension.
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy-Fatigue
FISH
fluorescence in situ hybridization
HDL
high-density lipoproteins
Hgb
hemoglobin
Ig
immunoglobulin
IgA
immunoglobulin A
IgG
immunoglobulin G
IgM
immunoglobulin M
IgVH
immunoglobulin variable heavy gene
INR
international normalized ratio
IPE
Iterative Parameter Estimate
IRC
independent review committee
ITT
intent-to-treat (population)
IV
intravenous 
IVIG
intravenous immunoglobulin
IWCLL
International Workshop on Chronic Lymphocytic Leukemia Criteria
IWRS
Interactive Web Response System
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JRD
Janssen Research & Development, LLC
LDH
lactic acid dehydrogenase 
LLN
lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging 
MMRM
Mixed Model for Repeated Measures
MRD
Minimal residual disease
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NE
not evaluable
NED
no evidence of disease
NHL
non-Hodgkin’s lymphoma
nPR
nodular partial response
ORR
overall response rate
OS
overall survival
PCYC
Pharmacyclics Inc.
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival 
PLT
platelets
PR
partial response
PRL
partial response with lymphocytosis
PRO
patient-reported outcome(s)
QLQ
quality of life questionnaire
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
stable disease
SLL
small lymphocytic lymphoma
SOC
system organ class
TEAE
treatment-emergent adverse events
TTR
time to response
VAS
Visual Analogue Scale
ULN
upper limit of normal
UNK
Unknown
WBC
white blood cell (count)
WHO
World Health Organization
Definitions of Terms
Study medication or 
study drug
Ibrutinib/placebo
Study treatment
Bendamustine hydrochloride, rituximab, and ibrutinib/placebo
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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 Phase 3 study is designed to evaluate the efficacy and safety of 
ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, in combination with bendamustine and 
rituximab (BR) in subjects with relapsed or refractory B-cell chronic lymphocytic leukemia
(CLL)/ small lymphocytic lymphoma (SLL).
The purpose of the statistical analysis plan (SAP) is to lay out key elements including definition 
and statistical methods for the planned analyses for the primary, secondary and safety endpoints.
1.1.
Trial Objectives
1.1.1 Primary Objective
The primary objective is to determine whether the addition of ibrutinib to BR significantly 
improves progression-free survival (PFS) compared with BR in subjects with relapsed or 
refractory CLL/SLL.
1.1.2 Secondary Objectives
The secondary objectives are to evaluate: 

the safety of ibrutinib in combination with BR

the overall response rate (ORR; complete response [CR] + complete response with 
incomplete marrow recovery [CRi] + partial response [PR] + nodular partial response 
[nPR])

the overall survival (OS)

the rate of minimal residual disease (MRD)-negative response 

improvement in hematologic parameters (hemoglobin, neutrophil count, platelet count)

improvement of disease-related symptoms (fatigue, night sweats, weight loss, fever, and 
abdominal discomfort due to splenomegaly)

patient-reported symptoms, functional status, and well-being as measured by European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
(EORTC-QLQ) C30, EORTC QLQ CLL 16, EQ-5D-5L, and Functional Assessment of 
Chronic Illness Therapy (FACIT)-Fatigue Scale
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
To characterize the pharmacokinetics (PK) of ibrutinib and explore its potential effect on 
bendamustine and rituximab PK, the potential relationships between ibrutinib metrics of 
exposure with relevant clinical or biomarker information

To examine biomarkers related to B-cell receptor (BCR) and compensatory signaling 
pathways and explore their association with resistance to ibrutinib treatment
1.2.
Trial Design
This is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study to determine 
the benefits and risks of combining ibrutinib and BR in subjects with relapsed or refractory 
B-cell CLL/SLL following at least 1 line of prior systemic therapy.
All subjects will receive background therapy with BR for a maximum of 6 cycles. A cycle will 
be defined as 28 days, with the exception of Cycle 1, which will be 29 days to allow for 
rituximab dosing prior to bendamustine and study medication. Approximately 580 subjects will 
be randomized in a 1:1 ratio to either Treatment Arm A (placebo) or Treatment Arm B (ibrutinib 
420 mg). Study medication will be administered orally once daily on a continuous schedule.
Stratification factors will include whether refractory to purine analog therapy (yes or no) and 
number of prior lines of therapy (1 or >1). For stratification, refractory is defined specifically as 
a failure to respond (ie, progressive disease [PD] or stable disease [SD]) to a purine analog or a 
recurrence of disease within 12 months of the last dose of purine analog therapy. Separate lines 
of therapy are defined as single or combination therapy regimens that are either separated by 
disease progression or refractory disease or by a treatment-free interval of 6 months or greater. In 
addition, a change of regimen due to insufficient response may be considered a separate line of 
therapy.
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. 
The Screening Phase will be up to 30 days prior to randomization. The Treatment Phase will 
extend from randomization until study treatment (bendamustine, rituximab, and 
ibrutinib/placebo) discontinuation. Subjects will receive both BR and ibrutinib or placebo for the 
first 6 cycles, and thereafter will receive study medication until disease progression or 
unacceptable toxicity. For subjects who discontinue BR prior to completing 6 cycles, treatment 
with study medication will continue. The Follow-up Phase will begin once a subject discontinues 
study treatment. Subjects who discontinue for reasons other than disease progression will 
continue to have disease evaluations according to the Time and Events Schedule. The Follow-up 
Phase will continue until death, loss to follow up, consent withdrawal, or study end, whichever 
occurs first. Study end is defined as when either 80% of the subjects have died or 4 years after 
the last subject is randomized into the study, whichever occurs first. 
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Assessment of tumor response and progression will be conducted in accordance with the 
International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Guidelines
(Hallek 2008). The investigator will evaluate sites of disease by radiological imaging, physical 
examination, or other procedures as necessary, and review of hematology and clinical chemistry 
results. A central laboratory will perform complete blood count (CBC) testing. The primary 
efficacy analysis of PFS will be based on assessment by an Independent Review Committee 
(IRC). Patient-reported symptoms, functional status, and well-being will also be measured. 
During the study, safety evaluations will include adverse event (AE) monitoring, physical 
examinations, concomitant medication usage, and clinical laboratory parameters (hematology, 
chemistry, coagulation). At each site visit, subjects will be evaluated for toxicity. Blood samples 
will be drawn for assessment of PK and biomarker parameters. All study evaluations will be 
conducted according to the Time and Events Schedule. 
An independent Data Monitoring Committee (DMC) will be formed and constituted according to 
regulatory agency guidelines. One interim analysis is planned for the study. Detailed information
regarding the composition and procedures of the DMC and interim analysis are provided in 
Section 3 and a separate DMC charter.
At investigator’s request, subjects who have IRC-confirmed disease progression and meet the 
IWCLL criteria for requiring subsequent anti-CLL therapy and other eligibility criteria may be 
considered for next-line ibrutinib treatment. If upon unblinding by a medical monitor separate 
from the study team it is determined that the subject was randomized to placebo (Treatment 
Arm A), the subject will be permitted to cross over to receive ibrutinib 420 mg orally, daily. 
Subjects will continue to be followed up for assessment of response and other study endpoints as 
specified in the Time and Events Schedule for next-line ibrutinib. Open-label next-line treatment 
with ibrutinib will continue until disease progression, unacceptable toxicity, withdrawal from 
study, or until the study end, whichever occurs earlier.
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis of this study is that the experimental treatment ibrutinib + BR compared 
with placebo + BR will significantly improve PFS, in subjects with relapsed or refractory 
CLL/SLL.
The statistical hypotheses are as follows:
H0: The PFS distributions of experimental treatment group, ST(t), and the placebo group, SP(t), 
are equal at all time points t:
ST(t) = SP(t), for all t > 0
versus
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H1: The PFS distributions of experimental treatment group, ST(t), are greater than the placebo 
group, SP(t), at least one time point t:
ST(t) > SP(t), for some t > 0
These hypotheses will be tested using stratified log-rank test and assessed within the context of a 
group sequential testing design as described in Sections 3.
1.4.
Sample Size Justification
A recent Phase 2 study reported median PFS in subjects with relapsed or refractory CLL treated 
with combination of BR is 15 months [1]. It is assumed that the PFS follows an exponential 
distribution with a constant hazard ratio.
Approximately 580 subjects (290 per treatment group) will be randomized to observe 342 PFS 
events. The study is designed to detect a hazard ratio of 0.7 for the ibrutinib + BR group relative 
to placebo + BR group (corresponding to an improvement of 43% in median PFS, e.g. from 15 
months to 21.5 months) with 90% power at a 1-sided significance level of 0.025, using a group 
sequential testing design as described in Section 3. Assuming the enrollment rate is on average 
32 subjects per month, the total study duration is expected to be approximately 33 months with 
18 months of enrollment and 15 months of follow up in order to observe 342 PFS events.
1.5.
Randomization 
Central randomization will be implemented in this study. Subjects will be randomly assigned to 1 
of 2 treatment groups in a 1:1 ratio 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 purine analog refractory 
status (yes vs. no), and prior lines of therapy (1 vs. >1). These stratification factors represent 
prognostic factors that may potentially affect treatment outcome and are included to eliminate 
bias and to increase the precision of overall treatment effect estimates. The interactive web 
response system (IWRS) will assign a unique treatment code, which will dictate the treatment 
assignment and matching study medication 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.
This is a double-blind study. The block size will be chosen to minimize the chance of accidental 
unblinding while sufficiently controlling for potential imbalance between treatment groups, and 
will be kept confidential as part of the randomization schedule. The randomization schedule will
be prepared by an independent statistician not otherwise involved with this study, and will be 
implemented within IWRS.
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1.6.
Blinding Procedures
It is the intent for all subjects, investigators, and study team members from the sponsor to remain 
blinded to treatment group assignment until the completion of the study and database is finalized. 
The IRC who performs tumor assessment will be blinded to study treatment as well. The 
exceptions are:

The independent DMC and the independent biostatistician and statistical programmer 
from Statistical Support Group (SSG) 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 serum concentration assays and analysis for PK.

Unblinded safety representative and Ethics Committee for serious adverse event (SAE) 
reporting.
It is planned in the protocol to analyze the data when the prespecified required number of PFS 
events is observed. While the study is ongoing, the results may require unblinding for review by 
independent DMC, and potentially by regulatory agencies. An unblinding plan including the
names of the members and the process will be prepared prior to performing the analysis.
Protocol amendment INT-3 described the circumstances and process for crossover and access to 
next-line ibrutinib for those subjects who have IRC confirmed disease progression and were 
previously on placebo with bendamustine and rituximab. The implementation of crossover aims 
to protect the primary endpoint by mitigating potential early dropout to access ibrutinib through 
other mechanisms. The steps taken to protect the integrity of the key efficacy endpoints during 
conduct of the crossover phase of the study and to minimize access to unblinded information are 
described in a separate document.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Study Medication
For the purpose of analysis, the term “study medication” refers to all 3 drugs, ibrutinib/placebo, 
bendamustine and rituximab.
2.2.
Analysis Sets
The analysis sets are:

Intent-to-Treat (ITT) population: defined as all subjects randomized into the study and 
who will be analyzed according to assigned treatment group, regardless of the actual 
treatment received. This population will be used for all analyses of efficacy and patient-
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reported outcome (PRO) endpoints, analyses of disposition, demographic, and baseline 
disease characteristics. 

Safety population: defined as all randomized subjects who receive at least one dose of 
ibrutinib or placebo. This population will be used for all safety analyses and analyses of 
exposure. All subjects will be analyzed according to the treatment which they actually 
received.

Per-protocol (PP) population: defined as all randomized subjects who undergo at least 
one post-baseline disease assessment (post-baseline tumor assessment by independent 
radiology reviewers/IRC) or died within 2 months and do not have major protocol 
violations as described below:
a.
did not meet all entry criteria
b. did not receive the treatment to which they were randomized
c.
had less than 67%  of study medication compliance
d. Received prohibited concomitant medications; specifically, other antineoplastic 
therapy during the treatment phase.
Subjects in this population will be analyzed according to the treatment to which they are 
randomized. This population will be used for sensitivity analysis for PFS.
2.3.
Baseline Definitions
Unless specified otherwise, the baseline value is defined as the last non-missing value collected 
on or before the administration of the first dose of study medication. For subjects who have been 
randomized but not treated with any dose, randomization date will be used as the reference date 
for baseline value calculation.
2.4.
Cycles
In defining treatment cycles in a combination therapy setting, the entire combination must be 
taken into account.  Therefore the nominal cycles as defined in protocol and recorded on the 
Case Report Form (CRF) will be used in the statistical analyses.
2.5.
Visit Windows
Visit windowing will be based on phases and cycles:
Screening: Before the first dose of study medication.
Treatment: Between the date of first dose of study medication and the date of the last dose of 
study medication. As noted above, the term “study medication” refers to all of the drugs used in 
the combination treatment.  
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The Treatment Phase will be subdivided by cycles, based on the nominal treatment cycles for the 
combination therapy as recorded on the CRF.
End of treatment: Between date of last dose of study medication + 1 and date of last dose of 
study medication+ 30 days. The assessments performed during the ‘End-of-Treatment Visit’ will 
be included in this phase. 
Follow-up: After the end of treatment until the study cut off.
Cycle-based analysis may be performed for safety parameters during the treatment up to date of 
last dose +30 days or End-of-Treatment visit whichever comes later.  For the analysis of lab 
grade by cycle, worst grade within each cycle will be used.
2.6.
Study Day and Cycle Day
Assessments will be presented chronologically by study day or cycle day as described below. 
For efficacy data, the randomization date is considered as the reference date (Day 1). For safety 
data, date of first dose of study medication (randomization date for subjects who have been 
randomized but not treated) will be used as the reference date (Day 1).
Reference date (Day 1) = randomization date (for efficacy data), or first dose date of study 
medication (for safety data)
Study Day = assessment date – reference date + 1 for assessment performed on or after the 
reference date;  assessment date – reference date for assessment performed before the reference 
date. 
Cycle Day = assessment date - date of the first dose for the cycle + 1. 
2.7.
Missing and Partial Dates
In general, imputation of missing dates will be made for AE onset date, AE resolution date, date 
of death, start and end dates of prior, concomitant and subsequent therapies, and date of initial 
diagnosis according to the following rules. Start date will be imputed before end date.  

If date is completely missing, no imputation will be made. 

If year is missing, no imputation will be made.

If only year is present but month and day are missing, then June 30th will be used.

If only day is missing but year and month are available, then the 15th of the month will 
be used. 
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However, the above imputations will be modified by the following rules:

For initial diagnosis if such imputed date is on or after the randomization date, then 
randomization date - 1 will be used. 

If such imputed date for prior therapies or initial diagnosis is on or after the randomization 
date, then randomization date - 1 will be used. If such imputed date for subsequent 
therapies is before date of last dose, then date of last dose +1 will be used.

The imputed start date for subsequent therapies will be adjusted sequentially using the 
following steps:
o
If the imputed start date is before the treatment discontinuation date or last dose 
date if no treatment discontinuation date but in the same year and month, then 
the treatment discontinuation date or last dose date if no treatment 
discontinuation date will be used. 
o
If subsequent therapy end date is not missing and is before the imputed 
subsequent therapy start date, then the subsequent therapy end date will be used 
as the start date.

If the imputed date is for a date of death and is before the last date that the subject is 
known to be alive, the latter date will be used.

The imputed AE start date will be adjusted sequentially using the following steps:
o
If the imputed date is in the same year and month as but day before the first dose 
date, then the first dose date will be used, or if it is in the same year and month 
as but day after the last dose date + 30 days, then the last dose date + 30 days 
will be used. 
o
If AE end date is not missing and the imputed AE start date is after the AE end 
date, then the AE end date will be used.
o
If the imputed AE start date and is after date of death, then date of death will be 
used
o
If the imputed AE start date is in the same month and year but after the 1st 
subsequent therapy start date, then 1st subsequent therapy start date will be used.
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
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.
2.8.
Treatment-Emergent Period
In general, the treatment-emergent period is defined as the time from first dose date through 30 
days after last dose date, or day before subsequent antineoplastic therapy, whichever occurs first.
For subjects in placebo group who receive cross-over ibrutinib therapy, treatment-emergent 
period before cross-over ibrutinib therapy is defined as the time from first dose date through 30 
days after last dose date, or day before subsequent antineoplastic therapy, or day before first dose 
date of crossover ibrutinib, whichever occurs first. Treatment-emergent period for cross-over 
ibrutinib therapy is defined as the time from the first dose date of crossover ibrutinib therapy
through 30 days after last dose date.
2.9.
Definition of Subgroups
Subgroup analysis will be performed for the selected variables to assess the internal consistency 
of the treatment benefit and/or safety. The subgroup variables and the cutoff values are subject to 
change if warranted to better represent the data.
Table 1. Subgroup Definition
Subgroup
Definition of Subgroup
Analysis Type
Age
<65, ≥65  yrs.
D, E, S
Sex
Male, Female
D, E, S
Race
White, Non-White
D, E, S
Geographic region
North America, Europe, Latin 
America, and Asia
D, E, S
Diagnosis 
CLL, SLL
D, E, S
Rai Stage at screening 
Stage 0-II, III-IV
E
Refractory to prior purine analogue 
therapy 
Refractory to prior purine analogue 
therapy, Yes  (defined as no response 
or failure within12 months),   No 
Refractory to prior purine analogue 
therapy (Response lasting 12 
months)
E
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Subgroup
Definition of Subgroup
Analysis Type
Baseline ECOG
0, 1 
E
Bulky Disease 
Yes (LDi 5 cm), no (LDi <5 cm),
E
Chromosome 11q Deletion
Yes, no
E
Elevated LDH at Baseline
No (<350 U/L),  Yes (350 U/L)
E
Cytopenias at Baseline
Yes, no
E
Serum β2 –microglobulin 
≤3.5 mg/L, > 3.5 mg/L
E
IgVH 
Mutated, Unmutated
E
ZAP-70
Elevated, Not Elevated 
E
CD38
Positive (≥30%), negative (<30%) 
E
complex karyotype
Yes, no
E
Refractory to purine analog therapy as 
recorded in IWRS 
Yes, no
E
Prior lines of therapy as recorded in 
IWRS
1,  >1
E
Concomitant use of any CYP3A 
inhibitor 
Yes, No
S
Concomitant use of strong CYP3A 
inhibitor 
Yes, No
S
Cytopenia is defined as yes if platelet count ≤ 100,000/uL, Hgb ≤ 11g/dL, or ANC ≤ 1500/uL is 
observed.
analysis type D= demographic and baseline disease characteristics
analysis type E= efficacy (PFS, OS, ORR)
analysis type S= safety (adverse events) 
ECOG= Eastern Cooperative Oncology Group; IgVH= immunoglobulin variable heavy gene;
IWRS= Interactive Web Response System; LDH= lactic acid dehydrogenase; LDi=longest 
diameter.
2.10.
Exposure Related Definitions
Treatment duration is the interval between date of first dose and end-of-treatment date.  If date of 
end of treatment is not available, use last available treatment date.
Number of treatment cycles = the last cycle number - the first cycle number + 1.
For ibrutinib/placebo, dosing information includes total dose received (the sum of total dose), 
average dose level per administration (the ratio of total dose and treatment duration) and relative 
dose intensity (the ratio of average dose level per administration and 420).
For background therapy (BR), dosing information includes total dose received (the sum of actual 
dose administered), average dose level per administration (the ratio of total dose and treatment 
duration in cycles), and relative dose intensity:
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Dose reduction for ibrutinib/placebo is defined as prescribing lower dose level (280 mg/day 
[level 1 reduction] or 140 mg/day [level 2 reduction]). For each subject, use the highest level of 
dose reduction to summarize categories - ‘One dose reduction’ and ‘Two dose reductions’. 
3.
INTERIM ANALYSIS AND DATA REVIEW COMMITTEE 
3.1.
Data Monitoring Committee
An independent DMC was formed to monitor data on a regular basis to ensure the safety of the 
subjects in this study, assess the evidence of benefit or adverse effects of ibrutinib, and to 
monitor the overall conduct of the study. At interim analysis, the DMC may make 
recommendations regarding study continuation if the prespecified stopping boundary is crossed 
for efficacy or futility. In addition to the planned interim analysis, the DMC will meet 
periodically to review the cumulative safety data throughout the trial. The DMC safety review 
will focus on deaths, treatment discontinuations, SAEs and Grade 3/4 AEs and AEs of special 
interest, and to identify any potential added toxicity when ibrutinib is combined with BR. Details 
are provided in the DMC Charter.
3.2.
Interim Analysis 
One interim analysis is planned using group sequential testing design. It is scheduled to be 
conducted when 50% of the PFS events (or approximately 171 PFS events) have occurred.
The O’Brien-Fleming boundaries [2] as implemented by Lan-DeMets spending function were 
used to control the 1-sided Type I error of 0.025 and Type II error of 0.10 for the comparison on 
PFS endpoint. The efficacy and futility monitoring plan is summarized in Table 2. The actual 
type I error rates to spend at each analysis may differ depending on the actual information 
fraction. The sample size and interim analysis boundaries are calculated using the software 
package East 5.4 (Cytel Software Corp., Cambridge, MA).
Table 2. Stopping Boundaries and Corresponding Observed Difference
Analysis
PFS Events 
(info)
Anticipated 
Time to 
Analysis§
Anticipated 
Enrollment 
(n)
Cumulative Error
Stopping Boundary
Alpha
Beta
p-value (1-sided)
Observed Hazard 
Ratio
Efficacy
Futility
Efficacy
Futility†‡
Efficacy
Futility
Interim
171 (50%)
19 month
580
0.002
0.020
<0.0015
≥0.3947
<0.634
≥ 0.960
Final
342 (100%)
33 month
580
0.025
0.100
<0.0245
≥0.0245
<0.807
≥ 0.807
§Assuming enrollment rate 32/month
† CP1 (conditional power assuming observed hazard ratio at interim is true) is 1.2%
‡ CP2 (conditional power assuming the original hazard ratio assumption is true) is 42.2%.
Type I error of 0.025 (1-sided), Type II error of 0.10, efficacy and futility boundaries are based on O’Brien-Fleming boundaries.
Observed hazard ratio are approximates
4.
SUBJECT AND TREATMENT 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 
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be conducted on the ITT population. Analyses of 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 (SD), median, minimum, and maximum. All categorical endpoints will be 
summarized using frequencies and percentages. Percentages will be calculated by dividing the 
number of subjects with the characteristic of interest by the number of subjects in the analysis 
population.
4.1.
Subject Disposition
Disposition information will be summarized for the ITT population and safety population.  
Subject enrollment will be summarized by region, country, and investigator.  The number of 
subjects undergoing, discontinuing and completing the study treatment as well as their reasons 
for treatment discontinuation will be summarized. 
Descriptive statistics will be provided for time on study. Time on study is defined the same way 
as OS with reversed censoring, i.e., subject who died 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
Subject demographics and baseline disease characteristics will be summarized using descriptive 
statistics.

Demographics and baseline characteristics: age, sex, race, ethnicity, geographic region, 
height (cm), weight (kg), systolic blood pressure/diastolic pressure (SBP/DBP (mmHg), 
body surface area (m2)

Baseline disease characteristics: time from initial diagnosis to randomization, time from 
progression/relapses since last line of treatment to randomization, diagnosis (CLL, SLL), 
baseline Eastern Cooperative Oncology Group (ECOG, baseline Rai stage, baseline Binet 
stage, bulky disease, cytopenia at baseline, 11q deletion, immunoglobulin variable heavy 
gene (IgVH) status, elevated lactate dehydrogenase (LDH) at baseline, serum β2 –
microglobulin

Hematology: leukocytes, lymphocytes, hemoglobin, platelets, neutrophils

Chemistry: creatinine, LDH, uric acid, liver function tests (alkaline phosphatase, 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin), and 
electrolytes (sodium, magnesium, potassium, and phosphate).
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4.3.
Prior and Concomitant Medications
For summarization purposes, medications will be coded to a generic term based on the World 
Health Organization (WHO) 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 through the date of last dose of study drug. Using this definition, a 
medication can be classified as both prior and concomitant.
Incidence of prior and concomitant medications will be summarized by Anatomical Therapeutic 
Chemical (ATC) class and drug generic term. Prior anticancer therapy will be summarized by 
type (e.g. radiotherapy, surgery, chemotherapy). Best response to last line of prior therapy will 
also be summarized. Concomitant medications of special interest will be provided: CYP3A/4 
inhibitors and inducers, growth factors, transfusions, anticoagulation and antiplatelets.
4.4.
Protocol Deviations
Subjects with eligibility and major protocol deviations will be listed by treatment group.
Protocol deviations will be based on clinical review, but not limited to, the following aspects: (1) 
eligibility criteria, (2) patient safety, (3) efficacy assessment deviation, (4)treatment compliance . 
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.
4.5.
Extent of Exposure
Descriptive statistics (n, mean, standard deviation, median, and range) will be provided for total 
number of cycles, treatment duration and dosing information for all study medications 
(ibrutinib/placebo, BR). 
The number and percentage of subjects with dose reduction and dose interruption will be 
summarized. In addition, subjects with dose modifications and reasons for dose modifications 
will be summarized. 
Details of exposure related definition is specified in Section 2.10.
5.
EFFICACY
Analysis of efficacy endpoints will be conducted on the ITT population. Table 3 summarizes the 
efficacy endpoints and analysis methods to be performed. The analyses on PROs are detailed in 
Section 7. Analyses to support HEMAR are described in Appendix 1. 
Table 3. Summary of Efficacy Analyses to be Performed
Endpoint
Analysis
Analysis Method
Population
Primary
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Endpoint
Analysis
Analysis Method
Population
PFS assessed by 
IRC
Primary
Stratified log-rank test, stratified Cox regression model, all 
PD and death considered as events regardless of 
subsequent antineoplastic therapy.
ITT; PP
Sensitivity 1)
Alternative censoring rule 1: subjects who received 
subsequent antineoplastic therapy are considered to 
have had a PFS event at the initiation of subsequent 
therapy
2)
Alternative censoring rule 2: subjects who received 
subsequent antineoplastic therapy are censored at the 
last disease assessment showing no evidence of PD 
before the use of subsequent therapy
3)
Alternative censoring rule 3: subjects will be censored 
at the last disease assessment if they progress or die 
after missing ≥2 planned disease assessment visits.
4)
Non-stratified log-rank test, non-stratified Cox 
regression model; evaluation of censoring reasons
5)
Investigator assessed PFS by stratified log-rank test 
and stratified Cox regression model; concordance rate 
between the IRC-determined PFS and investigator-
determined PFS 
ITT
Subgroup 
Non-stratified Cox regression model within each subgroup
ITT
Secondary
Overall Survival
Primary
Stratified log-rank test, stratified Cox regression model, all 
death considered as events regardless of any subsequent 
antineoplastic therapy including crossover
ITT
Subgroup 
Non-stratified Cox regression model within each subgroup
ITT
Sensitivity
1.
Which censor subject at the time of crossover for 
placebo subjects;
2.
Which censor ibrutinib subjects at subsequent 
therapy.
ITT
Overall Response 
Rate 
Primary
IRC assessed ORR CMH chi-square test, Logistic 
regression model 
ITT subjects with 
measurable 
disease at 
baseline
Sensitivity Investigator assessed ORR by CMH chi-square test, logistic 
regression model
ITT subjects with 
measurable 
disease at 
baseline
Subgroup
Logistic regression model
ITT subjects with 
measurable 
disease at 
baseline
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Endpoint
Analysis
Analysis Method
Population
Rate of MRD 
Negative Response
chi-square test
ITT  
Sustained 
Hematologic 
Improvement 
chi-square test 
ITT; ITT subjects 
with cytopenia at 
baseline
Disease-Related 
Symptom 
Improvement
Descriptive summary
ITT
Patient-Reported 
Outcome
Descriptive summary, mixed model with repeated 
measurements
ITT
Other 
Subsequent Therapy
Descriptive summary
ITT
Beta2-
microglobulin, IgA, 
IgG, and IgM
Descriptive summary
ITT
5.1.
Analysis Specifications
5.1.1.
Level of Significance
In general, all tests will be performed at a 2-sided significance level of 0.05, unless otherwise 
specified. All interval estimation will be reported using 2-sided 95% confidence intervals (CIs).
Statistical inference on the primary endpoint, PFS, at interim and final analysis will be conducted 
at 1-sided significance level of 0.025, under group sequential testing design per O’Brien-Fleming 
boundaries, as specified in Section 3.
Testing of Secondary Endpoints
The secondary endpoints are to be tested sequentially at the nominal 0.05 significance level (2-
sided). The order of these endpoints is as follows:
1.
ORR
2.
OS
3.
MRD negative rate
4. Time to improvement in FACIT fatigue score
5. Rate of sustained hemoglobin improvement 
6. Rate of sustained platelet improvement
A secondary hypothesis will be tested if and only if the primary hypothesis is rejected along with 
all the secondary hypotheses that precede it.
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5.1.2.
Data Handling Rules
Unless specified otherwise, missing values will not be imputed.  
5.1.3.
General Analysis Considerations
Descriptive statistics and subject listings will be used to summarize the data.  For continuous 
variables, number of observations, means, standard deviations, medians, and ranges will be used.  
For discrete variables, frequency will be summarized.  For time-to-event variables, Kaplan-Meier 
estimates will be provided. 
Unless otherwise specified, disease progression and disease response will be based on 
assessments from an IRC, according to principles adapted from 2008 International Working 
Group for CLL (IWCLL) Guidelines (Hallek 2008) [3]. Disease evaluations will include: 
physical examination, CBC, computed tomography (CT) scan of the neck, chest, abdomen, and 
pelvis, and bone marrow aspirate. Criteria for response categories, as well as the process and 
convention of the IRC are detailed in a separate IRC charter.
5.2.
Primary Efficacy Endpoint
5.2.1.
Progression Free Survival (PFS) based on IRC
The primary efficacy endpoint, PFS, is defined as the time between the date of randomization 
and the date of disease progression (as assessed by the IRC) or date of death due to any cause, 
whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to 
documented PD or death. The primary efficacy analysis will be based on the PFS determined by 
IRC and will be performed on the ITT population.
5.2.2.
Primary Analysis Methods for PFS
Kaplan-Meier method will be used to estimate the distribution of PFS for each treatment group. 
The median PFS and its 95% CI will be provided. PFS rate with 95% CI at selected landmark 
points will be provided.  The stratification factors to be used in the analysis are: refractory to 
purine analog therapy (yes vs. no), and number of prior lines of therapy (1 vs. >1) used in the 
randomization. The treatment effect of ibrutinib compared to placebo based on PFS will be 
tested with a stratified log-rank test. The hazard ratio for ibrutinib relative to placebo and its 
associated 95% CI will be calculated based on the stratified Cox proportional hazards model by 
the stratification factor at randomization.  
For primary analysis of PFS, all disease progression (assessed by IRC) or death documented in 
the study will be considered as events, including those that occur after subsequent antineoplastic 
therapy is started or study medication is discontinued. Subjects who are progression free and 
alive will be censored at the date of last disease assessment. Subjects with no baseline or any 
postbaseline disease assessment will be censored at the date of randomization.
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5.2.3.
Sensitivity Analysis of PFS
Sensitivity analysis will be performed for PFS as follows:
1. Use of subsequent antineoplastic therapy prior to documented PD or death 
Two alternative censoring rules will be performed for subjects who start subsequent 
antineoplastic therapy prior to first documentation of disease progression or death due to any 
cause: 
a. subjects will be considered to have had a PFS event at the initiation of subsequent 
therapy.
b. subjects will be censored at the last disease assessment showing no evident of PD 
before the use of subsequent antineoplastic therapy.
2. Disease assessment follow up: Subjects will be censored at the last disease assessment if they 
progress or die after missing ≥2 planned disease assessment visits. 
3. Non-stratified log-rank test and non-stratified Cox regression model will be conducted for 
PFS based on IRC assessment in ITT population. The reason for censoring will be 
summarized for PFS.
4. PFS based on PD assessed by investigators: For this sensitivity analysis, the same censoring 
rules and analysis methods used for primary analysis of IRC reported PFS will be used.  The 
concordance rate between the IRC-determined PFS and investigator-determined PFS will be 
evaluated. The number and percentage of PD events and censored cases determined by 
investigator and by IRC will be cross-tabulated.
5.2.4.
Subgroup Analysis of PFS
Subgroup analysis will be performed for the selected potential prognostic variables (as listed in 
Section 2.9) to assess the consistency and robustness of the treatment benefit for PFS. The non-
stratified log-rank test analysis method for PFS will be used for each of the subgroup analysis. 
Median PFS with 95% CI, and hazard ratio between the two treatment groups within each 
subgroup and their 95% CI will be calculated using non-stratified Cox regression model. 
Subgroup analysis will be presented graphically in forest plot.  
5.3.
Secondary Endpoints
5.3.1.
Overall Survival
Overall survival is defined as the time from date of randomization to date of death from any 
cause.  For primary analysis of OS, all deaths documented in the study will be considered as 
events, including those that occur after the date of first dose of ibrutinib for crossover subjects. 
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Survival time of living subjects will be censored on the last date a subject is known to be alive or 
lost to follow-up.
Overall survival will be analyzed using the same analysis methods as used for primary analysis 
of PFS (Section 5.2.2). 
The same subgroup analysis used for PFS will be performed for OS if the number of events 
within each subgroup is sufficient.
5.3.2.
Sensitivity Analysis of Overall Survival
Sensitivity analysis will be performed for OS as follows:
1. Which censor subject at the time of crossover for placebo patients;
2. Which censor ibrutinib patients at subsequent therapy.
5.3.3.
Overall Response Rate
Overall response rate is defined as the proportion of subjects achieving a best overall response of 
either CR, CRi, nPR, or PR as evaluated by IRC.
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. 
Overall response rate will be estimated according to the crude proportion of confirmed 
responders (PR or better) based on the best overall response and summarize by treatment arm. 
Overall response rate will be compared between treatment arms using Cochran-Mantel-Haenszel 
(CMH) chi-square test, adjusted for the two randomization stratification factors. Logistic 
regression analysis will also be performed to estimate an odds ratio and its associated 95% CI 
between the 2 treatment groups. 
Subjects who achieved PR by all parameters with the exception of reduction in ALC are 
considered PR with lymphocytosis (PRL). The ORR including PRL (per IRC assessment) will be 
summarized. 
For overall response rate based on investigators’ assessment, same analysis methods used for 
IRC reported overall response will be used. 
Subgroup analysis for ORR may be performed if the number of responders within each subgroup 
is sufficient.
5.3.4.
Rate of Minimal Residual Disease-Negative Response 
Rate of MRD-negative response is defined as the proportion of subjects who reach MRD-
negative disease status (<1 CLL cell per 10,000 leukocytes), as assessed by flow cytometry of a 
bone marrow aspirate/biopsy or peripheral blood sample. For subjects with both bone marrow 
aspirate/biopsy and peripheral blood sample available at the same visit, the bone marrow 
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aspirate/biopsy shall take precedence.   All randomized subjects will be included in this analysis.
Subjects with missing MRD data are considered non-responders. Chi-square test will be used for 
rate of MRD-negative response. Fisher’s exact test may be used if the rate in any treatment group 
is small.
5.3.5.
Sustained Hematologic Improvement 
Sustained hematologic improvement is defined as hematological improvement that is sustained 
continuously for ≥56 days without blood transfusion or growth factors:

Hemoglobin >11 g/dL if baseline ≤11 g/dL or increase ≥2 g/dL over baseline; 

Platelet counts >100 × 109/L if baseline ≤ 100 × 109/L or increase ≥50% over 
baseline;
Proportion of subjects achieving sustained hematological improvement will be summarized by 
treatment group. This proportion will be compared for the two treatment arms using chi-square 
test.
The analysis will be conducted on 1) ITT subjects 2) ITT subjects with cytopenia(s) at baseline. 
Subjects with cyctopenia(s) at baseline without any post-baseline hematologic assessment will be 
considered as having no improvement. 
5.3.6.
5.3.7.
Disease-Related Symptom Improvement 
The most common disease-related symptoms associated with CLL/SLL include fatigue, weight 
loss, fevers, night sweats, and abdominal discomfort/splenomegaly. Disease-related symptoms
will be assessed by investigator according to common terminology criteria for adverse events 
(CTCAE) criteria. Descriptive summary and shift tables will be provided at each scheduled time 
point.
5.4.
Other Efficacy Endpoints

Number of subjects with subsequent antineoplastic therapy will be summarized by therapy 
type. Listing of subjects with subsequent antineoplastic therapy will also be provided.

Time-to-next therapy and time-on-next therapy will be analyzed for subjects who have 
started subsequent antineoplastic therapy.  Time-to-next therapy is defined as the time from 
the date of randomization to the start date of any subsequent antineoplastic therapy. Time-
on-next therapy is calculated as the time interval between the start of subsequent 
antineoplastic therapy and the end of subsequent antineoplastic therapy (progressive disease, 
death, or the start of next line of subsequent therapy, whichever is earlier). Data will be 
censored at the last visit date, for subjects still on the same subsequent therapy at the clinical 
cutoff.
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
PFS2 will be analyzed for ITT subjects.  It is defined as the time interval between the date of 
randomization and date of event, which is defined as progressive disease as assessed by 
investigator that starts after the next line of subsequent antineoplastic therapy (including 
cross-over to ibrutinib), death from any cause, or the start of the second subsequent
antineoplastic therapy if no progressive disease is recorded. Those who do not receive 
subsequent therapy or do not experience the event as specified above are censored at the last 
disease assessment without second disease progression.

Beta2-microglobulin, Serum immunoglobulin (IgA, IgG, and IgM) will be descriptively 
summarized.
6.
SAFETY
Safety will be analyzed using the incidence and severity of AEs, laboratory tests, and 
electrocardiogram (ECG) measurements. Unless specified otherwise, all safety analyses will be 
based on the safety analysis set. Descriptive statistics will be reported for all safety data.  
Inferential statistics are not planned to be performed on safety data.
The baseline value for safety analysis is defined as the value collected at the time closest to and 
prior to the start of study medication.
Unless otherwise stated, safety data will be summarized by treatment arm as treated.
6.1.
Adverse Events
Table 4. Summary of Adverse Event Analyses to be Performed
Category
Analysis
Sorted By
Cut off
Drug-
Related 
TEAE
General
Overall summary

TEAEs
SOC+ PT+ toxicity grade;
PT+ toxicity grade
10%, 5%

Serious TEAEs
SOC+ PT + toxicity grade;
PT+ toxicity grade
2%

Grade 3 or worse TEAE
PT+ toxicity grade
2%

TEAEs leading to treatment 
discontinuation (ibrutinib/placebo, 
BR)
PT + toxicity grade

TEAEs leading to death
PT + toxicity grade
TEAEs leading to dose
modification or modification 
(ibrutinib/placebo, BR)
PT + toxicity grade
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Category
Analysis
Sorted By
Cut off
Drug-
Related 
TEAE
AEs of clinical interest
(Hemorrhagic events)
PT + toxicity grade
Other safety observations (e.g. 
other malignancies, eye disorder)
PT + toxicity grade
Deaths within 30 days of last dose Reason for death
Atrial Fibrillation and Atrial 
Flutter: overall summary 
Subgroup
Overall summary
TEAEs
SOC+ PT+ toxicity grade
Crossover Period
Overall summary

TEAEs
SOC+ PT+ toxicity grade

Serious TEAEs
SOC+ PT + toxicity grade
Exposure adjusted 
incidence rate 
Overall summary
TEAEs
SOC+ PT+ toxicity grade;
PT+ toxicity grade
1 per 100 
patient 
month
Serious TEAEs
SOC+ PT + toxicity grade;
PT+ toxicity grade
0.1 per 100 
patient 
month
6.1.1.
All Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). These coded AE terms are referred to 
as preferred terms (PT); classification into System Organ Class (SOC) is a result of the coding 
process.
Treatment-emergent AEs (TEAEs) are defined as 1) those that occur in TEAE period as defined 
in Section 2.8; 2) present before first dose, but worsened in toxicity grade during treatment; 3) 
had missing start date and its end date is during the treatment; 4) was a drug-related event. Drug-
related AEs are those assessed by investigator as being possible, probable or very likely related 
to study drug. To determine TEAE, partially missing AE start dates will be imputed according to 
the rules stated in Section 2.7.
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For each TEAE, the percentage of subjects who experience at least 1 occurrence of the given 
event will be summarized. Tables will be sorted by frequency in incidence (the highest to lowest 
incidence). 
For subjects using CYP3A inhibitor during treatment-emergent period, all TEAEs will be 
summarized by SOC, PT, maximum severity, any CYP3A inhibitor (Yes vs No), and strong 
CYP3A inhibitor (Yes vs No). 
For subjects who received cross-over ibrutinib therapy, all TEAEs collected in the treatment-
emergent period of cross-over ibrutinib therapy will be summarized.
6.2.
Adverse Events of Clinical Interest and other safety observations
Hemorrhagic events will be identified by hemorrhage Standardized MedDRA Query [SMQ] 
excluding laboratory terms and be tabulated. Major hemorrhage is a subset of hemorrhagic 
events which are grade ≥ 3 or serious or belong to central nervous system (CNS)
hemorrhage/hematoma.  
Other malignancies: are defined as new malignant tumors including solid tumors, skin 
malignancies and hematologic malignancies and are to be reported for the duration of study 
treatment and during any protocol-specified follow-up periods including post-progression 
follow-up for overall survival.
Adverse events of interest and other safety observations will be summarized by treatment arms.
6.3.
Deaths
A summary of the number of deaths during the treatment phase and up to 30 days after last dose 
will be provided, along with the primary cause of death. In particular, frequencies of deaths due
to study treatment-related adverse events will also be reported. A death is study medication-
related death if the primary cause is a drug related AE.
6.4.
Exposure-Adjusted Incidence Rates
6.4.1.
Restriction on the First Event
To adjust for unequal lengths of study treatment duration among subjects, and potentially 
between treatment groups, exposure adjusted incidence rate may also be summarized if the 
median treatment duration of one group is 20% longer than that of the other group.
The analysis restricts on the occurrence of the first event per subject and ignores the existence of 
later (multiple) events as these cannot be assumed to occur independent of previous events (e.g.
subjects suffering from infections may have in general a higher risk of having other 
complications and may even have a higher risk of getting other infections). For this reason the 
exposure-adjusted incidence rate (EAIR) should be interpreted as 'rate until the first event 
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occurs'. Rates estimated from several subjects can be averaged on the level of a PT, of an SOC, 
or on a global level.
6.4.2.
Duration of Exposure: Censored & Non-censored
The EAIR for a subject is derived from the duration of treatment exposure for that subject. When 
averaging incidence rates, a subject's duration of exposure is given either by 
a.
time to the earliest onset of the TEAE (non-censored data), or
b.
total duration of treatment, for subjects who did not experience the AE in question (censored 
data). 
Depending on whether a subject has an AE or not, the duration of exposure enters the 
denominator in its non-censored or censored form, respectively.
6.4.3.
Incidence Rate per Subject
The incidence rate for a specific event of a subject is the reciprocal of time t when the first event 
occurs:
 =

 .
6.4.4.
Average EAIR per Preferred Term
The EAIR for a specific PT is an average over all subjects as described before, i.e.
 ! =
∑
!#$#%&,
(
)*
∑
%&,
(
)*
, 
whereby 
a.
the TEAE enters the sum in the nominator unweighted (TEAEi =1, otherwise TEAEi =0), and
b.
the duration of exposure enters the denominator as:
 = +    , if occurring -non-censored data.
  	 	  	 if no event occurs (censored data)
6.4.5.
Average EAIR per SOC
The average EAIR per SOC considers the first event per subject per SOC only, and only one
(the corresponding) exposure time in the denominator:
/01 =
∑
!#$#234,
(
)*
∑
234,
(
)*
,
Note: This EAIR is an incidence rate per SOC.
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6.4.6.
Average EAIR on a Global Level
The average EAIR on a global level considers the overall first event per subject only, and only 
one (the corresponding) exposure time in the denominator:
567896 =
∑
!#$#
(
)*
∑

(
)*
,
whereby TEAEi represents the first TEAE among all TEAEs of subject i and ti as before 
(time when TEAE occurs (non-censored data) or total duration of treatment if no event occurs 
(censored data).
6.5.
Clinical Laboratory Tests
Laboratory data of hematology and serum chemistry up to 30 days after last dose or the end of 
treatment visit date, whichever is later, will be reported in SI units.
For hemoglobin, absolute neutrophil count (ANC), and platelets, toxicity will be assessed by the 
grading scale for hematologic toxicity in CLL studies in the IWCLL 2008 guidelines. Other 
laboratory results will be graded according to NCI-CTCAE version 4.03. Note that toxicity 
grading for creatinine increase will be based on the NCI CTC v4.03 criteria, but limited only to 
the part based on the upper limit of normal (ULN), the other part, that is based on change from 
baseline, will not be used for toxicity grading. Generic normal ranges will be applied whenever 
reference ranges are not available. 
The following laboratory tests will be analyzed: 

Hematology: hemoglobin, white blood cell (WBC), ANC, absolute lymphocyte count 
(ALC), and platelets

Coagulation (screening only): Prothrombin international normalized ratio (INR),
activated partial thromboplastin time (aPTT)

Chemistry: alkaline phosphatase, ALT, AST, bilirubin (total), creatinine, creatinine 
clearance (CrCl), LDH, magnesium, potassium, sodium, and uric acid
Descriptive statistics (mean, standard deviation, median and range) will be calculated for the raw 
data and for their changes from baseline at each time point of assessment as well as for the 
changes from baseline to the last value. Parameters will be summarized by toxicity grade. 
Change from baseline to the worst grade during the treatment will be provided as shift tables for 
selected parameters. In addition, treatment-emergent worsening in toxicity grade will be 
summarized for selected hematology and chemistry parameters. 
Liver function abnormality by Hy’s Law: For subjects with any elevated AT (AST or ALT) of 
>3xULN, ALP <2xULN, and associated with an increase in bilirubin (total) 2xULN, a listing 
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for all subjects with all such records will be provided and a summary table of the number of such 
subjects will be provided by treatment arm.
The frequencies of abnormal treatment emergent uric acid will be summarized by treatment arm.
6.5.1.
Creatinine Clearance
Creatinine clearance (CrCl) is calculated using the Cockroft-Gault formula:
            
   for males, the factor is 1 instead of 0.85
6.5.2.
Analysis of Lymphocytosis
For all subjects with baseline and any post-baseline ALC measurements, a summary of peak 
ALC values will be provided by treatment arm.
Lymphocytosis is defined as an elevation in ALC of ≥50% compared to baseline and to 
≥5x109/L (5,000/μL) at a post-baseline assessment. The number of subjects with at least one 
occurrence of lymphocytosis will be summarized. For subjects with lymphocytosis, resolution of 
lymphocytosis is defined as 1) a decrease of ALC value to the baseline level or lower, or 2) an 
achievement of ALC value that is below 5x109/L (5,000/μL), whichever occurs first.
The following analyses will be conducted for subjects with lymphocytosis by treatment arm: 

ALC at peak and time to peak ALC within the time period from the first dose of study drug 
to 9 months of first study treatment (Study day 270), 30 days following the last dose of 
study drug or initiation of subsequent antineoplastic therapy, whichever the earliest, 

Time to lymphocytosis (TTL) is defined as the time from first dose date of study treatment
to the first post-baseline ALC which meets the lymphocytosis criteria and will be 
summarized descriptively for subjects who developed lymphocytosis.

Duration of lymphocytosis (DOL) is defined as the duration of time from the earliest date on
which the ALC value met the lymphocytosis criteria at a post-baseline assessment to the 
earliest date on which a subsequent ALC value met the resolution criteria. Subjects who 
have developed lymphocytosis but not recovered will be censored at the last available ALC 
measurements at or prior to initiation of subsequent antineoplastic therapy.
6.6.
Electrocardiogram
QT prolongation and other clinically significant ECG abnormalities will be summarized and 
listed. Descriptive statistics will be calculated for the ECG parameters at baseline. 
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The ECG parameters that will be summarized are heart rate, RR interval, QT interval, and QTc. 
The QTc will be computed using Bazett’s correction, i.e., QTcB = :,/√, and Fridericia’s 
correction, i.e., QTcF = :,/√
=
.
All treatment-emergent abnormal findings will be tabulated, displaying the number of subjects 
with abnormal findings after dosing up to the end (Day 28) of the last cycle. An abnormal 
finding is considered to be treatment-emergent if it occurred during treatment and up to 30 days 
after the last dose.
7.
PATIENT-REPORTED OUTCOMES
Patient-reported outcomes will be measured by 4 questionnaires as described below. Refer to the 
Study PCI-32765CLL-3001 protocol for samples of PRO scales and data collection schedule.
7.1.1.
EORTC QLQ-C30
EORTC-QLQ-C30 includes 30 separate items resulting in 5 functional scales (physical 
functioning, role functioning, emotional functioning, cognitive functioning, and social 
functioning), 1 Global Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and 
pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties). Scores will be derived using validated scoring algorithms according to EORTC 
QLQ-C30 Scoring Manual (3rd Edition, 2001). EORTC QLQ-C30 improvement/worsening is 
defined as ≥10 points for each assessment post baseline. 
7.1.2.
EORTC QLQ-CLL 16
The EORTC QLQ-CLL 16 is a 16-item disease-specific module that comprises 5 domains of 
patient-reported health status important in CLL. There are three multi-item scales that include 
fatigue (2 items), treatment side effects and disease symptoms (8 items), and infection (4 items), 
and 2 single-item scales on social activities and future health worries. 
7.1.3.
EQ-5D-5L
The EQ-5D is a 5-item questionnaire and a “thermometer” 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 ordinal numbers. EQ-5D 
improvement/worsening is defined as ≥7 points for each assessment post baseline.
The scores for the 5 categorical dimensions will be 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 
in this study. 
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7.1.4.
FACIT-Fatigue
The FACIT-Fatigue Scale measures fatigue severity and impact on daily activities. It includes 13 
items that assess tiredness, weakness and difficulty conducting usual activities due to fatigue. 
Scores range from 0 to 52 with high scores indicating less fatigue.  FACIT 
improvement/worsening is defined as ≥3 points change for each assessment post-baseline.
7.1.5.
Exploratory analyses with Patient-reported outcome Questionnaires
In addition to the planned analyses on the domains and scales from each of the patient-reported 
outcome questionnaires, exploratory analyses at the individual item level will be conducted to 
better understand domains that show significant effects or trends toward significance.  Since the 
EORTC QLQ-CLL 16 is disease-specific, it is anticipated that most of the exploratory individual 
item analyses will be conducted on that questionnaire, including, but not limited to the following 
items:  “Did you have night sweats?”, “Did you feel lethargic?”, “Have you felt ‘slowed 
down’?”, “Were you limited in planning activities, for example meeting friends, in advance?”.  
However, individual item analyses may also be conducted on the EQ-5D-5L, EORTC QLQ-C, 
FACIT-Fatigue, depending upon the pattern of findings at the domain or scale level.  In each 
case where an individual item analysis is conducted, the analytic approach will replicate that 
described for the scale and domain scores.
7.1.6.
Analysis Methods
Descriptive statistics (number of observations, mean, standard deviation, median, minimum, 
maximum) at baseline and each post-baseline time point is reported by treatment group for 
FACIT-Fatigue total score, each scale of EORTC QLQ-C30 and EORTC QLQ-CLL 16, and EQ 
5D visual analogue scale and weighted utility score.  These descriptive statistics will also be 
summarized by the response categories contributing to the ORR. A responder analysis and 
presentation by minimal clinical difference will also be provided. 
Compliance
Compliance rates defined as the number of questionnaires received as a percentage of the 
number expected per protocol-specified collection schedule are assessed for FACIT-Fatigue, 
EORTC QLQ-C30, EORTC QLQ-CLL 16, and EQ-5D. 
Mixed Model for Repeated Measures
For each of the PRO measures of interest, a mixed-effects model with repeated measures 
(MMRM) analysis is conducted estimating change from baseline at each time point. ITT subjects 
who have a baseline value and at least 1 post-randomization value are included in the analysis. 
For each scale, change from baseline is fitted to a mixed-effects model including subjects as a 
random effect, and baseline value, treatment, time, treatment-by-time interaction, and 
randomization stratification factors as fixed effects. 
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Time to Improvement and Deterioration Analysis
Using a threshold value for improvement and deterioration specific to the PRO measures of 
interest, time to improvement and time to deterioration will be compared between treatment 
groups in ITT subjects. Subjects who have not experienced event at the time of analysis will be 
censored on the last known date without event.  Subjects with no on-study assessment or no 
baseline assessment will be censored at date of randomization.
Distributions of time-to-event variables will be estimated using the Kaplan-Meier product-limit 
method. Median times to event with 2-sided 95% confidence intervals will be estimated. The 
stratified log-rank test accounting for stratification factors will be used for treatment comparison. 
A stratified Cox proportional-hazards model will provide estimates of hazard ratios with 95% 
confidence intervals.  
Analysis Visits
To determine the scheduled time points, all PRO scores are to be assigned to a particular time 
window for a scheduled time point based on the rules presented in Table 5.  In the case that more 
than 1 score is found with a time window, the score closest to the window center will be used in 
the analysis. In the case that there are 2 values that are equidistant from the center, the value 
prior to the center will be used.
Details for target date for each scheduled visit and time interval between scheduled visits are 
provided in the table below:
Table 5. Visit Windows for PRO Assessments
EORTC QLQ-C30 and EQ-5D-5L
EORTC QLQ-CLL 16 and FACIT-Fatigue
Analysis visit (cycle)
Start
Target
End
Baseline
-30
1
1
Cycle 3
2
57
85
Cycle 5
86
113
141
Cycle 7
142
169
211
Cycle 10
212
253
295
Analysis visit (cycle)
Start
Target
End
Baseline
-30
1
1
Cycle 2
2
29
57
Cycle 4
58
85
113
Cycle 6
114
141
169
Cycle 8
170
197
225
Cycle 10
226
253
295
All Scales
Analysis visit (cycle)
Start
Target
End
Cycle 13
296
337
379
Cycle 16
380
421
463
Cycle 19
464
505
547
Cycle 22
548
589
631
Cycle 25
632
673
715
Cycle 28
716
757
799
Cycle 31
800
841
883
Cycle 34
884
925
967
Cycle 37
968
1009
1051
Each cycle is 28 days
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8.
PHARMACOKINETICS AND PHARMACODYNAMICS ANALYSIS
Details of analysis plan in PK/PD and results will be presented in a separate report.
9.
BIOMARKER ANALYSIS
Details of analysis plan in biomarker and results will be presented in a separate report.
10.
Changes to Protocol Specified Analyses
The following analyses are different from those described in the protocol:   

Hemoglobin >11 g/dL if baseline ≤11 g/dL or increase ≥2 g/dL over baseline; 

Platelet counts >100 × 109/L if baseline ≤ 100 × 109/L or increase ≥50% over 
baseline;

The term used for the secondary objective MRD-negative remissions is changed to 
MRD-negative response based on clinical interpretation. 

The definition for major hemorrhage is updated in alignment with the related post 
marketing commitment on major bleeding and allows consistent analysis for the 
ibrutinib clinical development program. The updated definition is based on searching 
and subtyping grade ≥ 3 or serious or central nervous system (CNS) 
hemorrhage/hematoma by hemorrhage SMQ excluding laboratory terms. The following 
types of events in protocol definition were removed because they are grade ≥ 3 or serious 
hemorrhage events according to NCI CTCAE criteria: intraocular bleeding causing loss 
of vision, the need for a transfusion of two or more units of red cells or an equivalent 
amount of whole blood, hospitalization or prolongation of hospitalization. Intracranial 
hemorrhage in protocol is included in the CNS hemorrhage/hematoma as a component 
of major hemorrhage.
11.
REFERENCES
1.
Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients with relapsed and/or 
refractory Chronic Lymphocytic Leukemia: A multicenter phase II trial of the German Chronic Lymphocytic 
Leukemia Study Group. J Clin Oncol. 2011;29:3559-3566.
2.
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549-556.
3.
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National 
Cancer Institute-Working Group 1996 guidelines. Blood. 2008; 111:5446-5456.
4.
Branson M and Whitehead J. Estimating a treatment effect in survival studies in which patients switch 
treatment. Stat Med 2002; 21:2449-2463. 
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12.
Appendix 1: Additional Exploratory Analysis to Support HEMAR
HEMAR analyses will be presented in a separate report.
12.1.
Subgroup Definition
The dataset will also be analyzed by a revised definition of refractory and relapse whereby 
refractory is defined as disease progression ≤ 6 months and relapse is defined as disease 
progression >6 months.
Based on this definition the below subgroup analysis will be performed for selected variables as 
described in sections 5.2 for the primary endpoint; 5.3 for secondary endpoints; section 6 for 
safety endpoints and section 7 for patient-reported outcomes.
Subgroup
Definition of Subgroup
Analysis Type
Age
<65, ≥65  
D, E, S
Sex
Male, Female
D, E, S
Race
White, Non-White
D, E, S
Geographic region
North America, Europe, Latin 
America, and Asia
D, E, S
Diagnosis 
CLL, SLL
D, E, S
Rai Stage at screening 
Stage 0-II, III-IV
E
Failure to respond to a purine 
analogue or a recurrence of disease 
after purine analog therapy 
No prior PA, within12 months,   12 
months
E
Baseline ECOG
0, 1 
E
Bulky Disease 
Yes (LDi 5 cm), no (LDi <5 cm),
E
Chromosome 11q Deletion
Yes, no
E
Elevated LDH at Baseline
No (<350 U/L),  Yes (350 U/L)
E
Cytopenias at Baseline
Yes, no
E
Serum β2 –microglobulin 
≤3.5 mg/L, > 3.5 mg/L
E
IgVH 
Mutated, Unmutated
E
ZAP-70
Elevated, Not Elevated 
E
CD38
Positive ( ≥30), negative (<30) 
E
complex karyotype
Yes, no
E
Refractory to purine analog therapy as 
recorded in IWRS 
Yes, no
E
Prior lines of therapy as recorded in 
IWRS
1,  >1
E
Concomitant use of any CYP3A 
inhibitor 
Yes, No
S
Concomitant use of strong CYP3A 
inhibitor 
Yes, No
S
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Subgroup
Definition of Subgroup
Analysis Type
Cytopenia is defined as yes if platelet count ≤ 100,000/uL, Hgb ≤ 11g/dL, or ANC ≤ 1500/uL is 
observed.
analysis type D= demographic and baseline disease characteristics
analysis type E= efficacy (PFS, OS, ORR)
analysis type S= safety (adverse events) 
ECOG= Eastern Cooperative Oncology Group; IgVH= immunoglobulin variable heavy gene;
IWRS= Interactive Web Response System; LDH= lactic acid dehydrogenase; LDi=longest 
diameter.
For all p-interaction values ≤0.20 detailed information on each endpoint will be provided. 
12.2.
Further endpoints for analyses (OR, RR, RD)

Disease-related symptoms that started or worsened from the first dose
o
Fatigue
o
Weight loss
o
Anorexia
o
Night Sweats
o
Abdominal Pain
o
Fever
12.2.1.
Subgroups for further endpoints from market access analysis
Endpoints of interest for market access will be analyzed also by pre-specified subgroups as 
described below:
Subgroup
Definition of Subgroup
Analysis Type
Age
<65, ≥65  
D, E, S
Sex
Male, Female
D, E, S
Race
White, Non-White
D, E, S
Geographic region
North America, Europe, Latin 
America, and Asia
D, E, S
Diagnosis 
CLL, SLL
D, E, S
Rai Stage at screening 
Stage 0-II, III-IV
E
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Subgroup
Definition of Subgroup
Analysis Type
Refractory to prior purine analogue 
therapy 
Refractory to prior purine analogue 
therapy, Yes  (defined as no response 
or failure within12 months),   No 
Refractory to prior purine analogue 
therapy (Response lasting 12 
months)
E
Baseline ECOG
0, 1 
E
Bulky Disease 
Yes (LDi 5 cm), no (LDi <5 cm),
E
Chromosome 11q Deletion
Yes, no
E
Elevated LDH at Baseline
No (<350 U/L),  Yes (350 U/L)
E
Cytopenias at Baseline
Yes, no
E
Serum β2 –microglobulin 
≤3.5 mg/L, > 3.5 mg/L
E
IgVH 
Mutated, Unmutated
E
ZAP-70
Elevated, Not Elevated 
E
CD38
Positive ( ≥30), negative (<30) 
E
complex karyotype
Yes, no
E
Refractory to purine analog therapy as 
recorded in IWRS 
Yes, no
E
Prior lines of therapy as recorded in 
IWRS
1,  >1
E
Concomitant use of CYP3A inhibitor 
Yes, No 
S
Concomitant use of strong CYP3A 
inhibitor 
Yes, No 
S
Cytopenia is defined as yes if platelet count ≤ 100,000/uL, Hgb ≤ 11g/dL, or ANC ≤ 1500/uL is 
observed.
analysis type D= demographic and baseline disease characteristics
analysis type E= efficacy (PFS, OS, ORR)
analysis type S= safety (adverse events) 
ECOG= Eastern Cooperative Oncology Group; IgVH= immunoglobulin variable heavy gene;
IWRS= Interactive Web Response System; LDH= lactic acid dehydrogenase; LDi=longest 
diameter.
12.3.
Cross-over correction for the Overall Survival Endpoint
The following constitutes an example for a IPCW-correction on the primary endpoints overall 
survival (OS) and progression-free survival (PFS). 
Database and variables
Database with 485 subjects providing information on overall and progression-free survival with 
variables
1. TIME_TO_DEATH, censor variable STATUS_DEATH 
2. TIME_TO_PFS, censor variable STATUS_PFS
Covariates considered by the IPCW approach: 
1. AMLtype (Acute Myeloid Leukemia) 
2. ECOG (Cooperative Oncology Group performance status) 
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3. AGE (Age) 
4. BMBLAST (Bone Marrow Blasts, % of abnormal leukemia cells) 
5. RACE 
6. GENDER 
7. CGRISK (Cytogenetic risk, based on chromosomal abnormalities) 
8. TRTMNT (2 Treatment arms) 
Tables delivered
Table 2.1: Overall survival, ITT analysis set 
Table 2.2: Progression-free survival, ITT analysis set 
IPCW approach and modification
Step 1: 
Create a panel data with monthly records per patient + new variable: cross over 
y/n per record. The panel data contain follow-up times from randomization until failure 
(death) or informative censoring (crossover) in monthly intervals. 
Step 2: 
Multiple logistic regression: model the probability to cross over dependent on 
variables assumed to cause informative censoring (see Section 0). The inverse of the 
prediction yields the weights for Step 3.
Step 3: 
Weighted Cox regression (alternatively a parametric approach: logistic, 
exponential, …)
Applying the IPCW method as described by Robins and Finkelstein (2000) on the present data is 
complicated by the following two reasons:
The assumption of proportional hazards required by the Cox regression (Step 3) is partially 
negated in the present data because the survival curves of the treatment arms cross (see CSR 
Figures 3 to 7, p. 90 and following pages).
Computing CIs from methods involving sample size inflating procedures like inverse 
probability weighting requires sophisticated approaches like, for instance, bootstrap 
procedures.
Considering these two points the original IPCW approach has been modified in Step 3 by 
replacing the weighted Cox regression by a weighted logistic regression modeling the time-
dependent probability of OS and PFS. This corresponds to a parametric approach based on the 
logistic model as the regression is applied on the panel data. Thus, the modified IPCW approach 
presented here involved the following 3 steps:
Step 1: 
Create a panel data with monthly records per patient + new variable: cross over 
y/n per record. 
Step 2: 
Multiple logistic regression to estimate the time-dependent probability to cross 
over dependent on covariates AMLtype, ECOG, AGE, BMBLAST, RACE, GENDER, 
CGRISK, and TRTMNT.
Step 3: 
Logistic regression on panel data yielding a time-dependent odds ratio, interpreted 
as a hazard ratio. 
Step 4: 
The results of logistic regression, Step 2, are
Effect
Estimate
Lower 
95% Upper 
95% 
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CL
CL
AMLTYPE 
[de 
novo 
vs 
secondary]
0.779
0.719
0.845
ECOG [0-1 vs 2]
1.491
1.359
1.637
AGE
0.922
0.915
0.929
BMBLAST [<= 30 vs >30]
0.915
0.839
0.998
RACE [non-white vs white]
1.189
1.064
1.328
SEX [female vs male]
1.320
1.221
1.426
CGRISK [intermediate vs poor]
1.456
1.342
1.580
month
1.059
1.055
1.063
Treatment [Dacogen vs TC]
0.788
0.730
0.850
Conclusions & recommendations
The hazard ratios of 0.702 and 0.659 for OS and PFS, respectively, and their significant CIs 
resulting from the modified IPCW analysis performed here can support the hypothesis of a 
treatment benefit in favor of Dacogen with respect to OS and PFS. This, however, should be 
considered in light of the following two restrictions, and leads to respective recommendations:
Possibility of overcompensation by weights
The weights resulting from Step 2 (logistic regression) adopt values of up to 60, as already 
described in the provided master thesis (see above, Section). This might revert the original 
intention to compensate for informative censoring into the opposite, i. e. into overcompensation 
of informative censoring, as shown for Weibull distributed survival times.
The present approach has reduced the risk of potential overcompensation by replacing the Cox 
regression by a logistic regression applied on panel data. The risk of overcompensation is 
reduced here because the weights modify the dispersion parameter of the binomial model 
underlying the logistic regression (in contrast to the Cox regression where the weights modify 
the location of the survival curves).
Recommendation: The present analysis could be complemented by non-parametric methods (e. 
g. Rank preserving structural failure time model, RPSFT) which do not depend on distribution 
assumptions and are less affected by weighting bias.
Modification of IPCW approach by parametric analysis
The Cox regression within the IPCW approach performed here (Step 3) has been replaced by a 
logistic regression. This is acceptable for the reasons outlined above. However, in contrast to the 
non-parametric Cox regression, the logistic regression is a parametric method based on the 
assumption that OS and PFS times follow a logistic distribution. Consequently, in the event that 
the logistic distribution is not the appropriate model for the distribution for times of OS and/or 
PFS, the present analysis has limited validity. On the other hand, as non-parametric methods 
based on a proportional hazards assumption also have limitations with respect to the present data 
(e.g. crossing of survival curves), the methodological spectrum for the current data set becomes 
narrow. 
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Recommendation: If a parametric approach should be avoided the aforementioned RPSFT 
method could become relevant for the analysis of these data in a twofold manner.
Final Statement
The IPCW method employed in this analysis is a powerful procedure for adjusting for non-
informative censoring (or switching of treatments), it is, however, not without its limitations. 
Nonetheless, the analysis appears to be supportive in the hypothesis that the true treatment effect 
is better than that observed in the ITT analysis.
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