A Randomized, Open-label, Phase 3 Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Subjects With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL).
Phase: PHASE3
Conditions: Leukemia, Lymphocytic, Chronic, B-Cell
Sponsor: Janssen Research & Development, LLC

1
Status: Approved,  Date: 19 December 2019
Janssen Research & Development *
Clinical Protocol
A Randomized, Open-label, Phase 3 study of the Combination of Ibrutinib plus Venetoclax 
versus Chlorambucil plus Obinutuzumab for the First-line Treatment of Subjects with 
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Protocol 54179060CLL3011; Phase 3
Amendment 4
JNJ-54179060 (ibrutinib)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout 
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information 
page that accompanies the protocol.
EudraCT NUMBER: 2017-004699-77
Status:
Approved
Date:
19 December 2019
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-149177930, 5.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03462719

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
2
Approved, Date: 19 December 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 16
Time and Events Schedules .................................................................................................................... 18
ABBREVIATIONS ...................................................................................................................................... 28
1.
INTRODUCTION................................................................................................................................ 30
1.1.
Chronic Lymphocytic Leukemia..................................................................................................... 30
1.2.
Treatment of Chronic Lymphocytic Leukemia ............................................................................... 30
1.3.
Ibrutinib........................................................................................................................................... 31
1.3.1.
Clinical Studies ........................................................................................................................... 32
1.3.1.1.
Clinical Pharmacokinetics........................................................................................................ 32
1.3.1.2.
Clinical Efficacy ....................................................................................................................... 32
1.3.1.2.1.
Ibrutinib Monotherapy and in Combination with Chemoimmunotherapy in CLL.................. 32
1.3.1.3.
Clinical Safety.......................................................................................................................... 33
1.4.
Venetoclax ..................................................................................................................................... 34
1.5.
Ibrutinib in Combination with Venetoclax in CLL ........................................................................... 35
1.6.
Overall Rationale for the Study...................................................................................................... 37
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 39
2.1.
Objectives and Endpoints .............................................................................................................. 39
2.2.
Hypothesis ..................................................................................................................................... 39
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 40
3.1.
Overview of Study Design.............................................................................................................. 40
3.2.
Study Design Rationale.................................................................................................................. 41
4.
SUBJECT POPULATION.................................................................................................................. 42
4.1.
Inclusion Criteria ............................................................................................................................ 42
4.2.
Exclusion Criteria ........................................................................................................................... 44
4.3.
Prohibitions and Restrictions ......................................................................................................... 45
5.
TREATMENT ALLOCATION ............................................................................................................ 46
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 46
6.1.
Treatment Arm A (Ibrutinib plus Venetoclax) Administration......................................................... 46
6.1.1.
Ibrutinib ....................................................................................................................................... 46
6.1.1.1.
Dosage and Administration ..................................................................................................... 46
6.1.1.2.
Ibrutinib Dose Modification ...................................................................................................... 47
6.1.1.2.1.
Ibrutinib Dose Modification for Subjects With Hepatic Impairment...................................... 48
6.1.2.
Venetoclax .................................................................................................................................. 48
6.1.2.1.
Dosage and Administration ..................................................................................................... 49
6.1.2.2.
Prophylaxis and Management of Tumor Lysis Syndrome....................................................... 50
6.1.2.3.
Venetoclax Dose Modification ................................................................................................. 52
6.2.
Treatment Arm B (Chlorambucil plus Obinutuzumab) Administration ........................................... 53
6.2.1.
Obinutuzumab ............................................................................................................................ 53
6.2.1.1.
Obinutuzumab Dosage and Administration............................................................................. 54
6.2.1.1.1.
Obinutuzumab Premedication.............................................................................................. 54

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
3
Approved, Date: 19 December 2019
6.2.1.2.
Obinutuzumab Dose Delays and Modifications....................................................................... 54
6.2.1.2.1.
Infusion Reactions................................................................................................................ 54
6.2.1.2.2.
Obinutuzumab Dose Delays ................................................................................................ 55
6.2.2.
Chlorambucil............................................................................................................................... 55
6.2.2.1.
Chlorambucil Dosage and Administration ............................................................................... 56
6.2.2.2.
Chlorambucil Dose Modifications ............................................................................................ 56
6.3.
Subsequent Therapy with Single-agent Ibrutinib ........................................................................... 57
7.
INTERVENTION COMPLIANCE....................................................................................................... 57
8.
CONCOMITANT THERAPY.............................................................................................................. 57
8.1.
Permitted Concomitant Medications .............................................................................................. 58
8.2.
Medications to be Used with Caution............................................................................................. 58
8.3.
Prohibited Concomitant Medications ............................................................................................. 58
9.
STUDY EVALUATIONS .................................................................................................................... 59
9.1.
Study Procedures........................................................................................................................... 59
9.1.1.
Overview..................................................................................................................................... 59
9.1.2.
Screening Phase ........................................................................................................................ 59
9.1.3.
Open-label Treatment Phase ..................................................................................................... 60
9.1.4.
Follow-up Phase......................................................................................................................... 61
9.1.5.
Subsequent Therapy Phase ....................................................................................................... 62
9.1.5.1.
Eligibility for the Subsequent Therapy Phase.......................................................................... 63
9.2.
Efficacy........................................................................................................................................... 63
9.2.1.
Evaluations ................................................................................................................................. 64
9.2.1.1.
Radiographic Imaging Assessments ....................................................................................... 64
9.2.1.2.
Definition of Measurable and Assessable Disease ................................................................. 64
9.2.1.3.
Bone Marrow Assessments..................................................................................................... 65
9.2.2.
Minimal Residual Disease Assessments.................................................................................... 65
9.2.3.
Response Categories ................................................................................................................. 66
9.2.4.
Patient-reported Outcomes ........................................................................................................ 68
9.3.
Pharmacokinetics........................................................................................................................... 69
9.3.1.
Pharmacokinetic Evaluations ..................................................................................................... 69
9.3.2.
Pharmacokinetic Analytical Procedures ..................................................................................... 70
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 70
9.4.
Biomarkers ..................................................................................................................................... 70
9.5.
Safety Evaluations ......................................................................................................................... 71
9.6.
Benefit-risk Evaluations.................................................................................................................. 73
9.7.
Sample Collection and Handling.................................................................................................... 74
10.
SUBJECT COMPLETION/ WITHDRAWAL...................................................................................... 74
10.1.
Completion ..................................................................................................................................... 74
10.2.
Discontinuation of Study Treatment............................................................................................... 74
10.3.
Withdrawal From the Study............................................................................................................ 74
10.4.
Withdrawal From the Use of Research Samples........................................................................... 75
11.
STATISTICAL METHODS................................................................................................................. 75
11.1.
Analysis Sets.................................................................................................................................. 75
11.2.
Sample Size Determination ........................................................................................................... 75
11.3.
Subject Information ........................................................................................................................ 76
11.4.
Efficacy Analyses ........................................................................................................................... 76
11.4.1.
Primary Endpoint ........................................................................................................................ 76
11.4.2.
Secondary Endpoints.................................................................................................................. 77
11.4.3.
PRO Endpoints ........................................................................................................................... 78
11.4.4.
Subsequent Therapy Evaluations............................................................................................... 78
11.5.
Pharmacokinetic Analyses............................................................................................................. 78
11.6.
Biomarker Analyses ....................................................................................................................... 78
11.7.
Safety Analyses ............................................................................................................................. 79

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
4
Approved, Date: 19 December 2019
11.8.
Benefit-Risk Analyses .................................................................................................................... 80
11.9.
Data Monitoring Committee ........................................................................................................... 80
12.
ADVERSE EVENT REPORTING ...................................................................................................... 80
12.1.
Definitions ...................................................................................................................................... 80
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 80
12.1.2.
Attribution Definitions.................................................................................................................. 81
12.1.3.
Severity Criteria .......................................................................................................................... 82
12.2.
Special Reporting Situations.......................................................................................................... 83
12.3.
Procedures..................................................................................................................................... 83
12.3.1.
All Adverse Events...................................................................................................................... 83
12.3.2.
Serious Adverse Events ............................................................................................................. 85
12.3.3.
Adverse Events of Special Interest............................................................................................. 86
12.3.4.
Other Malignancies..................................................................................................................... 86
12.3.5.
Eye-related Adverse Events ....................................................................................................... 86
12.3.6.
Pregnancy................................................................................................................................... 86
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 87
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 87
13.1.
Procedures..................................................................................................................................... 87
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 87
14.
STUDY INTERVENTION INFORMATION ........................................................................................ 87
14.1.
Physical Description of Study Interventions................................................................................... 87
14.2.
Packaging ...................................................................................................................................... 88
14.3.
Labeling.......................................................................................................................................... 88
14.4.
Preparation, Handling, and Storage............................................................................................... 88
14.5.
Intervention Accountability ............................................................................................................. 88
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 89
16.
ETHICAL ASPECTS ......................................................................................................................... 90
16.1.
Study-specific Design Considerations ........................................................................................... 90
16.2.
Regulatory Ethics Compliance....................................................................................................... 91
16.2.1.
Investigator Responsibilities ....................................................................................................... 91
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 91
16.2.3.
Informed Consent ....................................................................................................................... 92
16.2.4.
Privacy of Personal Data ............................................................................................................ 93
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 94
16.2.6.
Country Selection ....................................................................................................................... 94
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 94
17.1.
Protocol Amendments.................................................................................................................... 94
17.2.
Regulatory Documentation ............................................................................................................ 95
17.2.1.
Regulatory Approval/Notification ................................................................................................ 95
17.2.2.
Required Prestudy Documentation............................................................................................. 95
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 96
17.4.
Source Documentation................................................................................................................... 96
17.5.
Case Report Form Completion ...................................................................................................... 97
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 97
17.7.
Record Retention ........................................................................................................................... 98
17.8.
Monitoring ...................................................................................................................................... 98
17.9.
Study Completion/Termination....................................................................................................... 99
17.9.1.
Study Completion/End of Study.................................................................................................. 99
17.9.2.
Study Termination....................................................................................................................... 99
17.10.
On-Site Audits ................................................................................................................................ 99
17.11.
Use of Information and Publication.............................................................................................. 100
REFERENCES.......................................................................................................................................... 102

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
5
Approved, Date: 19 December 2019
INVESTIGATOR AGREEMENT ............................................................................................................... 129
LIST OF ATTACHMENTS
Attachment 1:
Ibrutinib Risks ........................................................................................................... 105
Attachment 2:
Cumulative Illness Rating Scale (CIRS)................................................................... 108
Attachment 3:
Contraceptive and Barrier Guidance and Collection of Pregnancy Information....... 109
Attachment 4:
Child-Pugh Scores for Subjects with Chronic Liver Impairment............................... 111
Attachment 5:
Inhibitors and Inducers of CYP3A ............................................................................ 112
Attachment 6:
Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of Tumor Lysis Syndrome (TLS) ............................................................ 113
Attachment 7:
Howard Criteria for Laboratory and Clinical Tumor Lysis Syndrome*...................... 116
Attachment 8:
Obinutuzumab Premedication for Infusion Reactions and Tumor Lysis 
Syndrome ................................................................................................................. 117
Attachment 9:
Medications to be Used with Precaution with Ibrutinib and Venetoclax................... 119
Attachment 10:
CLL and SLL Staging Criteria................................................................................... 121
Attachment 11:
EORTC QLQ-C30..................................................................................................... 123
Attachment 12:
EQ-5D-5L.................................................................................................................. 125
Attachment 13:
FACIT-Fatigue Scale................................................................................................ 128
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Time and Events Schedule for Treatment Arm A (Ibrutinib + Venetoclax)............................... 18
Table 2:
Time and Events Schedule for Treatment Arm B (Obinutuzumab + Chlorambucil)................. 21
Table 3:
Time and Events Schedule for Treatment and Post-Treatment Disease Evaluations 
Prior to Disease Progression Treatment Arm A and Treatment Arm Ba................................... 23
Table 4:
Time and Events Schedule for Subsequent Therapy with Single-agent Ibrutinib .................... 24
Table 5:
Efficacy Summary From Phase 3 Studies of Ibrutinib in CLL................................................... 33
Table 6:
Most Frequently Reported TEAEs in Subjects Receiving Ibrutinib as Monotherapy ............... 34
Table 7:
Ibrutinib Dose Modifications...................................................................................................... 48
Table 8:
TLS Prophylaxis Based on Tumor Burden from Clinical Trial Data (consider all 
comorbidities before final determination of prophylaxis and monitoring schedule).................. 51
Table 9:
Venetoclax Recommended Dose Modifications for Toxicities.................................................. 52
Table 10:
Dose Modification for Toxicity during Venetoclax Treatment ................................................... 53
Table 11:
Obinutuzumab Dosing Schedule .............................................................................................. 54
Table 12:
Dose Modification for Chlorambucil Due to Toxicity................................................................. 56
Table 13:
Criteria for Response Categories ............................................................................................. 67
Table 14:
iwCLL Grading Scale for Hematologic Toxicity in CLL Studies................................................ 83
FIGURES
Figure 1:
Disease Evaluation and Treatment Schedule .......................................................................... 26
Figure 2:
Disease Evaluation and Treatment Schedule for Subsequent Therapy with Single-
agent Ibrutinib ........................................................................................................................... 27
Figure 3:
Venetoclax Dose Ramp-up....................................................................................................... 49

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
6
Approved, Date: 19 December 2019
PROTOCOL AMENDMENTS
Protocol Version 
Date
Original Protocol
12 January 2018
Amendment 1
6 June 2018
Amendment 2
22 January 2019
Amendment 3
Amendment 4
12 August 2019
19 December 2019
Amendments below are listed beginning with the most recent amendment.
Amendment 4 (19 December 2019)
The overall reasons for the amendment: To update safety information to align with the ibrutinib Investigator’s 
Brochure (IB) to include information regarding cerebrovascular accidents as a new safety observation identified 
from the post-marketing setting, and to clarify that assessment of pulse/heart rate and blood pressure is expected at 
every protocol-specified visit.
Applicable Section(s)
Description of Change(s)
Rationale: To update the safety for ibrutinib, including information on cerebrovascular accidents.
Attachment 1,
Ibrutinib Risks
Safety information on ibrutinib updated to align with the current IB.
Rationale: To clarify that regular monitoring of pulse/heart rate and blood pressure is expected at every 
protocol-specified visit.
Table 1, Table 2, 
Table 3, and Table 4 
(Time and Events 
Schedules); 
9.5 Safety 
Evaluations
Additional pulse/heart rate and blood pressure assessments added.
Footnotes added to clarify that pulse/heart rate and blood pressure should be recorded in 
source documents but will not be routinely collected in the eCRF. 
Vital signs description updated to specify pulse/heart rate and blood pressure evaluation 
is expected at every visit, and guidelines on monitoring and management of 
cardiovascular toxicities was added. In addition, ECG text was updated to clarify the 
timing for assessment and optimal monitoring and management of cardiovascular 
toxicities (consider consultation with a cardiologist).
Rationale: To clarify the baseline evaluations to be conducted for those subjects who receive subsequent therapy 
with single-agent ibrutinib.
Table 4 (Time and 
Events Schedule)
The following baseline evaluations were added: medical history, CIRS score, ECOG 
PS, ECG, vitals, weight, and hepatitis testing. 
A clarifying footnote (footnote c) was added to specify that only new medical 
conditions since the initial screening period or medical conditions that have worsened 
since baseline should be captured in the case report form and CIRS only needs to be 
re-evaluated if new or worsening medical conditions are reported.
Rationale: To clarify that annual CT imaging during subsequent therapy with single-agent ibrutinib should 
coincide with disease evaluation visits.
Table 4 (Time and 
Events Schedule; 
footnote g)
CT imaging is expected for subjects who were initially treated with I+VEN (Treatment 
Arm A); this will occur at the following timepoints: baseline, Week 16, Week 48, and 
annually thereafter coinciding with the DE visits until progression.

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
7
Approved, Date: 19 December 2019
Applicable Section(s)
Description of Change(s)
Rationale: To clarify that subjects in Treatment Arm B remain eligible for subsequent therapy with single-agent 
ibrutinib even if they do not complete open-label therapy because this would not be expected to affect response 
and tolerability to ibrutinib.
Synopsis (Overview 
of Study Design); 
Figure 2; Section 3.1 
Overview of Study 
Design; Section 3.2 
Study Design 
Rationale;
9.1.5.1 Eligibility for 
the Subsequent 
Therapy Phase
Removed text specifying that treatment with I+VEN or G-Clb needs to be completed to 
be eligible for subsequent therapy with single-agent ibrutinib.
Figure 2 bullet on “completed study treatment” updated to specify that this pertains to 
Arm A. 
The text was updated to clarify that subjects randomized to Treatment Arm B may 
remain eligible for subsequent therapy even if the protocol-specified treatment is not 
completed.
Rationale: To clarify that serum chemistry and hematology assessments may be done outside of the treating 
institution for non-cycle visits.
Table 4 (Time and 
Events Schedule; 
footnote e)
Footnote “e” added to clarify that testing may be done outside of the treating institution 
for non-cycle visits.
Rationale: To clarify that medical history needs to be reviewed as complete before a subject is considered 
eligible to receive subsequent therapy with single-agent ibrutinib.
9.1.5 Subsequent 
Therapy Phase
Added that eligibility review should include review that medical history is complete.
Rationale: To remove specificity that a stratified analysis will be done for overall survival because the number of 
events may be too small in some of the strata.
11.4 Efficacy 
Analyses; 
11.4.2 Secondary 
Endpoints
Deleted term “stratified” when describing the overall survival analysis. The details will 
be specified in the final Statistical Analysis Plan.
Rationale: To add an external link for examples of CYP3A inhibitors and inducers.
Attachment 5
Inserted an additional link to FDA classification of CYP3A inhibitors and inducers.
Rationale: Throughout the protocol, minor grammatical, formatting, or spelling changes were made as needed.
Amendment 3 (12 August 2019)
The overall reason for the amendment: The primary reason for the amendment is to add a Subsequent Therapy
Phase in which eligible subjects who progressed after completing the Treatment Phase with either ibrutinib plus 
venetoclax (I+VEN; Treatment Arm A) or obinutuzumab plus chlorambucil (G-Clb; Treatment Arm B) can 
receive single-agent ibrutinib. Response data, as well as biomarker samples, will be collected to evaluate the 
efficacy of subsequent single-agent ibrutinib therapy in subjects previously treated with a fixed-duration of 
I+VEN.
Applicable Section(s)
Description of Change(s)
Rationale: A Subsequent Therapy Phase was added in which eligible subjects will be treated continuously with 
single-agent ibrutinib.

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
8
Approved, Date: 19 December 2019
Synopsis Overview of 
Study Design; 
3.1 Overview of Study 
Design; 5 Treatment 
Allocation; 
9.1.1 Overview; 
9.1.3 Open-label 
Treatment Phase; 
9.1.4 Follow-up Phase; 
9.1.5 Subsequent 
Therapy Phase (new 
section); 9.2 Efficacy; 
9.2.1.1 Radiographic 
Imaging Assessments; 
9.2.1.3 Bone Marrow 
Assessments; 
9.3.1 Pharmacokinetic 
Evaluations; 9.5 Safety 
Evaluations
Added description of the Subsequent Therapy Phase, including clarification of study 
evaluations and added clarifying text to description of Treatment Phase where 
appropriate 
Table 4 Time and 
Events Schedule for 
Subsequent Therapy
with Single-agent 
Ibrutinib (new table); 
Figure 2 Disease 
Evaluation and 
Treatment Schedule for
Subsequent Therapy
with Single-agent 
Ibrutinib (new figure)
Added the time and events schedule and schema for the Subsequent Therapy Phase
Synopsis Dosage and 
Administration; 
6 Dosage and 
Administration; 
6.3 Subsequent Therapy 
with Single-agent 
Ibrutinib (new section)
Added description of treatment to be administered in the Subsequent Therapy Phase
8 Concomitant Therapy
Clarified that concomitant therapy should be recorded during both the Treatment 
Phase and the Subsequent Therapy Phase
12.3.1 All Adverse 
Events
Clarified that AEs should be collected during the Subsequent Therapy Phase
1.6 Overall Rationale 
for the Study; 3.2 Study 
Design Rationale; 
16.1 Study-specific 
Design Considerations
Added rationale for the Subsequent Therapy Phase
Rationale: Eligibility criteria for the Subsequent Therapy Phase was added.
4. Subject Population; 
9.1.5.1 Eligibility for 
the Subsequent Therapy
Phase (new section)
Defined eligibility criteria for the Subsequent Therapy Phase and added a reference to 
this where overall study eligibility criteria are stated (Section 4).

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
9
Approved, Date: 19 December 2019
3.1 Overview of Study 
Design
Added statements that eligible subjects for the Subsequent Therapy Phase must have 
completed the treatment with I+VEN or G-Clb and subsequently develop progressive 
disease (as confirmed by the Independent Review Committee [IRC]) that requires 
treatment per International Workshop on Chronic Lymphocytic Leukemia [iwCLL] 
criteria)
Rationale: Clarification of response categories to be used for the Subsequent Therapy Phase was added.
9.2.3 Response 
Categories
Clarified that responses will be based on assessment by the investigator during the 
Subsequent Therapy Phase.
Noted that confirmation of responses by the IRC may be pursued by the sponsor for 
regulatory purposes.
Rationale: Evaluations, exploratory objective, and exploratory endpoints associated with the Subsequent 
Therapy Phase were added.
11.4.4 Subsequent 
Therapy Evaluations
Evaluations and exploratory endpoints for the Subsequent Therapy Phase were added.
Rationale: Clarified the purpose of the bone marrow aspirate and biopsy
Table 3 Time and 
Events Schedule for 
Treatment and 
Post-Treatment Disease 
Evaluations Prior to 
Disease Progression 
Treatment Arm A and 
Treatment Arm B
Added the following text to Footnote d to aligned with Section 9.2.1.3: The bone 
marrow aspirate and biopsy should be sent to a local laboratory for standard 
evaluation and response assessment. 
Rationale: Added a sample for biomarker assessment at DE8
Table 3 Time and 
Events Schedule for 
Treatment and 
Post-Treatment Disease 
Evaluations Prior to 
Disease Progression 
Treatment Arm A and 
Treatment Arm B
Added a sample for biomarker assessment at DE8 and associated footnote f.
16.1 Study-specific 
Design Considerations
Added maximum total volume of blood collected in the Subsequent Therapy Phase
Updated total volume of blood to be collected after the treatment period
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made, and minor 
corrections and alignments among sections were incorporated.
15 Study-specific 
Materials
Removed the reference to IWRS codes since this is not a blinded study.
REFERENCES
Removed references that are no longer applicable.

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
10
Approved, Date: 19 December 2019
Amendment 2 (22 January 2019)
The overall reason for the amendment: The primary reason for the amendment is to revise the duration of 
treatment in the I+VEN treatment arm of the trial based on available Phase 2 data with this combination. 
Applicable Section(s)
Description of Change(s)
Rationale: The protocol has been adapted to reflect recent scientific insights from relevant Phase 2 studies 
indicating that the removal of the last 3 cycles (cycles 16, 17, and 18) of ibrutinib monotherapy is appropriate. 
Synopsis: Dosage and 
Administration
Table 1 Time and Events Schedule 
for Treatment Arm A; Table 2 
Time and Events Schedule for 
Treatment Arm B; and Table 3
Time and Events Schedule for 
Treatment and Post-Treatment 
Disease Evaluations Prior to 
Disease Progression Arm A and B
Figure 1 Disease Evaluation and 
Treatment Schedule
1.5 Ibrutinib in Combination with 
Venetoclax in CLL
1.6 Overall Rationale for the Study
3.1 Overview of Study Design
6.1 Treatment Arm A (Ibrutinib 
and Venetoclax) Administration
9.1.3 Open-Label Treatment Phase
9.2.1.3 Bone Marrow Assessments 
9.2.2 Minimal Residual Disease 
Assessments
16.1 Study-Specific Design 
Considerations
REFERENCES
Update of data from relevant Phase 2 studies in which I+VEN has been 
investigated for the treatment of CLL.
For Treatment Arm A, removal of 3 additional cycles of ibrutinib 
monotherapy following completion of combination therapy (I+VEN) in 
relevant Time and Events Schedules, study overview figure, and text.
Adjustment of weeks on which Disease Evaluation visits with computed 
tomography (CT) imaging will occur as a result of the removal of 
3 additional cycles of ibrutinib monotherapy following completion of 
combination therapy (I+VEN), including clarification of when hematology 
laboratory assessments are to be performed.
Update of blood volume to be collected for subjects assigned to Treatment 
Arm A commensurate with the reduction in treatment cycles.
Clarification of procedure to collect samples for biomarker analysis.
Rationale: The protocol was updated to inform of additional effort to evaluate ibrutinib monotherapy as 
subsequent therapy for subjects who were initially exposed to and progressed on I+VEN combination therapy.
1.6 Overall Rationale for the Study
Language was included to inform of the possibility of enrolling subjects who 
relapsed or progressed after I+VEN therapy in this study in a clinical trial 
investigating the effectiveness of retreatment with ibrutinib.
Rationale: Minor revisions requested by a regulatory authority regarding concomitant medications were 
incorporated.
8.2 Medications to be Used with 
Caution
Clarification of the concomitant use of CYP3A4 inhibitors with ibrutinib 
and venetoclax.

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
11
Approved, Date: 19 December 2019
Rationale: The 18-month landmark was removed to avoid confusion on multiple minimal residual disease (MRD)
analyses.
11.4.2 Secondary Endpoints
The following statement was removed from the first secondary endpoint: 
Subjects without MRD measurement during the 18 months will be 
considered as MRD positive.
Rationale: Minor corrections and errors were addressed.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made, and minor 
corrections and alignments among sections were incorporated.
Amendment 1 (6 June 2018)
The overall reason for the amendment: The overall reason for the amendment is to address Health Authority 
feedback and to update protocol based on early pharmacokinetic (PK) results from ongoing Phase 2 study of 
I+VEN.
Applicable Section(s)
Description of Change(s)
Rationale: Changes have been made to the protocol to address Health Authority feedback.
Table 1 Time and Events 
Schedule for Treatment Arm A, 
footnote “h”; Table 2 Time and 
Events Schedule for Treatment 
Arm B, footnote “h”
Footnote added to specify that pregnancy testing must be done or repeated 
within 7 days before the first dose of study treatment.
8.2 Medications to be Used With 
Caution; 8.3 Prohibited 
Concomitant Medications
8.3 Prohibited Concomitant 
Medications
Text regarding prohibited use of strong CYP3A inhibitors during venetoclax 
administration was moved from Section 8.2 to Section 8.3 and a cross 
reference to Section 8.3 was added.
Text was added to specify that live vaccines must not be administered during 
study treatment phase.
12.1.1 Adverse Event 
Definitions and Classifications
Text regarding expectedness of adverse events (AEs) was revised for clarity.
12.3.1 All Adverse Events
Text was revised to clarify requirements for reporting of progression of 
disease.
Rationale: Based on early PK results from ongoing Phase 2 study of I+VEN, preliminary data, venetoclax PK 
sampling, and new dosing guidance were added to protocol.
Table 1 Time and Events 
Schedule for Treatment Arm A, 
Laboratory Assessments
New row added for collection of predose venetoclax PK samples in Cycles 5 
and 6 only. 
1.5 Ibrutinib in Combination 
With Venetoclax in CLL
Added summary of preliminary data from a Phase 2 study of I+VEN regarding 
venetoclax and ibrutinib exposures. 
Synopsis – Secondary 
Objectives; 2.1 Objectives and 
Endpoints
Secondary PK objective and endpoint were modified to account for venetoclax 
PK analysis.
6.1.1.2 Ibrutinib Dose 
Modification; 6.1.2.3 Venetoclax 
Dose Modification
Text revised to clarify that if an AEs is considered potentially related to both 
drugs for subjects in Treatment Arm A, the recommended first action should 
be venetoclax dose modification before ibrutinib dose modification.

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
12
Approved, Date: 19 December 2019
9.3 Pharmacokinetics; 
9.3.1 Pharmacokinetic 
Evaluations; 9.3.2 
Pharmacokinetic Analytical 
Procedures
9.3.3 Pharmacokinetic 
Parameters
11.5 Pharmacokinetic Analyses
Text added to specify that blood samples will be collected for PK analysis of 
venetoclax.
Text added to specify that PCI-45227 and venetoclax Ctrough,ss data will be 
summarized by descriptive statistics. Text regarding PK analyses moved to 
Section 11.5. 
Text added to specify that venetoclax PK data will be summarized by 
descriptive statistics and to describe ibrutinib and PCI-45227 analyses.
Rationale: According to the Chlorambucil Summary of Product Characteristics, patients with rare hereditary 
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take 
this medication.
4.2 Exclusion Criteria
New exclusion criterion 23 added excluding subjects with galactose intolerance, the Lapp 
lactase deficiency, or glucose-galactose malabsorption from study enrollment.
Rationale: To align with product labels for study treatments with respect to hypersensitivity to active substances 
or excipients.
4.2 Exclusion Criteria
New exclusion criterion 24 added excluding subjects with any contraindication to one of 
the study medications including hypersensitivity to the active substance or to any of the 
excipients of ibrutinib, venetoclax, obinutuzumab, or chlorambucil.
Rationale: To rectify missing biomarker data points. 
Table 1 Time and Events 
Schedule for Treatment Arm A, 
Laboratory Assessments
Table 2 Time and Events 
Schedule for Treatment Arm B, 
Laboratory Assessments, 
footnote “i”
9.4 Biomarkers
Cycle 4 Day 15 biomarker sampling added.
Cycle 4 Day 15 biomarker sampling added.
Footnote added to clarify that biomarker sample will be collected on subjects 
who are coming to Clinic for on-site chlorambucil administration on Cycle 4 
Day 15.
Text added to specify that samples may be evaluated for cytogenetics.
Rationale: Additional PK and biomarker samples in Treatment Arm A and Treatment Arm B will be collected.
16.1 Study-Specific Design 
Considerations
Blood volumes to be collected have been updated.
Rationale: Clarify the threshold by which the presence of a TP53 mutation is considered exclusionary.
4.2 Exclusion Criteria; 9.1.2 
Screening Phase; References
Text was added to specify that subjects with known presence of TP53
mutations detected at a threshold of 10% variable allele frequency will be 
excluded from the study.
New publication (Malcikova 2018) added to References and citation to this 
publication added.

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
13
Approved, Date: 19 December 2019
Rationale: Text was updated to align with the global protocol template.
16.2.5 Long-Term Retention of 
Samples for Additional Future 
Research
Sample storage retention was revised to from 2 years to 15 years after end of 
study.
Rationale: Additional references regarding CLL diagnosis are available.
4.1 Inclusion Criteria; 
References
New publication (Rawstron 2018) added to References and citation to this 
publication added.
Rationale: Revisions and modifications were made throughout the protocol to increase clarity, for consistency 
within this protocol, or to correct omissions and errors.
Synopsis – Subject Population
Bold text was added: Subjects with deletion of the short arm of chromosome 
17 (del17p) or known TP53 mutations are excluded.
Table 1 Time and Events 
Schedule for Treatment Arm A, 
Disease Evaluations; Table 2 
Time and Events Schedule for 
Treatment Arm B, Disease 
Evaluations
Text was revised to specify that disease evaluations (DEs) will be performed 
every 12 weeks after randomization through Week 60 84, then every 16 weeks 
through Week 156 164
Table 1 Time and Events 
Schedule for Treatment Arm A, 
Laboratory Assessments
Cycle 4 column header “D21” corrected to “D22”.
An “X” was added for Hematology at Screening for consistency with Table 3.
An “X” was added for Biomarker blood samples at Screening for consistency 
with Table 3.
Table 2 Time and Events 
Schedule for Treatment Arm B, 
Laboratory Assessments
An “X” was added for Biomarker blood samples at Screening for consistency 
with Table 3.
Table 3 Time and Events 
Schedule for Treatment and 
Post-Treatment Disease 
Evaluations Prior to Disease 
Progression Treatment Arm A 
and Treatment Arm B
For column “Weeks 84 through 164”, Week 8 added to DE range.
1.3 Ibrutinib
Text added to specify that Pharmacyclics LLC is an AbbVie Company. 
4.1 Inclusion Criteria; 
4.2 Exclusion Criteria; 
References; Attachment 2 
Cumulative Illness Rating Scale 
(CIRS)
New publication (Salvi 2008) added to References and Attachment and in-text
cross references added. Link to publication added to Attachment.
5 Treatment Allocation
The randomization will be balanced by using randomly permuted blocks and 
will be stratified by immunoglobulin heavy-chain variable mutational status 
(mutated vs. unmutated vs. not available) and presence of del11q (yes vs. no).

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
14
Approved, Date: 19 December 2019
6.1.1.2 Ibrutinib Dose 
Modification; 6.1.2.3 Venetoclax 
Dose Modification
6.2 Treatment Arm B 
(Chlorambucil plus
Obinutuzumab) Administration
6.2.1.2.1 Infusion Reactions
Cross reference to Attachment 5 corrected to Attachment 9.
Redundant text referring to chlorambucil and obinutuzumab product labels 
deleted.
Cross reference to Attachment 8 corrected to Table 10.
8.3 Prohibited Concomitant 
Medications
Text was revised to specify that:

any non-study anti-leukemic therapy is prohibited until disease 
progression has occurred

corticosteroids at dosages equivalent to prednisone >20 mg/day for 
>14 days are prohibited until disease progression has occurred
Text was added to align with existing content found in Attachment 9: warfarin
or other vitamin K antagonists should not be administered concomitantly with 
ibrutinib.
9.1.1 Overview
Text was added to specify that repeat blood samples may be taken for 
technical issues.
9.2.1.2 
Definition of 
Measurable and Assessable 
Disease
Text was added to clarify that measurable sites of disease are target lesions 
and lesions not included in the target lesion assessment should be considered 
as assessable (non-target) lesions.
Text in strikethrough was removed: Investigators should provide a qualitative 
assessment (ie, increased, decreased, normal, no change) of the spleen and 
liver at screening and in all subsequent DE visits.
9.2.2 Minimal Residual Disease 
Assessments
Text was added to specify that the first draw of the bone marrow aspirate 
should be sent for central MRD analysis.
9.2.3 Response Categories, 
Table 12: Criteria for Response 
Categories
Text in strikethrough was removed: Footnote pertaining to partial response 
(PR) has been revised: 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).
9.5 Safety Evaluations - Physical 
Examinations
Text in strikethrough was removed: The status (increased, decreased, normal, 
absent) of nodal lesions, the liver, and spleen must be reported at each DE
visit.
14.1 Physical Description of 
Study Interventions; 
14.2 Packaging; 
14.4 Preparation, Handling, and 
Storage
Text revised regarding study treatment description, packaging, handling, and 
storage.
Attachment 9 Medications to be 
Used with Precaution with 
Ibrutinib and Venetoclax
Antiplatelet Agents and 
Anticoagulants - Ibrutinib
Dose for ibrutinib dose reduction with moderate cytochrome p450 (CYP)
inhibitor use revised.
Text revised to remove redundant text and for clarity.
Attachment 10 CLL and SLL 
Staging Criteria
The Ann Arbor SLL Staging System with Cotswold’s Modifications was 
added.
Rationale: Minor corrections and errors were addressed.

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
15
Approved, Date: 19 December 2019
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
16
Approved, Date: 19 December 2019
SYNOPSIS
A Randomized, Open-label, Phase 3 study of the Combination of Ibrutinib plus Venetoclax versus 
Chlorambucil plus Obinutuzumab for the First-line Treatment of Subjects with Chronic Lymphocytic 
Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective of the study is to assess progression-free survival (PFS) from treatment with 
ibrutinib plus venetoclax (I+VEN) compared with obinutuzumab plus chlorambucil (G-Clb) as assessed 
by an Independent Review Committee (IRC).
Secondary Objectives
Key secondary objectives are to evaluate the following: rate of minimal residual disease (MRD)-negative 
remissions; overall response rate (ORR), including complete response (CR) rate, and response duration as 
assessed by an IRC; overall survival (OS); time-to-next treatment; trough levels of ibrutinib and 
venetoclax when given in combination; and safety.
Hypothesis
Treatment with the combination of I+VEN will result in longer PFS compared with G-Clb in subjects 
with previously untreated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
OVERVIEW OF STUDY DESIGN
This is a randomized (1:1), open-label, multicenter, Phase 3 study to determine the efficacy and safety of 
the combination of I+VEN, compared with G-Clb, in approximately 200 subjects with previously 
untreated CLL/SLL who meet the International Workshop on CLL (iwCLL) treatment criteria.
Randomization will be stratified by immunoglobulin heavy-chain variable region (IGHV) gene mutational 
status (mutated vs. unmutated vs. not available) and presence of deletion of the long arm of chromosome 
11 ([del11q] yes vs. no). Subjects with confirmed disease progression after I+VEN or G-Clb may be 
eligible for and choose to receive subsequent therapy with single-agent ibrutinib during the Subsequent 
Therapy Phase.
Subject participation will include a Screening Phase, a Treatment Phase (fixed-duration Treatment Arm A 
[I+VEN] or Treatment Arm B [G-Clb]), and a Follow-up Phase. Subjects from either treatment arm who 
subsequently develop IRC-confirmed progressive disease and have active disease requiring treatment may 
be eligible to receive single-agent ibrutinib until disease progression or unacceptable toxicity as part of 
the Subsequent Therapy Phase. Participation in this phase of the study is not mandatory and is based on 
investigator’s discretion. Study end is defined as approximately 5 years after the last subject is 
randomized into the study or after 50% of subjects have died, whichever occurs first.
SUBJECT POPULATION
Key eligibility criteria include the following: ≥65 years of age, or, 18 to 64 years of age and have at least 
1 of the following, a CIRS score >6 or creatinine clearance (CrCl) <70 mL/min; active disease status per
the iwCLL criteria with measurable nodal disease by CT; and Eastern Cooperative Oncology Group 
(ECOG) Performance Status (PS) grade of 0, 1, or 2. Subjects with deletion of the short arm of 
chromosome 17 (del17p) or known TP53 mutations are excluded.
DOSAGE AND ADMINISTRATION
Subjects randomly assigned to Treatment Arm A (I+VEN) will receive ibrutinib (420 mg/day orally) 
given as lead-in treatment for 3 cycles. Starting at Cycle 4, venetoclax dose ramp-up (from 20 mg to 

JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
17
Approved, Date: 19 December 2019
400 mg over 5 weeks) will begin, and venetoclax will be administered with ibrutinib for 12 cycles. 
Subjects randomly assigned to Treatment Arm B (G-Clb) will receive G-Clb for 6 cycles. Obinutuzumab 
will be administered intravenously at a dose of 1000 mg on Days 1, 8 and 15 in Cycle 1. In Cycles 2 to 6,
1000 mg obinutuzumab will be given on Day 1. Chlorambucil will be administered orally at a dose of 
0.5 mg/kg body weight, on Days 1 and 15 of Cycles 1 to 6. A cycle will be defined as 28 days. Subjects in 
the Subsequent Therapy Phase will receive continuous ibrutinib (420 mg/day orally) until disease 
progression or unacceptable toxicity.
EVALUATIONS
Efficacy evaluations will include imaging, physical examinations, evaluation of blood and bone marrow, 
disease-related symptoms, and assessment of patient-reported outcomes (PRO). Safety evaluations will 
include AE monitoring, physical examinations, laboratory tests, and review of concomitant medications.
To better understand the molecular and protein markers associated with response to and relapse following 
study treatment, bone marrow and peripheral blood samples will be collected. For subjects assigned to the
I+VEN treatment arm, sparse samples will be collected for pharmacokinetic (PK) analysis.
STATISTICAL METHODS
The primary efficacy endpoint of PFS will be determined by an IRC. The study is designed to detect a 
hazard ratio (HR) of 0.5 for the I+VEN group relative to G-Clb group (corresponding to an improvement 
of 100% in median PFS [eg, from 27 months to 54 months]) with 80% power at a 2-sided significance 
level of 0.05. The Kaplan-Meier method will be used to estimate the PFS for each treatment group, and 
the stratified log-rank test will be used to compare the PFS. An independent Data Monitoring Committee 
(DMC) will review safety data periodically.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
18
Approved, Date: 19 December 2019
Time and Events Schedules
NOTE: For Screening Visits, either Table 1 or Table 2 can be used with Table 3.
Table 1:
Time and Events Schedule for Treatment Arm A (Ibrutinib + Venetoclax)
TREATMENT ARM A: IBRUTINIB + VENETOCLAX (CYCLE VISIT SCHEDULE ONLY)
Phase
Screening
Treatment (1 cycle=28 days)
Post-treatment
Post-PD 
Follow-Up
Study Visits
Cycle 1-3
Cycle 3
Cycle 4
Cycle 5-6
Cycle 7-15
EOT Visit
(every 24 weeks)
Visit Day (D)
Up to 30 days 
prior to 
randomization
D1
D26
D1
D8
D15
D22
D1
D1
30 days 
(+7) after 
last dose
±7 days
Drug Administration Treatment (see Section 6)
Ibrutinib 420 mg daily
--------------------------------------------- Continuous Daily -------------------------------------------
Venetoclax 400 mg daily (after 
ramp-up)
Dose Ramp-up
Continuous Daily through Cycle 15
Clinic visit for study medication 
dispensation and accountability 
check
Required clinic visits on Day 1 of Cycles 1 through 8, 10, and 13. During cycles which do not 
require clinic attendance (Cycles 9, 11, 12, 14, and 15), dosing guidelines based on chemistry and 
hematology cutoffs outlined in Section 6 should be followed. Testing may be done outside of the 
treating institution.
TLS risk assessment and 
prophylaxis 
Cycle 1 Day 1
Xa
X
X
X
X
As needed per investigator’s assessment of 
TLS risk (see Section 6.1.2.2 )
Procedures
Informed consent
X
Medical history
X 
Pathology and FISH cytogeneticsb
X
IGHV mutational status (central 
lab)
X
Buccal swab
Cycle 1 only
ECG
Xc
ECOG PS
X
CIRS score
X
Vitals
X
Pulse/heart rate and blood pressure are expected in all protocol-specified visitsd
Weight
X
X
X
X
Patient reported outcomes
(EORTC QLQ-C30, EQ-5D-5L, 
FACIT-Fatigue)
Perform PROs on Day 1 of Cycles 1, 3, and 5 only. After Cycle 5, follow DE schedule in Table 3.
X
Xe

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
19
Approved, Date: 19 December 2019
TREATMENT ARM A: IBRUTINIB + VENETOCLAX (CYCLE VISIT SCHEDULE ONLY)
Phase
Screening
Treatment (1 cycle=28 days)
Post-treatment
Post-PD 
Follow-Up
Study Visits
Cycle 1-3
Cycle 3
Cycle 4
Cycle 5-6
Cycle 7-15
EOT Visit
(every 24 weeks)
Visit Day (D)
Up to 30 days 
prior to 
randomization
D1
D26
D1
D8
D15
D22
D1
D1
30 days 
(+7) after 
last dose
±7 days
Laboratory Assessments
Serum chemistry
X
Xf
Xg
Xg
Xg
Xg
Xg
Xg
Xg
X
Hematology
X
Xf
X
X
X
X
X
CrCl (Cockcroft-Gault)
X
Xf
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Coagulation panel
X
Hepatitis testing (see Section 4.2)
Xc
Pregnancy test for WOCBP
Xi
More frequent pregnancy testing may be performed as required by local regulations.
β2 microglobulin (local)
X
X
Cycle 10 or 
DE3 only
X
MRD peripheral blood analysis
Cycle 1 only
Biomarker blood samplesh
X
Cycles 1&2 only
X
X
X
Predose ibrutinib PK sample 
(plasma)
Cycles 2&3 only
X
Predose venetoclax PK sample 
(plasma)
X
Disease Evaluations: Will be performed every 12 weeks after randomization through Week72, then every 16 weeks through Week 152, then every 24 weeks thereafter until 
disease progression or death. See Table 3 for exact schedule of assessments.
Ongoing Subject Review
Concomitant medications
X
Continuous from the signing of ICF until 30 days after the last dose of study treatment or until the start of 
subsequent anti-leukemic therapy, whichever is first. Adverse events with onset >30 days after the last dose 
should be reported if considered related to study treatment.
Adverse events
X
Subsequent therapy 
X
Survival status (see Section 9.1.4)
X
Abbreviations: AE=adverse event; CIRS=Cumulative Illness Rating Scale; CrCl=Creatinine clearance; CR=complete response; CT=computed tomography; D=Day; DE=disease 
evaluation; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ=European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire; EOT=end-of-treatment; EQ-5D-5L=EuroQol 5 Dimension 5 Level questionnaire; FACIT=Functional Assessment of Chronic Illness Therapy; FISH=fluorescence in situ 
hybridization; ICF=informed consent form; IGHV=immunoglobulin heavy-chain variable region; LDH=lactate dehydrogenase; MRD=minimal residual disease; PD=progressive disease; 
PK=pharmacokinetic; PRO=patient-reported outcome; PS=performance status; TLS=tumor lysis syndrome; WOCBP=women of childbearing potential

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
20
Approved, Date: 19 December 2019
Footnotes:
a.
The 12-week CT scan is required to assess TLS risk before the start of venetoclax (See Table 3). Sponsor approval to start Cycle 4 will be dependent on completion of TLS risk 
assessment.
b.
Pathology report, including del17p and del11q by FISH must be sent to sponsor for review of eligibility prior to randomization.
c.
ECG and viral serology results obtained within 60 days of randomization are acceptable. 
d.
These assessments should be recorded in source documents but will not be routinely collected in the eCRF. Clinically significant abnormalities should be recorded as AEs and 
reported in the eCRF.
e.
After disease progression, ePRO assessment will be limited to the EQ-5D-5L questionnaire only for the first 2 Post-PD Visits.
f.
Laboratory values obtained prior to Cycle 1 Day 1 should be repeated if the blood sample was collected more than 72 hours prior to the anticipated start of study treatment. Test 
results should satisfy eligibility criteria for treatment to commence. 
g.
Serum chemistry and creatinine monitoring (see Section 6.1.2.2) must be assessed as part of TLS risk assessment. Abnormalities must be corrected 2-3 days before the start of 
venetoclax treatment and reassessed prior to each subsequent dose increase. After Cycle 6, additional tests for assessment of TLS risk (ie, uric acid, calcium, phosphate, LDH) may 
be done on as needed basis as determined by the treating physician.
h.
In addition to these timepoints, biomarker samples should be obtained at DE visits during which the first CR response or PD is documented (see Table 3).
i.
Pregnancy testing must be done or repeated within 7 days before the first dose of study treatment.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
21
Approved, Date: 19 December 2019
Table 2:
Time and Events Schedule for Treatment Arm B (Obinutuzumab + Chlorambucil)
TREATMENT ARM B: OBINUTUZUMAB + CHLORAMBUCIL (CYCLE VISIT SCHEDULE ONLY)
Phase
Screening
Treatment (1 cycle=28 days)
Post-treatment
Post-PD
Follow-Up
Study Visits
Cycle 1
Cycle 2-6
EOT 
Visit
(every 24 weeks)
Visit Day (D)
Up to 30 days 
prior to 
randomization
D1
D2
D8
D15
D1
D15b
30 days 
(+7) after 
last dose
±7 days
Study Drug Administration (Section 
6)
Obinutuzumab 100 mg IV
Xa
Obinutuzumab 900 mg IV
Xa
Obinutuzumab 1000 mg IV
X
X
X
Chlorambucil 0.5 mg/kg
X
X
X
Xb
IRR prophylaxis
X
X
X
X
X
Procedures
Informed consent
X
Medical history
X
Pathology and FISH cytogeneticsc
X
IGHV mutational status (central lab)
X
Buccal swab
X
ECG
Xd
ECOG
X
CIRS score
X
Vitals
X
Pulse/heart rate and blood pressure are expected in all protocol-specified visitse
Weight
X
X
X
Patient reported outcomes
(EORTC QLQ-C30, EQ-5D-5L, 
FACIT-Fatigue)
Perform PROs on Day 1 of Cycles 1, 3, 5 only. After Cycle 5, follow DE 
schedule in Table 3.
X
Xf
Laboratory Assessments
Serum chemistry
X
Xg
X
X
X
Xb
X
Hematology
X
Xg
X
X
X
Xb
X
Creatinine clearance
X
Xg
X
Coagulation panel
X
Hepatitis testing (Sec 4.2)
Xd
Pregnancy test for WOCBP
Xi
More frequent pregnancy testing may be performed as required by local regulations.
β2microglobulin
X
Cycle 4 
only
X

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
22
Approved, Date: 19 December 2019
TREATMENT ARM B: OBINUTUZUMAB + CHLORAMBUCIL (CYCLE VISIT SCHEDULE ONLY)
Phase
Screening
Treatment (1 cycle=28 days)
Post-treatment
Post-PD
Follow-Up
Study Visits
Cycle 1
Cycle 2-6
EOT 
Visit
(every 24 weeks)
Visit Day (D)
Up to 30 days 
prior to 
randomization
D1
D2
D8
D15
D1
D15b
30 days 
(+7) after 
last dose
±7 days
MRD peripheral blood analysis
X
Biomarker blood samplesh
X
X
Cycle 2 & 
4 only
Cycle 
4 
onlyj
X
Disease Evaluations: will be performed every 12 weeks after randomization through Week 72, then every 16 weeks through Week 152, then every 24 weeks thereafter 
until disease progression or death. See Table 3 for exact schedule of assessments.
Ongoing Subject Review
Concomitant medications
X
Continuous from the signing of ICF until 30 days after the last dose of study treatment or 
until the start of subsequent anti-leukemic therapy, if earlier. Adverse events with onset 
>30 days after the last dose should be reported if considered related to study treatment.
Adverse events
X
Subsequent therapy 
X
Survival status (see Section 9.1.4)
X
Abbreviations: AE=adverse event; CIRS=Cumulative Illness Rating Scale; CR=complete response; D=Day; DE=disease evaluation; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; EORTC QLQ=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EOT=end-of-treatment; EQ-5D-5L=EuroQol 5 
Dimension 5 Level questionnaire; FACIT=Functional Assessment of Chronic Illness Therapy; FISH=fluorescence in situ hybridization; ICF=informed consent form; 
IGHV=immunoglobulin heavy-chain variable region; IRR=infusion-related reaction; IV=intravenous; MRD=minimal residual disease; PD=progressive disease; PRO=patient-reported 
outcome; WOCBP=women of childbearing potential
Footnotes:
a.
Split first dose between Day 1 (100 mg) and Day 2 (900 mg). For subjects who tolerate the first 100 mg well and required no dose interruption or modification of the infusion rate, 
the full dose may be given on Day 1 (See Section 6.2.1.1) at investigator’s discretion.
b.
Predose laboratory tests may be done outside the treating institution on Day 15, Cycles 2-6. The investigator is required to assess these results, recommend dose interruptions or 
reductions as needed, and to approve home self-administration of chlorambucil on Day 15, Cycles 2-6.
c.
Pathology report, including del17p and del11q by FISH must be sent to sponsor for review of eligibility prior to randomization.
d.
ECG and viral serology results obtained within 60 days of randomization are acceptable.
e.
These assessments should be recorded in source documents but will not be routinely collected in the eCRF. Clinically significant abnormalities should be recorded as AEs and 
reported in the eCRF.
f.
After disease progression, ePRO assessment will be limited to the EQ-5D-5L questionnaire only for the first 2 Post-PD Visits.
g.
Laboratory values obtained prior to Cycle 1 Day 1 should be repeated if the blood sample was collected more than 72 hours prior to the anticipated start of study treatment. Test 
results should satisfy eligibility criteria for treatment to commence.
h.
In addition to these timepoints, biomarker samples should be obtained at DE visits during which the first CR response or PD is documented (see Table 3)
i.
Pregnancy testing must be done or repeated within 7 days before the first dose of study treatment.
j.
This sample will be collected on subjects who are coming to clinic for on-site chlorambucil administration on Cycle 4 Day 15.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
23
Approved, Date: 19 December 2019
Table 3:
Time and Events Schedule for Treatment and Post-Treatment Disease Evaluations Prior to Disease Progression Treatment Arm A and 
Treatment Arm Ba
Screening
Week 12
Week 24
Week 36
Week 48
Week 60
Week 72
Weeks 88 through 152
Week 176 onward
Disease Evaluation 
Up to 30 days 
prior to 
randomization
DE 1
DE 2
DE 3
DE 4
DE 5
DE 6
DE 7-11
(every 16 Weeks)
DE 12 onward
(every 24 Weeks)
Note: DE1 has window of -7 days; all other DE visits have a window of ±7 days.
CT Scan
Xb
Xc
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
Vitals
X
Pulse/heart rate and blood pressure are expected in all protocol-specified visitsd
Disease-related symptoms
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
Bone marrow aspirate
Xb
Xe
Xe
Bone marrow biopsy
Xb
Xe
Xe
MRD in subjects with PR or 
better
     Peripheral blood MRD
X
X
X
X
X
X
X
X
     Bone marrow aspirate MRD
Xb
Xe
Xe
Patient-reported outcomes
(EORTC QLQ-C30, EQ-5D-5L, 
FACIT-Fatigue)
X
X
X
X
X
X
X
Biomarker blood samplesf
X
X
Xg
Abbreviations: CR=complete response; CT=computed tomography; DE=disease evaluation; EORTC QLQ=European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire; EQ-5D-5L=EuroQol 5 Dimension 5 Level questionnaire; FACIT=Functional Assessment of Chronic Illness Therapy; MRD=minimal residual disease; PR=partial response; 
PD=progressive disease; TLS=tumor lysis syndrome.
Footnotes:
a.
After disease progression, follow Post-Treatment post-PD Follow-up Phase schedule of assessments in each respective treatment arm (Table 1 and Table 2).
b.
Standard of care CT scans meeting the Imaging Acquisition Guidelines standard done within 60 days of randomization and a bone marrow biopsy and aspirate done within 90 days 
of randomization may be used for screening. For subjects undergoing a bone marrow biopsy and aspirate during the screening, a sample of the aspirate and biopsy should be 
collected for biomarker assays and MRD testing. Archived bone marrow slides for biomarkers are acceptable.
c.
The 12-week CT scan is critical to assess TLS risk at the end of Cycle 3. This scan is required for both Treatment Arm A and Treatment Arm B.
d.
These assessments should be recorded in source documents but will not be routinely collected in the eCRF. Clinically significant abnormalities should be recorded as AEs and 
reported in the eCRF.
e.
For all subjects with a response of PR or better, a bone marrow aspirate and biopsy must be obtained and central assessment of bone marrow aspirate for MRD must be performed at 
DE3. The bone marrow aspirate and biopsy should be sent to a local laboratory for standard evaluation and response assessment. At DE6, a central bone marrow aspirate MRD 
assessment is required in all subjects with a response of PR or better. Bone marrow biopsy and aspirate for local evaluations are only required for subjects on the I+VEN treatment 
arm who were not confirmed CR at DE3. For subjects with a suspected PD based on new onset cytopenia, a bone marrow aspirate and biopsy should be obtained to confirm PD. A 
sample of the bone marrow aspirate, as well as bone marrow biopsy slides, should be sent to the sponsor for additional biomarker analyses.
f.
At DE3 and at any DE visit during which the first CR response or PD is documented.
g.
A blood sample for biomarker assessments will be collected at DE8.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
24
Approved, Date: 19 December 2019
Table 4:
Time and Events Schedule for Subsequent Therapy with Single-agent Ibrutinib
Phase
Subsequent Therapy (1 cycle = 28 days)
End-of-Treatment
Post-treatment,
Post-PD Follow-up
Study Visit
Cycle Visitsa
DE Visits
EOT Visit
Up to 
30 days 
prior to 
Cycle 1
Cycle 1 
Day1
Cycle 5
Day 1
All other 
cycle visits as 
indicated in 
Figure 2
Every 16 weeks × 3, then 
every 24 weeks until progression
(±7 days)
30 days (+7) after 
last dose
Every 24 weeks
(±7 days)
Study Drug Administration (see 
Section 6)
Ibrutinib 420 mg daily
------------------------------- Continuous Daily ---------------------------
Procedures
Review of informed consentb
X
Disease-related symptoms
X
X
Physical examination
X
X
Medical Historyc
X
CIRS scorec
X
ECOG PS
X
ECG
X
Vitals
X
Pulse/heart rate and blood pressure are expected in all protocol-specified visitsd
Weight
X
FISH cytogenetics
X
Laboratory Assessments
Serum chemistry
X
X
X
Xe
X
Hematology
X
X
X
Xe
X
X
Hepatitis testing (Section 4.2)
X
Pregnancy test for WOCBP
Xf
More frequent pregnancy testing may be performed as required by local regulations.
Efficacy Assessments
CT scang
X
X 
Biomarker blood samples
X
X
X (if PD or CR)
X
Ongoing Subject Review
Concomitant medication
Continuous from 30 days prior to start of single-agent ibrutinib to 30 days after the last dose of subsequent therapy, or until 
the start of subsequent anti-leukemic therapy, if earlier. AEs with onset >30 days after the last dose should be reported if 
considered related to ibrutinib.
Adverse events
Survival status 
X
Subsequent therapy (following 
single-agent ibrutinib)
X
Abbreviations: AE=adverse event; CR=complete response; CT=computed tomography; DE=disease evaluation; EOT=end-of-treatment; FISH=fluorescence in situ hybridization; 
G-Clb=obinutuzumab plus chlorambucil; I+VEN= ibrutinib plus venetoclax; PD=progressive disease; WOCBP=women of childbearing potential.
Footnotes:
a.
Cycle visits at the study site are required on Cycles 1, 2, and 3, then every 2 cycles until Cycle 13 and every 3 cycles thereafter.
b.
The investigator is expected to re-review the informed consent with the subject to ensure that he or she understands the purpose of, as well as the study procedures and required 
visits associated with, the Subsequent Therapy Phase.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
25
Approved, Date: 19 December 2019
c.
Only new medical conditions that have developed since the initial screening period or medical conditions that have worsened since baseline should be reported in the eCRF. 
CIRS score should be re-evaluated if new or worsening medical conditions are reported.
d.
These assessments should be recorded in source documents but will not be routinely collected in the eCRF. Clinically significant abnormalities should be recorded as AEs and 
reported in the eCRF.
e.
Testing may be done outside of the treating institution for non-cycle visits.
f.
Pregnancy testing must be done or repeated within 7 days before the first dose of study treatment.
g.
In the Subsequent Therapy Phase, CT imaging is expected for subjects who were initially treated with I+VEN (Treatment Arm A); this will occur at the following timepoints: 
baseline, Week 16, Week 48, and annually thereafter coinciding with the DE visits until progression. CT imaging studies meeting the Imaging Acquisition Guidelines done 
within 60 days of start of single-agent ibrutinib can be used as baseline. For subjects who were initially treated with G-Clb (Treatment Arm B), imaging is recommended only 
when clinically indicated and as determined by the investigator. 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
26
Approved, Date: 19 December 2019
Figure 1:
Disease Evaluation and Treatment Schedule
Abbreviations: BMA=bone marrow aspirate; BMB=bone marrow biopsy; C=Cycle; CR=complete response; DE=disease evaluation; EOT=end-of-treatment; G-Clb=obinutuzumab and 
chlorambucil; I+VEN=ibrutinib plus venetoclax; m=month; PR=partial response; w=week.
Notes:
0w/0m corresponds to date of randomization.
DE visits will occur every 12 weeks until DE6 at 72 weeks, then every 16 weeks until 152 weeks, then every 24 weeks until progression or death.
Imaging at 12, 36, 60, and 72 weeks, then every 16 weeks x 5, then every 24 weeks until progression or death. At DE visits that do not include a CT scan (24 and 48 weeks), the preceding 
radiographic assessment should be considered together with the current physical examination and peripheral blood evaluation in assessing the overall response for the visit.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
27
Approved, Date: 19 December 2019
Figure 2:
Disease Evaluation and Treatment Schedule for Subsequent Therapy with Single-agent Ibrutinib
Abbreviations: C=Cycle; CT=computed tomography; DE=disease evaluation; G-Clb=obinutuzumab plus chlorambucil; I+VEN=ibrutinib plus venetoclax; iwCLL=International 
Workshop on Chronic Lymphocytic Leukemia.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
28
Approved, Date: 19 December 2019
ABBREVIATIONS
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
β-hCG
-human chorionic gonadotropin
BCL-2
B-cell lymphoma-2
BCR
B-cell receptor
BTK
Bruton’s tyrosine kinase
CBC
complete blood count
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CIT
chemoimmunotherapy
CLL
chronic lymphocytic leukemia
CNS
central nervous system
CR
complete response
CrCl
creatinine clearance
CRi
complete response with an incomplete marrow recovery
CT
computed tomography
CYP
cytochrome p450
del11q
deletion of the long arm of chromosome 11
del17p
deletion of the short arm of chromosome 17
DMC
Data Monitoring Committee
DE
disease evaluation
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDC
electronic data capture
EORTC QLQ
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire
EQ-5D-5L
EuroQol 5 Dimension 5 Level questionnaire
ESMO
European Society for Medical Oncology
EU
European Union
FACIT
Functional Assessment of Chronic Illness Therapy
FCR
fludarabine, cyclophosphamide, and rituximab
FISH
fluorescence in situ hybridization
G-Clb
obinutuzumab plus chlorambucil 
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
HR
hazard ratio
I+VEN
ibrutinib plus venetoclax
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IGHV
immunoglobulin heavy-chain variable region
ILD
interstitial lung disease
INR
international normalized ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IRR
infusion-related reaction
ITT
intent-to-treat
iwCLL
International Workshop on Chronic Lymphocytic Leukemia
IWRS
Interactive Web Response System
MRD
minimal residual disease

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
29
Approved, Date: 19 December 2019
MRI
magnetic resonance imaging
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS
next-generation sequencing
nPR
nodular partial response
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PFS
progression-free survival
P-gp
P-glycoprotein
PQC
Product Quality Complaint
PR
partial response
PRL
partial response with lymphocytosis  
PRO
patient-reported outcome(s) (paper or electronic as appropriate for this study)
PS
Performance Status
SAE
serious adverse event
SAP
Statistical Analysis Plan
SIPPM
Site Investigational Product Procedures Manual
SLL
small lymphocytic lymphoma
TEAE
treatment-emergent adverse event
TLS
tumor lysis syndrome
ULN
upper limit of normal
US
United States
VAF
variable allele frequency
VAS
visual analog scale

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
30
Approved, Date: 19 December 2019
1.
INTRODUCTION
1.1.
Chronic Lymphocytic Leukemia
CLL and SLL are characterized by a spectrum of clinical manifestations, ranging from indolent 
disease requiring no treatment for decades, to markedly aggressive disease that requires urgent 
intervention.8,25 The International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 
developed guidelines to define the clinical context by which treatment should be initiated. These 
include progressive marrow failure (manifested by anemia or thrombocytopenia or both); 
massive or progressive splenomegaly; massive lymphadenopathy; progressive lymphocytosis 
with a rapid lymphocyte doubling time; worsening autoimmune cytopenias; or significant 
constitutional symptoms.28 Throughout this protocol, use of the term “CLL” refers to CLL and 
SLL.
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.2.
Treatment of Chronic Lymphocytic Leukemia
The type and intensity of initial therapy is guided by multiple factors. Patient age; presence or 
absence of comorbidities; and clinical or molecular disease risk features are foremost among
them. Current treatment guidelines from the European Society for Medical Oncology (ESMO) 
indicate that the choice of treatment for patients with previously untreated CLL should be based 
on the stage of disease, whether a patient is considered fit, and the presence or absence of 
deletion of the short arm of chromosome 17 (del17p) or TP53 mutation.15,18 Given the median 
age at diagnosis and first treatment of CLL, many patients fall into the “less fit” category.
For patients who are less fit due to comorbidities and have CLL without del17p or TP53
mutation, single-agent ibrutinib, or chlorambucil in combination with an anti-CD20 antibody 
(rituximab, ofatumumab, or obinutuzumab) are the recommended frontline treatment options.16
Data from randomized controlled clinical studies have shown that the addition of a newer 
anti-CD20 antibody, such as obinutuzumab, or ofatumumab, to chlorambucil provides 
improvement in median progression-free survival (PFS) compared with chlorambucil alone or 
rituximab plus chlorambucil.24,33 Median PFS after treatment with obinutuzumab plus 
chlorambucil (G-Clb) was 26.7 months, while median survival was not reached.23 Overall 
response was 77% with a 22% complete response (CR)/complete response with an incomplete 
marrow recovery (CRi) rate. MRD-negative remissions, defined as detection of <1 CLL cell in 
10,000 normal leukocytes by either polymerase chain reaction (PCR) assay or flow cytometry, 
were reported for 41% and 19% of the subjects with CR/CRi in peripheral blood and bone 
marrow, respectively.21 Anti-CD20 therapy administered in combination with cytotoxic 
chemotherapy to patients with CLL is often associated with increased rates of severe neutropenia 
(26% to 35%), or Grade 3 or higher infusion reactions (7% to 9% for rituximab, 10% for 
ofatumumab, 21% for obinutuzumab).22,33,46

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
31
Approved, Date: 19 December 2019
Ibrutinib is approved for the treatment of CLL (including del17p CLL). In the Phase 3 
RESONATE-2 study (PCYC-1115-CA) of first-line treatment of older patients with CLL, 
single-agent ibrutinib resulted in superior PFS (HR=0.16; P<0.001), OS (HR=0.16, p=0.0010) 
and ORR (86% vs. 35%, p<0.001) compared with chlorambucil.3 Adverse events (AEs) of any 
grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, 
cough, and nausea, and were mainly Grade 1-2. At median follow-up of 18.4 months, 87% of the 
patients in the ibrutinib group continued on therapy.3 Responses with single-agent ibrutinib are 
most often partial, although with longer follow-up, the quality of response improves and a higher 
rate of CR is achieved.4 Resolution of adenopathy is usually rapid, with efflux of cells into the 
blood, resulting in a transient lymphocytosis. These lymphocytes are composed of quiescent cells 
with inhibited signaling, activation and proliferation. This early lymphocytosis does not 
represent treatment failure.30 Ibrutinib treatment also is associated with rapid clearance of the 
disease from the spleen, and to a lesser extent, from the bone marrow, resulting in an overall 
reduction in tumor burden.19,31,56
For patients with active disease and who are considered “fit”, the combination of fludarabine, 
cyclophosphamide and rituximab (FCR) is the standard first-line therapy. In a randomized study, 
CR was reported in 44% of patients treated with FCR and median PFS was approximately 
5 years.20,29 MRD-negative remissions have been reported after FCR treatment, with rates of 
approximately 40%-60% in peripheral blood and 30% in bone marrow in the total population. 
Undetectable-MRD has been shown to correlate with longer PFS and OS in FCR-treated 
patients.2,51 MRD-negative remissions occur less frequently in patients with CLL with unmutated 
immunoglobulin heavy-chain variable region (IGHV) or del17p/TP53 mutations. Toxicity limits 
the use of FCR in older patients or those with comorbid conditions.52 For older but fit patients, 
bendamustine plus rituximab is also an option, although efficacy is lower than with FCR.14,15
For patients with del17p or TP53 mutations, the recommended therapy is ibrutinib. Idelalisib 
plus rituximab or venetoclax are also options if the patient is not suitable for ibrutinib or 
alternative therapies. Chemoimmunotherapy (CIT) regimens tend to show limited efficacy in 
patients with del17p/TP53 mutation, whereas the newer B-cell receptor (BCR)-targeted therapies 
have demonstrated efficacy across poor prognostic groups.37,57
1.3.
Ibrutinib
Ibrutinib (IMBRUVICA®) is an orally administered, covalently-binding inhibitor of Bruton’s 
tyrosine kinase (BTK) co-developed by Pharmacyclics LLC, an AbbVie Company, and Janssen 
Research & Development LLC for the treatment of B-cell malignancies. It has been approved for 
use in many regions, including the United States (US) and European Union (EU). There are 
currently a number of indications approved, including for the treatment of patients with CLL, 
including CLL with del17p, patients with mantle cell lymphoma who have received at least 
1 prior therapy, patients with Waldenström’s macroglobulinemia, patients with marginal zone 
lymphoma who require systemic therapy and have received at least one prior anti-CD20-based 
therapy, and adult patients with chronic graft versus host disease following the failure of 1 or 
more lines of systemic therapy.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
32
Approved, Date: 19 December 2019
For the most comprehensive nonclinical and clinical information regarding ibrutinib, refer to the 
latest version of the ibrutinib Investigator's Brochure (IB) and Addenda.
1.3.1.
Clinical Studies
1.3.1.1.
Clinical Pharmacokinetics
For a comprehensive summary of clinical pharmacokinetics, please refer to the latest version of 
the ibrutinib IB and Addenda.
1.3.1.2.
Clinical Efficacy
1.3.1.2.1.
Ibrutinib Monotherapy and in Combination with 
Chemoimmunotherapy in CLL
Data from 3 randomized, Phase 3 studies demonstrated the efficacy of ibrutinib monotherapy in 
subjects with treatment-naïve and previously treated CLL (compared with chlorambucil in 
Study PCYC-1115-CA
and ofatumumab in Study PCYC-1112-CA), and when used in 
combination with CIT in subjects with previously treated CLL (in combination with 
bendamustine and rituximab in Study CLL3001) (Table 5). For a list of ongoing studies, please 
refer to the ibrutinib IB.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
33
Approved, Date: 19 December 2019
Table 5:
Efficacy Summary From Phase 3 Studies of Ibrutinib in CLL
Study Number/Design
Study 
Population
Ibrutinib Dosing 
Schedule
Efficacy Results
PCYC-1115-CA: Phase 3, 
randomized, open-label, 
comparator (ibrutinib vs.
chlorambucil), 
monotherapy study in 
subjects ≥65 years of age 
Treatment-
naïve CLL
420 mg/day 
Ibrutinib superior to chlorambucil
Median time on study: 
18.4 months ibrutinib arm 
18.4 months chlorambucil arm
PFSa,b: HR 0.161 (95% CI: 0.091, 0.283), p<0.0001
Median PFSa,b: NR ibrutinib vs. 18.9 months chlorambucil 
ORRb,c: 82.4% ibrutinib vs. 35.3% chlorambucil, p<0.0001
ORR including PRLb,c: 86.0% ibrutinib vs. 35.3% 
chlorambucil, p<0.0001
OSc: HR 0.163 (95% CI: 0.048, 0.558), p=0.0010
PCYC-1112-CA: Phase 3, 
randomized, open-label, 
comparator (ibrutinib vs.
ofatumumab), 
monotherapy study 
Relapsed or 
refractory 
CLL
420 mg/day 
Ibrutinib superior to ofatumumab
Median time on study: 
9.6 months ibrutinib arm
9.2 months ofatumumab arm
PFSa,b: HR 0.215 (95% CI: 0.146, 0.317), p<0.0001
Median PFSa,b: NR ibrutinib vs. 8.1 months ofatumumab 
ORRb,c: 42.6% ibrutinib vs. 4.1% ofatumumab, p<0.0001
ORR including PRLb,c: 62.6% ibrutinib vs. 4.1% 
ofatumumab, p<0.0001 
OSc: HR 0.434 (95% CI: 0.238, 0.789), p=0.0049 
PCI-32765CLL3001: 
Phase 3, randomized, 
double-blinded, placebo 
controlled (ibrutinib+BR
vs. placebo+BR), 
combination therapy study
Relapsed or 
refractory 
CLL 
420mg/day 
Ibrutinib+BR superior to placebo +BR
Median time on study:
17.2 months ibrutinib+BR arm
16.8 months placebo+BR arm
PFSa,b: HR=0.203 (95% CI: 0.150, 0.276), p<0.0001
Median PFSb: NR ibrutinib+BR vs. 13.3 months 
placebo+BR 
ORRb,c: 82.7% ibrutinib+BR vs. 67.8% placebo+BR, 
p<0.0001 
MRD-negative response ratec: 12.8% ibrutinib+BR vs.
4.8% placebo+BR 
OSc: HR=0.628 (95% CI: 0.385, 1.024), p=0.0598
BR=bendamustine and rituximab; CI=confidence interval; CLL=chronic lymphocytic leukemia; HR=hazard ratio; 
MRD=minimal residual disease; NR=not reached; ORR=overall response rate; OS=overall survival; PFS=progression-free 
survival; PRL=partial response with lymphocytosis; SLL=small lymphocytic lymphoma.
Footnotes:
a.
Primary endpoint
b.
IRC assessed
c.
Secondary endpoint
1.3.1.3.
Clinical Safety
For the most comprehensive clinical safety information, please refer to the latest version of the 
ibrutinib IB and Addenda, including Section 5 Summary of data and guidance for the 
investigator.
Monotherapy Studies
As of 31 July 2017, 1523 subjects have been treated with ibrutinib monotherapy in 
sponsor-initiated clinical studies in B-cell lymphomas. The most frequently reported 
treatment-emergent adverse events (TEAEs) in subjects receiving ibrutinib as monotherapy 
(N=1523) are listed in Table 6.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
34
Approved, Date: 19 December 2019
Table 6:
Most Frequently Reported TEAEs in Subjects Receiving Ibrutinib as Monotherapy
Most Frequently Reported 
TEAEs ≥15%a
Most Frequently Reported 
Grade 3 or 4 TEAEs ≥3%a
Most Frequently Reported 
Serious TEAEs ≥2%b
Diarrhea
Neutropenia
Pneumonia
Fatigue
Pneumonia
Atrial fibrillation
Nausea
Thrombocytopenia
Pyrexia
Cough
Anemia
Febrile neutropenia
Pyrexia
Hypertension
Anemia
Diarrhea
Upper respiratory tract infection
Atrial fibrillation
Neutropenia
Fatigue
Edema peripheral
Thrombocytopenia
Muscle spasms
Abbreviation: TEAE=treatment-emergent adverse event
a Source: Table 5 of ibrutinib IB (Version 11)
b Source: Table 6 of ibrutinib IB (Version 11)
Combination Studies
Refer to the integrated data from combination therapy studies in subjects with B-cell 
malignancies in the latest version of the ibrutinib IB for a summary of the most frequently 
reported AEs observed with ibrutinib in combination studies. The overall safety profile of 
ibrutinib in combination with various chemo- and immunotherapies was consistent with the 
known safety profiles of ibrutinib and the background regimens evaluated, with no new safety 
signals identified for ibrutinib.
Risks
An overview of the potential risks associated with the administration of ibrutinib based on 
sponsor-initiated clinical studies is presented in the ibrutinib IB. A summary of risks is presented 
in Attachment 1. Unanticipated side effects that have not been previously observed may occur.
1.4.
Venetoclax
Venetoclax is an oral inhibitor of B-cell lymphoma-2 (BCL-2), an anti-apoptotic protein. 
Overexpression of BCL-2 has been demonstrated in CLL cells where it mediates tumor cell 
survival and has been associated with resistance to chemotherapy. The approved indications 
include the use of venetoclax monotherapy for the treatment of CLL in the presence of del17p or 
TP53 mutation in adult patients who are unsuitable for or have failed a BCR pathway inhibitor, 
and for the treatment of CLL in the absence of del17p or TP53 mutation in adult patients who 
have failed both CIT and a BCR pathway inhibitor. It is currently in development in combination 
with immunotherapy (rituximab or obinutuzumab) for the treatment of the broad population of 
relapsed/refractory CLL, as well as frontline CLL. 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
35
Approved, Date: 19 December 2019
In a Phase 1 study in patients with relapsed or refractory CLL (n=116), venetoclax treatment 
resulted in a 79% ORR, with a 20% rate of CR/CRi. Of the subjects with CR/CRi, 35% of those 
with available samples were shown to be MRD-negative in the bone marrow (5% of total 
population). Adverse events included mild diarrhea (in 52% of the patients), upper respiratory 
tract infection (48%), nausea (47%), and Grade 3 or 4 neutropenia (41%).47 Tumor lysis 
syndrome (TLS) is an important identified risk when initiating venetoclax. In the initial Phase 1 
dose-finding studies, which had a short titration phase and higher starting dose, the incidence of 
TLS was 13% and included 2 fatal events and 3 events of acute renal failure. However, the risk 
of TLS was reduced to 3% after revision of the dosing regimen and modification to prophylaxis 
and monitoring measures.54 In a Phase 2 study in relapsed patients with the poor prognostic 
cytogenetic abnormality, del17p (n=107), a 79% ORR and 8% CR/CRi rate were observed.50 The 
MRD-negative CR rate was 3%.53
1.5.
Ibrutinib in Combination with Venetoclax in CLL
Ibrutinib and venetoclax have complementary mechanisms of action targeting distinct B-cell 
pathways involved in the propagation of CLL cells. Ibrutinib arrests CLL cell proliferation.
Venetoclax is pro-apoptotic and induces early cell death.11,42 Ibrutinib also affects the adhesion 
and migration of CLL cells resulting in rapid efflux of CLL cells from tissue compartments, 
especially lymph node and spleen, into the peripheral blood. Venetoclax treatment results in 
effective clearance of the blood and bone marrow, but residual disease can be observed in lymph 
nodes. Together the 2 drugs are expected to provide complementary and effective clearance of 
disease from all compartments.
Preclinical studies evaluating CLL patient samples have demonstrated a surge in cellular 
apoptosis with concomitant inhibition of BTK and BCL-2 suggesting that the combination of 
ibrutinib plus venetoclax (I+VEN) is synergistic.6,42 A high-throughput screen combining 
ibrutinib with a number of novel agents revealed venetoclax to be the most synergistic 
combination partner across several B-cell malignancies.48 In a study to evaluate samples from 
patients treated with ibrutinib monotherapy to explore drugs that may have a synergistic effect 
with ibrutinib in facilitating cell death, venetoclax had the most potent cell killing. Ibrutinib 
decreased levels of myeloid cell leukemia 1, an anti-apoptotic protein, which is thought to 
explain, in part, the greater apoptosis seen with venetoclax when given in combination.6
Furthermore, ibrutinib treatment may generate overexpression of BCL-2 which increases cell 
sensitivity to venetoclax.10,17 This induction of CLL cell dependence on BCL-2 further supports 
synergy in concomitant use of venetoclax with ibrutinib. In a T-cell leukemia-1 adoptive transfer 
mouse model of CLL, the combination of I+VEN resulted in a more complete and durable 
response compared with either of the single agents alone.49 Early clinical data from an ongoing,
investigator-initiated study of the combination of I+VEN in patients with high-risk 
relapsed/refractory CLL (CLARITY Study) indicate that the combination is highly effective, 
with rapid clearance of disease and acceptable tolerability.32,34 In this study, patients are treated 
with ibrutinib for 8 weeks before venetoclax is started with the recommended 5-week ramp-up to 
400 mg/day. Treatment will continue for a period of 14 to 26 months, depending on 
MRD-negative status. Among the first 35 patients who have received 4 months of therapy 
(including 8 weeks of the combination I+VEN) a rapid reduction in CLL cells in the peripheral 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
36
Approved, Date: 19 December 2019
blood was observed, (median 3-log reduction). All 25 patients who have reached their 8-month 
response assessments (including 6 months of I+VEN) have had an objective response: 15/25 
(60%) achieved CR or CRi and 7/25 (28%) have achieved an MRD-negative remission in bone 
marrow. Tolerability was generally reported as good, with most AEs being Grade 1 or 2. There 
was a single case of Grade 3 asymptomatic TLS.32 More recent data as of December 2018 show 
that after 12 months of combined therapy (I+VEN), all patients have responded and 23/40 (58%) 
have achieved a complete remission. In addition, 27/31 (87%) had no morphological evidence of 
CLL in the bone marrow biopsy and 32/34 (94%) had less than 1% CLL cells in the bone 
marrow aspirate. Undetectable-MRD (ie <0.01%) was achieved in 23/40 (58%) patients in the 
peripheral blood and in 17/41 (41%) in the bone marrow.35
Another investigator-initiated study is evaluating the combination of I+VEN in subjects with 
relapsed/refractory CLL and in treatment-naïve subjects with CLL with at least 1 of the 
following high-risk features: del17p, mutated TP53, deletion of the long arm of chromosome 11, 
unmutated IGHV, or ≥65 years of age.38 Subjects were treated with single-agent ibrutinib for 
3 months, followed by addition of venetoclax with a weekly dose escalation to the target dose of 
400 mg daily. The primary endpoint is rate of CR/CRi. With a median follow-up of 7.5 months 
(range, 0.6-12.1 months), 61 subjects have completed treatment with single-agent ibrutinib and 
begun the combination with I+VEN. Three months of single-agent ibrutinib therapy reduced the 
TLS risk category for venetoclax treatment in 51% of subjects (ie, TLS risk decreased from 
high-
or medium-risk categories to medium-
or low-risk). In the 14 subjects with 
relapsed/refractory CLL who have completed at least 3 months of combination therapy, 100% 
had a response (9 CR/CRi, 5 partial response [PR]). In the 16 subjects with treatment-naïve, 
high-risk CLL who completed at least 3 months of the combination, 100% had a response 
(9 CR/CRi, 7 PR). Across both cohorts, 6 subjects were MRD-negative by Month 9. No 
unexpected AEs were observed. Grade 3-4 neutropenia and Grade 3-4 thrombocytopenia were
reported in 44% and 4% of subjects, respectively. There was 1 case of asymptomatic TLS, and 
no cases of clinical TLS.38 Recently reported results involving the treatment-naïve cohort show 
that at 6 months of the combination treatment, 24/34 (71%) patients achieved CR/CRi and 
14/34 (41%) achieved bone marrow undetectable-MRD remission. After 12 months of the 
combination, 23/25 (92%) of the patients were in CR/CRi with 17/25 (68%) achieving bone 
marrow undetectable-MRD remission.39
Study PCYC-1142-CA is an ongoing multicenter, Phase 2 study in subjects with treatment-naïve 
CLL. Treatment consists of open-label I+VEN for approximately 15 months. Subjects who attain 
MRD-negative status at Month 15 are randomized in a double-blind fashion to receive 
continuous treatment with ibrutinib or placebo until MRD-positivity, disease progression, or 
unacceptable toxicity. In the initial safety run-in of the study, a 3-month lead-in of single-agent 
ibrutinib before adding the venetoclax per standard dose ramp-up schedule, was tested in 
14 patients. No TLS was observed during the initial safety run-in. Early data presented after 
163 patients were enrolled showed an ORR of 100% in the 14 safety run-in patients 
(1/14 confirmed CR and 13/14 PR). Nine of 11 assessed patients had MRD-negative status in 
peripheral blood. Adverse events occurring in ≥20% of I+VEN exposed subjects included 
diarrhea (39%), fatigue (23%), nausea (23%), and arthralgia (21%). Grade 3 or higher AEs that 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
37
Approved, Date: 19 December 2019
occurred in ≥3% of subjects included neutropenia (10%), hypertension (3%),
and 
thrombocytopenia (3%). No clinical TLS was observed in this phase of the study.56
Based on preliminary data from the same study, venetoclax exposure (AUC) at 400 mg once 
daily appears to be approximately 1.7-fold higher with 420 mg ibrutinib (CLL, N=32) compared 
to venetoclax single-agent 400 mg daily exposure. Within the same dataset, ibrutinib exposures 
when dosed in combination with venetoclax were comparable to that observed at 420 mg of 
ibrutinib as a single agent. To date, no new safety signals have been identified, and investigators 
are advised to monitor subjects closely for signs of toxicity.
1.6.
Overall Rationale for the Study
This study is designed to evaluate whether the combination I+VEN will result in superior 
efficacy following a fixed duration of drug administration, compared with the combination 
G-Clb, in the first-line treatment of subjects with CLL. Obinutuzumab in combination with 
chlorambucil, given for the standard duration of 6 months, is indicated for the treatment of adult 
patients with previously untreated CLL and comorbidities that make them unsuitable for 
fludarabine-based therapy. Obinutuzumab in combination with chlorambucil was chosen as the 
comparator for this study based on its efficacy and safety. It is a standard of care given with 
fixed duration and is recommended by both US and EU treatment guidelines for use in this 
patient population.15,16,18,40
As single agents, both ibrutinib and venetoclax have demonstrated efficacy and acceptable safety 
for the treatment of patients with CLL. The combination of I+VEN was chosen based on 
complementary mechanisms of action of the drugs, preclinical synergistic activity, and 
promising early clinical data as described in Section 1.5. In the frontline treatment of CLL, 
ibrutinib monotherapy has demonstrated significant PFS and OS advantages compared with 
chlorambucil. However, CR occurs in approximately 20% of patients and undetectable-MRD has 
been reported rarely.1,3 Continuous therapy has been considered necessary to maintain the benefit 
of ibrutinib therapy, and continuous therapy is associated with increasing depth of response over 
time. Although ibrutinib has demonstrated efficacy and tolerability advantages in frontline 
treatment, some patients and physicians prefer fixed-duration alternatives, such as chlorambucil 
plus obinutuzumab, as their initial therapy to avoid long-term treatment. The strategy of 
combining ibrutinib with venetoclax is anticipated to result in higher rates of disease clearance in 
all body compartments as reflected by robust MRD-negativity and durable responses thus 
allowing discontinuation of therapy following a defined period of treatment. Development of the 
I+VEN regimen could provide patients with an effective alternative dosing option to continuous 
ibrutinib therapy and the clarity of knowing the length of their treatment period. Treating for a 
fixed duration, rather than until progression, may also preserve sensitivity to ibrutinib and 
venetoclax and allow for retreatment with either agent at the time of relapse. To investigate this, 
subjects who relapse or progress after first-line treatment with fixed-duration I+VEN 
(Treatment Arm A) may receive continuous single-agent ibrutinib, if eligible, in the Subsequent 
Therapy Phase.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
38
Approved, Date: 19 December 2019
During the Treatment Phase, subjects in this study will receive ibrutinib for 15 cycles 
(1 cycle=28 days). Venetoclax dose ramp up will begin at Cycle 4 and treatment with venetoclax 
will continue for 12 cycles (see Section 6.1). The rationale for the lead-in treatment with 
ibrutinib is to minimize the risk of TLS reported with venetoclax. TLS is a well-described 
phenomenon associated with treatment with venetoclax. Recent analysis of data from 3 studies of 
single-agent ibrutinib in relapsed/refractory and treatment-naïve CLL (N=424) demonstrated that 
the majority of patients who were at high risk for TLS at baseline on the basis of lymph node 
bulk and absolute lymphocyte count (ALC) were reduced to medium- or low-risk TLS categories 
within approximately 2 to 4 months of ibrutinib treatment.55 The approach of treating with 
single-agent ibrutinib prior to commencing treatment with venetoclax has been utilized in the 
ongoing Phase 2 studies of I+VEN described previously and appears to be successful in reducing 
TLS risk.
In the Subsequent Therapy Phase, eligible subjects initially treated with either I+VEN or G-Clb 
will receive single-agent ibrutinib until disease progression or unacceptable toxicity. Subjects 
who initially responded to fixed-duration treatment with I+VEN are expected to retain sensitivity 
to ibrutinib, supporting the use of the same agent after disease relapse. For subjects previously 
treated with G-Clb, single-agent ibrutinib is an appropriate and approved second-line treatment 
option.
The population of subjects selected for this study are those considered suitable for treatment with 
the comparator, obinutuzumab in combination with chlorambucil, ie, adult patients with 
previously untreated CLL and comorbidities that make them unsuitable for fludarabine-based 
therapy. Subjects with del17p or known TP53 mutation are excluded because chlorambucil plus 
CD20 antibody is not recommended therapy for such patients per ESMO guidelines. Subjects 
will be stratified based on IGHV mutational status and presence of del11q, as these are known 
prognostic factors for efficacy outcomes in the treatment of CLL.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
39
Approved, Date: 19 December 2019
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To compare the PFS of I+VEN with that of G-Clb

PFS, as assessed by an IRC, the duration from 
date of randomization to date of disease 
progression or death, whichever occurs first
Secondary

To compare the MRD-negative remission rate of 
I+VEN with that of G-Clb 

Proportion of subjects who reach MRD-negative 
disease 
status 
(ie, 
<1 CLL 
cell 
per 
10,000 leukocytes or <0.01%) in the bone 
marrow

To compare the ORR and CR rate of I+VEN with 
that of G-Clb

To determine the response duration

Rate of CR and rate of ORR (CR, CRi, nodular 
PR [nPR], and PR) for at least 2 months, based 
on IRC

Duration in days from the date of initial 
documentation of a response to the date of first 
documented evidence of progressive disease 
(PD) or death

To compare OS of I+VEN with that of G-Clb

Measured from the date of randomization to the 
date of death from any cause

To compare time-to-next treatment of I+VEN with 
that of G-Clb

The time from date of randomization to the start
date of any anti-leukemic therapy subsequent to 
the study treatment

To compare patient-reported health status and 
fatigue of I+VEN with that of G-Clb

Time to worsening in functional status and 
fatigue, as measured by the EuroQol 5 
Dimension 5 Level questionnaire (EQ-5D-5L), 
the European Organization for Research and 
Treatment 
of 
Cancer 
Quality 
of 
Life 
Questionnaire (EORTC QLQ)-C30, and the 
Functional Assessment of Chronic Illness 
Therapy (FACIT)-Fatigue scale

To evaluate the safety profile of I+VEN in subjects 
with previously untreated CLL 

Safety parameters including AEs and laboratory 
tests

To compare hematologic improvement of I+VEN 
with that of G-Clb

Improvement in hemoglobin lasting for 56 days
without transfusions or growth factors

Improvement in platelets lasting for 56 days 
without transfusions or growth factors  

To evaluate the trough levels of ibrutinib and 
venetoclax when given in combination

Descriptive statistics of ibrutinib and venetoclax 
trough levels in plasma 
Exploratory

To examine molecular and protein markers 
associated with response to and relapse following 
study treatment

To examine response to subsequent therapy with 
single-agent ibrutinib

Next-generation sequencing (NGS) and gene
expression profiling analyses 

ORR in subjects who received single-agent 
ibrutinib
2.2.
Hypothesis
Treatment with the combination of I+VEN will result in longer PFS compared with G-Clb in 
subjects with previously untreated CLL.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
40
Approved, Date: 19 December 2019
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, open-label, multicenter, Phase 3 study to determine the efficacy and safety 
of the combination of I+VEN, compared with G-Clb, administered to subjects with previously 
untreated CLL who meet the iwCLL treatment criteria.
Approximately 200 subjects will be randomly assigned in a 1:1 ratio to either Treatment Arm A 
(I+VEN) or Treatment Arm B (G-Clb). Stratification factors will include the IGHV mutational 
status (mutated vs. unmutated vs. not available) and presence of deletion of the long arm of 
chromosome 11 ([del11q] yes vs. no).
Subjects randomly assigned to Treatment Arm A (I+VEN) will receive ibrutinib for 15 cycles 
(1 cycle=28 days), starting with 3 cycles of ibrutinib monotherapy. Venetoclax dose ramp-up 
will begin at Cycle 4. The combination of I+VEN will be given for 12 cycles (through Cycle 15).
Subjects randomly assigned to Treatment Arm B (G-Clb) will receive G-Clb for 6 cycles. An 
independent Data Monitoring Committee (DMC) for safety review will be formed and 
constituted according to regulatory agency guidelines (see Section 11.9). Subjects who are 
eligible and choose to participate in the Subsequent Therapy Phase will receive subsequent 
single-agent ibrutinib until disease progression or unacceptable toxicity. 
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. 
The Screening Phase will be for a period of 30 days before randomization. The Treatment Phase 
will extend from randomization until study treatment discontinuation from fixed-duration 
treatment with I+VEN or G-Clb. The Follow-up Phase will begin once a subject discontinues 
treatment. Subjects who discontinue treatment for reasons other than disease progression in 
Treatment Phase will continue to have disease evaluations (DEs) according to Table 3. Subjects 
from either treatment arm who subsequently develop IRC-confirmed PD and have active disease 
requiring treatment may be eligible to receive single-agent ibrutinib given until disease
progression or unacceptable toxicity as part of the Subsequent Therapy Phase. Participation in 
this phase of the study is not mandatory and is based on investigator’s discretion. The Follow-up 
Phase will continue until death, lost to follow-up, consent withdrawal, or study end, whichever 
occurs first. Subjects who discontinue treatment for reasons other than disease progression in the 
Subsequent Therapy Phase will continue to have DEs according to Table 4. The primary analysis 
and reporting of the study will be conducted after 71 PFS events have been observed after 
randomization. Study end is defined as approximately 5 years after the last subject is randomized 
into the study or after 50% of the subjects have died, whichever comes first. Subjects receiving 
single-agent ibrutinib in the Subsequent Therapy Phase may be offered participation in a separate 
study on or before the end of the current study to ensure continuity of ibrutinib therapy.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
41
Approved, Date: 19 December 2019
Assessment of disease response and progression will be conducted in accordance with the 
iwCLL 2008 Guidelines.28 The investigator will evaluate sites of disease by physical 
examination and radiological imaging. The primary efficacy analysis of PFS will be based on the 
IRC assessment of PD in the intent-to-treat (ITT) population. Patient-reported health outcomes, 
functional status, and well-being will also be measured.
During the study, safety evaluations will include AE monitoring, physical examinations, review 
of concomitant medications, and evaluation of clinical laboratory parameters (hematology and 
chemistry). At each site visit, subjects will be assessed for toxicity. Blood samples will be drawn 
for pharmacokinetic (Treatment Arm A only) and biomarker studies. All study evaluations will 
be conducted per the Time and Events Schedule that corresponds to the assigned treatment arm
(Table 1 for Treatment Arm A, Table 2 for Treatment Arm B, Table 3 for DEs, and Table 4 for 
the Subsequent Therapy Phase).
3.2.
Study Design Rationale
This is a Phase 3, randomized study evaluating the combination I+VEN compared with the 
standard of care G-Clb, in the first-line treatment of subjects with CLL. The study will recruit 
subjects globally and is adequately powered to demonstrate an improvement in PFS with the 
I+VEN combination over the standard of care. This study design is widely employed to obtain 
data to support regulatory applications for new treatments.
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. Subjects will be stratified by IGHV
mutational status (mutated vs. unmutated vs. not available), a well-defined prognostic indicator 
for patients with CLL, and presence of del11q (yes vs. no).
The primary endpoint for the Phase 3 Study CLL3011 is independently reviewed PFS using the 
2008 iwCLL guidelines, including recent clarifications.26,27 Demonstration of an improvement in 
PFS is viewed as a clinical benefit and an acceptable primary endpoint for CLL. As such, it has 
served as the basis for regulatory approvals in CLL. The key secondary endpoints for this study 
include rate of MRD-negative remissions in the bone marrow, ORR, OS, and safety of the
combination. The endpoints of rate of MRD-negative remission, ORR, and OS are well-defined 
and recommended endpoints for the evaluation of new treatments for CLL.
The trial involves a novel combination regimen given at a finite duration. Treatment with I+VEN
is anticipated to lead to a lower rate of clonal evolution and resistance mutations. For this reason, 
blood and bone marrow samples will be collected at baseline and other prespecified timepoints to 
explore biomarkers predictive of response to and relapse following study treatment.
Subjects from either treatment arm who progress after I+VEN or G-Clb may become eligible to 
receive single-agent ibrutinib in the Subsequent Therapy Phase. Response data, as well as 
biomarker samples, will be collected to evaluate the efficacy of ibrutinib in subjects previously 
treated with I+VEN in a subsequent pooled analysis.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
42
Approved, Date: 19 December 2019
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed up to 30 days before randomization.
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, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed. 
Eligibility criteria for the Subsequent Therapy Phase are presented in Section 9.1.5.1. 
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Adult subjects who are:
a.
≥65 years old or, 
b.
18 to 64 years old and have at least 1 of the following:
1)
CIRS score 6 (see Attachment 2)48
2)
Creatinine clearance (CrCl) estimated <70 mL/min using Cockcroft-Gault equation
2. Diagnosis of CLL or SLL that meets iwCLL criteria.28,45
3. Active CLL/SLL requiring treatment per the iwCLL criteria.28
a.
Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia or thrombocytopenia or both;
b.
Massive (ie, at least 6 cm below the left costal margin) or progressive or symptomatic 
splenomegaly;
c.
Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic 
lymphadenopathy;
d.
Progressive lymphocytosis with an increase of more than 50% over a 2-month period or 
lymphocyte doubling time of less than 6 months;
e.
Constitutional symptoms, defined as 1 or more of the following:
1)
Unintentional weight loss ≥10% within the previous 6 months prior to the start of 
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; 
4)
Night sweats for more than 1 month without evidence of infection.
4. Measurable nodal disease (by CT), defined as at least one lymph node >1.5 cm in longest 
diameter.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
43
Approved, Date: 19 December 2019
5. ECOG PS Grade ≤2.
6. Adequate organ function defined as follows:
a.
Absolute neutrophil count (ANC) ≥750 cells/µL independent of growth factor support;
b.
Platelets ≥50,000 cells/µL independent of transfusion support for at least 7 days prior to 
randomization;
c.
Hemoglobin >8.0 g/dL independent of transfusion support for at least 7 days prior to 
randomization;
d.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x upper 
limit of normal (ULN);
e.
Total bilirubin ≤1.5 x ULN (unless due to Gilbert’s syndrome);
f.
Estimated CrCl ≥30 mL/min (Cockcroft-Gault equation).
7. Prothrombin time/international normalized ratio (INR) <1.5 x ULN and activated partial 
thromboplastin time (aPTT) <1.5 x ULN (unless abnormalities are unrelated to coagulopathy 
or bleeding disorder).
8. Woman of childbearing potential must have a negative, highly sensitive serum 
(-human chorionic gonadotropin [-hCG]) or urine pregnancy test at screening.
9. Women of childbearing potential must be practicing a highly effective, preferably 
user-independent method of birth control (failure rate of <1% per year when used 
consistently and correctly) during treatment with any drug in this study and for up to 1 month
after the last dose of venetoclax, 3 months after last dose of ibrutinib, 6 months after the last 
dose of chlorambucil, and 18 months after last dose of obinutuzumab, consistent with local 
regulations regarding the use of birth control methods for subject participating in clinical 
studies. Women using hormonal contraceptives should add a barrier method. 
Examples of highly effective methods of contraception are located in Attachment 3, 
Contraceptive and Barrier Guidance and Collection of Pregnancy Information.
10. Women must agree not to donate eggs for the purpose of assisted reproduction during 
treatment and for 3 months after the last dose of ibrutinib and 1 month after the last dose of 
venetoclax, 6 months after the last dose of chlorambucil, and 18 months after last dose of
obinutuzumab. 
11. During treatment and for a minimum of 1 spermatogenesis cycle (defined as 90 days) after 
receiving the last dose of any study treatment, in addition to the user-independent highly 
effective method of contraception, a man
a.
who is sexually active with a woman of childbearing potential must agree to use a 
barrier 
method
of 
contraception 
(eg, 
condom 
with 
spermicidal 
foam/gel/film/cream/suppository)
b. who is sexually active with a woman who is pregnant must use a condom
c.
must agree not to donate sperm for the purpose of reproduction 
12. Must sign an informed consent form (ICF) indicating that he or she understands the purpose 
of, and the procedures required for, the study. Subjects must be willing and able to adhere to 
the prohibitions and restrictions specified in this protocol.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
44
Approved, Date: 19 December 2019
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Prior anti-leukemic therapy for CLL or SLL.
2.
Presence of del17p or known TP53 mutation detected at a threshold of 10% variable allele 
frequency (VAF).40
3.
Major surgery within 4 weeks of first dose of study treatment. For definition of major 
surgery, see Section 4.3 or contact the medical monitor.
4.
Known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
5.
Central nervous system (CNS) involvement or suspected Richter’s syndrome.
6.
An individual organ/system impairment score of 4 as assessed by CIRS, except for the eyes, 
ears, nose, throat, and larynx system, limiting the ability to receive treatment in this study.48
7.
Uncontrolled 
autoimmune 
hemolytic 
anemia 
or 
autoimmune 
thrombocytopenia 
(Coombs positivity in the absence of hemolysis is not an exclusion).
8.
Chronic use of corticosteroids more than 20 mg/day of prednisone or its equivalent within 
7 days of initiation of study treatment.
9.
History of prior malignancy, except:
a.
Malignancy treated with curative intent and with no known active disease present for 
≥24 months 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;
d. Malignancy, which is considered cured with minimal risk of recurrence.
10. Received live, attenuated vaccine within 4 weeks of randomization.
11. History of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, or 
hepatic condition that in the opinion of the investigator would adversely affect a subject’s 
participation in the study.
12. Currently active, clinically significant Child-Pugh Class B or C hepatic impairment
according to the Child-Pugh classification (see Attachment 4 Child-Pugh classification).
13. 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 or put the study outcomes at undue risk.
14. Inability or difficulty swallowing capsules/tablets, malabsorption syndrome, or any disease 
or medical condition significantly affecting gastrointestinal function.
15. Stroke or intracranial hemorrhage within 6 months prior to randomization.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
45
Approved, Date: 19 December 2019
16. Active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or 
Class 3 or 4 congestive heart failure as defined by the New York Heart Association 
Functional Classification; or a history of myocardial infarction, unstable angina, or acute 
coronary syndrome within 6 months prior to randomization.
17. Anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) or 
ongoing treatment with agents known to be strong cytochrome (CYP) P450 3A inhibitors.
18. Positive test for HIV by history or at screening. 
19. Subjects who are positive for Hepatitis B core antibody, Hepatitis B surface antigen, or 
Hepatitis C antibody must have a negative PCR result before enrollment. Those who are 
PCR positive will be excluded.
20. Known allergy to either xanthine oxidase inhibitors or rasburicase.
21. Female subjects who are pregnant, breastfeeding, or planning to become pregnant while 
enrolled in this study or up to 1 month after the last dose of venetoclax, 3 months of last 
dose of ibrutinib, 6 months after the last dose of chlorambucil, or 18 months after last dose 
of obinutuzumab.
22. Male subjects who plan to father a child while enrolled in this study or within 90 days after 
the last dose of any study treatment.
23. Known hereditary galactose intolerance, the Lapp lactase deficiency, or glucose-galactose 
malabsorption.
24. Any contraindication to one of the study medications including hypersensitivity to the active 
substance or to any of the excipients of ibrutinib, venetoclax, obinutuzumab, or 
chlorambucil.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes after screening (based on available laboratory results or 
receipt of additional medical records), but before the first dose of study treatment such that he or 
she no longer meets all eligibility criteria, the subject should be excluded from participation in 
the study. Section 17.4, Source Documentation, describes the required documentation to support 
meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must adhere to the following prohibitions and restrictions during the study. 
Subjects on I+VEN should avoid consumption of foods or beverages containing grapefruit,
Seville oranges, and starfruit (carambola) as these inhibit CYP3A4/5 and alter drug metabolism. 
Precautions with concomitant medications and prohibited 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 ibrutinib:

For major surgical procedures, including any surgery or invasive procedure requiring sutures 
or staples for closure, ibrutinib should be held at least 7 days prior to the intervention and at 
least 7 days after the procedure, and restarted at the discretion of the investigator, when the 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
46
Approved, Date: 19 December 2019
surgical site is reasonably healed without serosanguineous drainage or the need for drainage 
tubes.

For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis), ibrutinib should be held for at least 3 days prior to the procedure and should 
not be restarted for at least 3 days after the procedure. For bone marrow biopsies that are 
performed while the subject is on study medication, it is not necessary to hold the study 
medications.

For emergency procedures, all study treatments 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 
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study for the Treatment Phase. Subjects will 
be randomly assigned to 1 of 2 treatment groups based on a computer-generated randomization 
schedule prepared before the study by or under the supervision of the sponsor. The 
randomization will be balanced by using permuted block and will be stratified by IGHV
mutational status (mutated vs. unmutated vs. not available) and presence of del11q (yes vs. no). 
The interactive web response system (IWRS) will assign a unique intervention code, which will 
dictate the intervention assignment and matching study intervention 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.
6.
DOSAGE AND ADMINISTRATION
Subjects will be randomly assigned 1:1 to receive I+VEN (Treatment Arm A; see Section 6.1) or 
G-Clb (Treatment Arm B; see Section 6.2) in the Treatment Phase. Eligible subjects who 
participate in the Subsequent Therapy Phase will receive single-agent ibrutinib (see Section 6.3).
6.1.
Treatment Arm A (Ibrutinib plus Venetoclax) Administration
Subjects randomly assigned to Treatment Arm A (I+VEN) will receive ibrutinib (420 mg/day 
orally) given as lead-in treatment for 3 cycles. Starting at Cycle 4 and contingent on completion 
of TLS risk assessment (see Section 6.1.2.2), venetoclax dose ramp-up (from 20 to 400 mg over 
5 weeks) will begin, and venetoclax will be administered with ibrutinib for 12 cycles through 
Cycle 15.
6.1.1.
Ibrutinib
6.1.1.1.
Dosage and Administration
Ibrutinib 420 mg (3 x 140 mg capsules) is administered orally once daily, starting at Cycle 1, 
Day 1. The capsules are to be taken around the same time each day with a glass of water. The 
capsules should be swallowed whole with water and should not be opened, broken, or chewed. 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
47
Approved, Date: 19 December 2019
During cycles with venetoclax combination dosing, ibrutinib and venetoclax should be taken 
together at the same time, with a glass of water and a meal. If a dose of ibrutinib 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.
6.1.1.2.
Ibrutinib Dose Modification
Treatment with ibrutinib should be temporarily stopped for unmanageable, potentially 
ibrutinib-related toxicity that is Grade ≥3 in severity. Ibrutinib may be temporarily stopped for a 
maximum of 28 consecutive days. Ibrutinib should be discontinued permanently in the event of a 
toxicity lasting more than 28 days, unless continued treatment is approved by the sponsor. 
The dose of ibrutinib must be modified according to the dose modification guidance in Table 7 if 
any of the following potentially drug-related toxicities occur:

ANC <500 cells/µL for more than 7 days. See Section 8.1 for instructions regarding the use 
of growth factor support.

Platelets <50,000 cells/µL in the presence of clinically significant bleeding.

Platelets <25,000 cells/µL.

Grade 3 nausea or Grade 3 or 4 vomiting or Grade 3 or 4 diarrhea, if persistent despite 
optimal anti-emetic or anti-diarrheal therapy. 

Any other Grade 4 or unmanageable Grade 3 toxicity.
If the dose of ibrutinib is reduced, the dose of ibrutinib may be re-escalated at investigator’s 
discretion after 2 dose-reduced cycles in the absence of a recurrence of the toxicity that led to the 
reduction. No dose escalation of ibrutinib above 420 mg is allowed in this study. Dose changes 
must be recorded in the Dose Administration electronic case report form (eCRF).

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
48
Approved, Date: 19 December 2019
Table 7:
Ibrutinib Dose Modifications
Occurrence
Action to be Taken 
First
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at original dose level
Second
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 1 dose level lower 
(ie, 280 mg/day dose)
Third
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 1 dose level lower 
(ie, 140 mg/day dose)
Fourth
Discontinue study drug
Note: For hematologic toxicities, restart of ibrutinib may be considered once the toxicity has resolved to study entry 
criteria level or better.
For dose modification during concomitant treatment with CYP3A inhibitors refer to 
Attachment 9.
During cycles with venetoclax combination dosing, the decision to dose modify a study drug due 
to a toxicity will be based on the investigator attribution of relatedness to a given drug. For 
example, if an AE occurs and is considered related to venetoclax but not ibrutinib, the dose of 
venetoclax should be modified while ibrutinib should remain the same. If the AE is considered 
potentially related to both drugs, adjusting the dose of venetoclax before ibrutinib is the 
recommended first action, taking into consideration the possibility of higher systemic exposure 
of venetoclax when administered in combination with ibrutinib. For cases where the investigator 
is uncertain of what action to take, the study monitor may be contacted for further discussion.
If ibrutinib is discontinued for toxicity, then treatment with venetoclax may be continued.
6.1.1.2.1.
Ibrutinib Dose Modification for Subjects With Hepatic Impairment
Ibrutinib is metabolized in the liver. Therefore, subjects with clinically significant hepatic 
impairment at the time of screening (Child-Pugh Class B or C) are excluded from study 
participation. For subjects who develop mild liver impairment while on study (Child-Pugh 
Class A), the recommended dose reduction for ibrutinib is to a level of 280 mg daily. For 
subjects who develop moderate liver impairment while on study (Child-Pugh Class B), the 
recommended dose reduction is to a level of 140 mg daily. For subjects who develop severe 
hepatic impairment (Child-Pugh Class C), ibrutinib must be held until resolved to moderate 
impairment (Child-Pugh Class B) or better. Monitor subjects for signs of toxicity and follow 
dose modification guidance as needed (see Attachment 4 for Child-Pugh classification).
6.1.2.
Venetoclax
For full details of the warnings, precautions and AEs associated with treatment with venetoclax, 
please refer to the product label.54

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
49
Approved, Date: 19 December 2019
6.1.2.1.
Dosage and Administration
Venetoclax tablets should be taken orally once daily with a meal and water around the same time 
each day. Venetoclax tablets should be swallowed whole and not chewed, crushed, or broken 
prior to swallowing. During cycles with ibrutinib combination dosing, ibrutinib and venetoclax 
should be taken together at the same time. If a subject misses a dose of venetoclax within 8 hours 
of the time it is usually taken, the subject should take the missed dose as soon as possible on the 
same day. If a subject misses a dose of venetoclax by more than 8 hours, the subject should not 
take the missed dose and should resume the usual dosing schedule the following day. If a subject
vomits following dosing, no additional dose should be taken that day. The next prescribed dose 
should be taken at the usual time the following day.
The starting dose is 20 mg of venetoclax once daily for 7 days. The dose must be gradually 
increased over a period of 5 weeks up to the recommended daily dose of 400 mg as shown in
Figure 3. 
Figure 3:
Venetoclax Dose Ramp-up
The 5-week dose-titration schedule is designed to gradually reduce tumor burden (debulk) and 
decrease the risk of TLS. 
The first dose of venetoclax will be delivered in the clinic (or in the hospital depending on 
TLS risk category) on Cycle 4 Day 1. Dose escalation will occur in accordance with specific 
risk-based TLS prophylaxis and monitoring measures that may include dose delays or dose 
reductions. After completion of the 5-week dose ramp-up, subsequent dosing is typically 
continued on an outpatient basis.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
50
Approved, Date: 19 December 2019
6.1.2.2.
Prophylaxis and Management of Tumor Lysis Syndrome
Venetoclax may cause a rapid reduction in tumor burden and thus poses a risk for TLS in the 
initial 5-week ramp-up phase. Changes in electrolytes consistent with TLS that require prompt 
management may occur as early as 6 to 8 hours following the first dose of venetoclax and at each 
dose increase. The risk of TLS is a continuum based on multiple factors, including tumor burden 
and comorbidities (Table 8). Subjects with high tumor burden are at a greater risk of TLS when 
initiating venetoclax. Reduced renal function further increases the risk. The risk may decrease as 
tumor burden decreases with treatment. 
Prior to initiating venetoclax, tumor burden assessment, including radiographic evaluation 
(eg, CT scan), must be performed for all subjects. Blood chemistry (potassium, uric acid, 
phosphorus, calcium, and creatinine) must be assessed as per the Time and Events Schedules and 
pre-existing abnormalities must be corrected. The prophylaxis measures listed below must be 
followed. More intensive measures should be employed as risk increases.
In all subjects, assess subject-specific factors for level of risk of TLS and provide prophylactic 
hydration and anti-hyperuricemics to subjects prior to the first dose of venetoclax to reduce the
risk of TLS. Employ more intensive measures (intravenous hydration, frequent monitoring, and 
hospitalization) as risk increases.
Subjects with baseline CrCl ≤50 mL/min or with high risk for TLS as defined by at least one 
lesion ≥10 cm, or at least one lesion ≥5 cm plus circulating lymphocytes >25,000 cells/µL,
should be hospitalized during the first 24 to 48 hours of treatment with 20 mg and 50 mg of 
venetoclax for TLS monitoring and intravenous hydration. Hospitalization should be considered 
for subjects who are at low or medium risk of TLS if they do not have immediate access to a 
facility capable of correcting TLS promptly, or are otherwise considered at risk for TLS.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
51
Approved, Date: 19 December 2019
Table 8:
TLS Prophylaxis Based on Tumor Burden from Clinical Trial Data (consider all 
comorbidities before final determination of prophylaxis and monitoring schedule)
Tumor Burden
Prophylaxis
Blood Chemistry Monitoringc,d
Hydrationa
Anti-
hyperuricemics
Setting and Frequency of 
Assessments
Low
All LN <5 cm 
AND 
ALC <25 x109/L 
Oral (1.5-2 L)/daily
Allopurinolb
Outpatient 

Predose, 6 to 8 hours, 
24 hours at first dose of 
20 mg and 50 mg 

Predose at subsequent 
ramp-up doses 
Medium
Any LN 5 cm to <10 cm 
OR 
ALC ≥25 x109/L 
Oral (1.5-2 L)/daily
and consider 
additional 
intravenous 
Allopurinolb
Outpatient 

Predose, 6 to 8 hours
and 24 hours at first 
dose of 20 mg and 
50 mg 

Predose at subsequent 
ramp-up doses 

Consider 
hospitalization for 
subjects with CrCl 
<80mL/min at first 
dose of 20 mg and 
50 mg; see below for 
monitoring in hospital 
High
Any LN ≥10 cm 
OR 
ALC ≥25 x109/L 
AND 
any LN ≥5 cm 
Oral (1.5-2 L)/daily
and intravenous 
(150-200 mL/hr as 
tolerated) 
Allopurinolb; 
consider rasburicase 
if baseline uric acid 
is elevated 
In hospital at first dose of 20 mg 
and 50 mg 

Predose, 4, 8,12 and 
24 hours 
Outpatient at subsequent ramp-up 
doses 

Predose, 6 to 8, and 
24 hours 
Any LN size or ALC
AND
CrCl ≤50 mL/min 
Abbreviations: ALC=absolute lymphocyte count; CrCL=creatinine clearance; LN=lymph node; TLS=tumor lysis syndrome. 
a.
Start oral hydration 2 days prior to the initiation of venetoclax. Administer intravenous hydration for any subject who cannot 
tolerate oral hydration.
b.
Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of venetoclax. 
c.
Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time.
d.
For subjects at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours with each subsequent ramp-up dose.
See Attachment 6 for recommendations for initial management of electrolyte abnormalities and 
prevention of TLS.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
52
Approved, Date: 19 December 2019
6.1.2.3.
Venetoclax Dose Modification
See Table 9 for dose modifications for toxicities related to venetoclax. For subjects who have 
had a dosing interruption greater than 1 week during the first 5 weeks of ramp-up phase or 
greater than 2 weeks when at the daily dose of 400 mg, reassess for risk of TLS to determine if 
re-initiation with a reduced dose is necessary (eg, all or some levels of the dose ramp-up 
schedule). During the ramp-up phase, continue the reduced dose for 1 week before increasing the 
dose. Consider discontinuing venetoclax for subjects who require dose reductions to less than 
100 mg for more than 2 weeks.
Table 9:
Venetoclax Recommended Dose Modifications for Toxicities
Event
Occurrence 
Action
Tumor Lysis Syndrome
Blood chemistry changes or 
symptoms suggestive of TLS 
(see Howard Criteria in 
Attachment 7)
Any
Withhold the next day’s dose. If resolved within 
24-48 hours of last dose, resume at the same dose.
For any blood chemistry changes requiring more than 
48 hours to resolve, resume at a reduced dose (see Table 10).
For any events of clinical TLSa, resume at a reduced dose following 
resolution (see Table 10).
Non-Hematologic Toxicities
Grade 3 or 4 non-hematologic 
toxicities 
1st occurrence 
Withhold venetoclax
Once the toxicity has resolved to Grade 1 or baseline level, venetoclax 
therapy may be resumed at the same dose. No dose modification is 
required. 
2nd and subsequent 
occurrences 
Withhold venetoclax.
Follow dose reduction guidelines in Table 10 when resuming treatment 
with venetoclax after resolution. A larger dose reduction may occur at 
the discretion of the investigator. 
Hematologic Toxicities
ANC <1000/µL with infection 
or fever;
ANC < 500/µL
Platelet <25,000/µL
Hb <8g/dL
1st occurrence 
Withhold venetoclax.
To reduce the infection risks associated with neutropenia, G-CSF may 
be administered with venetoclax if clinically indicated. Once the 
toxicity has resolved to study entry criteria level or better, venetoclax 
therapy may be resumed at the same dose. 
2nd and subsequent 
occurrence 
Withhold venetoclax.
Consider using G-CSF as clinically indicated.
Follow dose reduction guidelines in Table 10 when resuming treatment 
with venetoclax after resolution. Additional dose reductions may occur 
at the discretion of the physician. 
Abbreviations: ANC=absolute neutrophil count; G-CSF=granulocyte-colony stimulating factor; Hb=hemoglobin; TLS=tumor 
lysis syndrome
a
Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac 
arrhythmias, or sudden death and/or seizures.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
53
Approved, Date: 19 December 2019
Table 10:
Dose Modification for Toxicity during Venetoclax Treatment
Dose at Interruption, mg
Restart Dose, mga
400
300
300
200
200
100
100
50
50
20
20
10
a.
During the dose-titration phase, continue the reduced dose for 1 week before increasing the dose.
Use of strong CYP3A inhibitors is contraindicated during venetoclax initiation and dose 
ramp-up. For dose modification during concomitant treatment with CYP3A inhibitors refer to 
Attachment 9.
During cycles with I+VEN combination dosing, the decision to dose modify a study drug due to 
a toxicity will be based on the investigator attribution of relatedness to a given drug. For 
example, if an AE occurs and is considered related to venetoclax but not ibrutinib, the dose of 
venetoclax should be modified while ibrutinib should remain the same. If the AE is considered 
potentially related to both drugs, adjusting the dose of venetoclax before ibrutinib is the 
recommended first action, taking into consideration the possibility of higher systemic exposure 
of venetoclax when administered in combination with ibrutinib. For cases where the investigator 
is uncertain of what action to take, the study monitor may be contacted for further discussion.
If venetoclax is discontinued for toxicity, then treatment with ibrutinib may be continued.
6.2.
Treatment Arm B (Chlorambucil plus Obinutuzumab) Administration
Subjects randomly assigned to Treatment Arm B will receive 6 cycles (each cycle is defined as 
28 days) of G-Clb treatment in the absence of disease progression or treatment-limiting toxicity, 
as shown below. Obinutuzumab infusions will be administered in clinic as described in 
Section 6.2.1. Chlorambucil will be given in clinic on days that coincide with obinutuzumab 
infusions. On days in which chlorambucil is administered alone, it may be given in clinic or 
issued to the subject for home administration, as described in Section 6.2.2.1.

Obinutuzumab, 1000 mg infused IV on Days 1, 8 and 15 of Cycle 1, and on Day 1 of
Cycles 2 to 6 

Chlorambucil, 0.5 mg/kg body weight, on Days 1 and 15 of Cycles 1 to 6
6.2.1.
Obinutuzumab
For full details of the warnings, precautions and AEs associated with treatment with 
obinutuzumab, please refer to the product label.22

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
54
Approved, Date: 19 December 2019
6.2.1.1.
Obinutuzumab Dosage and Administration
Each dose of obinutuzumab is 1000 mg administered intravenously, per institutional standards, 
with the exception of the first infusion in Cycle 1 (Table 11). It is recommended that the initial 
1000 mg dose be administered over Day 1 (100 mg) and Day 2 (900 mg). For subjects who 
tolerate the initial 100 mg dose well and required no dose interruption or modification of the 
infusion rate, the treating physician may opt to administer the remaining 900 mg on Day 1. 
Obinutuzumab should be administered according to the following schedule:
Table 11:
Obinutuzumab Dosing Schedule
Day of
Treatment Cycle
Dose of
Obinutuzumab
Rate of infusion (in the absence of infusion 
reactions/hypersensitivity during previous infusions)
Cycle 1
Day 1
100 mg
Administer at 25 mg/hr over 4 hours. Do not increase the 
infusion rate.
Day 2 
(or Day 1 
continued)
900 mg
Administer at 50 mg/hr. The rate of the infusion may be 
escalated in increments of 50 mg/hr every 30 minutes to a 
maximum rate of 400 mg/hr.
Day 8
1000 mg
If no infusion reaction during the previous infusion and the 
final rate was 100 mg/hr or faster, infusions may be started at
a rate of 100 mg/hr and increased by 100 mg/hr increments 
every 30 minutes to a maximum of 400 mg/hr.
Day 15
1000 mg
Cycle 2-6
Day 1
1000 mg
If a planned dose of obinutuzumab is missed, it should be administered as soon as possible; do 
not wait until the next planned dose. The planned treatment interval should be maintained 
between doses. If appropriate, subjects who do not complete the Day 1 Cycle 1 dose may 
proceed to the Day 2 Cycle 1 dose.
6.2.1.1.1.
Obinutuzumab Premedication 
Premedication for infusion-related reactions (IRRs) and TLS is recommended; please see 
Attachment 8 for details regarding management of these risks.
6.2.1.2.
Obinutuzumab Dose Delays and Modifications
6.2.1.2.1.
Infusion Reactions
Medical management (eg, glucocorticoids, epinephrine, bronchodilators, and/or oxygen) should 
be provided for infusion reactions as needed. Subjects should be closely monitored during the 
entire infusion. Note that infusion reactions within 24 hours of receiving obinutuzumab have 
occurred. If a subject experiences an infusion reaction of any grade during infusion, adjust the 
infusion as follows:

Grade 4 (life-threatening): For any Grade 4 infusion reaction, including anaphylaxis and 
acute life-threatening respiratory symptoms, stop infusion immediately and permanently 
discontinue obinutuzumab therapy.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
55
Approved, Date: 19 December 2019

Grade 3 (severe): Interrupt infusion and manage symptoms. Upon resolution of symptoms, 
consider restarting obinutuzumab infusion at no more than half the previous rate (the rate 
being used at the time that the infusion reaction occurred) and, if subject does not experience 
any further infusion reaction symptoms, infusion rate escalation may resume at the 
increments and intervals as appropriate for the treatment dose (Table 11). Permanently 
discontinue treatment if subject experience a Grade 3 infusion-related symptom at 
rechallenge. Cycle 1 Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, 
but not increased further.

Grade 1 to 2 (mild to moderate): Reduce infusion rate or interrupt infusion and treat 
symptoms. Upon resolution of symptoms, continue or resume infusion and, if subject does 
not experience any further infusion reaction symptoms, infusion rate escalation may resume 
at the increments and intervals as appropriate for the treatment dose (Table 11). Cycle 1 
Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased 
further.
If the previous infusion rate was not well tolerated, instructions for the infusion rate of Cycle 1 
Days 1 and 2 should be used for subsequent cycles.
6.2.1.2.2.
Obinutuzumab Dose Delays
There will be no dose reductions for obinutuzumab. Obinutuzumab should be withheld for any 
unmanageable, potentially obinutuzumab-related toxicity that merits a dose delay in the opinion 
of the investigator. This includes active infections, severe or life-threatening cytopenia, or a 
Grade ≥2 non-hematologic toxicity. Obinutuzumab therapy should be withheld until toxicity has 
resolved to study entry criteria level or better for hematologic toxicities or at least Grade 1 for 
non-hematologic toxicities. In certain circumstances, therapy with obinutuzumab may be 
re-initiated despite an ongoing toxicity which has not resolved to Grade ≤1, provided it is 
clinically appropriate in the opinion of the investigator and it has been discussed with the 
medical monitor.
Investigators should refer to the current obinutuzumab package insert for a comprehensive list of 
potential adverse reactions,22 their prophylaxis and management. Particular attention should be 
paid to the Warnings and Precautions sections. Obinutuzumab may cause severe and 
life-threatening infusion reactions. Management of infusion reactions may require temporary 
interruptions, reductions in the rate of infusion, or treatment discontinuation. TLS has also been 
observed in patients treated with obinutuzumab and should be managed in accordance with the 
package insert.22
Obinutuzumab may be held for a maximum of 28 days due to toxicity. Obinutuzumab treatment 
should be discontinued in the event of a toxicity lasting >28 days, unless discussed with and 
approved by the medical monitor. If obinutuzumab is discontinued due to toxicity, then treatment 
with chlorambucil may be continued.
6.2.2.
Chlorambucil
For full details of the warnings, precautions and AEs associated with treatment with 
chlorambucil, please refer to the product label.39

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
56
Approved, Date: 19 December 2019
6.2.2.1.
Chlorambucil Dosage and Administration
Chlorambucil will be administered orally at a dose of 0.5 mg/kg body weight, on Days 1 and 15 
of Cycles 1 to 6 (each of 28-day duration). Chlorambucil tablets should be taken on an empty 
stomach (at least one hour before meals or 3 hours after meals). 
On Day 1 and Day 15 of Cycle 1, and on Day 1 of Cycles 2 to 6, chlorambucil will be given in 
clinic after the required serum chemistry and hematology testing has been completed and the 
results assessed by the treating physician. Chlorambucil for Day 15 of Cycles 2 to 6 may be 
issued to the subject for home administration during the Day 1 clinic visit for each respective 
cycle. Subjects must be advised to await instructions from the treating physician before taking 
the Day 15 dose of chlorambucil at home. Predose serum chemistry and hematology testing must 
be completed and the results assessed by the treating physician before each Day 15 dose of 
chlorambucil. However, these may be done outside the treating institution.
6.2.2.2.
Chlorambucil Dose Modifications
The guidelines for chlorambucil dose reductions are described in Table 12. A dose delay of up to 
28 days is permitted for chlorambucil. If the treatment is delayed for more than 28 days, 
chlorambucil should be discontinued. If severe or life-threatening cytopenia listed prevents 
treatment on Day 15 of any cycle, the Day 15 chlorambucil dose should be skipped. 
Chlorambucil administration on Day 1 of the following cycle will be given if the cytopenia 
resolves to Grade ≤2. If the cytopenia persists, chlorambucil administration should be delayed 
until the cytopenia improves to Grade ≤2.
Table 12:
Dose Modification for Chlorambucil Due to Toxicity
Toxicity
Chlorambucil Dose Action
Cytopenia defined as one of the following:
ANC <500/µL for ≥7 days
Platelet count <50,000/µL with bleeding
Platelet count <25,000/µL
Hgb <8.0 g/dL
Delay dosing for a maximum of 4 weeks
1st episode 
o Hold until recovery to study entry criteria levels 
or better 
o Decrease dose to 75% of initial dose
2nd episode
o Hold until recovery to study entry criteria levels 
or better
o Decrease dose to 50% of initial dose
3rd episode
o Discontinue chlorambucil
Grade 3 or 4 unmanageable, non-hematologic toxicity 
potentially related to study drug
Delay dosing for a maximum of 4 weeks
1st episode
o Hold until recovery to Grade ≤2
o Decrease dose to 75% of initial dose
2nd episode
o Hold until recovery to Grade ≤2
o Decrease dose to 50% of initial dose
3rd episode
o Discontinue chlorambucil

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
57
Approved, Date: 19 December 2019
If chlorambucil is discontinued due to toxicity, then treatment with obinutuzumab may be 
continued.
6.3.
Subsequent Therapy with Single-agent Ibrutinib
Ibrutinib 420 mg (3 × 140 mg capsules) will be administered orally once daily, starting at 
Cycle 1 Day 1 in the Subsequent Therapy Phase.
For subjects randomized to Treatment Arm A who received ibrutinib at a reduced dose, 
single-agent ibrutinib may be started at the previously tolerated dose and re-escalated to the full 
dose per investigator’s discretion.
Guidelines for ibrutinib administration are provided in Section 6.1.1.
7.
INTERVENTION COMPLIANCE
The investigator or designated study personnel will maintain a log of all study drugs dispensed 
and returned. Drug supplies for each subject will be inventoried and accounted for throughout 
the study. 
The study drugs are to be prescribed only by the principal investigator or a qualified physician 
listed as a sub-investigator on required forms. Records should be kept on the study drug 
accountability form provided by the sponsor or its designee (any alternative forms must be 
preapproved by the sponsor). Further instructions regarding accountability for study drugs are 
provided in the Site Investigational Product Procedures Manual (SIPPM). Administration of the 
study drugs must be recorded in the subject’s source documentation. The study drugs may not be 
used for any purpose other than that outlined in this protocol, including other human studies, 
animal investigations, or in vitro testing.
Instructions for proper self-administration and study drug storage conditions for at-home use will 
be provided. Precautions associated with the use of the study drugs and prohibited/restricted 
concomitant medications will be reviewed. The investigator or designated study site personnel 
will be responsible for providing additional instruction to any subject who is not compliant with 
taking the study drugs. In the absence of toxicity, if the dosing compliance is not 100%, then 
investigators or designated study site personnel should re-instruct subjects regarding proper 
dosing procedures, and the subject may continue study treatment.
8.
CONCOMITANT THERAPY
Relevant 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 or until the start of 
subsequent anti-leukemic therapy, whichever is first. Similarly, for subjects who are eligible to 
and who receive single-agent ibrutinib in the Subsequent Therapy Phase, concomitant therapies 
must be recorded at the time of the first dose and up to 30 days after the last dose of ibrutinib. 
Relevant concomitant therapies include drugs that are given for active medical conditions 
reported in the subject’s medical history and treatments instituted for a reported AE/SAE. In 
most cases, drugs under the following categories need not be reported: nutritional supplements 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
58
Approved, Date: 19 December 2019
(eg, multivitamins); prophylactic antiemetics and antinauseants; antiseptics and disinfectants;
contrast media; emollients and protectives (eg, moisturizers); ophthalmologics and otologics;
vaccines; sex hormones for contraception; and dermatologics.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
8.1.
Permitted Concomitant Medications
The subject should receive supportive care during study participation, including fluids and 
electrolyte replacement, and antibiotics when appropriate. Use of neutrophil growth factors 
(filgastrim and pegfilgrastim) or red blood cell growth factors is permitted per the American 
Society of Clinical Oncology guidelines or per the institution’s guidelines.41 Transfusions may be 
given in accordance with 
institutional policy. 
Use of 
anti-microbial prophylaxis 
(eg, Pneumocystis jirovecii pneumonia prophylaxis with sulfamethoxazole and trimethoprim or 
equivalent), per the institution’s guidelines, is recommended.
Short courses (<14 days) of corticosteroids for non-cancer related medical reasons (eg, joint 
inflammation, asthma exacerbation, and IRRs) are permitted at doses not exceeding 100 mg/day 
of prednisone or its equivalent. Treatment for autoimmune cytopenias is permitted for <14 days 
at doses that do not exceed 100 mg/day of prednisone or its equivalent.
8.2.
Medications to be Used with Caution

Drugs that may alter ibrutinib or venetoclax plasma concentrations (eg, strong and moderate 
CYP3A inhibitors/inducers (Attachment 5). Guidance on the use of these CYP3A 
inhibitors/inducers and required dose adjustments of ibrutinib and venetoclax are provided 
in Attachment 9. Note: Further information regarding the use of strong CYP3A inhibitors 
during venetoclax administration is provided in Section 8.3.

Drugs that may have their plasma concentration altered by ibrutinib or venetoclax 
(eg, narrow therapeutic index P-glycoprotein [P-gp]
substrates such as digoxin 
[Attachment 9])

Antiplatelet agents and anticoagulants (Attachment 9)
8.3.
Prohibited Concomitant Medications
Any non-study anti-leukemic therapy, including but not limited to chemotherapy, anticancer 
immunotherapy, small molecule targeted therapy, experimental therapy, or radiotherapy, is 
prohibited until disease progression has occurred. Localized, hormonal, or bone sparing 
treatment for non-B-cell malignancies and localized radiotherapy for medical conditions other 
than the underlying B-cell malignancies may be considered with approval of the medical 
monitor.

Live vaccines must not be administered during study treatment phases but may be 
considered in the Follow-up Phase after B-cell recovery and approval of the medical 
monitor.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
59
Approved, Date: 19 December 2019

Use of strong CYP3A inhibitors is contraindicated during venetoclax initiation and dose 
ramp up (Attachment 9).

Corticosteroids at dosages equivalent to prednisone >20 mg/day for >14 days are prohibited 
until disease progression has occurred (refer to Section 8.1 for exceptions and further 
guidance).

Warfarin or other vitamin K antagonists should not be administered concomitantly with 
ibrutinib (Attachment 9).
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The study is divided into a Screening Phase, a Treatment Phase (Treatment Arm A [I+VEN]) or 
Treatment Arm B [G-Clb]), and a Follow-up Phase. Eligible subjects may also participate in a 
Subsequent Therapy Phase. The Time and Events Schedules (Table 1, Table 2, Table 3 and 
Table 4) summarize the frequency and timing of efficacy, PRO, biomarker, and safety 
measurements applicable to this study. 
All visit-specific PRO assessments should be conducted before any tests, procedures, or other 
consultations for that visit, to prevent influencing subject perceptions. PRO assessments will be 
captured electronically. 
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 
(iwCLL grading scale for hematological toxicity in CLL studies) should be used to assess the 
severity of cytopenias (ie, neutropenia, anemia, thrombocytopenia, see Table 14). 
Additional serum or urine pregnancy tests may be performed, as necessary, or as 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 that typically 
required for medical management of this patient population. Repeat or unscheduled blood 
sampling may be taken for safety reasons or technical issues. 
9.1.2.
Screening Phase
Screening procedures will be performed up to 30 days before randomization. All subjects must 
sign an ICF 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 respective Time and Events Schedules. This evaluation will include a complete 
medical history, confirmation of CLL diagnosis, staging at study entry (Attachment 10), and 
laboratory tests. Pathology reports, including fluorescence in situ hybridization (FISH) analysis 
for del17p and del11q, will be collected for sponsor review. Subjects with known presence of 
TP53 mutations detected at a threshold of 10% VAF will be excluded from the study.40 Results 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
60
Approved, Date: 19 December 2019
from central IGHV testing and local del11q testing will be used for stratification and must be 
available prior to randomization. In addition, eCRFs relevant for evaluation of inclusion and
exclusion provisions must be completed before IWRS approval for randomization is issued.
The collection of AEs and concomitant medications will commence after the study informed 
consent is signed. For women of childbearing potential, a urine or serum β-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. 
Evaluation for disease-related symptoms, a full physical examination, a complete blood count 
(CBC), and CT scans (or magnetic resonance imaging [MRI; Section 9.2.1.1]) are anticipated 
components of DE. Results of radiologic assessments obtained prior to signing the informed 
consent may be used if performed within 60 days of randomization, if the Imaging Acquisition 
Guidelines standards are met. Subsequent radiologic assessments performed throughout the 
study must be of the same modality as performed during screening. A bone marrow evaluation is
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. Bone marrow aspirate or peripheral blood may be used to assess the subject’s 
cytogenetic profile using standard CLL FISH probes to detect abnormalities in chromosomes 17, 
13, 12, and 11. In addition, immunophenotyping should be performed on the aspirate or blood 
sample. Results will be collected in the eCRF. For subjects with SLL, a lymph node biopsy may 
be used for immunophenotyping, morphology, and FISH testing. For subjects undergoing a bone 
marrow biopsy and aspirate during the screening, a sample of the aspirate and biopsy should be 
collected for biomarker assays and MRD testing. Archived bone marrow slides for biomarkers 
are acceptable.
9.1.3.
Open-label Treatment Phase
The Treatment Phase will begin at randomization and will continue until disease progression, 
unacceptable toxicity, or other reasons as described in Section 10. Subjects should start study 
treatment within 72 hours after randomization. The results of laboratory testing taken on Cycle 1 
Day 1 of study treatment will be defined as the baseline values for safety assessments and 
treatment decisions. Laboratory values obtained prior to Cycle 1 Day 1 for the Treatment Phase
should be repeated if the blood sample was collected more than 72 hours prior to the anticipated 
start of study treatment. Test results should satisfy eligibility criteria for treatment to commence.
Subjects assigned to I+VEN will receive treatment as outlined in Section 6.1. Treatment begins 
with 3 cycles of ibrutinib monotherapy. Investigators must request approval from medical 
monitor to start the venetoclax dose ramp-up phase in Cycle 4 after TLS risk assessment is 
completed and the appropriate TLS prophylaxis is started (see Table 8). I+VEN combination 
therapy will be given for 12 cycles.
Subjects assigned to G-Clb will receive obinutuzumab infusions as outlined in Section 6.2. 
G-Clb will be given for 6 cycles.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
61
Approved, Date: 19 December 2019
Subjects will report to the study site on Day 1 of each cycle for study-related procedures outlined 
in the Time and Events Schedules (Table 1 or Table 2). Clinical evaluations and laboratory 
studies may be repeated more frequently, if indicated. Treatment will be dispensed once all 
predose evaluations have been completed and the investigator has decided that a subject may 
receive treatment. Instructions for home administration and storage conditions of study treatment 
should be reviewed. If a subject shows signs of progression on physical examination or 
laboratory assessment, study treatment may continue until progression is confirmed by additional 
modalities. If PD is diagnosed, then the subject should discontinue study treatment, complete the 
End-of-Treatment Visit within 30 days (+7-day window) of the last dose of study treatment, and 
enter the Follow-up Phase.
End-of-Treatment
An End-of-Treatment Visit will be scheduled within 30 days (+7-day window) of the last dose of 
study treatment in the Treatment Phase and in the Subsequent Therapy Phase for all subjects 
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 
anti-leukemic 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 is 
found in Section 12. Refer to the Time and Events Schedules 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 DEs as outlined in the 
Time and Events Schedule (Table 3). These subjects will also be followed for survival status.
Following disease progression, contact will be made every 24 weeks ± 7 days until study end to 
determine:

Subsequent anti-leukemic therapy

CLL treatment criteria supporting initiation of subsequent therapy

Occurrence of new malignancy

PRO score (EQ-5D-5L only for the first 2 post-PD visits)

Transformation to a more aggressive histology (Richter’s transformation)

Survival status.
The EQ-5D-5L questionnaire will be administered as shown in the Time and Events Schedules. 
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.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
62
Approved, Date: 19 December 2019
The Follow-up Phase will continue until the subject enters the Subsequent Therapy Phase
(if applicable), death, lost to follow-up, consent withdrawal, or study end, whichever occurs first. 
A subject who progresses on therapy with single-agent ibrutinib during the Subsequent Therapy 
Phase may re-enter the Follow-up Phase.
It is important for survival status to be assessed and the date of death documented for each 
randomized subject, regardless of whether the subject received study treatment. If information on 
survival status and subsequent therapy is obtained via telephone contact, then written 
documentation of the communication must be available for review in source documents. If a 
subject dies, then the date and cause of death are to be reported in the appropriate eCRF.
9.1.5.
Subsequent Therapy Phase
Before a subject is considered for inclusion in the Subsequent Therapy Phase, the investigator is 
expected to re-review the informed consent with the subject to ensure that he or she understands 
the purpose of, as well as the study procedures and required visits associated with, the 
Subsequent Therapy Phase. The eligibility criteria described in Section 9.1.5.1 will be reviewed
and a clinical evaluation will be performed, including medical history review, staging 
(Attachment 10), and laboratory tests (including FISH analysis for del17p, del11q, del13q, and 
trisomy 12 for sponsor review; see Table 4). Imaging is required prior to treatment in the 
Subsequent Therapy Phase for subjects initially treated with I+VEN (Treatment Arm A). Results 
of CT scans (or magnetic resonance imaging [MRI; Section 9.2.1.1]) obtained within 60 days 
before start of single-agent ibrutinib treatment can be used, if the Imaging Acquisition 
Guidelines standards are met. Approval from the medical monitor is required for treatment with 
single-agent ibrutinib and treatment should be started within 72 hours of approval.
The Subsequent Therapy Phase will begin at Cycle 1 Day 1 of treatment with single-agent 
ibrutinib and will continue until disease progression, unacceptable toxicity, or other reasons as 
described in Section 10.2. The results of laboratory testing obtained of Cycle 1 Day 1 of 
single-agent ibrutinib treatment will be defined as the baseline values for safety assessments and 
treatment decisions in the Subsequent Therapy Phase. Laboratory values obtained prior to 
Cycle 1 Day 1 of single-agent ibrutinib should be repeated if the blood sample was collected 
more than 72 hours prior to the anticipated start of study treatment. Test results should satisfy 
eligibility criteria for treatment to commence.
Subjects will receive treatment as outlined in Section 6.3. Subjects who tolerated a reduced dose 
of ibrutinib during the Treatment Phase may initiate ibrutinib as a single agent at the same lower 
dose, per investigator’s discretion. Escalation to the full dose should be considered if appropriate. 
Subjects will report to the study site as outlined in Table 4 and Figure 2. Clinical evaluations and 
laboratory studies may be repeated more frequently, if indicated. Treatment will be dispensed 
once all predose evaluations have been completed and the investigator has decided that a subject 
may receive treatment. Instructions for home administration and storage conditions of study 
treatment should be reviewed. If a subject shows signs of progression on physical examination or 
laboratory assessment, study treatment may continue until progression is confirmed by additional 
modalities. If PD is diagnosed, then the subject should discontinue study treatment, complete the 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
63
Approved, Date: 19 December 2019
End-of-Treatment Visit within 30 days (+7-day window) of the last dose of study treatment (see 
Section 9.1.3), and enter the Follow-up Phase.
9.1.5.1.
Eligibility for the Subsequent Therapy Phase 
Eligibility for the Subsequent Therapy Phase must be approved by the medical monitor
following an assessment of the eligibility parameters described below and a review of relevant 
inclusion/exclusion criteria for overall study entry in Section 4.1 and Section 4.2. 
Participation in the Subsequent Therapy Phase is not mandatory and is based on investigator’s 
discretion.
Inclusion Criteria for Subsequent Therapy with Single-agent Ibrutinib 
Study subjects must satisfy all of the following criteria to be eligible to receive single-agent 
ibrutinib and enter the Subsequent Therapy Phase. 
1.
Criterion modified per Amendment 4
1.1 Completed the initial fixed-duration Treatment Phase as described in the protocol. 
Subjects randomized to Treatment Arm B may remain eligible even if protocol-specified 
treatment is not completed.
2.
Progressive disease confirmed by IRC
3.
Exhibit active CLL/SLL requiring treatment per iwCLL criteria.
Exclusion Criteria for Subsequent Therapy with Single-agent Ibrutinib 
Any potential subject who meets any of the following criteria will be excluded from participating 
in the Subsequent Therapy Phase:
1.
Any potential subject who has received any subsequent anti-leukemic therapy after the 
Treatment Phase will be excluded from participating in the Subsequent Therapy Phase.
NOTE: Investigators should ensure that all criteria are met. If a subject’s clinical status changes 
after request for approval of subsequent therapy with single-agent ibrutinib, but before the first 
dose of study treatment such that he or she no longer meets all eligibility criteria, the subject 
should be excluded from treatment. 
9.2.
Efficacy
Efficacy evaluations will be conducted as specified in the Time and Events Schedule (Table 3
and Table 4) 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 should 
focus on examination of lymph nodes, the liver, and spleen. 

CBC with ALC.

CT scan of the neck, chest, abdomen, and pelvis. 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
64
Approved, Date: 19 December 2019

MRD: Collection of peripheral blood for central MRD analysis by flow cytometry should be 
done on all subjects with a response of PR or better. Collection of bone marrow aspirate for 
central MRD analysis by flow cytometry and NGS should be done in all responders.

PROs as measured by the EORTC-QLQ-C30 and EQ-5D-5L questionnaires, and the 
FACIT-Fatigue scale.
9.2.1.
Evaluations
9.2.1.1.
Radiographic Imaging Assessments
Disease response should 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 lymph nodes, the liver, and spleen should be evaluated. All imaging should be performed 
according to the Imaging Acquisition Guidelines (see materials in Section 15). Subjects who 
cannot tolerate IV contrast may have CT scans performed with oral contrast. If disease 
progression is suspected from physical examination or laboratory testing, additional modalities 
must be performed for confirmation. The subject may continue study treatment until disease 
progression is confirmed. CT scans should be performed according to the Time and Events 
Schedule (Table 3 and Table 4) until disease progression is confirmed, regardless of whether or 
not the subject remains on study treatment. In the Subsequent Therapy Phase, CT imaging is 
expected for subjects who were initially treated with I+VEN (Treatment Arm A). For subjects 
who were initially treated with G-Clb (Treatment Arm B), imaging is recommended only when 
clinically indicated and as determined by the investigator.
Magnetic resonance imaging may be used to evaluate sites of disease that cannot be adequately 
imaged using CT or in exceptional cases where CT scans with IV or oral contrast are
contraindicated. However, the imaging modality used must remain consistent from screening 
through all subsequent DEs. Brain imaging and positron emission tomography scans may be 
done only if clinically indicated.
9.2.1.2.
Definition of Measurable and Assessable Disease
Subjects must have at least 1 measurable site of disease (target lesion) to participate in the 
study.28 Measurable sites of disease are defined as lymph nodes or lymph node masses >1.5 cm 
in longest diameter. Measurements must be determined by CT or MRI imaging. Extranodal sites 
of disease are considered assessable, but not measurable. 
Up to 6 measurable sites of disease, clearly measurable in 2 perpendicular dimensions, will be 
followed for each subject. Measurable sites of disease should represent the extent of the subject’s 
disease. As much as possible, the selection of target lesions should be from different regions of 
the body. Additional lesions that are identified by radiologic imaging or physical examination 
but are not included in the target lesion assessment should be considered as assessable
(non-target) lesions and followed throughout the study. Investigators should provide a qualitative
assessment of the spleen and liver at screening and in all subsequent DE visits.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
65
Approved, Date: 19 December 2019
9.2.1.3.
Bone Marrow Assessments
A bone marrow aspirate and biopsy must be obtained during screening or up to 90 days before 
randomization. For subjects undergoing a baseline bone marrow assessment during the screening 
period, a sample of the bone marrow aspirate and biopsy should be collected for biomarker 
assays and MRD testing. Archived bone marrow slides for biomarkers are acceptable for patients 
who are not undergoing bone marrow assessments at screening. Standard CLL testing to assess 
morphology, immunophenotyping, and cytogenetic profile (by FISH) should be performed to 
completely characterize the diagnosis of CLL. A local bone marrow biopsy examination is 
expected to include morphologic evaluation and immunohistochemistry testing. For subjects 
with SLL, a lymph node biopsy may be used for similar tests. Instructions for the collection, 
handling, and shipment of bone marrow samples are outlined in a Laboratory Manual. 
Bone marrow aspirate and biopsy samples are collected from all subjects with response of PR or 
better at DE3 of the Treatment Phase. The bone marrow aspirate and biopsy should be sent to a 
local laboratory for standard evaluation and response assessment. An additional bone marrow 
aspirate sample will be sent to the central laboratory for MRD analysis (as described in 
Section 9.2.2). At DE6 of the Treatment Phase, a central bone marrow aspirate MRD assessment 
is required in all subjects with a response of PR or better. Bone marrow biopsy and aspirate for 
local evaluations are only required for subjects on the I+VEN treatment group who were not 
confirmed CR at DE3 of the Treatment Phase. For subjects with a suspected PD based on new 
onset cytopenia, a bone marrow aspirate and biopsy should be obtained to confirm PD locally.
During the Subsequent Therapy Phase, a bone marrow biopsy is indicated to confirm a CR. 
Additional bone marrow evaluations may be pursued at the investigator’s discretion.
9.2.2.
Minimal Residual Disease Assessments
An analytically validated 8-color flow cytometry assay will be used to assess MRD.44 Samples 
will be incubated with a cocktail of fluorochrome-labeled antibodies. 
One million viable events will be acquired on the FACSCanto II flow cytometer, and 
post-acquisition analysis will be performed to determine MRD-negativity. MRD-negativity is 
defined as <1 CLL cell per 10,000 leukocytes or <0.01%. Peripheral blood collection for MRD 
analyses will begin at 12 weeks after randomization (DE1) and will continue in both treatment 
arms at each DE visit until disease progression. A sample of bone marrow aspirate for MRD 
assessment for all responding subjects (ie, response of PR or better) must be sent to the sponsor 
at DE3 and DE6 (as described in Section 9.2.1.3). The first draw of the bone marrow aspirate 
should be sent for central MRD analysis. Additional instructions for the assessment of MRD are 
outlined in a separate Laboratory Manual.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
66
Approved, Date: 19 December 2019
9.2.3.
Response Categories
Assessment of response should include an evaluation for disease-related symptoms, physical 
examination, radiographic imaging, and blood and bone marrow testing (whenever applicable).
Response categories are defined in Table 13 and in the text immediately following. All responses 
must be confirmed by CT scans and must last for at least 56 days to be considered confirmed. 
For the purpose of study analyses, responses during the Treatment Phase will be determined by 
an IRC blinded to study treatment information and independent of investigators and personnel 
involved in the conduct of the study. As part of the central IRC review, imaging studies will be 
assessed by independent radiologists and relevant clinical data will be assessed by an 
independent oncologist. The IRC process will be described in detail in a separate charter.
During the Subsequent Therapy Phase, responses will be based on the investigator’s assessment. 
If needed, confirmation of responses by the IRC may be pursued by the sponsor for regulatory 
purposes.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
67
Approved, Date: 19 December 2019
Table 13:
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
Abbreviations: CLL=chronic lymphocytic leukemia; CR=complete response; CRi=complete response with an incomplete 
marrow recovery; PD=disease progression; PR=partial response
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 evidence of 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 subjects have to lack disease-related symptoms.
PR: At least 2 criteria from Group A plus 1 of the criteria from Group B must be met.
NOTE: If only 1 measurable Group A criterion is present at baseline (eg, enlarged lymph nodes but no other abnormality), per 
recent clarifications of the iwCLL criteria27,28 these subjects are still considered evaluable for PR if the given parameter improves 
by at least 50% for a minimum of 56 days. 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 56 days 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 criteria26,27,28

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
68
Approved, Date: 19 December 2019
Complete Response with an Incomplete Marrow Recovery (CRi): 
CRi is defined as a complete response with peripheral cytopenia and incomplete recovery of the 
bone marrow, manifested by persistent cytopenias. Subjects who have a CRi fulfill the criteria 
for a CR, but continue to have persistent anemia, thrombocytopenia, and/or neutropenia, with a 
hypocellular bone marrow confirmed by bone marrow biopsy. These cytopenias are considered 
due to drug toxicity in the bone marrow and are not related to CLL.
Nodular Partial Response (nPR): 
nPR is a response that meets the criteria for CR, but the bone marrow biopsy shows lymphoid 
nodules, reflecting residual disease.
Partial Response with Lymphocytosis (PRL): 
PRL is a response where subjects meet the criteria for a PR and have persistent lymphocytosis.
Stable Disease: 
Subjects who do not meet the criteria for CR, CRi, nPR, PR, PRL, 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, blood counts (hemoglobin and 
platelet count), or disease-related symptoms. Treatment-related lymphocytosis is isolated 
lymphocytosis that occurs when no other criteria for PD are met. It will not be considered PD.
9.2.4.
Patient-reported Outcomes
PRO assessments will be conducted as described in the Time and Events Schedules. Collection 
of PRO assessments will stop after the primary PFS analysis is completed. 
Three PRO instruments will be administered in this study: the European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30, the 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and the EuroQol 5 
Dimension 5 Level questionnaire (EQ-5D-5L). The EORTC QLQ-C30 is a 30-item general 
cancer assessment that incorporates 5 functional scales (physical, role, emotional, cognitive, and 
social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), a global health status 
and QoL scale (2 items), and 6 single items (dyspnea, insomnia, appetite loss, constipation, 
diarrhea, and financial difficulties). Scores range from 0 to 100 (for functional and global QoL 
scales, higher scores indicate a better level of functioning). Differences of ≥10 points on EORTC 
scales are considered clinically important.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
69
Approved, Date: 19 December 2019
The FACIT-Fatigue scale is a 13-item instrument designed to assess aspects of fatigue/tiredness 
in patients with cancer or other chronic diseases, including the impact on daily activities and 
functioning. Items are scored on a 0–4 response scale (0=not at all; 4=very much). All items are 
summed to create a single fatigue score ranging from 0 to 52, with higher scores indicating better 
functioning or less fatigue. A difference of ≥3 points in FACIT-Fatigue score is considered 
clinically important.
The EQ-5D-5L consists of a 5-item descriptive system and the EuroQol visual analog scale 
(EQ-5D VAS) of self-rated health, with scores ranging from 0 (worst imaginable health state) to 
100 (best imaginable health state). Responses for the 5 dimensions are combined into a 5-digit 
number describing a respondents’ health state that can be converted into a single index value or 
utility score (using the United Kingdom weights), ranging from –1 to 1, where lower scores 
indicate a worse health status. A minimum difference of ≥0.07 points change in utility score is 
considered clinically important; for the VAS health rating, a minimum important difference is 
≥7 points change.
9.3.
Pharmacokinetics
Plasma samples from venous blood collections for all subjects in Treatment Arm A will be used 
to evaluate the pharmacokinetics of ibrutinib and its metabolite PCI-45227, and venetoclax. 
Plasma collected for pharmacokinetic analyses may additionally be used to evaluate safety and 
efficacy questions, drug characteristics, or certain biomarkers for future research. Genetic 
analyses will not be performed on these samples. Subject confidentiality will be maintained.
9.3.1.
Pharmacokinetic Evaluations
Venous blood samples will be collected at steady-state from all subjects assigned to I+VEN 
treatment for measurement of trough plasma concentrations of ibrutinib, PCI-45227, and 
venetoclax at time points specified in the Time and Events Schedule for the Treatment Phase for 
Treatment Arm A (Table 1). These samples will be tested by the sponsor or sponsor's designee.
The exact dates and times of blood sampling must be recorded, together with the drug intake 
time on the day before sampling. Refer to the Laboratory Manual for sample collection 
requirements. Collected samples must be stored under the specified and controlled conditions for 
the temperatures indicated in the Laboratory Manual. Additional information about the 
collection, handling, and shipment of biological samples can be found in the Laboratory Manual.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
70
Approved, Date: 19 December 2019
9.3.2.
Pharmacokinetic Analytical Procedures
Pharmacokinetics
Plasma samples will be analyzed to determine concentrations of ibrutinib, PCI-45227, or
venetoclax. Analysis will be performed using validated, specific, and sensitive liquid 
chromatography/mass spectrometry/mass spectrometry methods by or under the supervision of 
the sponsor.
9.3.3.
Pharmacokinetic Parameters
The PK parameter is defined as:
Ctrough,ss=Concentration at end of dosing interval (24h) at steady-state
The ibrutinib, PCI-45227, and venetoclax Ctrough,ss data will be summarized by descriptive 
statistical methods.
9.4.
Biomarkers 
To better understand the mechanism of action of ibrutinib and to develop predictors of 
resistance, bone marrow, peripheral blood, and buccal swab samples will be collected as 
specified in the Time and Events Schedules. 
Plasma samples may be analyzed to identify biomarkers that may be related to treatment-induced 
changes and that may be indicative of response to and relapse following I+VEN treatment. Blood 
samples collected at screening will be analyzed for IGHV mutational status, a stratification factor 
for randomization. Additional blood samples collected may be evaluated for protein expression 
and other RNA/DNA signatures that may predict primary or acquired resistance. Bone marrow 
aspirate may be characterized by gene expression profiling and somatic mutation analysis by 
NGS to evaluate for potential biomarkers that may contribute to sensitivity or resistance to 
therapy in CLL. Samples may be evaluated by other similar technologies to evaluate protein or 
RNA expression, cytogenetics or for somatic DNA analysis.
Plasma and bone marrow samples will be evaluated for MRD by flow cytometry. MRD analysis 
by NGS-based methods may subsequently be performed. 
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the 
end of the study, it becomes clear that the analysis will not have sufficient scientific value for 
biomarker evaluation, or if there are not enough samples or responders to allow for adequate 
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy, 
completion of biomarker assessments is based on justification and intended utility of the data. 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
71
Approved, Date: 19 December 2019
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 must be followed by the investigator until resolution, until a 
clinically stable endpoint is reached, or until the end of the study.
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legal representative) for the duration of the study. Adverse events will be 
followed by the investigator as specified in Section 12. Non-hematologic AEs and hematologic 
AEs events will be graded according to specifications listed in Section 12.1.3. 
Clinical Laboratory Tests
Complete blood counts obtained per the Time and Events Schedules should be performed at the 
laboratory associated with the treating institution, 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 will have 
laboratory assessments conducted at a 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 Schedules. The investigator must review the laboratory report, document this 
review, and record any clinically relevant changes occurring during the study in the AE section 
of the eCRF. For example, laboratory abnormalities leading to an action regarding study 
treatment (dose change, dose interruption, cycle delay, or treatment discontinuation) 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 eCRF: 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. 
The following clinical laboratory tests must be performed by the laboratory facility associated 
with the study site, as specified in the Time and Events Schedules:

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
72
Approved, Date: 19 December 2019

Hematology Panel
-hemoglobin
-ANC
-white blood cell count
-ALC
-platelet count

Serum Chemistry Panel
-sodium
-albumin
-potassium
-total bilirubin
-creatinine
-uric acid
-ALT
-calcium
-AST
-phosphate
-alkaline phosphatase
-lactic acid dehydrogenase
For the convenience of subjects assigned to G-Clb treatment group, predose blood counts and 
serum chemistry testing on Day 15, Cycles 2 to 6, may be done outside the treating institution. 
Similarly, for subjects treated with I+VEN (Treatment Arm A in the Treatment Phase) or 
single-agent ibrutinib (in the Subsequent Therapy Phase), during cycles which do not require 
clinic attendance (see the Time and Events Schedule [Table 1, Table 4, Figure 1, and Figure 2]) 
serum chemistry and hematology monitoring may be done outside of the treating institution. 
However, in both circumstances, the treating physician must ensure that he/she has access to and 
is able to perform timely review of laboratory results from the outside facility. Furthermore, the 
treating physician must have a clear line of communication with subjects to ensure that treatment 
decisions made after review of outside laboratory reports are communicated directly to the 
subject. Only clinically relevant laboratory abnormalities (ie, those corresponding to an AE or a 
dose change) should be reported in the eCRF.

Coagulation
-aPTT
-INR

Hepatitis B Screening 
-Hepatitis B surface antigen
-Hepatitis B core antibody
Hepatitis B virus DNA PCR needs to be performed if Hepatitis B core antibody is positive. 
Hepatitis B virus DNA PCR must be negative in subjects who are Hepatitis B core antibody 
positive to be eligible for the study. During study treatment and for at least 12 months following 
the last dose of study treatment, regular monitoring of Hepatitis B DNA PCR and liver enzymes, 
and prophylactic antiviral medication, should be considered per published guidelines for subjects 
with a history of Hepatitis B infection.40

Hepatitis C Screening
-Hepatitis C antibody
Subjects who test positive for Hepatitis C antibody are eligible if previously treated and with a 
sustained viral response, defined as a negative viral load by Hepatitis C virus RNA PCR testing.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
73
Approved, Date: 19 December 2019

Urine or serum -hCG pregnancy testing for women of childbearing potential only 

Beta2-microglobulin

Additional laboratory tests (eg, absolute reticulocyte counts, Coombs tests, blood urea 
nitrogen, glucose, creatine phosphokinase, haptoglobin) obtained because of an AE must be 
documented at an unscheduled visit. 
Electrocardiogram
An electrocardiogram (ECG) will be performed for all subjects at study entry and during 
screening for subsequent therapy with ibrutinib. Testing should be obtained in a quiet setting 
without distractions (eg, television, cell phones). Abnormalities noted at baseline and during 
screening for subsequent therapy with ibrutinib should be included in the medical history. ECGs 
may be repeated at any time during the study if clinically indicated, particularly for subjects with 
symptoms related to cardiac arrhythmias. For optimal monitoring and management of 
cardiovascular toxicities while on the study, consider consultation with a cardiologist.
Vital Signs
Temperature, pulse/heart rate, and blood pressure will be recorded at screening. Assessment of 
pulse/heart rate and blood pressure is expected at every protocol-specified visit. Blood pressure 
and pulse/heart rate measurements should be preceded by at least 5 minutes of rest in a quiet 
setting without distractions (eg, television, cell phones). Clinically significant abnormalities 
should be recorded as AEs. If an abnormal heart rhythm is suspected, further investigation (ECG 
and/or Holter monitor) is required per investigator’s discretion.
Physical Examination 
A complete physical examination must be conducted at screening, in all DE visits (Treatment 
Phase, Subsequent Therapy Phase), and before the initiation of treatment with single-agent 
ibrutinib (Subsequent Therapy Phase). The status of nodal lesions, the liver, and spleen must be 
reported at each DE visit. Clinically significant abnormalities should be recorded as AEs. Weight 
will be measured as specified in the Time and Events Schedules.
9.6.
Benefit-risk Evaluations
Benefit-risk assessment of I+VEN compared with G-Clb will be conducted by comparing 
between-treatment differences of key efficacy and safety endpoints. Efficacy endpoints may 
include PFS, MRD-negative disease status, OS, time-to-next treatment, and improvement in 
PRO measures. Safety endpoints may include major hemorrhage, minor hemorrhage, leukostasis, 
serious infections, interstitial lung disease, atrial fibrillation, TLS, non-melanoma skin cancer, 
diarrhea, rash, hypertension, infusion reactions and other serious adverse events (SAEs). Safety 
endpoints that show no between-treatment differences will be noted but may be excluded from
the benefit-risk analyses. Adverse events not in this list, but that show a clinically meaningful 
between-treatment difference may be included.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
74
Approved, Date: 19 December 2019
9.7.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in a laboratory requisition 
form. Refer to the Time and Events Schedules for the timing and frequency of all sample 
collections. Instructions for the collection, handling, and shipment of samples are outlined in a 
separate Laboratory Manual.
10.
SUBJECT COMPLETION/ WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he or she dies before the end of the 
study, or has not been lost to follow-up or withdrawn consent before the end of study (see end of 
study definition in Section 17.9.1, Study Completion/End of Study). 
10.2.
Discontinuation of Study Treatment
Discontinuation of study treatment does 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 Schedules or DEs prior to progression). 
A subject's study treatment must 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, AE) 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 diagnosed with 
disease progression and provide documentation of the diagnosis for review by the 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 
other modalities (ie, CT scan, bone marrow biopsy).
10.3.
Withdrawal From the Study
A subject will be automatically withdrawn from the study for any of the following reasons:

Lost to follow-up;

Withdrawal of consent;

Sponsor discontinues study.
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 of treatment, 
withdrawal of consent, and/or failure to follow-up. All measures taken to establish contact with 
the subject must be documented.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
75
Approved, Date: 19 December 2019
When a subject withdraws before completing the study, the reason for withdrawal must be 
documented in the eCRF and in the source document. Study treatment assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. If a 
subject withdraws from the study before completing the assigned treatment, end-of-treatment 
assessments should be obtained. If the reason for withdrawal from the study is withdrawal of 
consent, then no additional assessments are allowed.
10.4.
Withdrawal From the Use of Research Samples
The subject may withdraw consent for use of samples collected for research (refer to 
Section 16.2.5, Long-Term Retention of Samples for Additional Future Research). In such a 
case, samples collected from the subject will be destroyed. Details of sample retention for 
research are presented in the main 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 (SAP).
11.1.
Analysis Sets
The 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 efficacy analyses including, but not limited to PFS, MRD-negativity,
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 that subjects 
actually received.
The pharmacokinetic-evaluable population is defined as all randomized subjects who received at 
least 1 dose of ibrutinib and had at least 1 post-treatment pharmacokinetic sample. 
The biomarker population will include all randomized subjects with sufficient malignant cells 
collected from at least 1 timepoint during the study.
11.2.
Sample Size Determination
This study is designed to evaluate the effect of treatment on PFS and is powered for this primary 
endpoint. A median PFS of 27 months is reported for the G-Clb when it is used to treat patients 
with treatment-naïve CLL.21 It is assumed that the PFS follows an exponential distribution with a 
constant hazard rate.
Utilizing a 1:1 randomization, this study will enroll approximately 200 subjects (100 subjects 
into I+VEN and 100 subjects into the G-Clb treatment groups) to observe 71 PFS events. No 
interim analysis is planned due to the small sample size and short accrual period of this study, 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
76
Approved, Date: 19 December 2019
plus the timing of interim analysis may not allow for PFS data to be mature for analysis. The 
study is designed to detect a HR of 0.5 for the I+VEN treatment group relative to the G-Clb 
group (corresponding to an improvement of 100% in median PFS, eg, from 27 months to 
54 months) with 80% power at a 2-sided significance level of 0.05. A uniform accrual rate of 
20 subjects per month will result in a study duration of approximately 32 months after the first 
subject is randomized, with 10 months of enrollment and 22 months of follow-up to observe 
71 PFS events.
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, weight, and 
blood pressure. Baseline disease characteristics (documented in the source documents and eCRF) 
will include time from initial diagnosis to randomization, histological diagnosis (CLL, SLL), 
stage of disease, and ECOG PS grade (0, 1, 2).
11.4.
Efficacy Analyses
Descriptive statistics will be used to summarize the data. For continuous variables, number of 
observations, means, standard deviations, medians, and ranges will be used. For discrete 
variables, frequency will be summarized. For time-to-event variables, Kaplan-Meier estimates 
will be provided. 
The comparisons between the 2 treatment groups will be performed as follows: for the 
continuous variable representing change from baseline to a postbaseline timepoint, analysis of 
variance will be used. For discrete variables, Cochran-Mantel-Haenszel chi-square test will be 
used. For time-to-event variables, log-rank test will be used. All tests will be conducted at a 
2-sided alpha level of 0.05, and 95% confidence intervals (CIs) will be provided, unless stated 
otherwise. 
11.4.1.
Primary Endpoint
The primary endpoint of PFS is defined as duration from the date of randomization to the date of 
disease progression or death, whichever occurs first. The primary efficacy analysis will be based 
on the IRC assessment of PD in the ITT population. 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 PFS between the 2 treatment groups, with stratification factors IGHV mutational 
status (mutated vs. unmutated vs. not available) and presence of del11q (yes vs. no). The median 
PFS will be provided for each treatment group and the HR for I+VEN relative to G-Clb and its 
associated 95% CI will be calculated based on the Cox proportional hazards model stratified by 
the stratification factor.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
77
Approved, Date: 19 December 2019
The sensitivity analyses for PFS based on investigator assessment and using different censoring 
mechanisms will be performed similarly. Other exploratory analyses, such as sensitivity analysis 
to address the potential effect of an unequal number of subject visits that could result in 
unscheduled tumor assessments because of the different treatment schedules in the 2 groups, will 
be performed as appropriate.
11.4.2.
Secondary Endpoints
The secondary endpoints are defined as follows:

MRD-negative rate is defined as the proportion of subjects who are MRD-negative in the 
bone marrow (ie, <1 CLL cell per 10,000 leukocytes or <0.01%). All randomized subjects 
will be included in this analysis.

CR rate is defined as the proportion of subjects who achieve CR.

ORR is defined as the proportion of subjects who achieve a response (CR, CRi, nPR, and
PR).

Duration of response is defined as duration in days from the date of initial documentation of 
a response to the date of first documented evidence of PD or death. 

OS is measured from the date of randomization to the date of the subject’s death from any 
cause. If the subject is alive or the vital status is unknown, the subject will be censored at the 
date the subject was last known to be alive.

Time-to-next treatment is measured from the date of randomization to the start date of any 
anti-leukemic treatment subsequent to the study treatment. Subjects without subsequent 
treatment will be censored at the date of the last site visit.

Sustained hemoglobin improvement rate, defined as the proportion of subjects who achieve 
an increase of hemoglobin levels from baseline by ≥2 g/dL and lasts for at least 56 days 
without blood transfusion or growth factors.

Sustained platelet improvement rate, defined the proportion of subjects who achieve an 
increase of platelet levels from baseline by ≥50% and lasts for at least 56 days without blood 
transfusion or growth factors.
For time-to-event endpoints, the Kaplan-Meier method will be used to estimate the distribution 
of OS (including the 24-month survival rate), duration of response and time-to-next treatment for 
each treatment group. Median times to event with 2-sided 95% CIs will be estimated. The log-
rank test accounting for stratification factor will be used for treatment comparison except for 
duration of response. A Cox proportional hazards model will be used to provide estimates of 
HRs with 95% CIs. 
For categorical endpoints, the Cochran-Mantel-Haenszel chi-square test with stratification factor 
will be used to compare the ORR, CR rate, the MRD-negativity remission rate and rates of 
hemoglobin and platelet improvement between the treatment groups. 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
78
Approved, Date: 19 December 2019
Hierarchical gatekeeping testing procedure will be implemented for key secondary efficacy 
endpoints of OS, ORR, CR rate, MRD-negative rate, time-to-next anti-leukemic treatment, and
time to worsening of PRO scores (Section 11.4.3) to maintain the overall control of study-wise 
Type I error. The sequential testing order of secondary efficacy endpoints and time to worsening 
for PRO endpoints will be determined later and specified in the SAP.
11.4.3.
PRO Endpoints
PRO measures listed in Section 9.2.4 will be analyzed using the methods specified in 
Section 11.4. For individual items and sub-scale scores within the PRO measures, descriptive 
statistics (mean, standard deviation, median, and range) will be calculated for each time point, 
for changes from baseline at each time point, as well as for changes from baseline to the last 
value. Mixed-model repeated measures will be used for longitudinal analysis of PRO score 
change for EORTC QLQ-C30 global health and physical function, FACIT-Fatigue total score, 
and EQ-5D-5L utility score and VAS score.
Time to worsening in the PRO scores from the EORTC QLQ-C30 (global health status and 
physical functioning scores) and FACIT-Fatigue (total score) and EQ-5D-5L utility score and 
VAS score is measured from the date of randomization to the start date of worsening. Worsening 
is defined by clinically important negative change (Section 9.2.4). Time to worsening in PRO 
scores will be compared using the similar approach for time-to-event secondary endpoints
(Section 11.4.2).
11.4.4.
Subsequent Therapy Evaluations
A pooled analysis of outcome after ibrutinib re-treatment may be pursued using data from the
current study and another clinical trial (ie, Study PCYC-1142-CA). Details of the statistical 
analysis will be described in a separate SAP, as applicable.
11.5.
Pharmacokinetic Analyses
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. Concentrations below the lowest quantifiable concentration 
will be treated as zero in the summary statistics. The number of subjects and samples excluded 
from the analysis will be clearly documented in the Clinical Study Report. Descriptive statistics 
will be used to summarize ibrutinib, PCI-45227, and venetoclax plasma concentrations at each 
sampling time point. Ibrutinib and PCI-45227 trough levels in presence and absence of 
venetoclax will be compared graphically.
11.6.
Biomarker Analyses
Biomarker studies are designed to identify molecular and protein markers associated with 
response to and relapse following therapy. 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, categorical, or survival model), depending 
on the endpoint. Results may be presented in a separate report.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
79
Approved, Date: 19 December 2019
11.7.
Safety Analyses
The safety analysis population will consist of all randomized subjects who receive at least 1 dose 
of study treatment. The number and percent of subjects with TEAEs will be summarized 
according to intensity using the NCI-CTCAE Version 4.03, drug relationship, and outcome. 
Laboratory data will be summarized and descriptive statistics will be calculated. Changes in 
physical examination parameters will be summarized.
The safety variables to be analyzed include AEs, clinical laboratory tests (hematology and 
chemistry), physical examination results, and deaths. Reduction in TLS risk will be assessed 
following ibrutinib monotherapy in Treatment Arm A (I+VEN). 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. 
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities. All reported AEs with onset during the treatment 
phases (ie, TEAEs, 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 AEs of special interest may be counted or listed. Adverse events of special interest will be
summarized similarly to TEAEs.
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.
Physical Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
80
Approved, Date: 19 December 2019
Physical examination findings will be summarized at each scheduled time point. Descriptive 
statistics will be calculated at baseline and for observed values and changes from baseline at each 
scheduled time point. Frequency tabulations of the abnormalities will be made.
11.8.
Benefit-Risk Analyses
For benefit-risk analyses, between-treatment differences will be shown with absolute rate or 
other difference measures and corresponding 95% CIs. Both continuous and dichotomized 
versions of continuous endpoints will be shown. Adverse events may be further characterized by 
their NCI-CTCAE grade. Results will be displayed in tabular and forest plot form. Additional 
details will be provided in the SAP.
11.9.
Data Monitoring Committee
An independent DMC will be established to monitor data on a regular basis to ensure the 
continuing safety of the subjects enrolled in this study. The DMC will consist of at least one 
medical expert in the relevant therapeutic area and at least one statistician. The committee will 
meet periodically to review safety data. After the review, the DMC will make recommendations 
regarding the conduct of the study. The DMC responsibilities, authorities, and procedures will be 
documented in a separate DMC charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
81
Approved, Date: 19 December 2019
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.3.1, All 
Adverse Events, for time of last AE recording).
Serious Adverse Event
An SAE 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 AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For ibrutinib, the expectedness of an AE will be 
determined by whether or not it is listed in the IB. For venetoclax, chlorambucil or 
obinutuzumab, the expectedness of an AE will be determined by whether or not it is listed in the
approved labels.22,39,54
Adverse Event Associated With the Use of the Intervention
An AE 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 AE that is not related to the use of the intervention.
Doubtful
An AE 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.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
82
Approved, Date: 19 December 2019
Possible
An AE that might be due to the use of the intervention. 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 AE that might be due to the use of the intervention. 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 AE 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 AE. The severity 
assessment for any non-hematologic AE or SAE should be completed using the NCI-CTCAE, 
Version 4.03 (see below for hematologic AEs and SAEs). Any AE or SAE not listed in the 
NCI-CTCAE Version 4.03 will be graded according to the investigator clinical judgment by 
using the standard grades as follows: 
Grade 1 Mild: Awareness of symptoms that are easily tolerated, causing minimal 
discomfort, and not interfering with everyday activities
Grade 2 Moderate: Sufficient discomfort is present to cause interference with normal 
activity
Grade 3 Severe: Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities
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
Evaluation of hematologic toxicity in subjects with advanced CLL must consider the high 
frequency of bone marrow involvement at the initiation of therapy. The standard hematologic 
grading system for solid tumors may not always apply since a substantial proportion of subjects 
will be considered to have Grade 2 to 4 hematologic toxicity before any therapy is given. 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
83
Approved, Date: 19 December 2019
Therefore, the scheme in Table 14 must be used to assess the severity of hematologic 
deterioration in the study, in accordance with the iwCLL recommendations.28
Table 14:
iwCLL Grading Scale for Hematologic Toxicity in CLL Studies
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 pre-treatment, in which case the subject 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 subject is not evaluable for toxicity referable to the ANC.
Reference: Hallek 200828
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study intervention that may require expedited reporting or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study intervention

Suspected abuse/misuse of a sponsor study intervention

Accidental or occupational exposure to a sponsor medicinal product

Medication error involving a sponsor product (with or without subject exposure to the 
sponsor medicinal product, eg, name confusion).
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All subjects who receive treatment will be considered evaluable for toxicity. All AEs and special 
reporting situations, whether serious or nonserious, will be reported from the time a signed and 
dated ICF is obtained until 30 days following the last dose of study treatment, or until the start of 
a subsequent systemic anti-leukemic therapy, if earlier. For subjects participating in the 
Subsequent Therapy Phase, all AEs shall be reported from the date of the first dose until 30 days 
after the last dose of ibrutinib, or until the start of a second subsequent 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 treatment must be followed 
until recovery to baseline or Grade ≤1 or until no further improvement is expected. Cardiac AEs 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
84
Approved, Date: 19 December 2019
of Grade 2 or higher will be followed until improvement to baseline or Grade ≤1 or no further 
improvement is expected. Any unresolved events will be followed for a maximum of 6 months. 
All AEs of special interest as defined in Section 12.3.3 related to bleeding or resulting in 
bleeding complications must be followed until recovery or until there is no further improvement.
Expected progression of disease should not be considered an AE (or SAE). However, if 
determined by the investigator to be more likely related to the study treatment than the 
underlying disease, the clinical signs or symptoms of progression and the possibility that the 
study treatment is enhancing disease progression, should be reported per the usual reporting 
requirements (see Section 12.1).
Asymptomatic treatment-related lymphocytosis should also not be considered an AE. Subjects 
with treatment-related lymphocytosis should remain on study treatment and continue with all 
study-related procedures.
Serious AEs, 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. Otherwise, all events that meet the definition of 
an SAE will be reported as SAEs, regardless of whether they are protocol-specific assessments.
All AEs, regardless of seriousness, severity, or presumed relationship to study treatment, must be 
recorded using medical terminology in the source document and the eCRF. 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 
eCRF their opinion concerning the relationship of the AE to study treatment. All measures 
required for AE 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 AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all SAEs 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:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
85
Approved, Date: 19 December 2019

Investigator’s name and 24-hour contact telephone number

Local sponsor’s name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number
12.3.2.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study site personnel within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form, which must be completed and signed by a physician from the study site and transmitted to 
the sponsor within 24 hours. The initial and follow-up reports of an SAE should be made by 
facsimile (fax).
All SAEs 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 intervention 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 an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject's participation in a study must be reported as an SAE, except hospitalizations 
for the following:

A standard procedure for protocol therapy administration 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, 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 AE.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
86
Approved, Date: 19 December 2019

A procedure planned before entry into the study (must be documented in the eCRF). 
Prolonged hospitalization for a complication considered to be at least possibly related to the 
study treatment remains a reportable SAE.
12.3.3.
Adverse Events of Special Interest
Specific AEs or groups of AEs will be followed as part of standard safety monitoring activities by 
the sponsor. These events should be reported to the sponsor within 24 hours of awareness 
irrespective of seriousness (ie, serious and nonserious AEs) following the procedure described 
above for SAEs and will require enhanced data collection.
Major Hemorrhage
Major hemorrhage is defined as:

Any treatment-emergent hemorrhagic AE of Grade 3 or higher.*

Any treatment-emergent SAE of bleeding of any grade.

Any treatment-emergent CNS hemorrhage/hematoma of any grade.
*All hemorrhagic AEs requiring a transfusion of red blood cells should be reported as a Grade 3 
or higher AEs per NCI-CTCAE Version 4.03.
12.3.4.
Other Malignancies
In addition to 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 OS. 
If observed, enter data in the corresponding eCRF.
12.3.5.
Eye-related Adverse Events
New or worsening eye-related symptoms that are Grade 2 or higher, or a symptom that was 
Grade 2 or higher at baseline and worsened during the study, should be evaluated by an 
ophthalmologist when appropriate.
12.3.6.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects 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, fetal death, stillbirth, and congenital anomalies, ectopic pregnancy) are considered 
SAEs and must be reported using the Serious Adverse Event Form. Any subject who becomes 
pregnant during the study must discontinue further study treatment. Follow-up information 
regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be required.
Venetoclax may cause infertility in male subjects (low or no sperm count) and treatment with 
chlorambucil may result in azoospermia (complete lack of sperm). The effect of ibrutinib and 
obinutuzumab on sperm is unknown. Therefore, pregnancies in partners of male subjects included 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
87
Approved, Date: 19 December 2019
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.
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 in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging (ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity). A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established 
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting 
of PQC information; all studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with an SAE, the study site personnel must report the PQC to the sponsor 
according to the SAE 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 in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY INTERVENTION INFORMATION
Throughout this section, “study drug” will refer to I+VEN, and study treatment will refer to 
ibrutinib, venetoclax, obinutuzumab, and chlorambucil. Refer to the SIPPM for additional 
guidance on study drug storage, preparation, and handling.
14.1.
Physical Description of Study Interventions
The ibrutinib is supplied as a gray, size 0, hard gelatin capsule containing 140 mg of ibrutinib. All 
formulation excipients are compendial and are commonly used in oral formulations. It will be 
manufactured and provided under the responsibility of the sponsor. Refer to the ibrutinib IB for a 
list of excipients.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
88
Approved, Date: 19 December 2019
Venetoclax tablets are provided as film coated tablets in blister packs. Venetoclax 10 mg, 50 mg, 
and 100 mg will be provided by the sponsor.
Obinutuzumab is supplied as 1000 mg/40 mL (25 mg/mL) single-dose vials. Obinutuzumab 
1000 mg will be provided by the sponsor.
Chlorambucil is supplied as brown, biconvex tablets containing 2 mg chlorambucil in amber 
glass bottles with child-resistant closures. Chlorambucil 2 mg will be provided by the sponsor.
14.2.
Packaging
All study drug will have labels bearing the appropriate label text as required by governing 
regulatory agencies.
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles.
Ibrutinib capsules are supplied in a bottle with a child-resistant closure.
Venetoclax 10 mg, 50 mg, and 100 mg will be packaged in child-resistant dosepaks.
Obinutuzumab 1000 mg will be packaged as a single non-child-resistant vial.
Chlorambucil 2 mg will be packaged as 1 child-resistant bottle.
14.3.
Labeling
Study treatment 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C to 30C)
(59°F to 86°F). Refer to the SIPPM for additional guidance on study drug preparation and 
handling.
Venetoclax, obinutuzumab, and chlorambucil should be stored according to the conditions as 
instructed on the drug label.
The study treatment must be stored in a secure area and administered only to subjects entered 
into the clinical study in accordance with the conditions specified in this protocol. Study site 
personnel will instruct subjects on how to store study medications for at-home use as indicated 
for this protocol. Subjects should be advised to keep all study medications out of reach and sight 
of children.
14.5.
Intervention Accountability
The investigator is responsible for ensuring that all study treatment received at the site is 
inventoried and accounted for throughout the study. The dispensing of study medications to the 
subject, and the return of these study medications 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 medication. All study treatment will be stored and 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
89
Approved, Date: 19 December 2019
disposed of according to the sponsor's instructions. Site staff must not combine contents of the 
study treatment containers.
Study treatment 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 treatment including that 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 oral study treatment, or used returned study 
medication for destruction, will be documented on the drug return form. When the site is an 
authorized destruction unit and study treatment supplies are destroyed on site, this must also be 
documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study treatments should be dispensed under the supervision of the investigator or a qualified 
member of the investigational staff, or by a hospital/clinic pharmacist. Study treatments will be 
supplied only to subjects participating in the study. Returned study treatments must not be 
dispensed again, even to the same subject. Study treatment may not be relabeled or reassigned 
for use by other subjects. The investigator agrees neither to dispense the study treatment from, 
nor store it at, any site other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Study Protocol

Subject study tools (diary card, emergency ID card etc, as applicable per country)

Investigator study tools and quick reference cards

Ibrutinib IB

Package inserts for venetoclax, chlorambucil, and obinutuzumab

Trial Center File, and corresponding site-specific documentation

SIPPM and Site Investigational Product Binder

Laboratory Manual and laboratory kits

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 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 Attachment 11, Attachment 12, 
and Attachment 13, but should not be used for collection of subject data. 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
90
Approved, Date: 19 December 2019

IWRS Manual 

eCRF Completion Guidelines
16.
ETHICAL ASPECTS
16.1.
Study-specific Design Considerations
This is a randomized, open-label, multicenter Phase 3 study to compare the efficacy and safety of 
I+VEN compared with the standard of care therapy G-Clb in subjects with newly diagnosed CLL
who are not suitable for fludarabine-based regimens. All subjects will receive active treatment 
(either I+VEN or G-Clb). G-Clb was chosen as the comparator for this study on the basis of its 
efficacy and safety, and because it is a standard of care regimen with fixed-duration regimen 
which is recommended by both US and EU treatment guidelines for use in this subject
population.15,16,18,40 While the G-Clb regimen is the current standard of care for patients with 
previously untreated CLL, the median PFS is less than 3 years. The rationale for the combination 
of I+VEN is supported by their complementary mechanisms of action and preclinical and clinical 
data showing its potential for deep, durable, MRD-negative responses which is anticipated to 
result in prolonged PFS (Section 1.5). Though each treatment has a different approach to therapy 
(eg, intravenous, cytotoxic drugs for 6 months versus oral, targeted therapies for 15 months), 
there is sufficient rationale for the I+VEN combination. 
Subjects who initially responded to fixed-duration treatment with I+VEN are expected to retain 
sensitivity to ibrutinib, supporting the use of the same agent after disease relapse. For subjects 
previously treated with G-Clb, single-agent ibrutinib is an appropriate and approved second-line 
treatment option.
All participating subjects will receive 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, including 
laboratory tests, will occur through regular clinic visits.
Potential subjects will be fully informed of the risks and requirements of the study. During the 
study, enrolled subjects will be given any new information that may affect their decision to 
continue participation. They will be informed 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 AEs of the study, and provide their consent voluntarily will be 
enrolled.
Subjects assigned to Treatment Arm A will have a maximum of approximately 508 mL of blood 
collected during the treatment period. Subjects assigned to Treatment Arm B will have a 
maximum of approximately 323 mL of blood collected during the treatment period. After the 
treatment period, approximately 34 to 84 mL of blood will be collected yearly in both treatment 
groups. During the Subsequent Therapy Phase, a maximum of approximately 176 mL will be 
collected during the first year of participation. Thereafter, a maximum of approximately 92 mL 
will be collected each subsequent year on treatment. This includes laboratory assessments 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
91
Approved, Date: 19 December 2019
associated with treatment, efficacy assessments (eg, MRD sampling), biomarker samples, and 
pharmacokinetic samples for subjects in Treatment Arm A. The volume of blood to be drawn is 
considered to be normal and acceptable for subjects participating in a cancer clinical study and is 
deemed reasonable over the time frame of the study.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

IB (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 approved of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
subjects, data or study conduct, unless required locally), the ICF, applicable recruiting materials, 
and subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
92
Approved, Date: 19 December 2019
During the study, the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study 
intervention

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB.
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data, or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s). 
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
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 ICF must be signed before performance of any study-related 
activity. The ICF 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 ICF should be in 
accordance with principles that originated in the Declaration of Helsinki, current ICH and GCP 
guidelines, applicable regulatory requirements, and sponsor policy.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
93
Approved, Date: 19 December 2019
Before enrollment in the study, the investigator or an authorized member of the study site 
personnel 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 ICF 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 ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the subject is obtained.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
94
Approved, Date: 19 December 2019
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA and biomarker research is not conducted under standards appropriate for the 
return of data to subjects. In addition, the sponsor cannot make decisions as to the significance of 
any findings resulting from exploratory research. Therefore, exploratory research data will not be 
returned to subjects or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years after end of study (or according 
to local regulations) for additional research. Samples will only be used to understand ibrutinib
and venetoclax, to understand CLL, to understand differential intervention responders, and to 
develop tests/assays related to ibrutinib and venetoclax and CLL. 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 10.4).
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 if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16.1.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
95
Approved, Date: 19 December 2019
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 listed in the Contact Information page(s), which will be provided as a separate
document. 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 eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated Clinical Trial Agreement, which includes the financial agreement

Any other documentation required by local regulations.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
96
Approved, Date: 19 December 2019
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of sub-investigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable.
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth (as allowed by local regulations). In cases where the subject is not randomized 
into the study, the date seen and date of birth (as allowed by local regulations) will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of 
study completion and reason for early discontinuation of study intervention or withdrawal from 
the study, if applicable. 
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 and source data collection methods 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.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
97
Approved, Date: 19 December 2019
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the eCRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the eCRF. Data in this system 
may be considered source documentation.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. All eCRF entries, 
corrections, and alterations must be made by the investigator or other authorized study site 
personnel. The investigator must confirm that all data entries in the eCRFs are accurate and 
correct.
Electronic data capture (eDC) will be used for this study. The study data will be transcribed by 
study site personnel from the source documents onto an electronic eCRF 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 eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs in 
English. Designated site personnel must complete the eCRF within the timelines specified by the 
site contract after a subject visit, and the forms should be available for review at the next 
scheduled monitoring visit.
If necessary, queries will be generated in the eDC tool. If corrections to a eCRF are needed after 
the initial entry into the eCRF, then this can be done in either of the following ways:

Investigator and study site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool)

Site manager or clinical data manager can generate a query for resolution by the investigator 
and study site personnel
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
associated personnel before the study, periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory into the sponsor's database. 
Written instructions will be provided for collection, preparation, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study personnel before the 
start of the study.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
98
Approved, Date: 19 December 2019
The sponsor will review eCRFs 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 eCRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will use a combination of monitoring techniques: central, remote and on-site 
monitoring to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
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 eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
eCRF are known to the sponsor and study site personnel and are accessible for verification by the 
sponsor study site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study site personnel. 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
99
Approved, Date: 19 December 2019
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the study site personnel. The sponsor expects that, during 
monitoring visits, the relevant study site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study site personnel will be available to provide an update on the progress 
of the study at the site. 
Central monitoring will take place for data identified by the sponsor as requiring central review.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed approximately 5 years after the last subject is randomized into 
the study or after 50% of the subjects have died, whichever comes first. The final data from the 
study site will be sent to the sponsor (or designee) after completion of the final subject 
assessment at that study site, in the time frame specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study intervention development.
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
100
Approved, Date: 19 December 2019
respected. The investigator and study site personnel are responsible for being present and 
available for consultation during routinely scheduled study site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding ibrutinib or the sponsor’s 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including 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.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of ibrutinib, and thus may be disclosed as 
required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of exploratory 
biomarker analyses performed after the Clinical Study Report has been issued will be reported in 
a separate report and will not require a revision of the Clinical Study Report. Study subject 
identifiers will not be used in publication of results. Any work created in connection with 
performance of the study and contained in the data that can benefit from copyright protection 
(except any publication by the investigator as provided for below) shall be the property of the
sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
101
Approved, Date: 19 December 2019
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 18 months after study end date, or the sponsor 
confirms there will be no multicenter study publication. Authorship of publications resulting 
from this study will be based on the guidelines on authorship, such as those described in the 
International Committee of Medical Journal Editors (ICMJE) Recommendations for the 
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which state 
that the named authors must have made a significant contribution to the conception or design of 
the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
102
Approved, Date: 19 December 2019
REFERENCES
1.
Barr P, Robak T, Owen C, et al. Updated efficacy and safety from the Phase 3 RESONATE-2 Study: Ibrutinib 
as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small 
lymphocytic leukemia. Blood. 2016;128:234.
2.
Bottcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of 
progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the 
randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30:980-988.
3.
Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic 
leukemia. N Engl J Med. 2015;373:2425-2437.
4.
Byrd JC, Furman R, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients 
with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125:2497-2506.
5.
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 
2004;127(1):3-11.
6.
Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and protein profiling suggests venetoclax
(ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res. 
2015;21:3705-3715.
7.
Child CG, Turcotte JG. Surgery and portal hypertension. In Child CG. The liver and portal hypertension. 
Philadelphia: Saunders. 1964. pp. 50-64. 
8.
Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352:804-815.
9.
Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis 
syndrome: an evidence-based review. J Clin Oncol. 2008;26(16):2767-2778.
10.
Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS. Ibrutinib therapy increases BCL-2 dependence
and enhances sensitivity to venetoclax in CLL. Blood. 2015;126:490.
11.
Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS. Bruton’s tyrosine kinase inhibition increases 
BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia. 
2017;31:2075-2084.
12.
Department of Medicine Clinical Pharmacology Drug Interactions Flockhart Table. Available at 
http://medicine.iupui.edu/clinpharm/ddis/main-table. Accessed 14 December 2019.
13.
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers. Accessed 18 December 2019.
14.
Eichhorst B, Fink A, Busch R et al. Frontline chemoimmunotherapy with bendamustine and rituximab (BR) 
versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukemia 
(CLL10): an international, open-label, randomized, Phase 3 non-inferiority trial. Lancet Oncol.
2016;17:928-942.
15.
Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines
for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(suppl 5):v78-v84.
16.
Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: eUpdate published online 
September 2016. Ann Oncol. 2016;27(Suppl 5):v143-144.
17.
Eldering E, Peperzak V, ter Burg H, Fernandes SM, Brown JR, Kater AP. BCL2 members as drug target and 
biomarkers for response to ibrutinib and venetoclax in CLL. Blood. 2016;128:2043. 
18.
ESMO Guidelines Committee eUpdate – Chronic lymphocytic leukaemia treatment recommendations. 27 June 
2017. Available at: http://www.esmo.org/Guidelines/Haematological-Malignancies/Chronic-Lymphocytic-
Leukaemia/eUpdate-Treatment-Recommendations. Accessed 19 December 2017.
19.
Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic 
lymphocytic leukaemia with TP53 aberrations: a Phase 2, single-arm trial. Lancet Oncol. 2015;16(2):169-176. 

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
103
Approved, Date: 19 December 2019
20.
Fischer, K. Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously 
untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127:208–215.
21.
GAZYVA [package insert]. San Francisco, CA: Genentech Inc 2017. 
22.
GAZYVARO [package insert]. Welwyn Garden City, United Kingdom: Roche Registration Limited 2017.
23.
Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting 
conditions. N Engl J Med. 2014;370:1101-1110.
24.
Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: 
updated results of the CLL11 study. Leukemia. 2015;29:1602–1604.
25.
Gribben JG, O’Brien S. Update on therapy of chronic lymphocytic leukemia. J Clin Oncol. 2011;29:544-550. 
26.
Hallek M, Cheson BD, Catovsky D, et al. Response assessment in chronic lymphocytic leukemia treated with 
novel agents causing an increase of peripheral blood lymphocytes. Blood 2012; e-letter, published June 04, 
2012. 
27.
Hallek M, Cheson BD, Catovsky D, et al. Clarification of IWCLL criteria for a partial response to therapy. 
Blood.
2013; 
e-letter, 
published 
November 
13, 
2013. 
Available 
at: 
http://www.bloodjournal.org/content/111/12/5446/tab-e-letters#clarification-of-iwcll-criteria-for-a-partial-
response-to-therapy.
28.
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.
29.
Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in 
patients with chronic lymphocytic leukaemia: a randomised, open-label, Phase 3 trial. Lancet. 
2010;376:1164-1174.
30.
Herman SE, Mustafa RZ, Gyamfi JA, et al. Ibrutinib inhibits BCR and NF-kB signaling and reduces tumor 
proliferation in tissue-resident cells of patients with CLL. Blood. 2014; 123:3286-3295.
31.
Herman SE, Niemann CU, Farooqui M, et al. Ibrutinib-induced lymphocytosis in patients with chronic 
lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. 2014;28(11):2188-2196.
32.
Hillmen P, Munir T, Rawstron A, et al. Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL 
(Bloodwise TAP CLARITY Study): high rates of overall response, complete remission and MRD eradication 
after 6 months of combination therapy. 2017. Presented at American Society of Hematology (ASH) 59th
Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 428. Available at: 
https://ash.confex.com/ash/2017/webprogram/Paper104020.html. Accessed 15 December 2017.
33.
Hillmen P, Robak T, Janssens A, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously 
untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-
label phase 3 trial. Lancet. 2015;385(9980):1873-1883.
34.
Hillmen P, Rawstron A, Munir T, et al. The initial report of the bloodwise tap CLARITY study combining 
ibrutinib and venetoclax in relapsed, refractory CLL shows acceptable safety and promising early indications 
of efficacy. Presented at: 2017 EHA Congress; June 22-25, 2017; Madrid, Spain. Abstract S770.
35.
Hillmen P, Rawstron A, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory CLL: results of the 
Bloodwise TAP Clarity Study. Blood. 2018;132:182.
36.
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364:1844-1854. 
37.
Jain N,
O’Brien S. Initial treatment of CLL: integrating biology and functional status. Blood. 
2015;126(4):463-470.
38.
Jain N, Thompson PA, Ferrajoli A, et al. Combined venetoclax and ibrutinib for patients with previously 
untreated high-risk CLL, and relapsed/refractory CLL: A phase II trial. Presented at American Society of 
Hematology (ASH) 59th Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 
429. Available at: https://ash.confex.com/ash/2017/webprogram/Paper106923.html. Accessed 15 December 
2017.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
104
Approved, Date: 19 December 2019
39.
Jain N, Keating MJ, Thompson PA, et al. Combined ibrutinib and venetoclax in patients with treatment-naïve 
high-risk chronic lymphocytic leukemia (CLL). Blood. 2018;132:696.
40.
Malcikova J, Tausch E, Rossi D, et al. ERIC recommendations for TP53 mutation analysis in chronic 
lymphocytic leukemia—update on methodological approaches and
results interpretation. Leukemia. 
2018;32:1070–1080.
41.
Ozer H, Armitage JO, Bennett CL, et al. 2000 update of recommendations for the use of hematopoietic colony
stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol. 2000;18:3558-3585.
42.
Portell C, Axelrod M, Brett K, et al. Synergistic cytotoxicity of ibrutinib and the BCL2 antagonist, ABT-199 
(GDC-0199) in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL): molecular analysis 
reveals mechanisms of target interactions. Blood. 2014;124:509.
43.
Pugh RN, Murray-Lyon IM, Dawson L, et al. “Transection of the oesophagus for bleeding oesophageal 
varices”. Br J Surgery. 1973;60:646-649.
44.
Rawstron AC, Villamor N, Ritgen M, et al. International standardized approach for flow cytometric residual 
disease monitoring in chronic lymphocytic leukaemia. Leukemia. 2007;21: 956–964.
45.
Rawstron AC, Kreuzer K-A, Soosapilla A, et al. Reproducible diagnosis of chronic lymphocytic leukemia by 
flow cytometry: An European research initiative on CLL (ERIC) & European Society for Clinical Cell 
Analysis (ESCCA) harmonisation project. Cytometry Part B. 2018;94B:121–128.
46.
RITUXAN [package insert]. South San Francisco, CA: Genentech, Inc. 2016.
47.
Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic 
leukemia. N Engl J Med. 2016;374:311-322.
48.
Salvi F, Miller MD, Grilli A, et al. A manual of guidelines to score the modified cumulative illness rating scale 
and its validation in acute hospitalized elderly patients. J Am Geriatr Soc. 2008;56:1926–1931.
49.
Slinger E, Balasubramanian S, Leverson J, Eldering E, Kater AP. Combinatorial treatment of chronic 
lymphocytic leukemia with ibrutinib and venetoclax is superior to treatment with single agents in the TCL1 
mouse model. Presented at American Society of Hematology (ASH) 59th Annual Meeting and Exposition; 
December 
9-12, 
2017; 
Atlanta, 
Georgia. 
Abstract 
3018.
Available 
at: 
https://ash.confex.com/ash/2017/webprogram/Paper104251.html. Accessed 15 December 2017.
50.
Stilgenbauer S, Eichhorst BF, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic 
leukemia with 17p deletion: a multicenter, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768-778.
51.
Strati P, Keating MJ, O’Brien SM, et al. Eradication of bone marrow minimal residual disease may prompt 
early treatment discontinuation in CLL. Blood. 2014;123:3727-3732. 
52.
Thompson PA, Tam CS, O’Brien, SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves 
long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127:303-309.
53.
VENCLEXTA [package insert]. N. Chicago, IL: AbbVie Inc 2016.
54.
VENCLYXTO [package insert]. Maidenhead, UK: AbbVie Ltd 2017.
55.
Wierda WG, Byrd JC, O’Brien S, et al. Tumor debulking and reduction in tumor lysis syndrome risk: analyses 
from single-agent ibrutinib studies. IWCLL 2017. Poster 106.
56.
Wierda et al. Phase 2 Captivate results of ibrutinib plus venetoclax in first-line chronic lymphocytic leukemia 
(CLL), J Clin Oncol. 2018. 26(15): suppl 7502-7502.
57.
Zenz T, Gribben JG, Hallek M, Döhner H, Keating MJ, Stilgenbauer S. Risk categories and refractory CLL in 
the era of chemoimmunotherapy. Blood. 2012;119(18):4101-4107.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
105
Approved, Date: 19 December 2019
Attachment 1: Ibrutinib Risks
For the most comprehensive clinical safety information, please refer to the latest version of the 
ibrutinib IB and Addenda.
HEMATOLOGIC
Leukostasis
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high 
number of circulating lymphocytes (>400,000/µL) may confer increased risk. These subjects 
should be closely monitored. Administer supportive care such as hydration and/or cytoreduction 
as indicated. Ibrutinib may be temporarily held and the medical monitor should be contacted.
Cytopenias
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Monitor CBCs monthly.
Lymphocytosis
Upon initiation of single-agent treatment with ibrutinib, a reversible increase in lymphocyte 
counts (ie, ≥50% increase from baseline and an absolute count >5,000/µL), often associated with 
reduction of lymphadenopathy, has been observed in most subjects (66%) with CLL. This 
observed lymphocytosis is a pharmacodynamic effect and should not be considered PD in the 
absence of other clinical findings. In CLL, lymphocytosis typically occurs during the first month 
of ibrutinib therapy and typically resolves within a median of 14 weeks. 
NON-HEMATOLOGIC
Bleeding-related Events
There have been reports of bleeding events in subjects treated with ibrutinib, both with and 
without thrombocytopenia. These include minor bleeding events such as contusion, epistaxis, 
and petechiae, and major bleeding events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria. In an in vitro platelet function study, inhibitory effects 
of ibrutinib on collagen-induced platelet aggregation were observed. Use of either anticoagulant 
or antiplatelet agents concomitantly with ibrutinib increases the risk of bleeding. A higher risk 
for major bleeding was observed with anticoagulant than with antiplatelet agents. Consider the 
risks and benefits of anticoagulant or antiplatelet therapy when co-administered with ibrutinib. 
Monitor for signs and symptoms of bleeding.
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. Subjects with congenital bleeding diathesis have not been 
studied. See Section 8.2 for guidance on concomitant use of anticoagulants, antiplatelet therapy 
and/or supplements. See Section 4.3 for guidance on ibrutinib management with surgeries or 
procedures.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
106
Approved, Date: 19 December 2019
Infections
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects 
treated with ibrutinib therapy. Some of these infections have been associated with hospitalization 
and death. Consider prophylaxis according to standard of care in subjects who are at increased 
risk for opportunistic infections (see Section 8.1). Although causality has not been established, 
cases of progressive multifocal leukoencephalopathy and Hepatitis B reactivation have occurred 
in subjects treated with ibrutinib. Subjects should be monitored for signs and symptoms (fever, 
chills, weakness, confusion, vomiting, and jaundice), and appropriate therapy should be 
instituted as indicated.
Interstitial Lung Disease 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. 
Monitor subjects for pulmonary symptoms indicative of ILD. If symptoms develop, follow the 
protocol dose modification guidelines (see Section 6.1.1.2). If symptoms persist, consider the 
risks and benefits of ibrutinib treatment and follow the dose modification guidelines 
(Section 6.1.1.2).
Cardiac Arrhythmias
Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia including some fatal 
events, have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac 
risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmia. 
Periodically monitor patients clinically for cardiac arrhythmia. Subjects who develop arrhythmic 
symptoms (eg, palpitations, light-headedness, syncope, chest discomfort, or new onset of 
dyspnea) should be evaluated clinically, and if indicated, have an ECG performed. For cardiac 
arrhythmias which persist, consider the risks and benefits of ibrutinib treatment, and follow the 
protocol dose modification guidelines (see Section 6.1.1.2).
Cerebrovascular Accidents
Although causality has not been established, cases of cerebrovascular accident, transient 
ischemic attack, and ischemic stroke including fatalities have been reported with the use of 
ibrutinib in the post-marketing setting, with and without concomitant atrial fibrillation and/or 
hypertension. Regular monitoring and appropriate treatment of conditions that can contribute to 
the occurrence of these events is recommended.
Tumor Lysis Syndrome
Tumor lysis syndrome has been reported with ibrutinib therapy. Subjects at risk of tumor lysis 
syndrome are those with high tumor burden prior to treatment. Monitor subjects closely and take 
appropriate precautions.
Non-melanoma Skin Cancer
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor subjects 
for the appearance of non-melanoma skin cancer.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
107
Approved, Date: 19 December 2019
Diarrhea
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation. These events are rarely severe and are generally managed with supportive 
therapies including antidiarrheals and antiemetics. Subjects should be monitored carefully for 
gastrointestinal AEs and cautioned to maintain fluid intake to avoid dehydration. Medical 
evaluation should be made to rule out other etiologies such as Clostridium difficile or other 
infectious agents. Should symptoms be severe or prolonged follow the protocol dose 
modification guidelines (see Section 6.1.1.2).
Rash
Rash has been commonly reported in subjects treated with either single-agent ibrutinib or in 
combination with chemotherapy. Rash occurred at a higher rate in the ibrutinib arm than in the 
ofatumumab arm in Study PCYC-1112-CA. Most rashes were mild to moderate in severity. 
Isolated cases of severe cutaneous adverse reactions (SCARs) including Stevens-Johnson 
syndrome (SJS) have been reported in subjects treated with ibrutinib. Subjects should be closely 
monitored for signs and symptoms suggestive of SCAR including SJS. Subjects receiving 
ibrutinib should be observed closely for rashes and treated symptomatically, including 
interruption of the suspected agent as appropriate. In addition, hypersensitivity-related events 
erythema, urticaria, angioedema have been reported.
Hypertension
Hypertension has occurred in subjects treated with ibrutinib. Regularly monitor blood pressure in 
subjects treated with ibrutinib and initiate or adjust antihypertensive medication throughout 
treatment with ibrutinib as appropriate.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
108
Approved, Date: 19 December 2019
Attachment 2: Cumulative Illness Rating Scale (CIRS)
Please take into account that CLL-induced illness or organ damage are not included in this rating
scale. The goal of this rating scale is to assess comorbidity other than CLL in the patient. If there
are 2 or more illness/impairments of one organ system, the illness/impairment with the highest
severity should be evaluated.
Organ system
If illness/impairment present, specify the
Score
illness/impairment with highest severity
Cardiac ______________________________________________
_____
Hypertension __________________________________________
_____
Vascular ______________________________________________
_____
Respiratory ____________________________________________
_____
Eye/ear/nose/throat/larynx ________________________________
_____
Upper gastrointestinal ___________________________________
_____
Lower gastrointestinal ___________________________________
_____
Hepatic/biliary _________________________________________
_____
Renal ________________________________________________
_____
Genitourinary __________________________________________
_____
Musculoskeletal _________________________________________
_____
Endocrine/metabolic ______________________________________
_____
Neurological ____________________________________________
_____
Psychiatric ______________________________________________
_____
Total score
_____
CIRS Rating of Comorbidity
Score
0 No problem Organ system not compromised.
1 Mild Illness/impairment with or without requirement of therapy,
excellent prognosis, patient with normal activity
2 Moderate Illness/impairment requiring therapy, good prognosis;
compromised activity of patients
3 Severe Illness/impairment with urgent requirement for therapy,
prognosis unclear, marked restriction in activity of patient.
4 Extremely severe Life-threatening illness/impairment, emergency case of therapy,
adverse prognosis.
Link to Manual of Guidelines to score the modified Cumulative Illness Rating Scale: 
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1532-5415.2008.01935.x
Source: Salvi F, Miller MD, Grilli A, et al. A manual of guidelines to score the modified cumulative illness 
rating scale and its validation in acute hospitalized elderly patients. J Am Geriatr Soc. 2008;56:1926–
1931.48

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
109
Approved, Date: 19 December 2019
Attachment 3: Contraceptive and Barrier Guidance and Collection of Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in 
the postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT), however in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
If there is a question about menopausal status in women on HRT, the woman will be 
required to use one of the non-estrogen-containing hormonal highly effective contraceptive 
methods if she wishes to continue HRT during the study.

permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral 
tubal occlusion/ligation procedures, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER-INDEPENDENT
Highly Effective Methods That Are User-Independent Failure rate of ≤1% per year when used 
consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 74 days.)

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
110
Approved, Date: 19 December 2019
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb
oral
intravaginal
transdermal
injectables

Progestogen-only hormone contraception associated with inhibition of ovulationb
oral
injectable

Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the subject.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not 
considered to be highly effective - failure rate of >1% per year)

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action.

Male or female condom with or without spermicidec

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus-interruptus)

Spermicides alone

Lactational amenorrhea method (LAM)
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for subjects 
participating in clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may 
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception 
may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
111
Approved, Date: 19 December 2019
Attachment 4: Child-Pugh Scores for Subjects with Chronic Liver Impairment
Measure
1 point
2 points
3 points
Total bilirubin, μmol/L (mg/dL)
<34 (<2)
34-50 (2-3)
>50 (>3)
Serum albumin, g/L (g/dL)
>35 (>3.5)
28-35 (2.8-3.5)
<28 (<2.8)
PT/INR
<1.7
1.71-2.30
>2.30
Ascites
None
Mild
Moderate to Severe
Hepatic encephalopathy
None
Grade I-II (or suppressed 
with medication)
Grade III-IV 
(or refractory)
Points
Class
5-6
A
7-9
B
10-15
C
Sources: 

7Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia: Saunders. 1964. pp. 50-64.

43Pugh RN, Murray-Lyon IM, Dawson L, et al. “Transection of the oesophagus for bleeding oesophageal 
varices”. The British journal of surgery, 1973;60: 646-649.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
112
Approved, Date: 19 December 2019
Attachment 5: Inhibitors and Inducers of CYP3A
The table below shows the classification of commonly used inhibitors and inducers of CYP3A enzymes. 
Further information can be found at the following websites: https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers13 and 
http://medicine.iupui.edu/clinpharm/ddis/main-table/.12
Inhibitors of CYP3A
Inducers of CYP3A
Strong inhibitors:
carbamazepine
Boceprevir
barbiturates
Clarithromycin
efavirenz
Cobicistat
glucocorticoids
Indinavir
modafinil
Itraconazole
nevirapine
Ketoconazole
oxcarbarzepine
Mibefradil
phenobarbital
Nefazodonene
phenytoin
Nelfinavir
pioglitazone
posaconazole
rifabutin
Ritonavir
rifampin
Saquinavir
St. John’s Wort
Suboxone
troglitazone
Telaprevir
Telithromycin
Troleandomycin
voriconazole
Moderate inhibitors:
Amiodarone
Amprenavir
Aprepitant
Atazanavir
Ciprofloxacin
Crizotinib
Darunavir
diltiazem 
Dronedarone
Erythromycin
Fluconazole
Fosamprenavir
grapefruit juice
Seville orange juice
Verapamil
Weak inhibitors:
Cimetidine
Fluvoxamine
All other inhibitors:
Chloramphenicol
Delaviridine
Gestodene
Mifepristone
Norfloxacin
Norfluoxetine
star fruit

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
113
Approved, Date: 19 December 2019
Attachment 6: Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of Tumor Lysis Syndrome (TLS)
Section 1: First Dose of Venetoclax or Dose Escalation

Within the first 24 hours after either the first dose or dose escalation, if any laboratory 
criteria below are met, the subject should be hospitalized for monitoring and the investigator 
notified. No additional venetoclax doses should be administered until resolution. A rapidly 
rising serum potassium is a medical emergency.

Nephrology (or other acute dialysis service) should be notified (per institutional standards to 
ensure emergency dialysis is available) on admission for any subject hospitalized 
prophylactically or in response to laboratory changes.

IV fluids (eg, day 5 1/2 normal saline) should be initiated at a rate of at least 1 mL/kg/hr 
rounded to the nearest 10 mL (target 150 to 200 mL/hr; not <50 mL/hr). Modification of 
fluid rate should also be considered for individuals with specific medical needs.

Monitor for symptoms or signs of TLS (eg, fever, chills, tachycardia, nausea, vomiting, 
diarrhea, diaphoresis, hypotension, muscle aches, weakness, paresthesias, mental status 
changes, confusion, seizures). If any clinical features are observed, recheck potassium, 
phosphorus, uric acid, calcium, and creatinine.

Vital signs should be taken at time of all blood draws or any Intervention.

The management recommendations below focus on the minimum initial responses required. 
If a diagnosis of TLS is established, ongoing intensive monitoring and multi-disciplinary 
management will be per institutional protocols.
In addition to the recommendations in the table below:

For potassium increase ≥0.5 mmol/L from baseline, or any value >5.0 mmol/L, recheck 
potassium, phosphorus, uric acid, calcium, and creatinine and follow first guideline.

For phosphorus increase of >0.5 mg/dL AND >4.5 mg/dL, administer phosphate binder and 
recheck potassium, phosphorus, uric acid, calcium, and creatinine.
Abnormality
Management Recommendations5,9
Hyperkalemia (including rapidly rising potassium)
Potassium ≥0.5 mmol/L increase
from prior value (even if potassium
within normal limits [WNL])
Recheck potassium, phosphorus, uric acid, calcium, and creatinine. If 
further ≥0.2 mmol/L increase in potassium, but still <ULN, manage as 
per potassium ≥ULN. Otherwise recheck.
Resume per protocol testing if change in potassium is <0.2 mmol/L, 
and potassium < ULN, and no other evidence of tumor lysis.
At discretion of Investigator, may recheck prior to hospitalization. If 
stable or decreased, and still WNL, hospitalization is at the discretion of 
the Investigator. Potassium, phosphorus, uric acid, calcium, and
creatinine must be rechecked within 24 hours.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
114
Approved, Date: 19 December 2019
Abnormality
Management Recommendations5,9
Potassium > upper limit of normal
Perform STAT ECG and commence telemetry.
Nephrology notification with consideration of initiating dialysis.
Administer Kayexalate 60 g (or Resonium A 60 g).
Administer furosemide 20 mg IV × 1.
Administer calcium gluconate 100 – 200 mg/kg IV slowly if there is 
ECG/telemetry evidence of life-threatening arrhythmias.
Recheck potassium, phosphorus, uric acid, calcium, and creatinine.
If potassium < ULN 1 hour later, repeat potassium, phosphorus, uric 
acid, calcium, and creatinine 1, 2 and 4 hours, if no other evidence of 
tumor lysis.
Potassium ≥6.0 mmol/L (6.0 mEq/L) 
and/or symptomatic (eg, muscle cramps, 
weakness, paresthesias, nausea, 
vomiting, diarrhea)
Perform STAT ECG and commence telemetry.
Nephrology (or other acute dialysis service) notified with 
consideration of initiating dialysis.
Administer Kayexalate 60 g (or Resonium A 60 g).
Administer furosemide 20 mg IV × 1.
Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV.
Administer sodium bicarbonate 1 to 2 mEq/kg IV push.
If sodium bicarbonate is used, rasburicase should not be used as this 
may exacerbate calcium phosphate precipitation.
Administer calcium gluconate 100 to 200 mg/kg IV slowly if there is 
ECG/telemetry evidence of life-threatening arrhythmias. Do not 
administer in same IV line as sodium bicarbonate.
Recheck potassium, phosphorus, uric acid, calcium, and creatinine.
Hyperuricemia
Uric acid ≥8.0 mg/dL (476 μmol/L)
Consider rasburicase (0.2 mg/kg as an intravenous infusion over 
30 minutes).
If rasburicase is used, sodium bicarbonate should not be used as this 
may exacerbate calcium phosphate precipitation.
Recheck potassium, phosphorus, uric acid, calcium, and creatinine.
Uric acid ≥10 mg/dL (595 μmol/L)
OR
Uric acid ≥8.0 mg/dL (476 μmol/L)
with 25% increase and creatinine
increase ≥0.3 mg/dL (≥0.027mmol/L) 
from predose level
Administer rasburicase (0.2 mg/kg as an intravenous infusion over 
30 minutes).
When rasburicase is used, sodium bicarbonate should not be used as this 
may exacerbate calcium phosphate precipitation.
Notify nephrology (or other acute dialysis service).
Recheck potassium, phosphorus, uric acid, calcium, and creatinine.
If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium, and creatinine 2 and 4 hours later, if no other 
evidence of tumor lysis.
Hypocalcemia
Calcium ≤ 7.0 mg/dL (1.75 mmol/L)
AND
Subject symptomatic (eg, muscle
cramps, hypotension, tetany, cardiac
arrhythmias)
Administer calcium gluconate 50 to 100 mg/kg IV slowly with ECG 
monitoring.
Telemetry.
Recheck potassium, phosphorus, uric acid, calcium, and creatinine.
If calcium normalized 1 hour later, repeat potassium, phosphorus, uric 
acid, calcium, and creatinine 2 and 4 hours later, if no other evidence of 
tumor lysis.
Calculate corrected calcium and check ionized calcium if albumin low

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
115
Approved, Date: 19 December 2019
Abnormality
Management Recommendations5,9
Hyperphosphatemia
Phosphorus ≥5.0 mg/dL (1.615 mmol/L) 
with ≥0.5 mg/dL (0.16 mmol/L) increase
Administer a phosphate binder (eg, aluminum hydroxide, calcium 
carbonate, sevelamer hydroxide, or lanthanum carbonate).
Nephrology (or other acute dialysis service) notification (dialysis 
required for phosphorus ≥10 mg/dL). 
Recheck potassium, phosphorus, uric acid, calcium, and creatinine.
If phosphorus <5.0 mg/dL 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium, and creatinine 2 and 4 hours later, if no other 
evidence of tumor lysis.
Creatinine
Increase ≥25% from baseline
Start or increase rate of IV fluids.
Recheck potassium, phosphorus, uric acid, calcium, and creatinine.
Section 2: Ongoing Dosing of Venetoclax
Management of electrolyte changes from last value at intervals >24 hours after either the first 
dose or dose escalation (eg, 48 or 72 hours) are as below.
Note: If the subject is hospitalized, no additional venetoclax doses should be administered until 
resolution.

For potassium, admit subject for any increase ≥1.0 mmol/L (1.0 mEq/L), or any level 
> ULN.

Refer to the management guidelines for electrolyte changes observed within the first 
24 hours after either the first dose or dose escalation (see table above).

If a smaller potassium increase is observed that does not meet the criteria for admission 
above, recheck potassium, phosphorus, uric acid, calcium, and creatinine in 24 hours and 
confirm no evidence of tumor lysis prior to further venetoclax dosing.

For uric acid, calcium, phosphorus and creatinine, refer to the management guidelines for 
electrolyte changes observed within the first 24 hours after either the first dose or dose 
escalation (see table above).
Sources
9Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an 
evidence-based review. J Clin Oncol.2008;26(16):2767-78.
5Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 
2004;127(1):3-11.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
116
Approved, Date: 19 December 2019
Attachment 7: Howard Criteria for Laboratory and Clinical Tumor Lysis Syndrome*
Metabolic Abnormality 
Criteria for Classification of 
Laboratory Tumor Lysis 
Syndrome
Criteria for Classification of 
Clinical Tumor Lysis Syndrome
Hyperuricemia 
Uric acid >8.0 mg/dL 
(475.8 μmol/liter) in adults or above 
the upper limit of the normal range 
for age in children
Hyperphosphatemia
Phosphorus >4.5 mg/dL 
(1.5 mmol/liter) in adults or 
>6.5 mg/dL (2.1 mmol/liter) in 
children
Hyperkalemia 
Potassium >6.0 mmol/liter 
Cardiac dysrhythmia or sudden death 
probably or definitely caused by 
hyperkalemia
Hypocalcemia  
Corrected calcium <7.0 mg/dL 
(1.75 mmol/liter) or ionized 
calcium <1.12 (0.3 mmol/liter)†
Cardiac dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(tetany, paresthesias, muscle 
twitching, carpopedal spasm, 
Trousseau’s sign, Chvostek’s sign, 
laryngospasm, or bronchospasm), 
hypotension, or heart failure probably 
or definitely caused by hypocalcemia
Acute kidney injury‡
Not applicable
Increase in the serum creatinine level 
of 0.3 mg/dL (26.5 μmol/liter) (or a 
single value >1.5 times the upper 
limit of the age-appropriate normal 
range if no baseline creatinine 
measurement is available) or the 
presence of oliguria, defined as an 
average urine output of 
<0.5 mL/kg/hr for 6 hr
* In laboratory TLS, 2 or more metabolic abnormalities must be present during the same 24-hour period within 3 days before 
the start of therapy or up to 7 days afterward. Clinical TLS requires the presence of laboratory TLS plus an increased 
creatinine level, seizures, cardiac dysrhythmia, or death.
† The corrected calcium level in milligrams per deciliter=measured calcium level in milligrams per deciliter + 0.8 × 
(4 − albumin in grams per deciliter).
‡ Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 μmol per liter) or a 
period of oliguria lasting 6 hours or more. By definition, if acute kidney injury is present, the patient has clinical TLS. Data 
about acute kidney injury are from Levin A, Warnock DG, Mehta RL, et al. Improving outcomes from acute kidney injury: 
report of an initiative. Am J Kidney Dis. 2007;50:1–4.
Source: 36Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364:1844-1854.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
117
Approved, Date: 19 December 2019
Attachment 8: Obinutuzumab Premedication for Infusion Reactions and Tumor Lysis Syndrome
Obinutuzumab Premedication for Infusion Reactions
Obinutuzumab can cause severe and life-threatening infusion reactions. Symptoms of infusion 
reactions may include hypotension, tachycardia, dyspnea, and respiratory symptoms 
(eg, bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). All subjects should 
be premedicated to reduce the risk of infusion reactions. Recommended premedications are 
summarized in table below. Because hypotension may occur during obinutuzumab infusion, 
consider withholding antihypertensive treatments for 12 hours prior to and throughout each 
obinutuzumab infusion and for the first hour after administration. 
Premedication Before Obinutuzumab Infusion
Day of
Treatment Cycle
Subjects requiring 
premedication
Premedication
Administration
Cycle 1, Day 1
All subjects
Intravenous corticosteroid1
(mandatory)
Completed at least 1 hour prior to 
obinutuzumab infusion.
Oral analgesic/anti-pyretic2
At least 30 minutes before 
obinutuzumab infusion.
Anti-histamine medicine3
Cycle 1, Day 2
All subjects
Intravenous corticosteroid1
(mandatory)
Completed at least 1 hour prior to 
obinutuzumab infusion.
Oral analgesic/anti-pyretic2
At least 30 minutes before 
obinutuzumab infusion.
Anti-histamine medicine3
All subsequent 
infusions
Subjects with no IRR
during the previous
infusion
Oral analgesic/anti-pyretic2
At least 30 minutes before 
obinutuzumab infusion.
Subjects with an IRR 
(Grade 1 -2) with the 
previous infusion 
Oral analgesic/anti-pyretic2
Anti-histamine medicine3
Subjects with a Grade 3
IRR with the previous
infusion OR
Patients with lymphocyte 
counts >25 x 109/L prior to
next treatment
Intravenous corticosteroid1
Completed at least 1 hour prior
to obinutuzumab infusion.
Oral analgesic/anti-pyretic2
Anti-histamine medicine3
At least 30 minutes before 
obinutuzumab infusion.
1100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone. Hydrocortisone
should not be used as it has not been effective in reducing rates of IRR.
2 eg, 1,000 mg acetaminophen/paracetamol
3 eg, 50 mg diphenhydramine

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
118
Approved, Date: 19 December 2019
Obinutuzumab Premedication for Tumor Lysis Syndrome
Subjects with high tumor burden, high circulating ALCs (>25 x 109/L) or renal impairment (CrCl 
<70 mL/min) are considered at risk for TLS and should be premedicated with 
anti-hyperurecemics (eg, allopurinol and/or rasburicase) and adequately hydrated 12-24 hours 
prior to obinutuzumab therapy. Prophylaxis should be continued prior to each infusion, as 
needed.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
119
Approved, Date: 19 December 2019
Attachment 9: Medications to be Used with Precaution with Ibrutinib and Venetoclax
CYP3A Inhibitors/Inducers
Management of Potential Ibrutinib and Venetoclax Interactions with CYP3A Inhibitors
Inhibitors
Venetoclax
Ibrutinib
Initiation and
Ramp-up Phase
Steady Daily Dose
(After Ramp-up Phase)
At any time
Strong CYP3A 
Inhibitor
Contraindicated
Avoid inhibitor use, consider 
alternate. If must be used, 
reduce the venetoclax dose by 
at least 75%
Avoid inhibitor use, consider 
alternative agent. If must be used, 
withhold ibrutinib for duration of 
inhibitor use, or reduce ibrutinib to 
140 mg
Moderate CYP3A 
Inhibitor
Avoid inhibitor use, consider alternative agent. If must 
be used, reduce the venetoclax dose by at least 50%
Avoid inhibitor use, consider 
alternative agent. If must be used, 
reduce ibrutinib to 280 mg
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and 
St. John’s Wort). Consider alternative agents with less CYP3A induction.
A list of common CYP3A inhibitors and inducers is provided in Attachment 5.
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib
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, to avoid a potential interaction in the 
gastrointestinal tract, narrow therapeutic range P-gp substrates such as digoxin, should be taken 
at least 6 hours before or after ibrutinib.
Drugs That May Have Their Plasma Concentrations Altered by Venetoclax
Venetoclax is a P-gp and BCRP substrate as well as a P-gp and BCRP inhibitor and weak 
OATP1B1 inhibitor in vitro. To avoid a potential interaction in the gastrointestinal tract, 
co-administration of narrow therapeutic index P-gp substrates such as digoxin with venetoclax 
should be avoided. If a narrow therapeutic index P-gp substrate must be used, it should be taken 
at least 6 hours before venetoclax.
Antiplatelet Agents and Anticoagulants
Ibrutinib
Warfarin or other vitamin K antagonists should not be administered concomitantly with 
ibrutinib. Supplements such as fish oil and vitamin E preparations should be avoided during 
treatment with ibrutinib. Use ibrutinib with caution in subjects requiring anticoagulants or 
medications that inhibit platelet function. 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 with congenital bleeding diathesis have not been studied.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
120
Approved, Date: 19 December 2019
Subjects requiring the initiation of therapeutic anticoagulation therapy (other than warfarin or a 
vitamin K antagonist) during the course of the study should be discussed with the medical 
monitor. If therapeutic anticoagulation is clinically indicated, treatment with ibrutinib should be held 
and not be restarted until the subject is clinically stable and has no signs of bleeding. Subjects should 
be observed closely for signs and symptoms of bleeding, and the risks and benefits of continuing 
ibrutinib treatment should be considered. No dose reduction is required when study drug is 
restarted.
Venetoclax
In a drug-drug interaction study in healthy subjects, administration of a single dose of venetoclax 
with warfarin resulted in an 18% to 28% increase in Cmax and area under the concentration-time 
curve to infinity of R-warfarin and S-warfarin. Because venetoclax was not dosed to steady-state, 
it is recommended that the INR be monitored closely in subjects receiving warfarin.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
121
Approved, Date: 19 December 2019
Attachment 10:
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 3 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 3 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.]

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
122
Approved, Date: 19 December 2019
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 2 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.

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
123
Approved, Date: 19 December 2019
Attachment 11:
EORTC QLQ-C30

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
124
Approved, Date: 19 December 2019

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
125
Approved, Date: 19 December 2019
Attachment 12: EQ-5D-5L

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
126
Approved, Date: 19 December 2019

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
127
Approved, Date: 19 December 2019

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
128
Approved, Date: 19 December 2019
Attachment 13:
FACIT-Fatigue Scale

JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060CLL3011 Amendment 4
129
Approved, Date: 19 December 2019
INVESTIGATOR AGREEMENT

COVID-19 Appendix
JNJ-54179060 (ibrutinib)
         Clinical Protocol 54179060CLL3011
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 24 April 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Protocol Title
A Randomized, Open-label, Phase 3 study of the Combination of Ibrutinib plus Venetoclax
versus Chlorambucil plus Obinutuzumab for the First-line Treatment of Subjects with 
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Protocol 54179060CLL3011; Phase 3
JNJ-54179060 (ibrutinib)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics, 
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; 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.
Status:
Approved
Date:
24 April 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-RIM-39672, 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
54179060CLL3011
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT03462719

COVID-19 Appendix
JNJ-54179060 (ibrutinib)
         Clinical Protocol 54179060CLL3011
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date:  24 April 2020
COVID-19 APPENDIX
GENERAL GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by subjects and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for 
study-related subject management in the event of disruption to the conduct of the study. This 
guidance does not supersede any local or government requirements or the clinical judgement of 
the investigator to protect the health and well-being of subjects and site staff. If at any time the 
investigator assesses that the risk of treatment may outweigh the benefits, study treatment will be 
interrupted, and study follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, subjects will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Subjects will also be questioned regarding general 
health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for subjects on study 
treatment, including follow up. Modifications to protocol-required assessments may be permitted 
after consultation between the subject and investigator, and with the agreement of the sponsor. 
Missed assessments/visits will be captured in the clinical trial management system for protocol 
deviations. Discontinuations of study treatment and withdrawal from the study should be 
documented with the prefix “COVID-19-related” in the Comments electronic case report form 
(eCRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
Modifications made to the study conduct as a result of the COVID-19 pandemic should be 
summarized in the clinical study report.

COVID-19 Appendix
JNJ-54179060 (ibrutinib)
         Clinical Protocol 54179060CLL3011
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date:  24 April 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL:
Subject Visits and Assessments

For subjects who are unable to come to the site for Disease Evaluation visits, the visit should 
be postponed and rescheduled as soon as possible. 

For subjects who are unable to come to the site for Cycle visits, contact (eg, telephone, 
videoconference, or other channels) with the subject should be made in advance, to collect 
information on the subject’s current health status and any new or ongoing adverse events and 
concomitant medications. The remote method that is used for contact with the subject must 
be allowable per local regulations and fully documented in the subject source record. 
Protocol-specified laboratory assessments and physical examinations should be obtained 
locally, if possible. Where local laboratories are used, it is important to ensure appropriate 
documentation of laboratory reference ranges. After reviewing all available information, and 
if the investigator assesses that continued treatment is acceptable, contact the site manager to 
discuss alternative solutions for the provision of study treatment to subjects (see alternatives 
below). The remote contact with the subject, the local laboratory results, and the sponsor 
discussion should be documented in the subject source record. Similarly, at a minimum, a 
comment must be entered in the Comments eCRF clearly designating as “COVID-19-related” 
and acknowledging the discussion between the investigator and the sponsor.

If the subject is not willing or able to go to a local clinic/laboratory, remote contact 
(eg, telephone, videoconference, or other channels) with the subject is recommended, as well 
as a thorough review of the subject’s medical history, prior labs, and most recent disease 
evaluation. The remote method chosen must be allowable per local regulations and fully 
documented in the subject source record. If appropriate, treatment should be interrupted until 
new laboratory assessments are made. However, if the investigator assesses that continued
treatment is acceptable despite the absence of new laboratory tests, contact the site manager 
to discuss alternative solutions for the provision of study medication to subjects (see possible 
alternatives below). Proper documentation of all discussions and decisions should be made in 
the subject source record and in the Comments eCRF.

If any change in subject status is identified that may impact the subject’s safety, then study 
treatment should be interrupted until the subject can be assessed. Any changes in study 
treatment (dose, frequency, interruption) needs to be clearly documented as 
“COVID-19-related”. When pandemic conditions improve, travel restrictions are lifted, and 
the subject is willing and able to come to the clinic, subjects should be scheduled for an 
in-clinic, follow-up visit.

All deviations from protocol-required assessments should be documented in detail within the 
subject’s source record and should be clearly designated as “COVID-19-related”. It must be 
documented if a visit is conducted remotely. Source documentation should detail how each 
assessment was collected (eg, remote vs. on-site, central vs. local laboratory, vital signs taken 
at home by caretaker vs. delegated in-home nursing).

COVID-19 Appendix
JNJ-54179060 (ibrutinib)
         Clinical Protocol 54179060CLL3011
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date:  24 April 2020
Study Drug Supply
If a subject is unable to travel to the site for a scheduled visit where study drug would be dispensed, 
the following alternate measures should be discussed with the study monitor and may be 
considered to ensure continuity of treatment, upon sponsor’s approval:

A caregiver or family member may pick up study drug on behalf of the subject if first 
discussed and agreed by the subject. The conversation with the subject must be documented 
in the subject source records. The subject must name the individual who will pick up study 
drug on their behalf. This is necessary for site staff to confirm the study drug is provided to 
the appropriate individual, ensure proper chain of custody of study drug, and to maintain 
subject privacy. Identification of who will pick up the study drug must be confirmed and
documented in the subject source record.

Investigative site staff may deliver study drug directly to the subject’s home. The chain of 
custody and transit conditions must be clearly documented within the subject source record.

If no other alternative is feasible, direct-to-patient shipment of study drug from the site may 
be considered with prior approval from the sponsor. Site staff need to obtain permission from 
the subject and record this in the subject source record for direct-to-patient shipments. It is
important to note this process is not allowed by the health authorities in all countries and a 
specific approval process must be followed with the sponsor before moving forward. If 
requested by the site, the sponsor will investigate local requirements and confirm health 
authority requirements for direct-to-patient shipment. If approval is granted by the sponsor, 
specific procedures including shipment conditions, preferred courier services, and 
documentation requirements will be communicated by the sponsor to the site.
If a subject is able to come to the site for a Cycle visit but anticipates being unable to come to the 
next Cycle visit, the investigator may dispense study treatment for the current cycle and an 
additional cycle, after agreement with the sponsor’s medical monitor. Prior to continuing treatment 
with the additional study treatment, the subject should obtain protocol-specified laboratory 
assessments and physical examinations locally, if possible, and the investigator should conduct a 
remote contact as described above. After reviewing all available information, if the investigator 
assesses that continued treatment is acceptable, the subject may continue treatment using the 
previously supplied additional study treatment. Proper documentation of all discussions and 
decisions should be made in the subject source record and in the Comments eCRF.
For subjects who have reason to believe they have been exposed to COVID-19 but do not 
yet have a confirmed diagnosis and/or are not showing symptoms of infection:

The investigator should consider the risk/benefit of continuing ibrutinib based on the 
individual subject’s underlying condition and the potential risks associated with COVID-19.

If the subject becomes symptomatic at any point, refer to guidance below for subjects with 
symptomatic COVID-19 infection.

COVID-19 Appendix
JNJ-54179060 (ibrutinib)
         Clinical Protocol 54179060CLL3011
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved,  Date:  24 April 2020
For subjects who have been diagnosed with COVID-19:

The investigator should contact the sponsor’s responsible medical officer to discuss plans for 
study treatment and follow-up.

The investigator should consider the risk/benefit of continuing ibrutinib based on the nature 
and status of the subject’s underlying condition and the potential risks associated with 
COVID-19.

As with all infections, the investigator should follow the protocol guidance which is to 
interrupt therapy for Grade 3 or higher non-hematologic AE (see Section 6.1), and resume 
once infection has resolved to Grade 1 or baseline (recovery). Given that severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new pathogen, a more cautious 
approach would be appropriate, with interruption for confirmed cases of SARS-CoV-2
infection of any grade.
On-site Monitoring Visits
In case on-site monitoring visits are not possible, as per institution policies, the sponsor’s site 
managers may contact the investigator to arrange remote monitoring visits. Additional on-site 
monitoring visits may be needed in the future to catch up on source data verification.
All of the above measures are recommended for consideration on a temporary basis during the 
COVID-19 pandemic to enable continuity of treatment and to ensure that subject assessments, 
particularly those assessing relapse and safety, continue as outlined in the protocol without 
imposing health risk to subjects, their families, and site staff. Every effort should be made to 
complete all protocol-required assessments. Investigators should use their clinical judgment and 
risk/benefit assessment in determining if a subject can continue study treatment in the absence of 
on-site clinic visits. If remote visits are not possible, or if in the investigator’s judgment, 
appropriate safety monitoring is not feasible in a remote setting, the investigator should consider 
temporarily interrupting study treatment (for a maximum of 28 consecutive days, unless reviewed 
and approved by the sponsor) or discontinuing study treatment.

COVID-19 Appendix
JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060CLL3011
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved,  Date: 24 April 2020
INVESTIGATOR AGREEMENT
PPD