Conditions: Hematologic Neoplasms
Keywords: Hematologic Neoplasms JNJ54179060 Ibrutinib Nivolumab
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 144
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the safety and to establish the recommended phase 2 dose (RP2D) for the combination of ibrutinib and nivolumab in participants with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), follicular cell lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Once the dose is optimized, the combination will be assessed for Pharmacokinetics, Pharmacodynamics, and preliminary efficacy, further safety in participants with CLL/SLL, FL or DLBCL and in participants with Richter syndrome.

Detailed description:
This is an open-label study, which consists of Part A (Dose Optimization Cohorts) and Part B (Expansion Cohorts). Part A consists of two dose optimization cohorts (cohort A1 and cohort A2) will determine the RP2D for the combination based on safety, pharmacokinetic, and pharmacodynamic assessments in participants with relapsed/refractory CLL/SLL or B-cell non-Hodgkin lymphoma (B-NHL). Part B consists 3 participant populations to further evaluate the safety and clinical activity of ibrutinib in combination with nivolumab: Cohort B1 (participants with CLL/SLL with del 17p or del 11q), Cohort B2 (participants with FL), Cohort B3 (participants with DLBCL) and Cohort B4 (participants with Richter syndrome). Part A and B will consist of Screening Period (28 days before enrollment), Treatment Period and Follow up Period (every 3 months until death or the end of study). Participants will receive nivolumab intravenously (Day 1 of every cycle) and ibrutinib orally once daily on a 14-day cycle. Efficacy will primarily be evaluated by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) and International Working Group (IWG) for lymphoma guidelines. Participants' safety will be monitored throughout the study. Further exploration of pharmacokinetic/pharmacodynamic and biomarker information will be assessed throughout the trial.

Arms:
arm 1: Participants will receive ibrutinib 420 milligram (mg) capsule orally once daily and nivolumab intravenously as 3 milligram/kilogram (mg/kg) every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. arm 2: Participants will receive ibrutinib 560 mg capsule orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. arm 3: Participants will receive ibrutinib recommended Phase 2 dose (RP2D) orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. arm 4: Participants will receive ibrutinib recommended Phase 2 dose (RP2D) orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. arm 5: Participants will receive ibrutinib recommended Phase 2 dose (RP2D) orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. arm 6: Participants will receive ibrutinib recommended Phase 2 dose (RP2D) orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity.

Interventions: intervention 1: Ibrutinib intervention 2: Nivolumab
Intervention descriptions: intervention 1: Participants will receive oral capsule of ibrutinib once daily as either 420 mg or 560 mg or at recommended Phase 2 dose in any of the cohort. intervention 2: Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 12 October 2020
Janssen Research & Development*
Clinical Protocol
A Phase 1/2a Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and 
Preliminary Efficacy of the Combination of Ibrutinib with Nivolumab in Subjects with 
Hematologic Malignancies
Protocol PCI-32765LYM1002; Phase 1/2a
AMENDMENT 7
JNJ-54179060 (ibrutinib)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen
Infectious Diseases BVBA; Janssen Sciences Ireland UC; or Janssen Research & Development, LLC. The
term “sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
This compound is being investigated in Phase 1, 2, and 3 clinical studies. 
This compound is approved for marketing in 3 indications.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2014-005191-28
Status:
Approved
Date:
12 October 2020
Prepared by:
Janssen Research & Development, LLC  
EDMS number:
EDMS-ERI-76842019, 9.0
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.
NCT02329847


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 23
ABBREVIATIONS ...................................................................................................................................... 36
1.
INTRODUCTION................................................................................................................................ 38
1.1.
Background .................................................................................................................................... 38
1.2.
Ibrutinib........................................................................................................................................... 39
1.2.1.
Non-clinical Ibrutinib Data........................................................................................................... 40
1.2.2.
Clinical Safety of Ibrutinib ........................................................................................................... 41
1.2.3.
Clinical Pharmacology Data........................................................................................................ 43
1.2.4.
Clinical Efficacy of Ibrutinib......................................................................................................... 44
1.3.
Nivolumab ...................................................................................................................................... 45
1.3.1.
Non-clinical Nivolumab Data....................................................................................................... 45
1.3.2.
Clinical Safety of Nivolumab....................................................................................................... 47
1.3.3.
Clinical Efficacy of Nivolumab .................................................................................................... 49
1.4.
Overall Rationale for the Study...................................................................................................... 49
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 51
2.1.
Objectives ...................................................................................................................................... 51
2.2.
Hypothesis ..................................................................................................................................... 51
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 52
3.1.
Overview of Study Design.............................................................................................................. 52
3.2.
Study Design Rationale.................................................................................................................. 55
3.3.
Safety Monitoring ........................................................................................................................... 57
3.3.1.
Evaluation of Dose-limiting Toxicity............................................................................................ 57
3.3.2.
Dose Optimization – Part A ........................................................................................................ 58
3.3.3.
Dose Expansion - Part B (Recommended Phase 2 Dose)......................................................... 58
4.
SUBJECT POPULATION.................................................................................................................. 58
4.1.
Inclusion Criteria ............................................................................................................................ 59
4.1.1.
Additional Inclusion Criteria for Part A: Dose Optimization Cohorts .......................................... 60
4.1.2.
Additional Inclusion Criteria for Part B: Expansion Cohorts ....................................................... 60
4.2.
Exclusion Criteria ........................................................................................................................... 63
4.3.
Prohibitions and Restrictions ......................................................................................................... 65
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 65
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 65
6.1.
Study Treatment Administration..................................................................................................... 65
6.1.1.
Dose Optimization Cohorts......................................................................................................... 66
6.1.2.
Dosing Schedule......................................................................................................................... 66
6.2.
Ibrutinib Administration................................................................................................................... 67
6.3.
Nivolumab Administration .............................................................................................................. 68
6.3.1.
Interactive Web Response System ............................................................................................ 68
6.4.
Dose Modifications......................................................................................................................... 68
6.4.1.
Ibrutinib Dose Modifications ....................................................................................................... 69
6.4.2.
Nivolumab Dose Modifications ................................................................................................... 69
6.4.3.
Guidelines for Dose Modification................................................................................................ 69


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7.
TREATMENT COMPLIANCE............................................................................................................ 73
8.
GUIDELINES FOR MANAGEMENT OF IMMUNE RELATED ADVERSE EVENTS AND 
ADVERSE EVENTS OF CLINICAL INTEREST ............................................................................... 74
8.1.
Gastrointestinal AE ........................................................................................................................ 74
8.2.
Hepatic Adverse Events................................................................................................................. 75
8.3.
Endocrinopathies ........................................................................................................................... 76
8.4.
Rash............................................................................................................................................... 76
8.5.
Renal Adverse Events.................................................................................................................... 77
8.6.
Neurological Adverse Events......................................................................................................... 77
8.7.
Pulmonary AE ................................................................................................................................ 78
8.8.
Uveitis and Visual Complaints ....................................................................................................... 79
8.9.
Lipase/Amylase Elevations ............................................................................................................ 79
8.10.
Infection.......................................................................................................................................... 79
8.11.
Treatment of Nivolumab Related Infusion Reactions .................................................................... 80
9.
CONCOMITANT THERAPY.............................................................................................................. 81
9.1.
Supportive Care ............................................................................................................................. 81
9.2.
Permitted Medications.................................................................................................................... 81
9.3.
Prohibited Medications................................................................................................................... 82
9.4.
Concomitant Medications to be Avoided, or to be Used with Caution........................................... 82
9.5.
Subsequent Therapies................................................................................................................... 83
10.
STUDY EVALUATIONS .................................................................................................................... 83
10.1.
Efficacy (Assessment of Disease Response and Progressive Disease)....................................... 83
10.2.
Treatment After Initial Evidence of Disease Progression .............................................................. 85
10.3.
Pharmacokinetics........................................................................................................................... 87
10.3.1.
Sample Collection....................................................................................................................... 87
10.3.2.
Evaluations ................................................................................................................................. 87
10.3.3.
Analytical Procedures................................................................................................................. 87
10.3.4.
Pharmacokinetic Parameters ..................................................................................................... 87
10.4.
Immunogenicity Assessment ......................................................................................................... 88
10.5.
Biomarkers ..................................................................................................................................... 88
10.6.
Safety Evaluations ......................................................................................................................... 90
11.
SUBJECT COMPLETION/TREATMENT DISCONTINUATION/WITHDRAWAL............................. 93
11.1.
Completion ..................................................................................................................................... 93
11.2.
Discontinuation of Study Treatment............................................................................................... 93
11.3.
Withdrawal From the Study............................................................................................................ 93
12.
STATISTICAL METHODS................................................................................................................. 94
12.1.
Subject Information ........................................................................................................................ 94
12.2.
Safety Analyses ............................................................................................................................. 94
12.3.
Sample Size Determination ........................................................................................................... 95
12.4.
Efficacy Analyses ........................................................................................................................... 96
12.5.
Pharmacokinetic Analyses............................................................................................................. 96
12.6.
Biomarker Analyses ....................................................................................................................... 97
12.7.
Study Evaluation Team.................................................................................................................. 97
13.
ADVERSE EVENT REPORTING ...................................................................................................... 97
13.1.
Definitions ...................................................................................................................................... 98
13.1.1.
Adverse Event Definitions and Classifications ........................................................................... 98
13.1.2.
Attribution Definitions.................................................................................................................. 99
13.1.3.
Severity Criteria ........................................................................................................................ 100
13.2.
Special Reporting Situations........................................................................................................ 100
13.2.1.
Nivolumab................................................................................................................................. 101
13.2.2.
Other......................................................................................................................................... 101
13.3.
Procedures................................................................................................................................... 101
13.3.1.
All Adverse Events.................................................................................................................... 101


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13.3.2.
Serious Adverse Events ........................................................................................................... 102
13.3.3.
Adverse Events of Special Interest (AESI)............................................................................... 103
13.3.4.
Pregnancy................................................................................................................................. 104
13.4.
Contacting Sponsor Regarding Safety......................................................................................... 104
14.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 104
14.1.
Procedures................................................................................................................................... 104
14.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 104
15.
STUDY DRUG INFORMATION....................................................................................................... 105
15.1.
Physical Description of Study Drug.............................................................................................. 105
15.2.
Packaging .................................................................................................................................... 105
15.3.
Labeling........................................................................................................................................ 105
15.4.
Preparation, Handling, and Storage............................................................................................. 105
15.5.
Drug Accountability ...................................................................................................................... 105
16.
STUDY-SPECIFIC MATERIALS..................................................................................................... 106
17.
ETHICAL ASPECTS ....................................................................................................................... 106
17.1.
Study-Specific Design Considerations......................................................................................... 106
17.2.
Regulatory Ethics Compliance..................................................................................................... 107
17.2.1.
Investigator Responsibilities ..................................................................................................... 107
17.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 107
17.2.3.
Informed Consent ..................................................................................................................... 108
17.2.4.
Privacy of Personal Data .......................................................................................................... 109
17.2.5.
Country Selection ..................................................................................................................... 110
18.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 111
18.1.
Protocol Amendments.................................................................................................................. 111
18.2.
Regulatory Documentation .......................................................................................................... 111
18.2.1.
Required Prestudy Documentation........................................................................................... 111
18.2.2.
Regulatory Approval/Notification .............................................................................................. 112
18.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 112
18.4.
Source Documentation................................................................................................................. 112
18.5.
Case Report Form Completion .................................................................................................... 113
18.6.
Data Quality Assurance/Quality Control ...................................................................................... 114
18.7.
Record Retention ......................................................................................................................... 114
18.8.
Monitoring .................................................................................................................................... 115
18.9.
Study Completion/Termination..................................................................................................... 115
18.9.1.
Study Completion ..................................................................................................................... 115
18.9.2.
Study Termination..................................................................................................................... 115
18.10.
On-Site Audits .............................................................................................................................. 116
18.11.
Use of Information and Publication.............................................................................................. 116
REFERENCES.......................................................................................................................................... 118
ATTACHMENTS....................................................................................................................................... 121
Attachment 1:
Modified Toxicity Probability Interval............................................................................... 121
Attachment 2:
Modified Diet in Renal Disease (MDRD) Formulas ........................................................ 122
Attachment 3:
New York Heart Association Criteria............................................................................... 123
Attachment 4:
ECOG Performance Status Scale................................................................................... 124
Attachment 5:
Efficacy procedures......................................................................................................... 125
Attachment 6:
Criteria for Response ...................................................................................................... 127
Attachment 6.1: International Workshop on Chronic Lymphocytic Leukemia (IWCLL) ............................ 127
Attachment 6.2: Evaluation, Staging, and Response Assessment for Non-Hodgkin Lymphoma: 
The Lugano Classification (according to Cheson 2014)................................................. 129
Attachment 7:
Instruction for Concomitant Medications to be Used with Precaution ............................ 133
Attachment 8:
Inhibitors and Inducers of CYP3A................................................................................... 135


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INVESTIGATOR AGREEMENT ............................................................................................................... 136
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Time and Events Schedule....................................................................................................... 28
Table 2:
Time and Events Schedule for Pharmacokinetic and Pharmacodynamic Assessments 
p................................................................................................................................................. 34
Table 3:
Median IC50 Values of Ibrutinib Toward Selected Tec and Src/Ab1 Family Kinases ............... 40
Table 4:
Ibrutinib and Nivolumab Dose Levels: Part A (Dose Optimization Cohorts) ............................ 66
Table 5:
Ibrutinib and Nivolumab Dosing Schedule................................................................................ 66
Table 6:
Ibrutinib Dosing......................................................................................................................... 67
Table 7:
Dose Reduction for Ibrutinib ..................................................................................................... 69
Table 8:
Dose Adjustments for Related Non-hematologic and Related Hematologic Toxicities............ 70
Table 9:
Dose Adjustments for Immune-related Adverse Events........................................................... 71
Table 10:
Management of Immune-related Gastrointestinal Adverse Events .......................................... 75
Table 11:
Management of Immune-related Hepatic Adverse Events....................................................... 75
Table 12:
Management of Endocrinopathies............................................................................................ 76
Table 13:
Management of Rash................................................................................................................ 77
Table 14:
Management of Renal Adverse Events .................................................................................... 77
Table 15:
Management of Neurological Adverse Events ......................................................................... 78
Table 16:
Management of Pulmonary Adverse Events ............................................................................ 78
Table 17:
Management of Uveitis and Visual Complaints ........................................................................ 79
Table 18:
Management of Infusion Reactions .......................................................................................... 80
Table 19:
Prohibited Concomitant Medications ........................................................................................ 82
Table 20:
Concomitant Medications to be Avoided or to be Used with Caution....................................... 83
Table 21:
Response Criteria ..................................................................................................................... 84
Table 22:
Study Therapy after First Evidence of Progressive Disease .................................................... 85
Table 23:
Biomarker Assessments ........................................................................................................... 88
FIGURES
Figure 1:
Study Design Overview............................................................................................................. 52


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Status: Approved,  Date: 12 October 2020
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
15 Dec 2014
Amendment 1
29 Jan 2015
Amendment 2
19 Jun 2015
Amendment 3
23 Nov 2015
Amendment 4
02 Mar 2016
Amendment 5
18 Apr 2017
Amendment 6
12 Dec 2018
Amendment 7
12 Oct 2020
Amendments are listed beginning with the most recent amendment.
Amendment 7 (12 Oct 2020)
The overall reasons for the amendment: To further reduce all assessments after the clinical cutoff date and 
provide treatment for subjects until the end of study endpoint is reached. Since primary and secondary objectives 
have been analyzed and published, reduction of assessments for subjects who are currently on treatment or in 
(survival) follow up until the End of Study assessment are performed.
Applicable Section(s)
Rationale: To further reduce data collection for ongoing subjects 
Table 1: Time and 
event schedule
Based on the established safety profile of the study drugs, safety data collection limited to: 
SAEs and Grade ≥3 AEs that are at least possibly related to treatment, AEs leading to 
discontinuation or modification, efficacy assessments, and study treatment administration.
Footnote ‘a’ added to allow subjects who discontinued treatment during follow up to 
terminate survival follow up and complete end of study assessments.
Rationale: To terminate PK and pharmacodynamic assessments 
Table 2: Time and 
Events Schedule for 
Pharmacokinetic and 
Pharmacodynamic 
Assessments
Footnote ‘p’ added to confirm no PK, pharmacodynamic assessments, or biomarker 
samples will be obtained
Rationale: To permit ibrutinib single agent treatment if subjects meet CAN3001 rollover criteria 
6.4 Dose 
modifications
Added text to cease single agent ibrutinib therapy unless subjects are rolling over to the 
long-term extension study CAN3001.
Rationale: To terminate study treatment following disease progression
10.2 Treatment after 
initial evidence of 
disease progression
Added text to prohibit continuation on study treatment following disease progression.
Rationale: To terminate collection of PD and PK samples
10.3.1
Added text to terminate collection of PD and PK samples.


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Rationale: To terminate collection of biomarker samples
10.5 Biomarkers
Added text to terminate collection of biomarker samples.
Rationale: To reference updates to Table 1 regarding collection of adverse event data
13.3.1 All Adverse 
events
Added reference to Table 1
Amendment 6 (12 Dec 2018)
The overall reason for the amendment: To reduce the pharmacokinetic (PK) and biomarker assessments after 
the clinical cutoff date; this will not have any impact on safety of primary endpoint of the trial.
Applicable Section(s)
Description of Change(s)
Rationale: To render consistency within the hypothesis statement in the synopsis and report body.
Synopsis –
Objectives and 
Hypothesis
Cohort B4 was added during Protocol Amendment 4 prepared in March 2016. Although 
this new cohort was reflected in Section 2.2. Hypothesis, it was not reflected within the 
hypothesis statement included in the Synopsis of Protocol Amendment 4. This also was 
not reflected in Protocol Amendment 5. This oversight is now being corrected in Protocol 
Amendment 6.
Rationale: To reduce the intensity of data collection as the primary endpoint for this study has already been met.
Table 2: Time and 
Events Schedule for 
Pharmacokinetic and 
Pharmacodynamic 
Assessments
Added footnote ‘o’ indicating that assessments at Q8 cycles, at Q16 cycles, and at 
complete response are no longer required post clinical cutoff. Additionally, tumor biopsy 
and bone marrow (BM) aspirate/biopsy at progression; ibrutinib PK, nivolumab PK, and 
nivolumab anti-drug antibody (ADA) at end of treatment (EOT); and nivolumab PK, and 
nivolumab ADA at follow-up 1 (FU1, 100 days after last dose of nivolumab) will no 
longer be required post clinical cutoff. Also, ibrutinib pharmacodynamic (PD) and 
biomarker assessment at FU will no longer be required post clinical cutoff.
Rationale: To reduce the intensity of data collected after the clinical cutoff date as the primary endpoint for this 
study has already been met.
Synopsis – Overview 
of Study Design; 
Table 1: Time and 
Events Schedule;
3.1. Overview of 
Study Design;
13.3.1 All adverse 
events
Added a statement that after the clinical cutoff only the following data will be collected 
on eCRF: serious adverse events (SAEs) and adverse events (AEs) Grade ≥3, laboratory 
assessments (Grade ≥3 or clinically significant), efficacy, survival status, and treatment 
administration.
Added the following statement: After the clinical cutoff, only SAEs and Grade ≥3 AEs 
will be collected.


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Status: Approved,  Date: 12 October 2020
Applicable Section(s)
Description of Change(s)
Table 1: Time and 
Events Schedule
In addition to the note above, the following changes were made to the Time and Events 
Schedule:
1. Deleted a note within the Time and Events Schedule emphasizing that after EOT (within 
30 days after the last dose of ibrutinib or nivolumab, whichever treatment occurred last) 
only SAEs and Grade 3 or higher AEs that are at least possibly related to the study 
treatment will be reported. 
2. Added a note within the Time and Events Schedule emphasizing that post clinical 
cutoff, disease assessments, using CT imaging with oral and IV contrast, will be 
performed Q12 cycles or per local standards (but at a minimum of Q26 weeks).
Rationale: To only conduct limited biomarker assessments post the clinical cutoff date as the primary endpoint for 
this study has already been met.
Synopsis –
Biomarker 
Evaluations;
Table 1: Time and 
Events Schedule;
Table 2: Time and 
Events Schedule for 
Pharmacokinetic and 
Pharmacodynamic 
Assessments;
10.5 Biomarkers
Removed the requirement of biomarker assessments (bone marrow aspirate/biopsy) post 
clinical cutoff.
Rationale: To remove the requirement of conducting PK assessments post the clinical cutoff date as the primary 
endpoint for this study has already been met.
Synopsis –
Pharmacokinetic 
Evaluations;
Table 2: Time and 
Events Schedule for 
Pharmacokinetic and 
Pharmacodynamic 
Assessments;
10.3.1 Sample 
Collection
Removed the requirement of PK assessments post clinical cutoff.
Rationale: To incorporate appropriate changes specified within the Janssen protocol templates released after 
Protocol Amendment 5 was issued.
Title Page;
Added "Janssen Pharmaceutica NV" to the Sponsorship Statement.


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Applicable Section(s)
Description of Change(s)
11.3 Withdrawal 
from the Study;
Added the following text:
If a subject is lost to follow-up, every reasonable effort must be made by the study-site 
personnel to contact the subject and determine the reason for discontinuation/withdrawal. 
The measures taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. If a subject discontinues study 
treatment and withdraws from the study before the onset of disease progression, end-of-
treatment and post- treatment assessments should be obtained. If the reason for withdrawal 
from the study is withdrawal of consent then no additional assessments are allowed.
18.11 Use of 
Information and 
Publication
Changed the time for submitting combined study results for publication from within 
12 months to 18 months.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


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Amendment 5 (18 April 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: The overall reason for the amendment is for clarification of protocol 
wording related to the primary analysis, to ensure wording is consistent and clear throughout the protocol
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of scheduled adverse event, concomitant medication, and efficacy assessments after the 
end of treatment.
Synopsis Overview of Study Design, Table 1 
Time and Events Schedule;
3.1. Overview of Study Design; Objectives; 
10.1. Efficacy (Assessment of Disease 
Response and Progressive Disease); 12.7 
Study Evaluation Team
Reworded Study Evaluation Team (SET) review to state that 
subjects may be evaluated by SET for Part B.
Defined end of study as the last subject who completed the End 
of Treatment (EOT) assessment.
Clarified minimum data collection during the period between 
primary analysis and the end of study to include: SAEs, AE 
Grade ≥3, laboratory assessments, efficacy, survival status, and 
treatment administration. Also clarified that concomitant 
medication collected after EOT assessment will include only 
subsequent anti-lymphoma treatment.
Clarified that during the Follow-up period efficacy assessments 
will be conducted at least every 6 months up to disease 
progression or start of subsequent therapy.
Rationale: Update reference to CYP3A inhibits and inducers
9.4. Concomitant Medications to be Avoided, 
or to be Used with Caution (Table 20); 
Attachment 7; Attachment 8
Replaced 
‘http://www.pharmacologyweekly.com/content/pages/online-
drug-therapy-tables (Pharmacology Weekly)’ with 
‘http://medicine.iupui.edu/clinpharm/ddis/main-table/’
Rationale: Update with standard of care consideration for prophylactic treatment of opportunistic infection.
1.2.2 Clinical Safety of Ibrutinib; 8.10 
Infection; References
New text and reference added for consideration of antimicrobial 
prophylaxis in accordance with standard practice in subjects 
who are at increased risk for opportunistic infections.
Rationale: Update with Adverse Events of Special Interest / Major Hemorrhage sections to align with other 
ongoing ibrutinib protocols.
13.3.3 Adverse Events of Special Interest 
(AESI)
Specific adverse events or groups of adverse events will be 
followed as part of standard safety monitoring activities by the 
Sponsor. These events will be reported to the sponsor within 
24 hours of awareness irrespective of seriousness (ie, serious 
and nonserious adverse events) following the procedure 
described above for serious adverse events and will require 
enhanced data collection.


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13.3.3.1 Major Hemorrhage
Major hemorrhage is defined as: Treatment-emergent 
hemorrhagic adverse events of Grade 3 or higher. 
•
Any treatment-emergent hemorrhagic adverse events of 
Grade 3 or higher. All hemorrhagic events requiring a 
transfusion of red blood cells should be reported as Grade 3 or 
higher AE per CTCAE. 
•
Any treatment-emergent serious adverse event of bleeding 
of any grade. 
•
Any treatment-emergent central nervous system 
hemorrhage/hematoma of any grade.
Rationale: Update to storage recommendations for ibrutinib
15.4 Preparation, Handling, and Storage
The recommended storage condition for ibrutinib capsules is 
controlled room temperature (15oC to 25oC) with excursions 
permitted to 30°C (86°F).
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.


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Status: Approved,  Date: 12 October 2020
Amendment 4 (02 Mar 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: The overall reason for the amendment is to add a Richter syndrome 
cohort (B4). There is some evidence that ibrutinib has potential as a novel therapeutic approach for patients with 
Richter syndrome. In an investigator-initiated study (Tsang 2015)56 one subject achieved a CR while 2 subjects 
experienced PR. All 3 subjects reported an improvement of constitutional symptoms. In addition, in a Phase 1b/2 
study 3 subjects with Richter syndrome received a combination regimen of ibrutinib and the anti-CD20 antibody 
ofatumumab (Jaglowski 2015)28 Of these, 2 subjects experienced disease stabilization for 471 and 137 days 
respectively, while 1 subject achieved a PR which lasted for 4.6 months (Jaglowski 2015)28.
Applicable Section(s)
Description of Change(s)
Rationale: A Richter syndrome cohort (B4) is added and the overall number of subjects has been revised.
Synopsis,
Time & Events Schedule Table 2 (footnotes d 
and l),
1.1 Background,
1.2.4 Richter syndrome (new paragraph),
2.1 Objectives, Primary (Part B),
2.2 Hypothesis,
3.1 Overview of Study Design,
3.2 Study Design Rationale,
4.1.2 Additional Inclusion Criteria for Part B: 
Expansion Cohorts,
4.2 Exclusion Criteria,
6.1.2 Dosing Schedule, Table 5;
10.1 Efficacy (Assessment of Disease Response 
and Progressive Disease), Table 21;
12.3 Sample Size Determination,
12.4 Efficacy Analyses,
References
The new Richter syndrome cohort (B4) is described 
throughout the protocol and new inclusion criteria specific for 
Richter syndrome are added. The exclusion of Richter 
syndrome is removed. 
The overall number of subjects is increased to 158 and to 140 
in Part B. 
Rationale: The response criteria used for SLL and Richter syndrome is clarified.
Synopsis, Efficacy Evaluations/Endpoints;
10.1 Efficacy (Assessment of Disease Response 
and Progressive Disease), Table 21
It is clarified that the Response Assessment of Non-Hodgkin 
Lymphoma is to be used for SLL and Richter syndrome 
subjects.
Rationale: The collection of concomitant medications is clarified.
Time & Events Schedule 
(Table 1), 
9 Concomitant Therapy
Concomitant medications will be collected for 30 days after 
the last dose of ibrutinib, 100 days after the last dose of 
nivolumab, or, afterwards, during the follow-up of a related 
SAE (if applicable).
Rationale: The end of study definition is clarified to allow for subjects who are still on study after the End of 
Treatment visit and 100 days of follow-up after the nivolumab infusion.
3.1 Overview of Study Design
End of study is defined as the last assessment for the last 
subject in the study (eg, the last follow-up visit or death).
Rationale: Updates have been made based on Janssen protocol template changes. These are of an instructional 
nature and do not affect study design.


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Title page,
13 Adverse Event Reporting,
13.2.2 Other,
13.3.1 All Adverse Events,
13.3.3 Pregnancy,
15.5 Drug Accountability,
Template changes include:
New text on the method of detecting adverse events and 
serious adverse events is added.
Inadvertent or Accidental or occupational exposure to a 
sponsor study drug
The sponsor will also report to the investigator (and the head 
of the investigational institute where required) all suspected 
unexpected serious adverse events that are unlisted 
(unexpected) and associated with the use of the study drug.
All initial reports of pregnancy in female subjects or 
partners of male subjects must be reported to the sponsor by 
the study-site personnel within 24 hours of their knowledge of 
the event using the appropriate pregnancy notification form. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, 
fetal death, stillbirth, and congenital anomalies, ectopic 
pregnancy) are considered serious adverse events and must be 
reported using the Serious Adverse Event Form.
Unused study drug, and study drug returned by the subject, 
must be available for verification by the sponsor's study site 
monitor during on-site monitoring visits.
Study drug should be dispensed under the supervision of the 
investigator or a qualified member of the study-site personnel, 
or by a hospital/clinic pharmacist. Study drug will be supplied 
only to subjects participating in the study. Returned study 
drug must not be dispensed again, even to the same 
subject. Study drug may not be relabeled or reassigned for use 
by other subjects. The investigator agrees neither to dispense 
the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor. The dispensing of 
study drug to the subject, and the return of study drug 
from the subject (if applicable), must be documented on 
the drug accountability form. Subjects, or their legally 
acceptable representatives where applicable, must be 
instructed to return all original containers, whether empty 
or containing study drug.
17.2.5 Country Selection,
This study will only be conducted in those countries where the 
intent is to launch or otherwise help ensure access to the 
developed product, if the need for the product persists,
unless explicitly addressed as a specific ethical consideration 
in Section 17.1, Study-Specific Design Considerations.


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18.4 Source Documentation,
18.5 Case Report Form Completion,
At a minimum, source documentation 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 to confirm data collected in the 
eCRF: subject identification, eligibility, and study 
identification; study discussion and date of signed informed 
consent; dates of visits; results of safety and efficacy 
parameters as required by the protocol; record of all adverse 
events and follow-up of adverse events; concomitant 
medication; drug receipt/dispensing/return records; study 
drug administration information; and date of study completion 
and reason for early discontinuation of study drug or 
withdrawal from the study, if applicable. 
In addition, The author of an entry in the source documents 
should be identifiable.
At a minimum, the type and level of detail of source data 
available for a subject should be consistent with that
commonly recorded at the study site as a basis for standard 
medical care. Specific details required as source data for the 
study 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).
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 and 
electronic source is utilized, references made to the CRF in 
the protocol include the electronic source system but 
information collected through electronic source may not be 
limited to that found in the CRF.
Case report forms are prepared and provided by the sponsor
for each subject in electronic format. Electronic data capture 
(eDC) will be used for this study. All data relating to the
study must be recorded in CRF. All CRF entries, 
corrections, and alterations must be made by the 
investigator or authorized study-site personnel. The 
investigator must verify that all data entries in the CRF 
are accurate and correct. The study data will be transcribed 
by study-site personnel from the source documents onto an 
eCRF, if applicable. Study-specific data will be and 
transmitted in a secure manner to the sponsor. within the 
timeframe agreed upon between the sponsor and the study site. 
The electronic file will be considered to be the 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 documents documentation. 
All data relating to the study must be recorded in the eCRFs
prepared by the sponsor. Data must be entered into eCRFs in 
English. Study site personnel must complete the eCRF The 
CRF must be completed as soon as possible after a subject 
visit, and the forms should be available for review at the next 
scheduled monitoring visit. All subjective measurements (eg, 
pain scale information or other questionnaires) will be 
completed by the same individual who made the initial 
baseline determinations whenever possible. The investigator 


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must verify that all data entries in the eCRFs are accurate and 
correct. 
18.8 Monitoring
All eCRF entries, corrections, and alterations must be made by 
the investigator or other authorized study site personnel. If 
necessary, queries will be generated in the eDC tool. The 
investigator or study site personnel must adjust the eCRF (if 
applicable) and complete the query.
If necessary, queries will be generated in the eDC tool. If 
corrections to a CRF are needed after the initial entry into the 
CRF, this can be done in 3 different 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).

Sponsor or sponsor delegate Study site manager can 
generate a query for resolution by the study-site 
personnel.

Clinical data manager can generate a query for resolution 
by the study site personnel.
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 eCRFs with the hospital or 
clinic records (source documents). CRF with the source 
documents (eg, hospital/clinic/physician’s office medical 
records).
Direct access to source documents documentation (medical 
records) must be allowed for the purpose of verifying that the 
data recorded data in the eCRF are consistent with the original 
source data. Findings from this review of eCRFs and source 
documents will be discussed with the study-site personnel. The 
sponsor expects that, during monitoring visits, the relevant 
study-site personnel will be available, the source 
documentation documents will be accessible, and a suitable 
environment will be provided for review of study-related 
documents.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were 
made.


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Status: Approved,  Date: 12 October 2020
Amendment 3 (23 November 2015)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.  
The overall reason for the amendment: The overall reason for the amendment is to clarify that baseline 
assessments should occur prior to study treatment initiation regardless of whether a subject is enrolled in run-in 
phase or not.
Applicable Section(s)
Description of Change(s)
Rationale: Baseline assessments should occur prior to study treatment initiation regardless of whether a subject 
is enrolled in run-in phase or not.
Table 1: Time and 
Events Schedule
The column header for Cycle 1 Day 1 treatment period was renamed “Baseline 
Assessment” and additional revisions were made to clarify that assessments are to be 
collected prior to study drug administration regardless of whether a subject is enrolled in 
run-in phase or not:
The column header for the Screening Period was revised to indicate that assessments are 
to be collected up to 28 days before the start of any study treatment
Text was added to “Notes” for pregnancy, hematology and serum chemistry assessments 
for clarification.
Rationale: Clarification regarding collection of 12-lead ECG assessment was added.
Table 1: Time and 
Events Schedule 
Text was revised in the “Notes” for 12-lead electrocardiogram (ECG) to indicate that the 
baseline predose ECG is to be collected prior to any study treatment, and the Cycle 2 
Day 1 predose ECG is to be collected within 1 hour prior to nivolumab dosing
Text was added to clarify that the baseline postdose ECGs are to be collected on Cycle 1
Day 1, immediately after nivolumab infusion and 2 hours after ibrutinib dosing.
Rationale: Timing of biomarker sample collection was clarified.
Table 2: Time and 
Events Schedule for 
Pharmacokinetic and 
Pharmacodynamic 
Assessments 
Footnote “f” revised to specify that biomarker assessment can be collected within 
48 hours after last intake of ibrutinib.
Rationale: Samples collected for pharmacokinetic assessment may be used to document the presence of 
circulating metabolites.
10.3.3 Analytical 
Procedure
Text was added to allow that if required, some plasma samples may be analyzed to 
document the presence of circulating metabolites using a qualified research method.
Rationale: Clarification regarding availability of screening laboratory results.
10.6 Safety 
Evaluations
Text was revised to clarify that screening laboratory results must be available to the 
investigator for evaluation before the first dose of any study drug.
Rationale: Clarification regarding period during which blood is collected, and correction to remove redundant 
text.
17.1 Study-Specific 
Design 
Considerations
Text was revised to clarify that the total blood volume to be collected is estimated to be 
approximately 25 mL at screening and approximately 60 mL at baseline.


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Applicable Section(s)
Description of Change(s)
Rationale: Trephine biopsies are not required; therefore immunohistochemistry (IHC) analysis is not required. 
Table 1: Time and 
Events Schedule 
Laboratory 
Assessments
Text regarding IHC analysis deleted.
Attachment 5 
Efficacy Procedures
Bone Marrow 
Assessment
If bone marrow involvement can be confirmed with morphology, IHC or flow 
cytometry need not be done.
Rationale: Alignment with Company Core Data Sheet (CCDS).
Attachment 7 
Instruction for 
Concomitant 
Medications to be 
Used With Precaution
Text regarding concomitant use of CYP inhibitors was revised to align with CCDS.
Rationale: The clinical study protocol template has been updated.
4 Subject Population
Text was revised to specify that the investigator must consult with the appropriate 
sponsor representative and resolve any issues before enrolling a subject in the study. 
Waivers are not allowed.
13.3.3 Pregnancy
Text regarding reporting of pregnancies in partners of male subjects included in the 
study was revised for clarity.
17.2.2 Independent 
Ethics Committee or 
Institutional Review 
Board.
Text regarding IEC/IRB review and approval of the final protocol and amendments was 
revised to allow for local requirements.
18.10 On-site Audits
Text regarding audits of source documents was revised.
18.11 Use of 
Information and 
Publication
Text was regarding direct transmission of central laboratory results was deleted: 
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


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Status: Approved,  Date: 12 October 2020
Amendment 2 (19 June 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: The primary reasons for the amendment are to remove the interim 
analysis and to revise the dose modification criteria for hematologic toxicities and rash.
The interim analysis in study Part B has been removed for the following reasons: (1) rapid accrual is expected, 
(2) the potential for delayed clinical response due to the specific mode of action of the immunotherapeutic agent 
nivolumab, and (3) to increase the number of subjects to ensure the required number of response-evaluable subjects 
are enrolled. 
The hematologic dose modifications are revised to align with IMBRUVICA® prescribing information in which 
treatment emergent Grade 3 or 4 cytopenias are described. These Grade 3 and 4 cytopenias are readily manageable 
as outlined in the prescribing information. The study is conducted in subjects with advanced hematologic 
malignancies and it can be anticipated that Grade 3 or 4 hematologic toxicities observed with the combination 
regimen would be primarily caused by ibrutinib rather than nivolumab. The addition of nivolumab, which does not 
seem to affect the hematopoietic system, may not alter the recovery or outcome of hematologic toxicities in subjects 
receiving the combination regimen. By applying the dose modifications outlined in the nivolumab (OPDIVO®) 
prescribing information to hematologic toxicities, the opportunity to establish the safety profile and explore the 
preliminary efficacy of the ibrutinib and nivolumab combination regimen is severely restricted. Therefore, the dose 
modifications for hematologic toxicities should follow the ibrutinib (IMBRUVICA®), rather than the nivolumab 
(OPDIVO®), prescribing information. At the time of this amendment, 6 subjects have been treated with ibrutinib 
420 mg/day plus nivolumab 3mg/kg every two weeks. One subject experienced a DLT (Grade 3 increased 
bilirubin); one subject experienced grade 4 neutropenia which recovered within 4 days. Based on this amendment 
and following the IMBRUVICA® prescribing information, grade 4 neutropenia that is manageable (eg, recovered 
within 7 days; see Table 8) would no longer result in discontinuation of study therapy and thus no longer constitute 
a DLT.
The dose modifications criteria for rash are updated to reflect the label for nivolumab (OPDIVO®).
Applicable Section(s)
Description of Change(s)
Rationale: Remove the interim analysis and increase the number of subjects enrolled in Part B, as described 
above.
Synopsis (Overview 
of Study Design, 
Statistical Methods),
3.1 Overview of 
Study Design,
12.3 Sample Size 
Determination,
12.4 Interim Analysis 
(removed)
The interim analysis is removed.
The statistical power in Part B will be increased to 80%. By maintaining the same 
statistical assumptions (Overall Response Rate [ORR] under null hypothesis: 20%; ORR 
under alternative hypothesis: at least 38%; one-sided α of 0.1), the number of subjects in 
each treatment arm of Part B will increase from 30 to 35 to accrue at least 32 evaluable 
subjects. 
The overall number of subjects is increased to 123 and to 105 in Part B. Enrollment in 
each Cohort in Part B is increased to 35 subjects each.
The probability to correctly reject the null hypothesis when alternative hypothesis is true 
was changed from 0.7 to 0.8.
Rationale: Changes are made to account for other efficacy response (eg, PFS) along with ORR and safety 
concerns when the SET undertakes the review of Part B data.


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Synopsis (Overview 
of Study Design, 
Statistical Methods),
3.1 Overview of 
Study Design,
12 Statistical 
Methods, 12.4 
Interim Analysis 
(removed), 
12.8 Study 
Evaluation Team
Removed the following text for consistency: All analyses will be descriptive. No formal 
statistical inference will be made.
Removed text for Part B regarding determining early stopping criteria or continuation of 
each cohort and specified that the SET will review efficacy endpoints including but not 
limited to ORR, and that the SET can review safety concerns on an ad hoc basis.
Rationale: Table 8, which provides dose adjustments for related non-hematologic and related hematologic 
toxicities and Table 9, which provides dose adjustments for rash, have been revised taking into consideration the 
ibrutinib and nivolumab prescribing information, respectively.  
6.4.3 Guidelines for 
Dose Modification, 
Table 8, Table 9

Under hematologic toxicity, removed the section “General” and revised the 
guidelines for neutropenia and thrombocytopenia. Added febrile neutropenia.

Revised the guidelines for rash.

Changed to <12 weeks to ≤12 weeks throughout the tables.

The reason to qualify a DLT is indirectly updated by revision to the dose 
modification tables; however, the DLT definition remains the same, per Section 
3.3.1. Under the category of other lab values, for the first event of a Grade 3 
toxicity, clarification that resolution not just to Grade ≤1 but also to the baseline 
value.
Rationale: Modified assessments for hematology, serum chemistry, coagulation panel, thyroid function, 
β2 microglobulin and serum Ig, and bone marrow aspirate/biopsy.  Overall volume of blood to be drawn in the 
first year has increased.
Table 1: Time and 
Events Schedule, 
17.1 Study-Specific 
Design 
Considerations

Hematology: to be repeated every week during the first 4 weeks; thereafter, on Day 
1, prior to start of each cycle.

Serum chemistry: to be performed on Day 1 of every cycle. Previously this was 
every 2 cycles starting at Cycle 3.

β2 microglobulin and serum Ig: clarified only for FL and CLL/SLL.

Bone marrow aspirate/biopsy: at least 1 assessment is required.  The extent of bone 
marrow involvement must be documented at screening.

Coagulation panel, thyroid function, and β2 microglobulin/serum Ig should be 
performed within 48 hrs. prior to the start of applicable cycle.
Rationale: Revised the wording regarding diarrhea in the Introduction to better align with the Investigator’s 
Brochure for ibrutinib.
1.2.2 Clinical Safety 
of Ibrutinib
Updated text regarding the clinical experience of ibrutinib regarding diarrhea. 
Rationale: To update general information for biomarker analyses, per current protocol template wording.
10.5 Biomarkers
Added text regarding biomarker analyses, per the current protocol template.
Rationale: Clarified that Grade ≥ 3 events of clinical interest related to nivolumab will have same reporting 
timelines as for serious adverse events. 
13.2.1 Nivolumab
Clarified that the reporting of events of clinical interest related to nivolumab applies to 
Grade ≥3. 


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Rationale: Subjects with small lymphocytic lymphoma (SLL) will be included in the study population.  Criteria 
for inclusion have been added and references to CLL throughout have been updated to CLL/SLL where 
appropriate.
Synopsis, 1 
Introduction, Table 1, 
1.1 Background, 2.1 
Objectives, 2.2 
Hypothesis, 3.1 
Overview of Study 
Design, Figure 1, 3.2 
Study Design 
Rationale, 4.1.1 
Additional Inclusion 
Criteria for Part A: 
Dose Optimization, 
4.1.2 Additional 
Inclusion Criteria for 
Part B: Expansion 
Cohorts, 12.3 Sample 
Size Determination
Criteria number 14, 15, and 16 have been modified accordingly to allow inclusion of 
subjects with SLL into the study. 
The criteria describing disease requirements for CLL were combined into one criterion, 
#13, and the new criteria for SLL added to criterion #14.
Synopsis, 2.2 
Hypothesis
The hypothesis will evaluate and describe as opposed to test the overall response rate.
Table 23
Footnote #1 and #12
For consistency with Table 1 and 2, bone marrow must be evaluated within 90 days 
prior to enrollment, not the start of study therapy. 
Synopsis, 
Abbreviations, 1.2.4 
Clinical Efficacy of 
Ibrutinib, 12.3 
Sample Size 
Determination, 12.4 
Efficacy Analyses
Where appropriate, objective response rate was changed to overall response rate. 
Rationale: Previously, the ibrutinib pharmacodynamic/biomarkers collected at Cycle 1 predose were to be taken 
from Cohorts A1, A2, and B3 that did not have an ibrutinib run-in.  These samples will now be collected from all 
subjects. 
Clarification that the fine needle aspirate (FNA) at the C3D1 timepoint may be collected from C2D1 onwards.
Blood volume for pharmacokinetic and biomarker assessments collected from subjects in the run-in visit has been 
added.
Table 2, 17.1 Study-
Specific Design 
Considerations
Footnote “d” deleted from C1D1 predose pharmacodynamic/biomarker sample.
Footnote “l” revised to add that the C3D1 timepoint for the FNA can be taken from 
C2D1 onwards.
Subjects in Cohorts B1and B2 will have an additional 43 mL of blood collected for 
ibrutinib pharmacodynamics and biomarkers during the run-in visit.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


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Amendment 1 (29 Jan 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: The overall primary reasons for the amendment are to align with the 
approved nivolumab United States (US) prescribing information and to incorporate feedback from US Food and 
Drug Administration (FDA) into the protocol.
Applicable Section(s)
Description of Change(s)
Rationale: Align with approved nivolumab US prescribing information.
6.4.3 Guidelines for 
Dose Modification
Tables 8 and 9 were revised to align with the approved nivolumab US prescribing 
information.
Rationale:  To incorporate feedback from the FDA into the protocol.
4.2 Exclusion Criteria
Text added to exclusion criterion #6 to specify that subjects who have congenital long 
QT syndrome or QTcF >470 ms at Screening will be excluded from this study.
Time and Events 
Schedule (Table 1); 
10.6 Safety 
Evaluations 
(Electrocardiogram)
Text added to specify timings and methods for ECG assessment of QT interval.
9.2 Permitted 
Medications
Text added: “The use of glucocorticoids is allowed for clinical management of AEs. 
However, inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks is a reason for discontinuation of study therapy.”
Synopsis- Statistical 
Methods; 3.3.2 Dose 
Optimization – Part 
A; 12.3 Sample Size 
Determination
Text was revised to specify that a minimum of 6 subjects, instead of a minimum of 
3 subjects, may be treated in each cohort in Part A.
List of References
One new reference (to Fridericia publication) was added.
Rationale: Correction.
Time and Events 
Schedule for 
Pharmacokinetic and 
Pharmacodynamic 
Assessments 
(Table 2)
The following text was deleted from Footnote a: “Assessment only for expansion part of 
the study (Part B): mandatory for Cohort B2 only, other cohorts per SET decision.”
Rationale: To maintain consistency within protocol and for alignment with changes made to Section 6.4.3.
3.3.1 Evaluation of 
Dose-limiting 
Toxicity
Text regarding non-hematologic and hematologic adverse events was deleted. Text 
regarding central nervous system hemorrhage of any grade was retained and grouped 
with other listed adverse events.


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Applicable Section(s)
Description of Change(s)
Rationale: Alignment of information between Sections 3.1 and 6.
6.4.1 Ibrutinib Dose 
Modification
Text regarding ibrutinib intra-patient dose escalation was added: “In Part A, intra-
patient dose escalation may be requested by the investigator and discussed with the 
medical monitor once a subsequent higher combination dose has been declared 
acceptable by the SET for subjects who (1) have received at least 4 cycles of 
combination treatment at the assigned dose level, and (2) have not experienced a DLT or 
therapy-related SAE. Subjects whose dose has been escalated will not be considered for 
the safety evaluation in the subsequent dose level and the determination of the RP2D.”
Rationale: Correction.
8.2 Hepatic Adverse 
Events
In Table 11, “I-O therapy” revised to “study treatment”. 
Rationale: Clarification.
9.3 Prohibited 
Medications
Footnote #3 to Table 19 revised and was split into 2 footnotes for clarity. 
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


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Status: Approved,  Date: 12 October 2020
SYNOPSIS
A Phase 1/2a Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary 
Efficacy of the Combination of Ibrutinib with Nivolumab in Subjects with Hematologic Malignancies
Ibrutinib, (IMBRUVICA®; PCI-32765; JNJ-54179060), is a first-in-class, potent, orally-administered, 
covalently-binding small molecule inhibitor of Bruton’s tyrosine kinase (BTK) currently being 
co-developed by Janssen Research & Development, LLC (JRD) and Pharmacyclics LLC. for the treatment 
of B-cell malignancies.
Nivolumab (BMS-936558) is a fully human, IgG4 () isotype, monoclonal antibody (mAb) that binds the 
programmed-cell death 1 (PD-1) receptor and is being developed by Bristol Myers Squibb for the treatment 
of hematological cancers and solid tumors.
OBJECTIVES AND HYPOTHESIS
Primary Objective
Part A (Dose Optimization Cohorts): The primary objective of Part A is to determine whether ibrutinib 
and nivolumab can be safely combined and to establish the recommended Phase 2 dose (RP2D) for this 
combination in subjects with hematological disorders.
Part B (Expansion Cohorts): The primary objective of Part B is to determine the preliminary activity of the 
ibrutinib/nivolumab combination regimen in subjects with relapsed/refractory CLL/SLL and poor 
prognosis (deletion 17p or deletion 11q), relapsed/refractory FL, relapsed/refractory DLBCL, and in 
subjects with Richter syndrome in comparison to historical results.
Secondary Objectives
The secondary objectives are:

To evaluate the safety profile of the ibrutinib and nivolumab combination regimen 

To assess overall response rate, duration of response, duration of stable disease, progression-free 
survival rate at 1 year, and overall survival at 1 year of the ibrutinib and nivolumab combination 
regimen 

To characterize and explore the pharmacokinetic profile of ibrutinib and nivolumab compared with 
existing single-agent treatment data; and the potential relationships between ibrutinib and nivolumab 
metrics of exposure with relevant clinical or biomarker information (Part A and B) 
Exploratory Objectives

To characterize the molecular effects of the ibrutinib and nivolumab combination regimen on tumor 
cells and the immune response; and identify biomarkers of response or resistance to the combination 

To evaluate the immunogenicity of nivolumab
Hypothesis
In Part A (Dose Optimizations), the study will evaluate and describe whether ibrutinib, administered at 
daily oral doses between 420 mg and up to 560 mg, can be safely combined with nivolumab 3 mg/kg 
administered IV every 2 weeks such that ≤30% of subjects with CLL/SLL or NHL experience a DLT.
In Part B (Dose Expansion; Cohorts B1, B2, B3, and B4), the study will evaluate and describe whether 
ibrutinib combined with nivolumab can result in an overall response rate of more than 20%.


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OVERVIEW OF STUDY DESIGN
This is an open-label Phase 1/2a study, which consists of Part A (Dose Optimization Cohorts) and Part B 
(Expansion Cohorts). In the context of this study, a treatment ‘cycle’ is defined as a course of treatment of 
14 days starting with the intravenous administration of nivolumab on Day 1 of each cycle along with once 
daily oral intake of ibrutinib on all days. 
It is anticipated that approximately 158 subjects will be enrolled throughout the study; up to 18 subjects in 
the dose optimization period (Part A) and approximately 140 subjects during the expansion period (Part B).
Part A (Dose Optimization Cohorts) is designed to determine the RP2D for the combination based on safety, 
pharmacokinetic, and pharmacodynamic assessments. Two dose optimization cohorts will be explored, 
applying the Modified Toxicity Probability Interval (mTPI) design to evaluate subjects with 
relapsed/refractory CLL/SLL or B-NHL.
Part B (Dose Expansion Cohorts) will be open for enrollment after the RP2D is determined in Part A. In 
Part B, further assessment of the RP2D will be explored in 4 subject populations to further evaluate the 
safety and clinical activity of ibrutinib in combination with nivolumab. During the expansion period, 
subjects with CLL/SLL with del 17p or 11q (Cohort B1), FL (Cohort B2), DLBCL (Cohort B3), and Richter 
syndrome (Cohort B4) will be enrolled. Approximately 35 subjects will be enrolled in each of the expansion 
cohorts. The subjects will be treated at the RP2D level selected to further assess the safety, 
pharmacokinetics, pharmacodynamics, pharmacogenomics, and activity of the combination.
The average duration of study therapy is expected to be approximately 6 months.
In Part A of the study, a Study Evaluation Team (SET), consisting of the principal investigators, sponsor 
medical monitors, and the sponsor’s clinical pharmacologist, or their designees, and the sponsor statistician 
will review all available data upon completion of the first 2 treatment cycles (ie, 4 weeks of study therapy) 
for all subjects at each dose cohort to determine DLTs, if dose escalation is acceptable, and ultimately to 
determine the recommended Phase 2 dose.
In Part B of the study, all subjects in each cohort may be evaluated for response by the SET and additional 
functional representatives from Janssen, as applicable. The SET along with optional other internal members 
may review safety data on an ad hoc basis, and efficacy endpoints (including but not limited to ORR).
The End-of-Treatment Visit will occur within 30 days after the last dose of ibrutinib or nivolumab, 
whichever treatment occurred last.
During the Follow-up Period, long-term safety, survival status, disease progression, subsequent aniticancer 
therapy, and occurrence of other primary malignancy data will be collected as well as ADA sampling if 
applicable. During the Follow-up Period, subjects should be followed for safety up to 30 days after the last 
dose of ibrutinib or 100 days after the last nivolumab infusion, whichever is later. The safety includes 
adverse event reporting and laboratory assessments (at the first follow up). Thereafter, follow-up visits will 
be completed approximately every 3 months until death or the end of study. Subjects who have developed 
treatment-related Grade 3 or higher toxicity at the end of treatment will be assessed until recovery to Grade 
≤1 or baseline, deemed irreversible, or until end of study. Adverse events leading to discontinuation will be 
followed up until resolution or return to baseline, or end of study, whichever occur first.




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The efficacy endpoints are defined as follows, based on the IWCLL or the Lugano Classification by Cheson 
(2014), as appropriate for the disease:

Overall response rate (ORR), which is defined as the proportion of evaluable subjects who achieve CR 
or PR, as assessed by the investigators.

Duration of response (DOR) will be calculated from the date of initial documentation of a response 
(CR or PR) to the date of first documented evidence of progressive disease (or relapse for subjects who 
experience CR during the study) or death. Subjects who are progression-free and alive or have unknown 
status will be censored at the last tumor assessment.

Progression-free survival (PFS) is defined as the duration from the date of first dose of study drug until 
the date of first documented evidence of progressive disease (or relapse for subjects who experience 
CR during the study) or death, whichever comes first. Subjects who are progression-free and alive or 
have unknown status will be censored at the last tumor assessment.

Overall survival (OS) is measured from the date of first dose of study drug to the date of the subject’s 
death. If the subject is alive or the vital status is unknown, the subject will be censored at the date the 
subject was last known to be alive.
PHARMACOKINETIC EVALUATIONS
Blood samples will be collected from all subjects for determination of plasma concentrations of ibrutinib 
and the PCI-45227 metabolite (if possible and judged relevant), as well as serum concentrations of 
nivolumab. Pharmacokinetic assessments will not be conducted post clinical cutoff.
IMMUNOGENICITY EVALUATIONS
Subjects will be monitored for anti-nivolumab antibodies throughout the study. Blood for serum 
anti-nivolumab antibody testing should be collected.
BIOMARKER EVALUATIONS 
Biomarkers will be assessed in all subjects to further characterize the pharmacodynamic profile and to 
investigate the molecular efficacy of the ibrutinib and nivolumab combination regimen. 
Biomarkers will be analyzed in:

Tumor tissue 

Blood samples (collected serially)

Fine-needle aspirates (from affected lymph nodes)

Bone marrow aspirates or biopsies
After clinical cutoff, some biomarker assessments (bone marrow aspirate/biopsy) will no longer be 
conducted.
SAFETY EVALUATIONS
Safety assessments will be based on medical review of adverse event reports and the results of vital sign 
measurements, electrocardiograms, physical examinations, clinical laboratory tests and ECOG performance 
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STATISTICAL METHODS
This is a Phase 1/2a dose optimization and expansion study. For Part A, a statistical design based on the 
approach described in Ji, et al. (2010) and Ji and Wang (2013) will be used. This method requires a 
definition of an equivalence interval (EI), [0.25; 0.30], in which any dose is considered as a potential 
candidate for the true MTD, where 0.30 is the targeted DLT rate. Defining an EI results in the partition of 
the unit interval (0, 1) into 3 subintervals; (0; 0.25), [0.25, 0.30], and (0.30; 1). Doses in these 3 intervals 
are deemed lower, close to, and higher than the MTD, respectively. At least 6 and up to 9 subjects may be 
treated in each cohort in Part A. Approximately 18 subjects may be enrolled in Part A.
Part B, Cohorts B1 (CLL/SLL), B2 (FL), B3 (DLBCL), and B4 (Richter syndrome) are designed to evaluate 
the feasibility and safety of treating subjects with ibrutinib in combination with nivolumab and to evaluate 
preliminary activity. The sample size is calculated based on the following assumptions (denoting the true 
response rate of ibrutinib in combination with nivolumab as p):

The overall response rate under null hypothesis is 20% 

The overall response rate under alternative hypothesis is at least 38% 

The probability to mistakenly rejecting the null hypothesis when it is actually true is 0.1 (one-sided). 

The probability to correctly rejecting null hypothesis when alternative hypothesis is true is at least 0.8
Under the above assumptions, the study will enroll approximately 35 subjects to get at least 32 response-
evaluable subjects in each cohort of Part B (dose expansion, Cohorts B1, B2, B3, and B4). 
Approximately 158 subjects (with up to 18 subjects in Part A and approximately 140 subjects in the Part 
B, dose expansion) will be enrolled in this study.
Part A: Individual best tumor responses and duration of response (defined as the time from first response 
to progression) will be listed for each dose cohort.
Part B: The following efficacy analyses will be performed to explore the clinical activity of ibrutinib in 
combination with nivolumab in each cohort in the treated population unless otherwise stated: 

Overall response rate (CR or PR) will be calculated with 95% CI for each disease-specific cohort (B1, 
B2, B3, and B4) on the response-evaluable population.

Progression-free survival and overall survival at 1 year will be evaluated using Kaplan-Meier method. 

Duration of response and duration of stable disease will be evaluated if there are sufficient data for 
responders within each cohort.
















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ADA=anti-drug antibodies; CR=complete response; EOT=End of Treatment; FNA=fine needle aspirate;  FU=Followup; PD=pharmacodynamic; PK=pharmacokinetic
a.
Predose samples should be taken just prior to the administration (preferably within 30 minutes, however predose collection up to 4 hours before study drug 
administration would be acceptable). If the infusion is delayed and a predose sample was already collected, there is no need to collect an additional predose sample. 
b.
When both study drugs are given, predose samples should be obtained prior to administration of any study drug.
c.
Required for Cohort B1 and B2 only.
d.
Cohorts A1, A2, B3, and B4 that did not have an ibrutinib run-in.
e.
If not done in Cycle 13, postdose samples for ibrutinib PK can be collected at a subsequent cycle.
f.
If possible, the EOT sample should be obtained within 48 hours after last intake of ibrutinib.
g. Submission of tumor tissue from a biopsy performed during screening is mandatory (diagnostic block or slides), archival tissue is acceptable if fresh biopsy is not 
available.
h.
Extent of disease involvement in the bone marrow must be documented at screening based on the results of a bone marrow biopsy/aspirate performed within 90 
days prior to enrollment or a bone marrow biopsy/aspirate performed during the screening period. If bone marrow biopsy/aspirate is performed during screening 
(after obtaining informed consent), submission of bone marrow aspirate is encouraged. 
i.
If the bone marrow was involved by lymphoma at baseline, a bone marrow biopsy and/or aspirate will be required to confirm a CR. Submission of bone marrow 
aspirate to the central lab is required if clinically feasible.
j. 
Subjects are required to undergo tumor and/or bone marrow biopsies from C13 onwards if clinically indicated. When tumor biopsy is performed, submission of 
tumor biopsy to the central lab is required if clinically feasible.
k. Samples, including fresh biopsy upon progression, are to be taken ± 7 days at the discretion of the investigator.
l. 
Applicable to Part B : Only required for subjects (as clinically indicated) in Cohort B1 (mandatory), B2 (mandatory), and optional for B3 and B4. C3D1 timepoint 
can be taken from C2D1 onwards.
m. Sampling at clinical visit End-of-treatment per T&E   Table 1 (approx. 30 days post Ibrutinib dose).
n. During FU to be repeated until progressive disease.
o. After clinical cutoff: Assessment is no longer required.
p.
Pharmacokinetic, pharmacodynamic or biomarker samples will not be obtained at any visit, including follow up,  after implementation of protocol amendment 7.  


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ABBREVIATIONS
ADA
anti-drug antibody
AE
adverse event
AESI
adverse events of special interest
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
BCR
B-cell receptor
BM
bone marrow
B-NHL
B-cell non-Hodgkin lymphoma
BTK
Bruton’s tyrosine kinase
CI
confidence interval
CLL
chronic lymphocytic leukemia
CR
complete response
Cmax
maximum observed plasma concentration
CMV
cytomegalovirus
CT
computed tomography
CV
coefficient of variation
DILI
drug-induced-liver-injuries
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDC
electronic data capture
EI
equivalence interval 
EOT
end of treatment
ERK
extracellular signal-regulated kinase
FISH
fluorescence in situ hybridization
FL
follicular cell lymphoma
FU1
follow up 1
GCB
germinal-center –B-cell like 
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HER
human epidermal growth factor receptor 
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFNγ
interferon gamma
IHC
immunohistochemistry
IL-2
interleukin 2
irAE
immune-related adverse event
INR
international normalized ratio
IRB
Institutional Review Board
ITK
interleukin-2-inducible T-cell kinase
ITSM
distal immunoreceptor tyrosine-based switch motif
IV
intravenous
IWCLL
International Workshop on Chronic Lymphocytic Leukemia 
IWRS
interactive web response system
LC-MS/MS
liquid chromatography/mass spectrometry/mass spectrometry
LDT
lymphocyte doubling time
LFT
liver function test
mAb
monoclonal antibody


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MCL
mantle cell lymphoma
MDRD
Modified Diet in Renal Disease (formula)
MedDRA
Medical Dictionary for Regulatory Activities
MLR
mixed lymphocyte reaction
MM
multiple myeloma
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTPI
Modified Toxicity Probability Interval 
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin's lymphoma
NSAIDs
nonsteroidal anti-inflammatory drugs
NSCLC
non-small-cell lung cancer
ORR
overall  response rate
PD
pharmacodynamic
PD-1
programmed-cell death 1
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PQC
Product Quality Complaint
PR
partial response
PRL
partial response with lymphocytosis
QTcF
QT interval corrected for heart rate, using Fridericia formula
RCC
renal-cell cancer
RP2D
recommended phase 2 dose 
SET
Study Evaluation Team
SIPPM
Site Investigational Product Procedures Manual
SJS
Stevens-Johnson Syndrome 
SLL
small lymphocytic lymphoma
TCR
T-cell receptor
Th2
T-helper type 2
ULN
upper limit of normal
WHO
World Health Organization
WM
Waldenström's macroglobulinemia
WOCBP
women of childbearing potential


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1.
INTRODUCTION
Ibrutinib, (IMBRUVICA®; PCI-32765; JNJ-54179060), is a first-in-class, orally administered, 
potent inhibitor of Bruton’s tyrosine kinase (BTK), a mediator of critical B-cell signaling pathways 
implicated in the pathogenesis of B-cell cancers. Ibrutinib is currently being co-developed by 
Janssen Research & Development, LLC (JRD) and Pharmacyclics LLC. It has demonstrated 
single-agent activity and an acceptable safety profile in several B-cell lymphomas, including 
relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). 
Ibrutinib and PCI-32765 refer to the same molecule; hereafter, ibrutinib will be used.
Ibrutinib is currently being evaluated in over 26 ongoing and 9 completed company-sponsored 
clinical studies in healthy volunteers and in subjects with recurrent B-cell lymphomas, including 
CLL/small lymphocytic lymphoma (SLL), MCL, follicular lymphoma (FL), diffuse large B-cell 
lymphoma (DLBCL), multiple myeloma (MM), Waldenström’s macroglobulinemia (WM), and 
marginal zone lymphoma (MZL).
Nivolumab (BMS-936558) is a fully human, IgG4 () isotype, monoclonal antibody (mAb) that 
binds PD-1. Blockade of the PD-1 pathway by nivolumab was studied using the mixed lymphocyte 
reaction (MLR). PD-1 blockade resulted in a reproducible enhancement of both proliferation and 
IFN-release in the MLR. The effect of nivolumab on antigen-specific recall response was 
investigated using a CMV-restimulation assay with human peripheral blood mononuclear cells 
(PBMCs), and was evaluated by ELISA. These data indicated that nivolumab, versus an isotype-
matched control antibody, augmented IFN-secretion from CMV-specific memory T-cells in a 
dose-dependent manner. PD-1 blockade by nivolumab is therefore considered a promising 
immunotherapeutic option.
Relevant clinical and nonclinical information are discussed within this section. For the most 
comprehensive nonclinical and clinical information regarding the efficacy and safety of ibrutinib 
and nivolumab, refer to the latest version of the ibrutinib and nivolumab Investigator's Brochures, 
Addenda, and Supplements. The term "sponsor" used throughout this document refers to the 
entities listed in the Contact Information page(s), which will be provided as a separate document.
1.1.
Background
Conventional treatment regimens of cytotoxic chemotherapy and/or agents targeting oncogenic 
signal-transduction pathways can lead to substantial remission rates in patients with hematologic 
malignancies and solid tumors by eliminating actively dividing tumor cells. Ibrutinib is a potent 
small-molecule inhibitor of BTK-mediated B-cell receptor signaling and has demonstrated 
encouraging clinical efficacy in B-cell malignancies. However, the therapeutic efficacy of standard 
anti-proliferative treatments including ibrutinib is often limited by the emergence of molecular 
resistance leading to the occurrence of clinical disease relapse. It is widely believed that the 
expansion of sub-populations of initially quiescent tumor stem cells are responsible for the disease 
relapse due to inherited or acquired resistance to anti-proliferative therapies. In order to better 
target the specific tumor stem cell populations, therapeutic strategies activating the immune system 
have been successfully explored (Brody 2011).7 The addition of passive immunotherapies with 
antibodies directed against relevant antigens and receptors expressed on proliferating tumor cells 


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and stem cells have already transformed the standard-of-care in selected hematologic malignancies 
and solid tumors. More recently, major clinical progress has been observed with active 
immunotherapies addressing molecular mechanisms of evasion of immune-mediated tumor 
destruction. Multiple therapeutic approaches are currently being pursued to overcome the immune-
tolerance of tumors (Drake 2014).15 Of these the blockade of immune-checkpoint receptor-ligand 
interactions between tumor cells and tumor-specific T-lymphocytes (Drake 2014)15 has emerged 
as the most promising novel therapy. Among the immunotherapies targeting immune-checkpoints, 
antibodies directed against the PD-1 receptor expressed on tumor-specific T-lymphocytes such as 
nivolumab, have demonstrated astonishing single-agent efficacy in patients with advanced 
melanoma, 
renal 
cell 
cancer 
(RCC), 
non-small-cell lung cancer (NSCLC) and other solid tumor indications (Robert 2013; 
Dranoff 2013; Sznol 2013).47,16,52 Limited clinical data also indicate activity of anti-PD 1 antibody 
therapy in patients with hematologic malignancies (Brody 2011; Shi 2013)7,50 suggesting a very 
broad 
clinical 
potential 
for 
specific 
immune 
check 
point 
inhibitors 
(Robert 2013; Sznol 2013).47,52 Clinical studies are underway to further investigate the efficacy of 
PD-1 immune check-point inhibition in hematologic malignancies (Armand 2013).3
Pre-clinical data obtained in relevant tumor models as well as early clinical data indicate that due 
to 
the 
different 
mode-of-action, 
anti-proliferative 
therapies 
targeting 
oncogenic 
signal-transduction pathways can be safely combined with antibody-mediated PD-1 
immune-checkpoint blockade (Sznol 2013).52 More importantly, based on the different onset of 
clinical activity, which is often early with signal-transduction inhibitors and frequently delayed 
with immune-checkpoint inhibitors, these treatments may ultimately complement one another, 
leading to a more pronounced anti-tumor activity in sensitive tumor indications (Sznol 2013).52
The current study is designed to explore the safety, pharmacokinetic, and pharmacodynamic 
profile of a novel treatment regimen combining ibrutinib administered on a daily oral schedule 
with nivolumab administered intravenously every 2 weeks. The aim of the Phase 1 portion of the 
study (Part A) is to establish the recommended phase 2 dose (RP2D) for the combination in 
subjects with relapsed or refractory B-cell NHL. In the Phase 2a portion of the study (Part B), 
subjects with hematologic malignancies, for which ibrutinib or nivolumab may be considered to 
have single-agent activity, will be enrolled into 3 expansion cohorts. The purpose of the Phase 2a 
portion is to generate additional safety data and to explore the efficacy of this novel combination 
regimen. The expansion cohorts will include subjects with either advanced CLL/SLL harboring a 
deletion 17p or 11q deletion (Cohort B1), FL (Cohort B2), DLBCL (Cohort B3), or Richter 
syndrome (Cohort B4). 
1.2.
Ibrutinib 
Ibrutinib or 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl) -1H-pyrazolo[3,4 d] pyrimidin-1-yl]-1-
piperidin-1-yl]prop-2-en-1-one, is a small molecule tyrosine kinase inhibitor with a molecular 
weight of 440.50 g/mole (anhydrous basis). 




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1.2.2.
Clinical Safety of Ibrutinib
As outlined in detail in the Investigator’s Brochure, safety data are available for subjects who have 
received ibrutinib either as monotherapy or in combination therapy regimens. Discontinuation of 
ibrutinib treatment due to AEs has been infrequent and was most commonly associated with 
complications of disease progression or infectious events.
General safety - Monotherapy
Among subjects receiving ibrutinib as monotherapy in nonrandomized studies (N=1061), the most 
frequently reported treatment-emergent adverse events (>10%) were:

diarrhea

fatigue

nausea

cough

anemia
The most frequently reported nonhematologic Grade 3 or 4 adverse events (>2%) were pneumonia, 
fatigue, hypertension, and atrial fibrillation.
The most commonly reported hematologic Grade 3 or 4 adverse events (>5%) were neutropenia, 
thrombocytopenia, and anemia. 
The most frequently reported SAEs (any grade) that were considered related to ibrutinib were 
pneumonia, atrial fibrillation, and febrile neutropenia.
General safety – Combination Therapy
In subjects (n=136) treated with ibrutinib in combination with standard chemo/immunotherapy, 
the most frequently reported treatment-emergent adverse events (>20%) were:

diarrhea

nausea

neutropenia

fatigue

peripheral sensory neuropathy

upper respiratory tract infection

vomiting

anemia

thrombocytopenia


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The most frequently reported nonhematologic Grade 3 or 4 adverse events (>4%) were pneumonia, 
diarrhea, cellulitis, and urinary tract infection. 
The most commonly reported hematologic Grade 3 or 4 adverse events (>4%) were neutropenia, 
febrile neutropenia, thrombocytopenia, and anemia.
The most frequently reported serious adverse events that were considered related to ibrutinib (note: 
some of these events were also reported as related to other study drug) were febrile neutropenia, 
pneumonia, cellulitis, and hypotension.
Adverse events of clinical concern
Bleeding-related events: There have been reports of hemorrhagic events in patients treated with 
ibrutinib, both with and without thrombocytopenia. These include minor hemorrhagic events such 
as contusion, epistaxis, and petechiae; and major hemorrhagic events including gastrointestinal 
bleeding, intracranial hemorrhage, and hematuria.
Lymphocytosis and Leukostasis: Reversible increase of lymphocyte counts (≥ 50% from 
baseline and absolute count > 5,000/μl) often associated with reduction of lymphadenopathy have 
been observed during the first weeks of ibrutinib therapy (median onset: 1.1 weeks; median 
resolution: 8 weeks). There were isolated cases of leukostasis reported in patients treated with 
ibrutinib. A high number of circulating lymphocytes (> 400000/mcL) may confer increased risk.
Infections: Fatal and non-fatal infections have occurred with ibrutinib therapy. At least 35% of 
subjects with CLL had Grade 3 or greater infections per NCI Common Terminology Criteria for 
Adverse Events (CTCAE). The most commonly reported infections include pneumonia, cellulitis, 
urinary tract infection and sepsis. Isolated cases of JC virus reactivation resulting in progressive 
multifocal encephalopathy (PML) have been observed and resulted in death. Two cases in subjects 
with relapsed CLL have been reported. One case occurred after multiple prior rituximab regimens 
and less than one year after the last dose of rituximab and high dose steroid administration. The 
second case occurred during concomitant administration of rituximab, bendamustine and ibrutinib. 
Consider prophylaxis according to standard of care in subjects who are at increased risk for 
opportunistic infections (reference Section 8.10).
Diarrhea: Diarrhea is the most frequently reported nonhematologic adverse event with ibrutinib 
monotherapy and combination therapy. Other frequently reported gastrointestinal events include 
nausea, vomiting, and constipation. These events are rarely severe, and are generally managed 
with supportive therapies including antidiarrheals and antiemetics. Subjects should be monitored 
carefully for gastrointestinal adverse events and cautioned to maintain fluid intake to avoid 
dehydration. Medical evaluation should be made to rule out other etiologies such as 
Clostridium difficile or other infectious agents. Should symptoms be severe or prolonged, ibrutinib 
treatment should be modified as directed in the protocol.
Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia and 
anemia) were reported in patients treated with ibrutinib.


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Cardiac events: Atrial fibrillation and atrial flutter have been reported in patients treated with 
ibrutinib, particularly in patients with cardiac risk factors, acute infections, and a previous history 
of atrial fibrillation. There is no evidence of QT prolongation with increasing doses of ibrutinib.
Other malignancies: Other malignancies, most frequently skin cancers (18/357 subjects or 5%), 
have occurred in patients treated with ibrutinib.
Rash: Rash has been commonly reported in subjects treated with either single agent ibrutinib or 
in combination with chemotherapy. Most rashes were mild to moderate in severity. 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 
a randomized, comparator-controlled study, Study 1112. Most rashes were mild to moderate in 
severity. One case of Stevens-Johnson Syndrome (SJS), with a fatal outcome, was reported in a 
subject with CLL. The subject received ibrutinib (420 mg/day) and was also receiving various 
antibiotics and antigout medication (allopurinol) known to be associated with SJS.
Tumor lysis syndrome: TLS has been reported with ibrutinib therapy.
1.2.3.
Clinical Pharmacology Data
In vitro preclinical data show that ibrutinib is metabolized primarily by CYP3A. Its absolute 
bioavailability was 2.9% and highly variable, as determined in a study in 8 healthy subjects (PCI-
32765CLL1011). The interaction with a strong CYP3A inhibitor was determined in Study PCI-
32765CLL1002, an open-label drug-drug interaction study in 18 healthy men, in which ibrutinib 
was administered alone at a 120 mg dose or in combination with ketoconazole at a 40 mg dose. 
Results demonstrated that ketoconazole, a strong CYP3A4 inhibitor, increased ibrutinib exposure 
(maximum observed plasma concentration [Cmax] and area under the plasma concentration versus 
time curve from time zero to the time corresponding to the last quantifiable concentration [AUC0-
last]) by 29- and 24-fold, respectively. The maximal observed ibrutinib exposure (AUC) was ≤ 2-
fold in 37 patients treated with mild and/or moderate CYP3A inhibitors when compared with the 
ibrutinib exposure in 76 patients not treated concomitantly with CYP3A inhibitors. Clinical safety 
data in 66 patients treated with moderate (n=47) or strong CYP3A inhibitors (n=19) did not reveal 
meaningful increases in toxicities. Guidance on concomitant use of ibrutinib with CYP3A 
inhibitors or inducers is provided in Attachment 8.


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1.2.4.
Clinical Efficacy of Ibrutinib
The clinical benefit of ibrutinib was first demonstrated in a Phase 1 dose-escalation study of 
ibrutinib in subjects with recurrent B-cell lymphomas with ORRs ranging from 85.7% in subjects 
with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell 
lymphoma (MCL) to 33.3% in subjects with diffuse large B-cell lymphoma (DLBCL). These 
findings were further demonstrated in subsequent Phase 2 studies in subjects with previously 
treated MCL or CLL/SLL, and a randomized, comparator-controlled Phase 3 pivotal study in 
subjects with previously treated CLL/SLL. Activity was also demonstrated in other histologies 
(follicular lymphoma, Waldenström’s macroglobulinemia, marginal zone lymphoma, multiple 
myeloma) and with combination therapy (fludarabine, cyclophosphamide, rituximab; 
bendamustine + rituximab; and ofatumumab).
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
In the Phase 2 study PCYC-1102-CA, subjects with relapsed or refractory or treatment-naïve 
CLL/SLL were treated with 420 mg or 840 mg daily continuously until disease progression or 
until the subject could no longer tolerate the treatment. Ibrutinib produced an overall response rate 
of 78.4% in 51 subjects with relapsed/refractory disease. Responses were rapid (median of 1.8 
months) and durable. Objective responses appeared independent of poor-risk factors including 
cytogenetics such as deletion of the short arm of chromosome 17 ie, del(17p13.1) or deletion of 
the long arm of chromosome 11 ie, del(11q21-q23). At Month 24, the proportion of subjects treated 
with the 420 mg/day dose who were alive and progression-free was 82.3%, and the overall survival 
rate was 89.6%. The 840 mg dose level did not appear to improve efficacy. Therefore, 420 mg 
daily dose was chosen as the recommended dose for further development in CLL/SLL. 
An analysis of long-term follow-up in subjects with CLL/SLL from the Phase 2 Study 1102 and 
the 1103 extension study showed that efficacy was sustained over time. Overall response rate 
(ORR) (per IRC assessment) was 83.9% in treatment-naïve subjects and 76.2% in previously 
treated subjects. The ORR when including PR-L (per IRC assessment) was 90.3% and 79.2%, 
respectively. At 30 months, the PFS rate was 96.3% for treatment-naïve subjects and 68.4% for 
previously treated subjects.
In a Phase 3 randomized, comparator-controlled, pivotal study in subjects with CLL/SLL 
(Study 1112), ibrutinib improved efficacy outcomes in subjects with previously treated CLL/SLL 
compared to that ofatumumab. Analysis of PFS (per the Independent Review Committee [IRC]) 
demonstrated a statistically significant reduction in the risk of disease progression or death in the 
ibrutinib arm compared to the ofatumumab arm (HR=0.215, p<0.0001). Analysis of OS showed 
that subjects in the ibrutinib arm had a statistically significant reduction in the risk of death 
(HR=0.434, p=0.0049). The ORR (IRC assessment) was significantly higher (p<0.0001) for 
subjects in the ibrutinib arm (42.6%) than those in the ofatumumab arm (4.1%). The ORR, when 
including partial response with lymphocytosis (PR-L) (per IRC assessment), was 62.6% for the 
ibrutinib arm and 4.1% for the ofatumumab arm (p<0.0001).


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Follicular Lymphoma (FL) 
In the Phase I study PCYC-04573, sixteen subjects enrolled to the dose-escalation phase had a 
diagnosis of FL (Fowler 2012).18 Eleven subjects received ibrutinib at doses that achieved full 
BTK occupancy (ie, 2.5 mg/kg or higher). Median time on ibrutinib was 7 months 
(0 to 29 months) and time to response was 4.6 months. Overall response rate was 54.5% 
(3 CRs, 2 PRs). Responses were durable (median response duration: 12.3 months). Three patients 
had chemorefractory disease; 2 of these patients responded (1 CR, 1 PR). On the basis of these 
very encouraging early efficacy data the single-arm, multicenter Phase 2 study 
PCI-32765FLR2002 was initiated. 
Diffuse Large B-cell Lymphoma (DLBCL) 
In a Phase 2 study of ibrutinib in subjects with DLBCL (Study 1106), an interim analysis of 
response in DLBCL showed an ORR of 25% (CR 9% and PR 16%) with a median time on study 
of 3.9 months. An analysis of response by molecular subtype demonstrated that subjects with 
molecular subtype activated B-cell-like (ABC) (non-germinal-cell B-cell-like [GCB]) had an ORR 
of 41% (CR 17% and PR 24%) and among subjects with the GCB subtype, ORR was 5% (CR 0% 
and PR 5%).
Richter syndrome
Only limited data are currently available on the clinical efficacy of ibrutinib in subjects with 
Richter syndrome defined as the transformation of CLL into an aggressive lymphoma, most 
commonly DLBCL (Parikh 2014)45. In an investigator-initiated study, 4 subjects with Richter 
syndrome, all heavily pretreated, received ibrutinib as single-agent therapy (Tsang 2015)56 of 
which 3 subjects were evaluable for disease response. The median duration of ibrutinib therapy 
was 6.1 months (range of 2.8 to 10.8 months). One subject achieved a CR while 2 subjects 
experienced PR. All 3 subjects reported an improvement of constitutional symptoms. The authors 
concluded that ibrutinib has potential as a novel therapeutic approach for patients with Richter 
syndrome (Tsang 2015)56. In a Phase 1b/2 study, 3 subjects with Richter syndrome received a 
combination 
regimen 
of 
ibrutinib 
and 
the 
anti-CD20 
antibody 
ofatumumab 
(Jaglowski 2015)28. Of these, 2 subjects experienced disease stabilization for 471 and 137 days 
respectively, while 1 subject achieved a PR which lasted for 4.6 months (Jaglowski 2015)28.
1.3.
Nivolumab
Nivolumab (BMS-936558) is a fully human, IgG4 () isotype, mAb that binds PD-1. 
1.3.1.
Non-clinical Nivolumab Data
Preclinical animal models of tumors have shown that blockade by PD-1 by monoclonal antibodies 
(mAbs) can enhance the anti-tumor immune response and result in tumor rejection. Antitumor 
activity by PD-1 blockade functions in PD-L1-positive tumors as well as in tumors that are 
negative for the expression of PD-L1(Blank 2004, Dong 2002, Hirano 2005, Iwai 2002, Iwai 2005, 
Strome 2003).5,14,25,26,27,51 This suggests that host mechanisms (ie, expression of PD-L1 in antigen-
presenting cells) limit the antitumor response. Consequently, both PD-L1 positive and negative 


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tumors may be targeted using this approach. In humans, constitutive PD-L1 expression is normally 
limited to macrophage-lineage cells, although expression of PD-L1 can be induced on other 
hematologic cells as well, including activated T cells. However, aberrant expression of PD-L1 by 
tumor cells has been reported in a number of human malignancies, including NHL (Azuma 2008, 
Konishi 2004, Ohigashi 2005, Thompson 2005a, Thompson 2004, Thompson 2005b, Tsushima 
2006).4,31,41,54,53,55,57 PD-L1 expressed by tumor cells, including FL and DLBCL, has been shown 
to enhance apoptosis of activated tumors. Moreover, the expression of PD-L1 may protect the 
tumor cells from the induction of apoptosis by effector T cells (Andorsky 2011, Chen 2013, 
Nishimura and Honjo 2001).1,11,36 Retrospective analyses of several human tumor types suggest 
that tumor over-expression (as measured by immunohistochemistry (IHC)) of PD-L1 may permit 
immune evasion by tumors.
Programmed death receptor-1 (PD-1, CD279), a 55 kD type I transmembrane protein, is a member 
of the CD28 family of T-cell costimulatory receptors that also includes CD28, CTLA-4, ICOS, 
and BTLA (Freeman 2000).20 PD-1 contains an intracellular membrane proximal immunoreceptor 
tyrosine inhibitory motif and a membrane distal immunoreceptor tyrosine-based switch motif 
(ITSM). Two ligands specific for PD-1 have been identified: PD-L1 (B7-H1/CD274) and PD-L2 
(B7-DC/CD273). PD-L1 and PD-L2 have been shown to down-regulate T-cell activation upon 
binding to PD-1 in both murine and human systems (Carter 2002, Latchman 2001).9,32 PD-1 
delivers a negative signal by the recruitment of SHP-2 to the phosphorylated tyrosine residue in 
the ITSM in its cytoplasmic region (Chemnitz 2004, Sheppard 2004).10,49 PD-1 is primarily 
expressed on activated T cells, B cells, and myeloid cells. Further evidence for a negative 
regulatory role of PD-1 comes from studies of PD-1 deficient mice. PD-1-deficient mice develop 
various autoimmune phenotypes, including dilated cardiomyopathy, a lupus-like syndrome with 
arthritis and nephritis, and accelerated diabetes mellitus (Nishimura 1999, Nishimura 2001, 
Okazaki 2003).37,38,42 The emergence of these autoimmune phenotypes is dependent upon the 
genetic background of the mouse strain and many of these phenotypes emerge at different times 
and show variable penetrance. In addition to the phenotypes of null mutations, PD-1 inhibition by 
antibody-mediated blockade in several murine models has been found to play a role in the 
development of autoimmune diseases such as encephalomyelitis, graft-versus-host disease, and 
type I diabetes (Blazar 2003, Salama 2003).6,48 Taken together, these results suggest that PD-1 
blockade has the potential to activate anti-self T-cell responses, but these responses are variable 
and dependent upon various host genetic factors. Thus, PD-1 deficiency or inhibition is not 
accompanied by a universal loss of tolerance to self-antigens.
Preclinical animal models of tumors have shown that blockade by PD-1 by monoclonal antibodies 
(mAbs) can enhance the anti-tumor immune response and result in tumor rejection. Antitumor 
activity by PD-1 blockade functions in PD-L1-positive tumors as well as in tumors that are 
negative for the expression of PD-L1 (Blank 2004, Dong 2002, Hirano 2005, Iwai 2002, Iwai 
2005, Strome 2003).5,14,25,26,27,51


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Interestingly, recent clinical studies have also demonstrated influence of PD-L1/PD1 interaction 
as a major mechanism for immune evasion in CLL in preclinical models. Aberrant PD-L1 
expression in myeloid cells was shown to be a major culprit for immune deregulation in a murine 
CLL model (Hanna 2014).24 Furthermore, it is also demonstrated that T cell and myeloid cell 
immune defects can be generated in the wild type mice by the adoptive transfer (AT) of murine 
CLL cells. The group also demonstrated in vivo that early PD-L1 blockade in CLL results in 
restoration of effector function of the myeloid and T cells translating to effective anti-tumor 
response. These findings are highly suggestive that targeting PD-L1/PD1 can be a novel strategy 
in CLL, especially with novel drugs in the high risk group of CLL where the efficacy of novel 
drugs have been demonstrated to be inferior.
1.3.2.
Clinical Safety of Nivolumab
A total of 39 and 306 subjects with selected recurrent or treatment-refractory malignancies have 
been treated in a completed Phase 1 single-dose study (MDX1106-01) and a completed Phase 1 
multidose study (CA209003 or MDX1106-03), respectively. As the safety profile from 
MDX1106-03 to date is consistent with that observed for MDX1106-01, only data from the larger 
and more recent study (MDX1106-03 or CA209003) is presented here. 
A review of the safety data by tumor type (RCC, NSCLC, metastatic castration-resistant prostate 
cancer, colorectal cancer, and melanoma) did not show any clinically meaningful differences in 
the proportion of subjects with AEs noted across tumor types.
Overall, the safety profile of nivolumab monotherapy was generally manageable and was 
consistent with the mechanism of action of nivolumab. No MTD was reached at doses tested up to 
10 mg/kg Q2W. The nature, frequency, and severity of any causality and treatment-related safety 
events were similar across tumor types.
The following were the key safety findings for the subjects in MDX1106-03 or CA209003

Drug-related AEs (any grade) were reported in 75.2%, and drug-related Grade 3-4 AEs were 
reported in 17.0% of subjects.

The most frequently reported drug-related AE was fatigue (28.1%). Other drug-related AEs 
Grade 3-4 reported in more than 2 subjects were pneumonitis (1.3%), lymphopenia (1.3%), 
diarrhea (1.0%), abdominal pain (1.0%), CD4 lymphocytes decreased (1.0%), and 
hypophosphatemia (1.0%).

The most frequently reported drug-related SAE was pneumonitis (7 subjects, 2.3%). 
Drug-related Grade 3-4 pneumonitis was reported in 4 (1.3%).

The most frequently reported drug-related select AE categories (any grade) were skin (24.5%), 
GI (14.1%), and endocrine (9.5%).

AEs belonging to the pulmonary and renal select AE categories were unexpected, drug-related 
toxicities associated with the use of nivolumab.

AEs belonging to select AE categories were generally manageable and reversible with the use 
of immunosuppressants.


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Deaths
The majority of the deaths were due to disease progression. Three subjects (1.0%) died due to 
study drug toxicity at the time of database lock; 2 out of 3 subjects died within 100 days of last 
dose of nivolumab, and 1 died > 100 days after the last dose of nivolumab. The reported causes of 
death for these 3 subjects were:

Non-drug-related cardiopulmonary arrest due to complications from Grade 5 sepsis 
(drug-related)

Drug-related sepsis

Drug-related respiratory failure secondary to pneumonitis and progressive disease
After database lock for the final CSR, 2 subjects were reported to have died; both were subjects 
with NSCLC treated with 3-mg/kg nivolumab. The reported causes of death for these 2 subjects 
were:

Drug-related pneumonitis

Non-drug-related infection after experiencing drug-related Grade 3 pneumonitis
Although not considered to be the primary cause of death in all 5 subjects described above, 
pneumonitis was considered a contributory factor in each case.
Preliminary new non-clinical safety findings of adverse pregnancy outcomes and infant losses in 
the absence of overt maternal toxicity have been reported. The findings of increased late stage 
pregnancy loss and early infant deaths/euthanasia in nivolumab exposed pregnant monkeys 
suggest a potential risk to human pregnancy if there is continued treatment with nivolumab during 
pregnancy.
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the BMS-936558 (nivolumab) Investigator Brochure (IB).
Adverse Event Management Algorithms
Because of the potential for clinically meaningful nivolumab-related AEs requiring early 
recognition and prompt intervention, management algorithms have been developed for suspected 
pulmonary toxicity, gastrointestinal, hepatotoxicity, endocrinopathy, skin toxicity, neurological 
toxicity, and nephrotoxicity.
The algorithms recommended for utilization are contained in Section 8 of the protocol.


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1.3.3.
Clinical Efficacy of Nivolumab
In CA209003 (MDX1106-03), the clinical activity of nivolumab was demonstrated in various 
tumor types and across a range of doses (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg). 
For monotherapy in NSCLC, the overall objective response rate was 17%; the most active doses 
were 3 mg/kg and 10 mg/kg. Only a single response was reported at 1 mg/kg. Responses were 
observed in subjects with NSCLC (both squamous and nonsquamous subtypes) with a median 
duration of response of 17 months. A summary of ORR, progression-free survival rate (PFSR), 
and overall survival (OS) rate for NSCLC subjects by histology is provided in the Investigator’s 
Brochure.
For melanoma subjects who were administered nivolumab monotherapy Q2W at doses ranging 
from 0.1 mg/kg to 10 mg/kg, the ORR was 31% (N = 107). The majority of responses were durable 
and exceeded 6 months. A summary of ORR, PFSR, and OS rate for subjects with melanoma is 
provided in the Investigator’s Brochure.
The ORR was 21% (N = 34) for RCC subjects who were administered nivolumab monotherapy 
Q2W at doses of 1 mg/kg or 10 mg/kg. The majority of responses were durable and exceeded 
6 months. A summary of ORR, PFSR, and OS rate for subjects with RCC is provided in IB.
Results from a Phase I study including 29 patients with B-NHL showed activity of nivolumab in 
patients with relapsed DLBCL and FL (Lesokhin 2014).33 The patients were heavily pretreated 
including prior autologous transplant and > 3 lines of prior chemotherapy. The total number of 
patients with DLBCL was 11, CR is reported in 1 (9%), PR in 3 (27%), and SD in 3 (27%) of 
patients with PFS of 24% at 24 weeks. The total number of patients with FL in the study was 11; 
CR was reported in 1 (10%), PR in 3 (30%), SD in 6 (60%) of patients with PFS of 24% at 
24 weeks. 
1.4.
Overall Rationale for the Study
Unpublished data obtained in a model of A20 murine B-cell lymphoma tumors xenografted onto 
immune-competent BALB/C mice indicate a potent and synergistic anti-tumor efficacy of a 
combination treatment of ibrutinib and an antibody against the murine PD-1 ligand PD-L1. It is of 
importance that the enhanced anti-tumor efficacy of the ibrutinib and anti-PD-L1 antibody 
combination treatment was observed in a lymphoma model resistant to ibrutinib monotherapy. 
These experimental data give rise to separate scientific hypotheses:
a.
The PD-1/PD-L1 axis is a mechanism of intrinsic or acquired resistance to ibrutinib in tumors 
otherwise sensitive to its inhibitory activity and/or
b.
Ibrutinib has immune-modulatory activity potentiating the anti-tumor activity of 
PD-1/PD-L1 immune checkpoint inhibition.


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Recent data have shown that the tumor microenvironment plays an important role in the clinical 
course of the disease and the outcome of patients with NHL. Lymph nodes in patients with NHL 
contain not just malignant B cells but normal immune cells including T cells, intratumoral 
macrophages, monocytes, dendritic cells, and natural-killer cells (Ansell 2013).2 Although this 
tumor microenvironment supports the growth and survival of malignant B cells, the malignant 
B cells also define the constitution of the tumor microenvironment. The composition of this 
microenvironment and the presence of specific immune cells have prognostic significance for 
patients with FL (Dave 2004; Richendollar 2011).13,46 In addition, expression data obtained from 
biopsies of NHL patients indicate that malignant B cells modulate immune surveillance by driving 
the differentiation and function of intratumoral T cells (Ansell 2013).2 Malignant B cells have been 
found 
to 
express 
multiple 
ligands 
responsible 
for 
inducing 
regulatory 
T 
cells 
(Treg cells) and suppressing intratumoral effector T cells. 
Of particular interest is the interaction between the PD-L1, a member of the B7 family (B7-H1) of 
co-stimulatory molecules which is frequently over-expressed on malignant B-cells (Richendollar 
2011)46 and its cognate receptor PD-1, a member of the CD28 receptor family, expressed on 
activated, effector T-cells. In CLL, overexpression of both PD-1 and PD-L1 has been detected 
(Grzywnowicz 2012)22 while PD-1 expression appears to be of importance in FL (Carreras 2009).8
The PD-1/PD-L1 interaction between malignant B-cells and effector T-cells results in a 
suppression of the cellular immune response directed against the malignant B-cells. This 
suppression occurs through decreased induction of various cytokines, decreased expression of T-
cell survival proteins, impaired cytotoxic capabilities and most through a direct inhibition of the 
proliferation of activated T-cells (Gzywnowicz 2012).22 PD-1/PD-L1 thereby attenuates the T-cell 
response, leading to “T-cell exhaustion” and the maintenance of peripheral immune tolerance in 
lymphoma (Chen 2013; McClanahan 2012).11,34
Ibrutinib has Immunomodulatory Activity in Lymphoma
Bruton’s tyrosine kinase, the molecular target of ibrutinib, is a member of the non-receptor 
TEC-kinase family, which also includes the structurally homologous tyrosine-protein kinase 
(TEC), the IL2-inducible T cell kinase (ITK) and the endothelial/epithelial tyrosine kinase 
BMX/ETK. 
Intracellular tyrosine kinase is active in T-cell malignancies and has been linked to tumor immune 
evasion and survival through its critical role in T-helper type 2 (Th2) cell differentiation 
(Dubovsky 2013).17 Recent experimental data demonstrate that ibrutinib, in addition to blocking 
BTK, also irreversibly binds to ITK. In relevant in vitro and in vivo models, ibrutinib inhibited 
ITK-mediated downstream activation of T-cell receptor (TCR) stimulation in Th2 polarized CD4-
T helper cells. Th1 cells were not affected possibly because they express a kinase that can 
compensate for loss of ITK signaling. Consistent with these findings, a blocking of Th2 cell 
activation and dominance of a Th1-profile was induced upon ibrutinib exposure of CD4 T-cell 
populations isolated from CLL patients in vitro (Dubovsky 2013).17 Similarly, a Th-1 skewed 
cytokine pattern was detected in clinical samples obtained from ibrutinib treated CLL patients 
(Dubovsky 2013; Niemann 2013).17,35 It has been proposed that the stimulation and expansion of 


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Th2 polarized CD4 T-cells constitutes a specific molecular mechanism of immune evasion 
observed in solid tumors and leukemias (Dubovsky 2013).17
This identification of ibrutinib as an inhibitor of ITK-mediated TCR signaling in Th2-polarized 
CD4-T-cells may address and reverse this specific molecular mechanism. In consequence, the 
therapeutic activity of ibrutinib as a single-agent immunomodulator or in combination with T-cell 
based cancer immunotherapies (Dubovsky 2013)17 including antibodies targeting the PD-1/PD-L1 
axis should be explored.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
Part A (Dose Optimization Cohorts): The primary objective of Part A is to determine whether 
ibrutinib and nivolumab can be safely combined and to establish the recommended Phase 2 dose
(RP2D) for this combination in subjects with hematological disorders.
Part B (Expansion Cohorts): The primary objective of Part B is to determine the preliminary 
activity of the ibrutinib/nivolumab combination regimen in subjects with relapsed/refractory 
CLL/SLL and poor prognosis (deletion 17p or deletion 11q), relapsed/refractory FL,  
relapsed/refractory DLBCL, or Richter syndrome in comparison to historical results.
Secondary Objectives
The secondary objectives are:

To evaluate the safety profile of the ibrutinib and nivolumab combination regimen 

To assess overall response rate (ORR), duration of response, duration of stable disease, 
progression-free survival rate at 1 year, and overall survival at 1 year of the ibrutinib and 
nivolumab combination regimen 

To characterize and explore the pharmacokinetic profile of ibrutinib and nivolumab compared 
with existing single-agent treatment data; and the potential relationships between ibrutinib and 
nivolumab metrics of exposure with relevant clinical or biomarker information (Part A and B) 
Exploratory Objectives

To characterize the molecular effects of the ibrutinib and nivolumab combination regimen on 
tumor cells and the immune response; and identify biomarkers of response or resistance to the 
combination 

To evaluate the immunogenicity of nivolumab
2.2.
Hypothesis
In Part A (Dose Optimizations), the study will evaluate and describe whether ibrutinib, 
administered at daily oral doses between 420 mg and up to 560 mg, can be safely combined with 


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nivolumab 3 mg/kg administered IV every 2 weeks such that ≤30% of subjects with CLL/SLL or 
NHL experience a DLT.
In Part B (Dose Expansion; Cohorts B1, B2, B3, and B4), the study will evaluate and describe 
whether ibrutinib combined with nivolumab can result in an overall response rate of more than 
20%.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is an open-label Phase 1/2a study, which consists of Part A (Dose Optimization Cohorts) and 
Part B (Expansion Cohorts). In the context of this study, a treatment ‘cycle’ is defined as a course 
of treatment of 14 days starting with the intravenous administration of nivolumab on Day 1 of each 
cycle along with once daily oral intake of ibrutinib on all days. 
It is anticipated that approximately 158 subjects will be enrolled throughout the study; up to 
18 subjects in the dose optimization period (Part A) and approximately 140 subjects during the 
expansion period (Part B).
Figure 1:
Study Design Overview


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Part A (Dose Optimization Cohorts) is designed to determine the RP2D for the combination 
based on safety, pharmacokinetic, and pharmacodynamic assessments. Two dose optimization 
cohorts will be explored, applying the Modified Toxicity Probability Interval (mTPI) design to 
evaluate subjects with relapsed/refractory CLL/SLL or B-NHL.
Part B (Dose Expansion Cohorts) will be open for enrollment after the RP2D is determined in 
Part A. In Part B, further assessment of the RP2D will be explored in 3 subject populations to 
further evaluate the safety and clinical activity of ibrutinib in combination with nivolumab. During 
the expansion period, subjects with CLL/SLL with del 17p or 11q (Cohort B1), FL (Cohort B2), 
DLBCL (Cohort B3), and Richter syndrome (Cohort B4) will be enrolled. Approximately 35 
subjects will be enrolled in each of the expansion cohorts. The subjects will be treated at the RP2D 
level 
selected 
to 
further 
assess 
the 
safety, 
pharmacokinetics, 
pharmacodynamics, 
pharmacogenomics, and activity of the combination.
Part A and Part B of the study will be divided into 3 periods: 

Screening Period: pretreatment screening period of up to 28 days before enrollment

Treatment Period: open-label treatment period ending at the End-of-Treatment Visit 

Follow-up Period: posttreatment follow-up period until the end of study (when all subjects 
have completed the End-of-Treatment Visit). Refer to   Table 1 for a complete list of 
procedures to be performed during the study.
During the Treatment Period, all subjects will be closely monitored for safety. Toxicities (AEs and 
laboratory abnormalities) will be evaluated and graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE Version 4).
Preliminary activity and clinical response will be evaluated every 5 cycles for the first 15 months, 
thereafter every 12 cycles until progression, at the end of treatment, and every 6 months in follow-
up, in the event the subject has not progressed while on therapy and did not start subsequent 
therapy. Lymphoma including Richter syndrome will be evaluated for response according to the 
Lugano Classification (Cheson 2014);12 CLL will be evaluated according to International 
Workshop on Chronic Lymphocytic Leukemia (IWCLL) (Hallek 2008), see Section 10.1.23
Identical methodology should be used for disease assessment at baseline and throughout the course 
of the study.
Subjects will be assigned to receive oral daily doses of ibrutinib (self-administered) in combination 
with intravenous nivolumab on Day 1 of each cycle starting from Dose Level 1 (Table 4). In Cohort 
B1 and B2, to assess pharmacokinetic and pharmacodynamic characteristics of ibrutinib 
monotherapy, ibrutinib will be given at the recommended Phase 2 dose over an initial period of 
seven days prior to the first dose of nivolumab (Day -7 to -1). Refer to the Dosage and 
Administration schedule (Section 6) for further detail. Protocol specified treatment modifications 
for ibrutinib and nivolumab will be implemented as necessary (Section 6.4). Additional dosing or 
schedule changes for ibrutinib or nivolumab can be requested by the Study Evaluation Team (SET) 
based on preliminary clinical data during dose optimization. Doses may be held or reduced based 
on the severity of and the recovery from previous toxicity. Dose re-escalation may be allowed after 


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recovery from toxicity following consultation with the Sponsor. In Part A intra-patient dose 
escalation may be requested by the investigator and discussed with the medical monitor once a 
subsequent higher combination dose has been declared acceptable by the SET for subjects who (1) 
have received at least 4 cycles of combination treatment at the assigned dose level, and (2) have 
not experienced a DLT or therapy-related SAE. Subjects whose dose has been escalated will not 
be considered for the safety evaluation in the subsequent dose level and the determination of the 
RP2D.
The study treatment will be continued until:

documented confirmed disease progression (except in cases of clinical improvement/stability; 
see Section 11.2)

unacceptable toxicity

intercurrent illness that prevents further administration of treatment

subject refuses further therapy

investigator’s decision to withdraw the subject

pregnancy of the subject

noncompliance with study treatment or procedure requirements
The average duration of study therapy is expected to be approximately 6 months.
In Part A of the study, a SET, consisting of the principal investigators, sponsor medical monitors, 
and the sponsor’s clinical pharmacologist, or their designees, and the sponsor statistician will 
review all available data upon completion of the first 2 treatment cycles (ie, 4 weeks of study 
therapy) for all subjects at each dose cohort to determine DLTs, if dose escalation is acceptable, 
and ultimately to determine the recommended Phase 2 dose.
In Part B of the study, all subjects in each cohort may be evaluated for response by the SET and 
additional functional representatives from Janssen, as applicable. The SET along with optional 
other internal members may review safety on an ad hoc basis, and efficacy endpoints (including 
but not limited to ORR). 
The End-of-Treatment Visit will occur within 30 days after the last dose of ibrutinib or nivolumab, 
whichever treatment occurred last.
During the Follow-up Period, long-term safety, survival status, disease progression, subsequent 
anticancer therapy, and occurrence of other primary malignancy data will be collected as well as 
anti-drug antibody (ADA) sampling if applicable. During the Follow-up Period, subjects should 
be followed for safety up to 30 days after the last dose of ibrutinib or 100 days after the last 
nivolumab infusion, whichever is later. The safety follow-up includes adverse event reporting and 
laboratory assessments (at the first follow-up). Thereafter, follow-up visits will be completed 
approximately every 3 months until death or the end of study. Subjects who have developed 
treatment-related Grade 3 or higher toxicity at the end of treatment will be assessed until recovery 
to Grade ≤1 or baseline, deemed irreversible, or until end of study. Adverse events leading to 


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discontinuation will be followed up until resolution or return to baseline, or end of study, 
whichever occur first.
The primary analysis of the study will be performed 6 months after the last subject has received 
the first dose of study medication, or earlier if that subject discontinues study therapy. After the 
cutoff for primary analysis, subjects who are receiving study treatment can continue treatment per 
protocol until progression, unacceptable toxicity, withdrawal of consent, or other reason as listed 
in Section 11.2. End of study is defined as the last subject who completed the EOT Treatment 
assessment.
After the clinical cutoff at a minimum the following data will be collected on eCRF: SAEs and 
AEs Grade ≥3, laboratory assessments (Grade ≥3 or clinically significant), efficacy, survival 
status, and treatment administration. Data collected from the primary analysis until end of study 
will be summarized in a clinical study report addendum. 
3.2.
Study Design Rationale
Rationale for Ibrutinib Dose and Regimen Selection
The recommended monotherapy dose and schedule for ibrutinib is:

CLL/SLL: 420 mg given orally per day 

B-cell malignancies including follicular lymphoma and Richter syndrome: 560 mg given 
orally per day 
The starting dose of ibrutinib will be the recommended monotherapy dose for CLL (420 mg). 
Given that the mechanism of action of ibrutinib and nivolumab are distinct, as well as the fact that 
both compounds have very favorable safety profiles, combination treatment with both compounds 
together is not expected to result in additive toxicity.
In Part A, cohorts of 420 mg/day and 560 mg/day of ibrutinib will be explored as outlined in 
Section 6. Upon recommendation of the SET and in agreement with the study sponsor, additional 
dose cohorts and alternative dosing schedules may be explored. However, the starting dose of 
ibrutinib will not be increased above 560 mg/day or decreased below 420 mg/day.
Rationale for Nivolumab Dose and Regimen Selection
Single-dose pharmacokinetics (PK) of nivolumab were evaluated in 39 subjects with multiple 
tumor types in study MDX1106-01 in the dose range of 0.3 to 10 mg/kg. The median Tmax across 
single doses ranged from 1.6 to 3 hours with individual values ranging from 0.9 to 7 hours. The 
PK of nivolumab is linear in the range of 0.3 to 10 mg/kg with dose proportional increase in Cmax
and AUC(inf) with low to moderate inter-subject variability observed at each dose level (ie, 
coefficient of variation (CV) ranging from 7 to 45%). Geometric mean clearance (CL) after a 
single intravenous (IV) dose ranged from 0.13 to 0.19 mL/h/kg, while mean volume of distribution 
(Vz) varied between 83 to 113 mL/kg across doses. The mean terminal thalf of nivolumab is 17 to 
25 days, which is consistent with the half-life of endogenous IgG4, indicating that the elimination 


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mechanism of nivolumab may be similar to IgG4. Both elimination and distribution of nivolumab 
appear to be independent of dose in the dose range studied.
A preliminary population PK model was developed by nonlinear mixed effect modeling using data 
from 350 subjects from MDX1106-01, MDX1106-02 and CA209003. The body weight 
normalized dosing produces approximately constant trough concentrations over a wide range of 
body weight, and hence is appropriate for future clinical trials of nivolumab. Clearance of 
nivolumab is similar in all tumor types studied and is independent of dose range studied 
(0.1 to 10 mg/kg).
The dose and schedule selected for evaluation in this study, 3 mg/kg every 2 weeks, has been 
evaluated in solid tumors in the ongoing CA209003 study. Nivolumab was adequately tolerated 
up to 10 mg/kg, the highest dose level tested, and no MTD was identified. Anti-tumor activity was 
observed at dose levels ranging from 1 to 10 mg/kg in melanoma, NSCLC, and RCC, as well as at 
dose levels of 0.1 and 0.3 mg/kg in melanoma. The antitumor activity of nivolumab tended to 
increase with dose, as did the incidence of SAEs. The anti-tumor activity of nivolumab in RCC 
was investigated at dose levels of 1 and 10 mg/kg, with the higher activity observed at 10 mg/kg. 
The observed anti-tumor activity in melanoma, and NSCLC was highest at 3 mg/kg, suggesting 
that anti-tumor activity approaches a plateau at dose levels of 3 mg/kg and above. The ongoing 
CA209039 study in hematologic malignancies includes 2 dose levels: 1 mg/kg and 3 mg/kg every 
2 weeks. The 3 mg/kg dose level has been shown to be adequately tolerable and this dose has been 
expanded in select tumor types for further evaluation. Objective responses have been observed at 
both dose levels in study CA209039. Based upon the totality of available data across the program, 
a dose of 3 mg/kg every 2 weeks is selected as the dose anticipated to maximize the benefit-risk 
ratio.
Refer to the current BMS-936558 (nivolumab) Investigator Brochure for additional information.
Rationale for Subject Population
In this study patients will be enrolled (1) whose tumor is amenable to therapy with either ibrutinib 
and/or nivolumab based on efficacy data generated in previous studies but (2) who are in need of 
effective therapies.  This includes patients with CLL/SLL whose disease presents with the 
recurrent chromosomal abnormalities del 17p or del 11q which are associated with rapid 
progression, poor response to chemotherapy, and shorter survival. Similarly, the particular 
populations of patients with relapsed and/or refractory FL, DLBCL or Richter syndrome selected 
for this study are in need of additional effective therapeutic options.
Rationale for Pharmacokinetic Analysis
Pharmacokinetics of ibrutinib and nivolumab when administered in combination will be evaluated 
in this study as specified in Table 2.


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Rationale for Anti-Nivolumab Antibodies
The emergence of antibodies against nivolumab has been low, but as this is a new combination 
treatment regimen the development of anti-drug antibodies will be monitored. Anti-nivolumab 
antibodies will be evaluated in the study as specified in Table 2.
Rationale for Pharmacodynamic and Biomarker Analysis
This study is based on the hypothesis that the combination of these 2 drugs will potentiate each 
other, and therefore the biomarker and pharmacodynamics evaluations are important in 
understanding the mechanism of action of the combination. Biomarker sampling during the course 
of the study will help to examine changes in the immune system and in the tumor. Fine needle 
aspirates from lymph nodes will be collected at baseline and at C3D1 in selected cohorts, in order 
to examine the possible changes in the T-cell subtypes within the tumor microenvironment, as 
these may differ from the peripheral blood compartment. Tumor biopsies obtained at screening 
and post-progression may contribute to understanding the mechanism of resistance to drug 
treatment and may aid in the development of biomarkers to identify subjects in need of additional 
or modified therapy.
Peripheral blood and tumor tissue will be collected prior to therapy and at selected timepoints on 
treatment as outlined in   Table 1 and Table 2 unless restricted by local requirements. 
3.3.
Safety Monitoring
The function and composition of the SET is described in Section 12.7. Upon completion of the 
first 2 cycles for all subjects in each dose cohort, there will be a review of all available safety data 
(at the time of decision-making) by the SET.
Decisions on DLT determination, dose escalations or de-escalations, changes in the timing of 
pharmacokinetic/ADA or pharmacodynamic sampling, exploration of alternative schedule(s), 
cycle duration, or other study conduct recommendations, will be made by the SET and documented 
in a SET decision document and distributed to investigators. The Institutional Review Board (IRB) 
will be notified before implementation of any SET decision, if required. This document will be 
provided in the sponsor’s instruction manual and retained in the study master file and in the study 
center’s files.
3.3.1.
Evaluation of Dose-limiting Toxicity
Dose-limiting toxicities will be assessed during the first and second treatment cycle (ie, first 
28 days of study therapy) starting with the first day of combination therapy (ibrutinib and 
nivolumab). Only AEs that occur during this time period, and after a subject has received at least 
one dose of nivolumab and one dose of ibrutinib, will be considered for DLT. Adverse events 
fulfilling the criteria of DLT need to be reviewed and confirmed by the SET. In addition, all AEs 
occurring while a subject is participating in the study will be reviewed by the SET as part of the 
continued safety evaluation (Section 12.7). All subjects in Part A will be evaluated for DLTs. 
Subjects who are not evaluable for DLT may be replaced; the safety profile of subjects who were 
replaced will be included in the SET review.


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The following AEs considered to have at least a possible relationship to study therapy by the 
investigators and confirmed by the SET will qualify as DLTs:

Any AE that requires discontinuation of study drug (see also Section 6.4.3, Table 8, and 
Table 9)

Any AE that results in a delay of dosing for more than 2 weeks within the DLT period

Central nervous system hemorrhage of any grade.
3.3.2.
Dose Optimization – Part A
During the dose optimization stage, subjects will be entered in each dose level based on a modified 
Toxicity Probability Interval (mTPI) method (Ji and Wang 2013).30 The size of the group can be 
changed as indicated by safety. A minimum of 6 and up to 9 subjects may be treated in each dose 
cohort.
After the last subject in each group has completed treatment in the DLT observation period, the 
SET will evaluate all safety and pharmacokinetic data and make the decision whether to escalate, 
stay at the current dose or de-escalate the dose cohort with the second group of subjects treated, 
based on the guidelines outlined in Attachment 1. 
3.3.3.
Dose Expansion - Part B (Recommended Phase 2 Dose)
The dose for the expansion part of this study (Part B) will be determined based on either:

The highest planned dose (ibrutinib 560 mg daily + nivolumab 3 mg/kg every 2 weeks) in the 
dose optimization schedule

A lower dose determined by the SET following a review of all available safety and efficacy 
data from the dose optimization part of the study (Part A)
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 28 days before administration of the study 
drug. The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues before 
enrolling a subject in the study. Waivers are not allowed. 
For a discussion of the statistical considerations of subject selection, refer to Section 12.3, Sample 
Size Determination.


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4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study.  In 
addition, subjects enrolled to each cohort must satisfy cohort-specific criteria as listed below.
1.
Subject must be 18 years of age or older.
2. 
Eastern Cooperative Oncology Group (ECOG) performance status grade 0, 1, or 2 
(Attachment 4)
3.
Adequate bone marrow, liver, and renal function defined as:

Absolute neutrophil count (ANC) ≥1.5 x 109cells/L (ie, ≥1500/ µL).  

Platelets ≥75 x 109cells/L (ie, ≥75,000/µL) without transfusion support within
7 days prior to test.

Hemoglobin ≥8g/dL  without transfusion support within 7 days prior to test

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x 
upper limit of normal (ULN)

Total bilirubin <2mg/dL (unless due to Gilbert’s syndrome).

Creatinine determined by serum creatinine levels ≤1.5 x ULN or a calculated 
creatinine clearance of ≥50 mL/min/1.73 m2 (see Attachment 2 for Modified Diet 
in Renal Disease [MDRD] formula)
4.
Women of childbearing potential (WOCBP) and men who are sexually active with a 
woman of childbearing potential must be practicing a highly effective method of birth 
control during and after the study, consistent with local regulations regarding the use of 
birth control methods for subjects participating in clinical studies. These restrictions 
apply for the duration of treatment with study drug plus 5 half-lives of study drug plus 
30 days (duration of ovulatory cycle) for a total of 23 weeks post nivolumab treatment 
or 3 months post ibrutinib completion (whichever occurs last).
5.
Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug plus 5 
half-lives of study drug plus 90 days (duration of sperm turnover) for a total of 31 weeks 
post nivolumab treatment or 12 weeks post ibrutinib completion (whichever occurs 
last).
6.
Women of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the 
start of study drug.


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7.
Men must agree to not donate sperm during or for a total of 31 weeks post nivolumab 
treatment or 3 months post ibrutinib completion (whichever occurs last) and a woman 
must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction 
during or for a total of 23 weeks post nivolumab treatment or 3 months post ibrutinib 
completion (whichever occurs last).
8.
Must sign (or their legally-acceptable representatives must sign) an informed consent 
document indicating that they understand the purpose of and procedures required for 
the study, including biomarkers, and are willing to participate in the study.
9.
Subject is able to swallow capsules and is able to take or tolerate oral medications on a 
continuous basis.
4.1.1.
Additional Inclusion Criteria for Part A: Dose Optimization Cohorts
10.
Histologically confirmed and documented B-NHL (FL and DLBCL) or CLL/SLL 
(deletion 17p or deletion 11q as determined by FISH analysis) as conducted by the local 
lab.
11.
Relapsed or refractory disease after at least 1 but not more than 4 lines of prior, systemic 
therapy.
12.
Measurable disease defined as: 

B-NHL: At least 1 measurable site of disease according to the Lugano 
Classification (see Attachment 6.2). The site of disease must be greater than 
1.5 cm in the long axis regardless of short axis measurement or greater than 1.0 
cm in the short axis regardless of long axis measurement, and clearly measurable 
in 2 perpendicular dimensions

CLL: ≥5,000 leukemia cells/μL
4.1.2.
Additional Inclusion Criteria for Part B: Expansion Cohorts
Cohort B1: Chronic Lymphocytic Leukemia/or Small Lymphocytic Lymphoma
13.
Criterion modified per amendment
13.1 Diagnosis of CLL requires the following:

Lymphocytosis with ≥5,000 B-lymphocytes/µL.

Prolymphocytes ≤55% of total blood lymphocytes.
14.
Criterion modified per amendment
14.1 Diagnosis of SLL requires measurable disease


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15.
Criterion modified per amendment
15.1 CLL/SLL with deletion of short arm of chromosome 17 ie, del(17p13.1) or 
deletion of the long arm of chromosome 11 ie, del(11q21-q23) as defined by del 
(17p) or del (11q) in ≥20% of cells based on interphase FISH and documented in 
subject’s record prior to start of study therapy.
16.
Criterion modified per amendment
16.1 Relapsed or refractory CLL/SLL following at least 1 prior line of systemic therapy 
(consisting of at least 2 cycles of a chemotherapy containing regimen)
17.
Active disease meeting at least 1 of the criteria outlined by the IWCLL 
(Attachment 6.1):

Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia or thrombocytopenia

Massive (ie, at least 6 cm below the left costal margin), progressive, or 
symptomatic splenomegaly

Massive nodes (ie, at least 10 cm in longest diameter), progressive, or symptomatic 
lymphadenopathy

Progressive lymphocytosis with an increase of more than 50% over a 2-month 
period or a lymphocyte doubling time (LDT) of less than 6 months (which may be 
extrapolated). Lymphocyte doubling time can be obtained by linear regression 
extrapolation of absolute lymphocyte count (ALC) obtained at intervals of 2 weeks 
over an observation period of 2 to 3 months. For patients with initial ALC of less 
than 30 x 109/L (30,000/µL), LDT should not be used as a single parameter to 
define indication for treatment. In addition, factors contributing to lymphocytosis 
or lymphadenopathy other than CLL (eg, infections) should be excluded

Constitutional symptoms, defined as 1 or more of the following disease-related 
symptoms or signs:

Unintentional weight loss of >10% within the previous 6 months prior to 
screening

Significant fatigue (inability to work or perform usual activities)

Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without evidence 
of infection; or

Night sweats for more than 1 month without evidence of infection


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Cohort B2: Follicular Lymphoma
18.
Histologically confirmed initial diagnosis of FL of Grade 1, 2, or 3a according to World 
Health Organization (WHO) criteria without pathological evidence of transformation.
19.
Relapsed or refractory disease defined as:

Previously treated with at least 2 prior lines of therapy using different treatment 
regimens and separated by disease progression or relapse

Received or not eligible for prior treatment with a CD20 antibody combination 
chemotherapy regimen
20.
At least 1 measurable site of disease according to the Lugano Classification 
(Attachment 6.2).
Cohort B3: Diffuse Large B-cell Lymphoma
21.
Histologically-confirmed DLBCL.
22.
Previously treated with a standard, rituximab and anthracycline-containing systemic 
chemotherapy regimen (such as R-CHOP), or
Received or not eligible for high-dose chemotherapy and autologous stem cell 
transplantation (HD-ASCT)
Of Note: Additional, prior salvage chemotherapy regimens are allowed
23.
At least 1 measurable site of disease based on the Revised Response Criteria for 
Malignant Lymphoma (Attachment 6.2).
Cohort B4: Richter Syndrome
24.
Histologically-confirmed Richter syndrome defined as transformation of CLL or SLL 
into an aggressive lymphoma
25.
Previously treated with at least one line of standard, systemic chemotherapy or not 
eligible for standard therapy
26.
At least 1 measurable site of disease based on the Revised Response Criteria for 
Malignant Lymphoma (Attachment 6.2).


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4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1. 
Major surgery within 4 weeks of the first dose of ibrutinib.
2.
Diagnosed or treated for malignancy other than the indication under study except for:

Malignancy treated with curative intent and with no known active disease present 
for ≥3 years before the first dose of ibrutinib or nivolumab

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease

Adequately treated cervical carcinoma in situ without evidence of disease
3.
History of stroke or intracranial hemorrhage within 6 months prior to the first dose of 
ibrutinib.
4.
Requires anticoagulation with warfarin or equivalent vitamin K antagonists 
(eg, phenprocoumon).
5.
Requires treatment with strong CYP3A inhibitors (Attachment 8).
6
Criterion modified per amendment 1
6.1 Clinically significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the 
New York Heart Association Functional Classification (Attachment 3), or congenital long 
QT syndrome, or QT interval corrected for heart rate, using Fridericia formula21 (QTcF) 
at Screening >470 ms.
7.

Subjects with a history of Human Immunodeficiency Virus (HIV) 

Subjects who have active infection or are chronic carriers of Hepatitis B or 
Hepatitis C.
8.
History of disallowed therapies:

Prior treatment/exposure with ibrutinib or other BTK inhibitor

Prior exposure to anti-PD1, anti-PDL1, anti-PD-L2, anti-CD137 or anti-cytotoxic 
T-lymphocyte associated antigen 4 (CTLA-4) antibody 

Concurrent enrollment in another therapeutic investigational clinical study


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9.
Prior anti-tumor therapy including (all times measured prior to start of study therapy)

nitrosoureas within 6 weeks

chemotherapy within 3 weeks 

therapeutic antibodies within 4 weeks

radio- or toxin-immunoconjugates within 10 weeks

radiation therapy within 3 weeks

investigational agents within 3 weeks

carmustine (BCNU) 1000 mg received as part of pre-transplant conditioning  
regimen

chest radiation 24 weeks prior to first dose of the study drug
10.
Criterion revised per Amendment 4
10.1 Known central nervous system (CNS) lymphoma.
11.
Received an allogeneic hematopoietic SCT.
12.
Any uncontrolled active systemic infection, active non-infectious pneumonitis, evidence 
or history of interstitial lung disease, or any life-threatening illness, medical condition, or 
organ system dysfunction which, in the investigator’s opinion, could compromise the 
subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put 
the study outcomes at undue risk.
13.
Any active autoimmune disease or a documented history of autoimmune disease 
(excluded/exception to the rule: subjects with vitiligo or resolved childhood 
asthma/atopy, type I diabetes mellitus, subjects with hypothyroidisms stable on hormone 
replacement, Sjorgen’s syndrome, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger).
14.
Any syndrome that requires systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalents) or other immunosuppressive medications within 14 days of study 
drug administration. Of note: Inhaled or topical steroids, and adrenal replacement doses 
> 10 mg daily prednisone equivalents, are permitted in the absence of active autoimmune 
disease.
15.
A woman who is pregnant or breast feeding.
16.
Subject is or has an immediate family member (spouse or children) who is investigational 
site or sponsor staff directly involved with this trial, unless prospective IRB approval 
(by chair or designee) is given allowing exception to this criterion for a specific subject.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's status changes (including laboratory results or receipt of additional medical records) 


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after screening but before the first dose of study drug is given such that he or she no longer meets 
all eligibility criteria, the subject may be re-evaluated at a later timepoint to assess eligibility. 
4.3.
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and restrictions 
during the course of the study to be eligible for participation:
1.
Requires surgery or invasive procedures:

For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 
and nivolumab should be held at least 7 days prior to the intervention and should be 
held at least 7 days after the procedure, and restarted at the discretion of the investigator 
when the surgical site is reasonably healed without serosanguineous drainage or the 
need for drainage tubes

For minor procedures (such as a central line placement, tissue or needle biopsy, 
thoracentesis, or paracentesis) ibrutinib and nivolumab should be held for at least 
3 days prior to the procedure and should not be restarted for at least 3 days after the 
procedure. For bone marrow biopsies that are performed while the subject is on 
ibrutinib, it is not necessary to hold ibrutinib for these procedures

For emergency procedures, ibrutinib and nivolumab should be held after the procedure 
until the surgical site is reasonably healed, for at least 7 days after the urgent surgical 
procedure
2.
Foods or beverages containing grapefruit or Seville oranges should be avoided, as these 
contain certain ingredients that inhibit CYP3A.
3.
Prohibited medications and precautions with concomitant medications as detailed in 
Section 9.
5.
TREATMENT ALLOCATION AND BLINDING
Randomization will not be used in this study. Subjects will be sequentially assigned to treatment. 
No blinding is required as this is an open-label study. All subjects enrolled will receive open-label 
treatment with ibrutinib capsules and nivolumab infusions.
6.
DOSAGE AND ADMINISTRATION
6.1.
Study Treatment Administration
For the purposes of this study, ‘study drug’ or ‘study therapy’ refers to both ibrutinib and/or 
nivolumab. All dosing information must be recorded in the Dosage Administration page of the 
eCRF. A treatment and study design scheme is provided in Figure 1.
The duration of each treatment cycle is 14 days. Day 1 or start day of a new cycle is triggered by 
the infusion of nivolumab. The cycle duration may be changed based on decision by the SET 
(Section 3.3). Study drugs will be administered until disease progression or unacceptable toxicity, 






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There is limited data on the effects of ibrutinib overdose.  No Maximum Tolerated Dose was 
reached in the Phase 1 study in which patients received up to 12.5 mg/kg/day (1,400 mg).  There 
is no specific antidote for ibrutinib.  Subjects who ingest more than the recommended dosage 
should be closely monitored and given appropriate supportive treatment.
6.3.
Nivolumab Administration
Eligible subjects will receive treatment with nivolumab at a dose of 3 mg/kg given as a 60-minute 
IV infusion on Day 1 of every 14-day cycle. If the subject’s weight on the day of dosing differs by 
> 10% from the weight used to calculate the dose, the dose must be recalculated. All doses should 
be rounded to the nearest milligram.
There are no premedications recommended for nivolumab on the first cycle. If an acute infusion 
reaction is noted, subjects should be managed according to guidelines provided in Section 8.11.
Subjects may receive nivolumab infusions with no less than 12 days between doses and no more 
than 3 days after the scheduled dosing date. A dose given after the 3-day window is considered a 
dose delay. A maximum delay of 42 days between doses is allowed.
6.3.1.
Interactive Web Response System
Drug supply for nivolumab will be managed through IWRS at least for Part B. 
For IWRS, 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. Details on the use of IWRS will be provided in the IWRS manual. 
The subject should receive their dose of study medication within 1 day of vial assignment 
following call to IWRS.
6.4.
Dose Modifications
Treatment modifications may be made to both ibrutinib and nivolumab. Changes in dose apply 
only to ibrutinib. Nivolumab will be given at fixed dose, treatment modifications are primarily 
dose delays.
Adjustments of study drug dose should be overseen by the principal- or sub-investigator(s) unless 
an immediate safety risk is apparent. The dose adjustments are applicable to all subsequent 
treatment cycles.
Note: The recommendation to discontinue study therapy applies to both study drugs. If appropriate 
and after consultation with the Sponsor, subjects may receive ibrutinib alone. Following 
implementation of amendment 7, treatment with single agent ibrutinib will be discontinued and an 
End of Trial visit will be performed for patients not scheduled to rollover into long-term extension 
study CAN3001. Patients scheduled to roll over into Study CAN3001 will continue treatment. 












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provide additional instruction to reeducate any subject who is not compliant with the ibrutinib 
schedule. 
Nivolumab will be administered as an IV infusion by qualified study-site personnel and the details 
of each administration will be recorded in the eCRF; date, start and stop time of the infusions, 
dose, volume infused. 
The site pharmacist will maintain a log of all nivolumab vials prepared for infusion and 
administration and all ibrutinib dispensed and returned. Drug supplies for each subject will be 
inventoried and accounted for throughout the study. 
8.
GUIDELINES FOR MANAGEMENT OF IMMUNE RELATED ADVERSE 
EVENTS AND ADVERSE EVENTS OF CLINICAL INTEREST
Therapy with immuno-oncology agents such as nivolumab can lead to specific immune-related 
adverse events (eg, irAE) that differ in nature, severity and duration as compared to adverse events 
caused by agents with a different mode of action. A detailed summary of the irAE observed in the 
nivolumab program can be found in the IB. 
Early recognition and management of these irAE may mitigate more severe toxicity. However, 
differential diagnoses including non-inflammatory etiologies as well as the impact of the 
underlying malignant disease and/or concomitant medication should be evaluated according to 
standard medical practice. 
Management algorithms have been developed to assist investigators in assessing and managing 
specific irAE and additional details on these management algorithms can be found in the 
Nivolumab Investigator’s Brochure, Appendix 2 “Management Algorithms”.
Of note: Guidelines for dose modifications are provided in Section 6.4.3.
8.1.
Gastrointestinal AE
Diarrhea and colitis have been observed in subjects receiving nivolumab. Early recognition and 
treatment of diarrhea and colitis are critical to their management. Subjects should be advised to 
seek immediate medical evaluation if they develop new-onset diarrhea, blood in stool, or severe 
abdominal pain or if they have worsening of baseline diarrhea. In subjects with pre-existing 
diverticulosis and/or diverticulitis receiving concomitant medication with corticosteroids, non-
steroidal anti-inflammatory drugs (NSAIDs), and opioid analgesics together with nivolumab, 
diverticular perforation has been observed.














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9.
CONCOMITANT THERAPY
Concomitant medications and any medications used to treat or support AEs will be collected in 
the eCRF and recorded in the source documents throughout the study beginning with signing of 
informed consent form to 30 days after the last dose of ibrutinib, 100 days after the last dose of 
nivolumab, or, afterwards, during the follow-up of a related SAE (if applicable). Otherwise, in 
Follow-up Period, only subsequent anti-lymphoma/neoplastic therapy should be documented (see 
Section 9.5). The sponsor must be notified in advance (or as soon as possible thereafter) of any 
instances in which prohibited therapies are administered (eg, CYP3A inhibitors, vitamin K 
antagonists). All medications (prescriptions or over the counter medications) continued at the start 
of the study or started during the study and different from the study drug must be documented in 
the concomitant therapy section of the eCRF.
9.1.
Supportive Care
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids are permitted, even if >10 mg/day prednisone equivalents. A brief course of 
corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
9.2.
Permitted Medications
All concomitant medications (except those listed in Section 9.3) for medical conditions other than 
those investigated in the study are permitted, as clinically indicated. For subjects receiving prostate 
cancer androgen-deprivation-therapy (ADT) prior to the enrollment into the study may be 
continued upon consultation and in agreement with the medical monitor. The use of growth factors 
and transfusion is permitted in this study according to institutional or other guidelines (eg, 
American Society of Clinical Oncology guidelines, Ozer 2000).44 However, prophylactic use 
during the DLT evaluation period in Part A is not permitted. The use of glucocorticoids is allowed 
for clinical management of AEs. However, inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks is a reason for discontinuation of study 
therapy.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
There were isolated cases of leukostasis reported in patients treated with ibrutinib. Subjects at risk 
of leukostasis (>400000/mm3 circulating lymphocytes) should be closely monitored and 
supportive care such as hydration and/or leukapheresis administered as indicated. Ibrutinib may 
be temporarily held and the medical monitor should be contacted.










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10.2.1.1.
Circumstances in which Post-progression Treatment is Permitted
Subjects meeting progression defined by relapsed disease (after CR) or progressive disease (after 
PR, SD) may continue receiving study medication beyond investigator assessed progression as 
long as they meet the following criteria:

Continue to meet all other study protocol eligibility criteria

Investigator-assessed clinical benefit, and do not have rapid disease progression 

Stable performance status 

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression 

Patients will be re-consented with an informed consent document describing any reasonably 
foreseeable risks or discomfort and other alternative treatment options 

Tolerance of study therapy 
The decision to continue treatment beyond investigator-assessed progression should be discussed 
with the Sponsor and documented in the study records. The assessment of clinical benefit should 
take into account whether the subject is clinically deteriorating and unlikely to receive further 
benefit from continued treatment.
10.2.1.2.
Assessments for Subjects with Post-progression Treatment
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden volume from time of initial progression 
(including all target lesions and new measurable lesions). 
Further progression is evaluated by a subsequent CT or MRI which is performed at least 4 weeks 
from previous CT or MRI. The tumor burden volume from time of initial progression should be 
used as the reference baseline for comparison with the post-progression assessment.
New lesions are considered measurable at the time of initial progression if the long axis is more 
than 15 mm regardless of the short axis. If a lymph node has a long axis of 11 to 15 mm, it should 
only be considered measurable if its short axis is more than 10 mm.
Any new lesion considered non-measurable at the time of or after initial progression may become 
measurable and therefore included in the tumor burden determination.
10.2.1.3.
Radiographic Assessment for Subjects who Discontinue Study Drug 
during Post-progression Treatment
For subjects that discontinue post-progression treatment, no additional radiographic assessments 
will be required. Upon treatment discontinuation, these subjects will continue in the Follow-up 
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10.3.
Pharmacokinetics 
10.3.1.
Sample Collection
The Laboratory Manual provides further information regarding handling and shipment of blood 
samples. Pharmacokinetic assessments will not be conducted post clinical cutoff. Following 
implementation of amendment 7, collection of PD or PK samples will no longer be required.  
10.3.2.
Evaluations 
Blood samples will be collected from all subjects for determination of plasma concentrations of 
ibrutinib and the PCI-45227 metabolite (if possible and judged relevant), as well as serum 
concentrations of nivolumab according to the Time and Events Schedule (Table 2). These sparse 
samples may be used for the development of a population-based pharmacokinetic model. 
Samples for pharmacokinetic and immunogenicity assessment will be collected for all subjects 
receiving nivolumab. Table 2 lists the sampling schedule to be followed for pharmacokinetics and 
immunogenicity. All timepoints are relative to the start of study drug administration. All on 
treatment PK timepoints are intended to align with days on which study drug is administered. If it 
is known that a dose is going to be delayed, then the predose sample should be collected just prior 
to the delayed dose. However, if a predose sample is collected, but the dose is subsequently 
delayed, an additional predose sample should not be collected. Further details of blood collection 
and processing will be provided in the procedure manual. 
10.3.3.
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of ibrutinib and the metabolite PCI-
45227 using a validated, specific, and sensitive LC-MS/MS method by or under the supervision 
of the sponsor.  If required, some plasma samples may be analyzed to document the presence of 
circulating metabolites using a qualified research method.
Serum samples will be analyzed for nivolumab by a validated method. In addition, selected serum 
samples may be analyzed by an exploratory analytical method that measures nivolumab for 
technology exploration purposes; exploratory results will not be reported.
10.3.4.
Pharmacokinetic Parameters 
Population pharmacokinetic analysis of plasma/serum concentration-time data of ibrutinib and 
nivolumab may be performed using nonlinear mixed-effects modeling (NONMEM), with the aim 
of providing estimates of pharmacokinetic parameters (eg, oral clearance) or metrics of systemic 
exposure (eg, area under the plasma/serum concentration-time curve within the dosing interval). 
Model-derived plasma/serum concentrations or metrics of exposure parameters (eg, Cmax or AUC) 
may be subjected to further analyses to explore pharmacokinetic correlation between exposure and 
relevant clinical or biomarker information.
If deemed useful, Cmax and partial AUCs for ibrutinib and the dihydrodiol metabolite PCI-45227 
may be derived using non-compartmental analysis, as well as metabolite/parent ratios.










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Subjects should rest in a supine position for at least 5 minutes before ECG collection and should 
refrain from talking or moving arms or legs. Twelve-lead ECGs will be recorded at a paper speed 
of 25 mm per second until 4 regular consecutive complexes are available. The ECGs will be 
performed and interpreted by qualified site personnel. The results must be recorded and filed in 
the source documents.
If vital signs or blood draws are scheduled at the same time points as ECG recordings, the sequence 
of procedures should be as follows: ECG first, vital signs measurement second, and any type of 
blood draw (eg, PK, safety, biomarker) third.
The measured QT data will be corrected for heart rate using Fridericia (QTcF) correction method,21
according to the following formula/method (with QT, RR and QTc expressed in ms):

Fridericia Correction21
Vital Signs 
Temperature, heart rate, blood pressure, and pulse oximetry will be recorded at the following 
times: Screening, prior to and within 1 hour after each nivolumab infusion, at the end of treatment, 
and as clinically indicated. Blood pressure and heart rate measurements should be preceded by at 
least 5 minutes of rest in a quiet setting without distractions (eg, television, cell phones).
Physical Examination 
A full physical examination will be performed at screening. Subsequently, directed physical 
examination (includes all organ systems that were previously abnormal or involved with disease 
and documentation of any clinically relevant abnormalities in any organ) will be performed at the 
timepoints specified in the Time and Events Schedule (  Table 1). Height will be measured at 
Screening only; weight will be periodically measured. Lymphoma symptoms reported at screening 
should be reviewed and recorded during the directed physical examination.
Renal Toxicity Evaluation
The glomerular filtration rate (GFR) will be determined according to Modified Diet in Renal 
Disease Formula (Attachment 2).  The GFR will be evaluated at screening and as clinically 
indicated.
ECOG Performance Status
The ECOG performance status scale will be used to grade changes in the subject’s daily living 
activities. ECOG performance status scale is provided in Attachment 4. The frequency of ECOG 
performance status assessment is provided in   Table 1.


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11.
SUBJECT COMPLETION/TREATMENT DISCONTINUATION/WITHDRAWAL
11.1.
Completion
A subject will be considered to have completed the study if he or she has died, has not been lost to 
follow up, or has not withdrawn consent from the study at the time when the primary analysis will 
be conducted (6 months after the last patient’s first dose).
11.2.
Discontinuation of Study Treatment 
If a subject's study treatment must be discontinued, this will not result in automatic withdrawal of 
the subject from the study. 
Study treatment should be discontinued if:

The investigator believes that for safety reasons (eg, AE, for criteria that require 
discontinuation, please refer to Table 8 and Table 9 in Section 6.4.3) it is in the best interest 
of the subject to discontinue study treatment

The subject becomes pregnant

The subject experiences overt disease progression or relapse 

Unacceptable toxicity

Treatment interruption of >6 weeks (unless otherwise approved by the Sponsor for non-drug 
related reasons)

The subject refuses further treatment 

A serious protocol violation has occurred, as determined by the principal investigator or the 
sponsor
If a subject discontinues study treatment before the onset of disease progression, end of treatment 
and posttreatment assessments should be obtained and follow-up of scheduled assessments should 
be continued, including assessment of anti-nivolumab antibodies and nivolumab exposure 100 
days after discontinuation of nivolumab. The reason(s) a subject discontinues treatment will be 
recorded on the eCRF.
11.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

The sponsor discontinues the study
If a subject is lost to follow-up, every reasonable effort must be made by the study-site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. If a subject discontinues study treatment and 


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withdraws from the study before the onset of disease progression, end-of-treatment and 
post-treatment assessments should be obtained. If the reason for withdrawal from the study is 
withdrawal of consent then no additional assessments are allowed.
12.
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. 
Summary statistics for continuous variables will include the mean, standard deviation, median, 
and range. Categorical data will be presented as frequencies and percentages.
12.1.
Subject Information
The analysis populations for this study are defined as: 

The Treated Population will consist of all subjects who receive at least 1 dose of study drug 
(either ibrutinib or nivolumab). The Treated Population will be used for all safety and efficacy 
analysis unless otherwise stated. 

The Response Evaluable Population will consist of all subjects who receive at least 1 dose of 
both study drugs (ibrutinib and nivolumab), and have a pretreatment, and at least 
1 posttreatment disease assessment; unless no post-baseline scan was performed due to AE 
possibly related to treatment.

The Pharmacokinetic/Pharmacodynamic Population will consist of all subjects who receive at 
least 1 dose of study drug (either ibrutinib or nivolumab) and have at least 1 posttreatment 
sample collected during treatment to determine the concentration or pharmacodynamic 
biomarker response.
12.2.
Safety Analyses 
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the most 
current version of the Medical Dictionary for Regulatory Activities (MedDRA). Toxicities will be 
graded for severity according to NCI-CTCAE, version 4. All reported AEs with onset during the 
Treatment Period (ie, treatment-emergent adverse events [TEAEs], and AEs that have worsened 
since baseline) will be included in the analysis. 
Specifically, the following will be summarized:

Incidence of DLT (Part A)

All adverse events

Grade 3 or higher adverse events

Serious adverse events

Adverse events leading to discontinuation of treatment


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
Adverse events leading to death

Adverse events of special interest
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline. 
Parameters with predefined toxicity grades will be summarized. Change from baseline to the worst 
grade experienced by the subject during the study will be provided as shift tables.
Vital Signs
Descriptive statistics of heart rate and blood pressure (systolic and diastolic) (supine) values and 
changes from baseline will be summarized. The percentage of subjects with clinically important 
changes from baseline will be summarized.
12.3.
Sample Size Determination
This is a Phase 1/2a dose optimization and expansion study. For Part A, a statistical design based 
on the approach described in Ji, et al. (2010)30 and Ji and Wang (2013)29,30 will be used. This 
method requires a definition of an equivalence interval (EI), [0.25; 0.30], in which any dose is 
considered as a potential candidate for the true MTD, where 0.30 is the targeted DLT rate. Defining 
an EI results in the partition of the unit interval (0, 1) into 3 subintervals; (0; 0.25), [0.25, 0.30], 
and (0.30; 1). Doses in these 3 intervals are deemed lower, close to, and higher than the MTD, 
respectively. At least 6, and up to 9 subjects may be treated in each cohort in Part A. Approximately 
18 subjects may be enrolled in Part A.
Part B, Cohorts B1 (CLL/SLL), B2 (FL), B3 (DLBCL), and B4 (Richter syndrome) are designed 
to evaluate the feasibility and safety of treating subjects with ibrutinib in combination with 
nivolumab and to evaluate preliminary activity. The sample size is calculated based on the 
following assumptions (denoting the true response rate of ibrutinib in combination with nivolumab 
as p):

The overall response rate under null hypothesis is 20% 

The overall  response rate under alternative hypothesis is at least 38% 

The probability to mistakenly rejecting the null hypothesis when it is actually true is 0.1 (one-
sided). 

The probability to correctly rejecting null hypothesis when alternative hypothesis is true is at 
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Under the above assumptions, the study will enroll approximately 35 subjects to get at least 
32 response-evaluable subjects in each cohort of Part B (dose expansion; Cohorts B1, B2, B3, and 
B4). 
Approximately 158 subjects (with up to 18 subjects in Part A and approximately 140 subjects in 
the Part B, dose expansion) will be enrolled in this study.
12.4.
Efficacy Analyses
Part A: Individual best tumor responses and duration of response (defined as the time from first 
response to progression) will be listed for each dose cohort.
Part B: The following efficacy analyses will be performed to explore the clinical activity of 
ibrutinib in combination with nivolumab in each cohort in the treated population unless otherwise 
stated: 

Overall response rate (CR or PR) will be calculated with 95% CI for each disease-specific 
cohort B1, B2, B3, and B4 on the response-evaluable population.

Progression-free survival and overall survival at 1 year will be evaluated using Kaplan-Meier 
method. 

Duration of response and duration of stable disease will be evaluated if there are sufficient 
data for responders within each cohort.
12.5.
Pharmacokinetic Analyses 
The plasma concentration data for ibrutinib and, if possible and judged relevant, the metabolite 
PCI-45227, and serum concentrations of nivolumab at each timepoint will be summarized using 
descriptive statistics. Ibrutinib and nivolumab data will be listed by dose cohort for all subjects 
with available plasma/serum concentrations. Subjects will be excluded from the pharmacokinetic 
analysis if their data do not allow for accurate assessment of the pharmacokinetic (eg, incomplete 
administration of the study agent; concentration data not sufficient for pharmacokinetic parameter 
calculation due to missing pharmacokinetic draws at multiple visits; or early discontinuation from 
the study).
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration data presentation. Concentrations below the lowest quantifiable 
concentration will be treated as zero in the summary statistics and for the calculation of 
pharmacokinetic parameters. All subjects and samples excluded from the analysis will be clearly 
documented in the study report.
If non-compartmental analysis for ibrutinib/PCI-45227 is performed, results will be summarized 
using descriptive statistics.
Population pharmacokinetic analysis of ibrutinib plasma concentration-time data may be 
performed using NONMEM. Data may be combined with data from other studies to support a 
relevant structural population-based pharmacokinetic model. Available subject characteristics 


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(demographics, laboratory variables, genotypes, etc.) will be tested as potential covariates 
affecting pharmacokinetic parameters. 
Model-derived 
exposure 
parameters 
may 
be 
subjected 
to 
further 
explore 
pharmacokinetic/pharmacodynamic correlation between exposure with relevant clinical or 
biomarker information.
Ibrutinib and nivolumab concentration data may be compared to observed concentration data 
and/or concentration estimates from the existing population PK models of ibrutinib/nivolumab, as 
appropriate. 
If additional population PK analyses of ibrutinib and/or nivolumab are performed using data from 
this study, the results relevant for this study will be communicated, but an additional modeling 
report may be generated and will not be part of the study report for this study.
12.6.
Biomarker Analyses 
Analyses are planned to identify biomarkers that are indicative of the mechanisms of action of the 
drug or predictive of efficacy for the combination.  The associations of biomarkers with clinical 
response or time-to-event endpoints will be assessed using the appropriate statistical methods 
(analysis of variance [ANOVA], categorical, or survival model), depending on the endpoint.  
Correlation of baseline expression levels or changes in expression levels with response or time-to-
event endpoints will identify responsive (or resistant) subgroups.
12.7.
Study Evaluation Team
The SET will monitor data on an ongoing basis during dose optimization to ensure the continuing 
safety of the subjects enrolled in the study. The SET will consist of the principal investigators, 
sponsor medical monitors, the sponsor’s clinical pharmacologist, or their designees, and the 
sponsor’s statistician. Medical safety assessment representatives or other functions experts will be 
consulted as needed.
The SET will convene regularly; and at a minimum after each dose level completes the DLT 
assessment period. The SET may convene at additional times for data review or for any 
safety-related issues; a SET meeting can be requested by any SET member. In addition the SET 
and additional functional representatives from Janssen, as applicable, may review the data for 
expansion cohorts (Part B) for the efficacy endpoints including but not limited to ORR along with 
any safety concerns.
See Section 3.3 for further details on the SET decision-making process.
13.
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 


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information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events or serious adverse events. 
Open-ended and nonleading verbal questioning of the subject is the preferred method to inquire 
about adverse event occurrence. 
Solicited Adverse Events
Solicited adverse events are predefined local and systemic events for which the subject is 
specifically questioned.
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the subject is specifically not 
questioned.
13.1.
Definitions
13.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 13.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:


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
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

Development of a new malignancy that is not associated with the disease under study

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.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must be 
reported as a serious and unexpected suspected adverse reaction even if it is a component of the 
study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For ibrutinib and nivolumab, the expectedness of an adverse 
event will be determined by whether or not it is listed in the respective Investigator's Brochure. 
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 13.1.2.
13.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.


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Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s), 
concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in 
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
13.1.3.
Severity Criteria
The severity assessment for an adverse event or serious adverse event should be completed using 
the NCI CTCAE Version 4. Any adverse event or serious adverse event not listed in the 
NCI CTCAE Version 4 will be graded according to 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 of disabling adverse event
Grade 5: Death related to the adverse event
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
13.2.
Special Reporting Situations
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.


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13.2.1.
Nivolumab
For instructions on how to handle events of clinical interest related to nivolumab, please refer to 
Section 8 and the nivolumab Investigator’s Brochure, Appendix 2. These events (Grade ≥3) will 
be reported using the same timelines used for reporting SAEs. These events include:

Colitis

Endocrine

Uveitis

Hepatic

Pneumonitis

Renal 

Skin

Immune-related AEs
13.2.2.
Other
Other safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to the 
sponsor study drug, eg, name confusion)
13.3.
Procedures
13.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until 30 days after the last dose of ibrutinib or 
100 days after the last nivolumab infusion, whichever is later. Afterwards, report only SAEs that 
are at least possibly related to study treatment. After the clinical cutoff, only SAEs and Grade ≥3 
AEs will be collected. Serious adverse events, including those spontaneously reported to the 
investigator within 30 days after the last dose of study therapy, 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.
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to Section 13.1.1). 
Death should not be recorded as an adverse event or serious adverse event, but as the outcome of 
an adverse event. The event that resulted in the death should be reported as a serious adverse event. 


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All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and eCRF; reporting on  
eCRF after CCO (per amendment #6 and 7 further revisions apply per Table 1[collection of SAEs 
and Grade ≥3 AEs, AEs leading to discontinuation or modification, laboratory assessments {Grade 
≥3 or clinically significant}]). 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 adverse event to study therapy. All measures 
required for adverse event management must be recorded in the source document and reported 
according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse events that are unlisted 
(unexpected) and associated with the use of the study drug. The investigator (or sponsor where 
required) must report these events to the appropriate Independent Ethics Committee/Institutional 
Review Board (IEC/IRB) that approved the protocol unless otherwise required and documented 
by the IEC/IRB. 
For all studies with an outpatient phase, the subject must be provided with a "wallet (study) card" 
and instructed to carry this card with them for the duration of the study indicating the following: 

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number
13.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, and 
transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious adverse 
event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the subject's participation in the study, must be followed until any of the 
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
The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious 
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs 
during the course of a subject's participation in a study must be reported as a serious adverse event, 
except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the eCRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.
13.3.3.
Adverse Events of Special Interest (AESI)
Specific adverse events or groups of adverse events will be followed as part of standard safety 
monitoring activities by the Sponsor. These events will be reported to the sponsor within 24 hours 
of awareness irrespective of seriousness (ie, serious and nonserious adverse events) following the 
procedure described above for serious adverse events and will require enhanced data collection.  
13.3.3.1.
Major Hemorrhage
Major hemorrhage is defined as: Treatment-emergent hemorrhagic adverse events of Grade 3 or 
higher. 

Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher. All hemorrhagic 
events requiring a transfusion of red blood cells should be reported as Grade 3 or higher AE 
per CTCAE. 

Any treatment-emergent serious adverse event of bleeding of any grade. 

Any treatment-emergent central nervous system hemorrhage/hematoma of any grade.


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13.3.4.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported to 
the sponsor by the study-site personnel within 24 hours of their knowledge of the event using the 
appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, and congenital anomalies, ectopic pregnancy) are considered 
serious adverse events and must be reported using the Serious Adverse Event Form. Any subject 
who becomes pregnant during the study must promptly discontinue further study treatment. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
13.4.
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.
14.
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.
14.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 13.3.2, Serious Adverse Events). A sample of the suspected product should be maintained 
for further investigation if requested by the sponsor.
14.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.


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15.
STUDY DRUG INFORMATION
15.1.
Physical Description of Study Drug
Ibrutinib (PCI-32765) is provided as white opaque, size 0, hard gelatin capsules containing 140 mg 
of ibrutinib. All formulation excipients are compendia and are commonly used in oral 
formulations. Refer to the Ibrutinib Investigator's Brochure for a list of excipients.
Nivolumab (BMS-936558-01 Solution for Injection) is a clear to opalescent colorless to pale 
yellow liquid and may contain particles. Each vial contains 100 mg nivolumab in a 10 mL solution 
(10 mg/mL). 
15.2.
Packaging
Ibrutinib capsules are packaged in opaque high-density polyethylene plastic bottles with labels 
bearing the appropriate label text as required by governing regulatory agencies. All bottles will 
utilize child resistant packaging.
Nivolumab (BMS-936558 100 mg, 10 mg/mL) will be packaged in an open-label fashion. Each 
BMS-936558, 10 mL vial is packaged in a carton, and are not subject or treatment arm specific. 
Vial assignments by subjects will be made through the IWRS to track usage and resupply.
15.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Study 
drug supplies will contain a study-specific label with a unique identification number.
15.4.
Preparation, Handling, and Storage
The recommended storage condition for ibrutinib capsules is controlled room temperature (15oC 
to 25oC) with excursions permitted to 30°C (86°F). Current stability data indicate that the capsules 
will be stable for the duration of the clinical study under the labeled storage conditions. Study staff 
will instruct subjects on how to store medication for at-home use as indicated for this protocol. 
Nivolumab should be stored at 2° to 8°C and protected from light and freezing.
Refer to the pharmacy manual/study site investigational product manual for additional guidance 
on study drug handling and storage conditions.
15.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The study drug administered to the subject must be 
documented on the drug accountability eCRF page. All study drug will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 


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environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the drug return form. When the study site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member of 
the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to
subjects participating in the study. Returned study drug must not be dispensed again, even to the 
same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects, or their legally acceptable representatives where applicable, must 
be instructed to return all original containers, whether empty or containing study drug.
16.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Brochure for ibrutinib

Investigator Brochure for nivolumab

Site Investigational Product Procedures Manual

Laboratory manual

NCI-CTCAE Version 4.0

IWRS Manual

Sample ICF

Subject diaries
17.
ETHICAL ASPECTS
17.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.


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The total blood volume to be collected is estimated to be approximately 25 mL at screening and 
approximately 60 mL at baseline. Samples for PK and biomarker analysis from Cycle 3 to Cycle 25 
total approximately 110 mL. Approximately 10 mL for safety laboratory testing will be collected 
every cycle. Within the first year the total amount of blood drawn is estimated to be 530 mL, a 
volume approximating the volume of a single blood donation (500 mL). Subjects in Cohorts B1 and 
B2 will have an additional 43 mL of blood collected for ibrutinib pharmacodynamics and biomarkers 
during the run-in visit.
17.2.
Regulatory Ethics Compliance
17.2.1.
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.
17.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
subjects, data or study conduct, unless required locally), the ICF, applicable recruiting materials, 
and subject compensation programs, and the sponsor has received a copy of this approval. This 


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approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB
(at least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

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 (if applicable, the notification will be submitted through the head of 
investigational institution). 
17.2.3.
Informed Consent
Each subject (or a legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved by 
both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read and 


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understand. The informed consent should be in accordance with principles that originated in the 
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and 
sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is voluntary 
and that they may withdraw consent to participate at any time. They will be informed that choosing 
not to participate will not affect the care the subject will receive for the treatment of his or her 
disease. Subjects will be told that alternative treatments are available if they refuse to take part and 
that such refusal will not prejudice future treatment. Finally, they will be told that the investigator 
will maintain a subject identification register for the purposes of long-term follow up if needed 
and that their records may be accessed by health authorities and authorized sponsor personnel 
without violating the confidentiality of the subject, to the extent permitted by the applicable law(s) 
or regulations. By signing the ICF the subject or legally acceptable representative is authorizing 
such access, including permission to obtain information about his or her survival status, and agrees 
to allow his or her study physician to recontact the subject for the purpose of obtaining consent for 
additional safety evaluations, if needed, and subsequent disease-related treatments, or to obtain 
information about his or her survival status.
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
When prior consent of the subject is not possible and the subject's legally acceptable representative 
is not available, enrollment procedures should be described in the protocol with documented 
approval/favorable opinion by the IEC/IRB to protect the rights, safety, and well-being of the 
subject and to ensure compliance with applicable regulatory requirements. The subject or legally 
acceptable representative must be informed about the study as soon as possible and give consent 
to continue.
17.2.4.
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 


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technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for study-related 
monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also addresses the 
transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps will 
be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory pharmacodynamic/biomarker/PK/immunogenicity 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.
17.2.5.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product, if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 17.1, Study-Specific
Design 
Considerations.


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18.
ADMINISTRATIVE REQUIREMENTS
18.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be 
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involves only logistic or administrative aspects of the study, the IRB (and IEC where 
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
(see Contact Information page(s) provided separately). Except in emergency situations, this 
contact should be made before implementing any departure from the protocol. In all cases, contact 
with the sponsor must be made as soon as possible to discuss the situation and agree on an 
appropriate course of action. The data recorded in the eCRF and source documents will reflect any 
departure from the protocol, and the source documents will describe this departure and the 
circumstances requiring it.
18.2.
Regulatory Documentation
18.2.1.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable


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
Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
18.2.2.
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.
18.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
18.4.
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 adverse events and follow-up of adverse events; concomitant medication;
drug receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable. 


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The author of an entry in the source documents should be identifiable.
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).
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
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 an electronic source is utilized, references made to the CRF in 
the protocol include the electronic source system but information collected through electronic 
source may not be limited to that found in the CRF.
18.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
Electronic data capture (eDC) will be used for this study. All data relating to the study must be 
recorded in CRF. All CRF entries, corrections, and alterations must be made by the investigator 
or authorized study-site personnel. The investigator must verify that all data entries in the CRF are 
accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
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 documents. Data must be entered into 
eCRFs in English. The CRF must be completed as soon as possible after a subject visit, and the 
forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be completed 
by the same individual who made the initial baseline determinations whenever possible. 
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after the 
initial entry into the CRF, this can be done in either of the following ways:


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
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).

Sponsor or sponsor delegate can generate a query for resolution by the study-site personnel.
18.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. 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 study database they will 
be verified for accuracy and consistency with the data sources.
18.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
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.


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18.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the CRF 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. 
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.
18.9.
Study Completion/Termination
18.9.1.
Study Completion
The study is considered completed with the last visit for the last subject participating in the study. 
The final data from the study site will be sent to the sponsor (or designee) after completion of the 
final subject visit at that study site, in the time frame specified in the Clinical Trial Agreement.
18.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development


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18.10. 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 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.
18.11. Use of Information and Publication
All information, including but not limited to information regarding ibrutinib or nivolumab 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 pharmacogenomic or 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 or nivolumab, 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. Results of pharmacogenomic or 
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 


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site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will 
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and substudy approaches, secondary results generally should not be 
published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual study site until the combined results from the completed study have been 
submitted for publication, within 18 months of the availability of the final data (tables, listings, 
graphs), or the sponsor confirms there will be no multicenter study publication. Authorship of 
publications resulting from this study will be based on the guidelines on authorship, such as those 
described in the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, which 
state that the named authors must have made a significant contribution to the design of the study 
or analysis and interpretation of the data, provided critical review of the paper, and given final 
approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law.


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REFERENCES
1.
Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM. Programmed death ligand 1 is 
expressed by non-hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res. 
2011;17(13):4232-4244.
2.
Ansell SM. Malignant B cells at the helm in follicular lymphoma. J Clin Oncol. 2013;31(21):2641-2642. 
3.
Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with 
pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results 
of an international phase II trial. J Clin Oncol. 2013;31(33):4199-4206.
4.
Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptotic receptor on cancer 
cells. Blood. 2008;111(7):3635-3643.
5.
Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF. PD-L1/B7H-1 inhibits the effector 
phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004;64(3):1140-1145.
6.
Blazar BR, Carreno BM, Panoskaltsis-Mortari A, et al. Blockade of programmed death-1 engagement 
accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol. 
2003;171(3):1272-1277.
7.
Brody J, Kohrt H, Marabelle A, Levy R. Active and passive immunotherapy for lymphoma: proving principles 
and improving results. J Clin Oncol. 2011;29(14):1864-1875.
8.
Carreras J, Lopez-Guillermo A, Roncador G, et al. High numbers of tumor-infiltrating programmed cell death 
1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J Clin 
Oncol. 2009;27(9):1470-1476. 
9.
Carter L, Fouser LA, Jussif J, et al. PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells 
and is overcome by IL-2.Eur J Immunol. 2002;32(3):634-643.
10.
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor 
tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor 
ligation prevents T cell activation.J Immunol. 2004;173(2):945-954.
11.
Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell 
lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19(13):3462-3473.
12.
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059-
3067.
13.
Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular features of 
tumor-infiltrating immune cells. N Engl J Med. 2004;351(21):2159-2169.
14.
Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential 
mechanism of immune evasion. Nat Med. 2002;8(8):793-800. Erratum in: Nat Med 2002 Sep;8(9):1039. 
15.
Drake CG, Lipson EJ, Brahmer JR. Breathing new life into immunotherapy: review of melanoma, lung and 
kidney cancer. Nat Rev Clin Oncol. 2014;11(1):24-37. 
16.
Dranoff G. Immunotherapy at large: Balancing tumor immunity and inflammatory pathology. Nat Med. 
2013;19(9):1100-1101.
17.
Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a 
Th1-selective pressure in T lymphocytes. Blood. 2013;122(15):2539-2549.
18.
Fowler NH, Advani RH, Jeff Sharman J, et al. The Bruton's tyrosine kinase inhibitor ibrutinib (PCI-32765) is 
active and tolerated in relapsed follicular lymphoma. Blood 2012;120:Abstr 156.
19.
Flowers CAR, Seidenfeld J, Bow EL, et al. Antimicrobial prophylaxis and outpatient management of fever and 
neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice 
guideline. J Clin Oncol. 2013 Feb 20;31(6):794-810.
20.
Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family 
member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034.


JNJ-54179060 (ibrutinib)
Clinical Protocol PCI-32765LYM1002 Amendment 7
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Status: Approved,  Date: 12 October 2020
21.
Fridericia LS. The duration of systole in the electrocardiogram of normal subjects and patients with heart 
disease. Acta Medica Scand. 1920;53:469-486.
22.
Grzywnowicz M, Zaleska J, Mertens D, et al. Programmed death-1 and its ligand are novel immunotolerant 
molecules expressed on leukemic B cells in chronic lymphocytic leukemia. PLoS One. 2012;7(4):e35178. 
23.
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(12):5446-5456.
24.
Hanna B, McClanahan F, Clear AJ, et al. Immune checkpoint blockade with anti-PD-L1 prevents immune 
dysfunction and CLL development in the TCL1 adoptive transfer mouse model. Blood 2014; 124: Abstr 717.
25.
Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates 
cancer therapeutic immunity. Cancer Res. 2005;65(3):1089-1096.
26.
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the 
escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 
2002;99(19):12293-12297
27.
Iwai Y, Terawaki S, Honjo T. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor 
cells by enhanced recruitment of effector T cells. Int Immunol. 2005;17(2):133-144.
28.
Jaglowski SM, Jones JA, Nagar V, et al. Safety and activity of BTK inhibitor ibrutinib combined with 
ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015;126(7):842-850.
29.
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-finding trials. Clin 
Trials. 2010;7(6):653-663.
30.
Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable method than the 3 + 3 
design for practical phase I trials. J Clin Oncol. 2013;31(14):1785-1791.
31.
Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-
small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. 
Clin Cancer Res. 2004;10(15):5094-5100.
32.
Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. 
Nat Immunol. 2001;2(3):261-268.
33.
Lesokhin AM, Ansell SM, Armand P, et al. Preliminary Results of a Phase I Study of Nivolumab (BMS-
936558) in Patients with Relapsed or Refractory Lymphoid Malignancies. Blood. 2014; 124: Abstr 291.
34.
McClanahan F, Hielscher T, Rieger M, et al. Final results of a randomized trial comparing 1, 3, or 6 infusions of 
Rituximab plus 6 cycles CHOP provide valuable preliminary data towards a more cost-effective and safer 
treatment of advanced follicular lymphoma. Am J Hematol. 2012;87(10):E68-71.
35.
Niemann CU, Biancotto A, Chang BY, et al. Cytokine and T-cell phenotypic changes upon in vivo ibrutinib 
therapy for CLL – targeting both CLL cells and the tumor-microenvironment [abstract].  ASH 2013. Abstract 
2856.
36.
Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 
2001;22(5):265-268.
37.
Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by 
disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11(2):141-
151.
38.
Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient 
mice. Science. 2001;291(5502):319-322.
39.
Nivolumab [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2014.
40.
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549 556.
41.
Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death-1 ligand-1 and programmed 
death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 2005;11(8):2947-2953.


JNJ-54179060 (ibrutinib)
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Status: Approved,  Date: 12 October 2020
42.
Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are responsible for dilated 
cardiomyopathy in PD-1-deficient mice. Nat Med. 2003;9(12):1477-1483.
43.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5(6):649-655.
44.
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. American Society of Clinical Oncology 
Growth Factors Expert Panel. J Clin Oncol. 2000;18(20):3558-3585.
45.
Parikh SA, Kay NE, Shanafelt TD. How we treat Richter syndrome. Blood. 2014;123(11):1647-1657.
46.
Richendollar BG, Pohlman B, Elson P, Hsi ED. Follicular programmed death 1-positive lymphocytes in the 
tumor microenvironment are an independent prognostic factor in follicular lymphoma. Hum Pathol. 
2011;42(4):552-557.
47.
Robert C, Soria JC, Eggermont AM. Drug of the year: programmed death-1 receptor/programmed death-1 
ligand-1 receptor monoclonal antibodies. Eur J Cancer. 2013;49(14):2968-2971. 
48.
Salama AD, Chitnis T, Imitola J, et al. Critical role of the programmed death-1 (PD-1) pathway in regulation 
of experimental autoimmune encephalomyelitis. J Exp Med. 2003;198(1):71-78. Erratum in: J Exp Med. 2003 
Aug 18;198(4):677. 
49.
Sheppard KA, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the 
ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574(1-3):37-41.
50.
Shi L, Chen S, Yang L, Li Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with 
hematological malignancies. J Hematol Oncol. 2013;6(1):74. 
51.
Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous 
cell carcinoma.Cancer Res. 2003;63(19):6501-6505.
52.
Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. 
Clin Cancer Res. 2013;19(5):1021-1034.
53.
Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator 
of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A. 2004;101(49):17174-
17179.
54.
Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory molecule B7-H1 in primary and metastatic clear 
cell renal cell carcinoma. Cancer. 2005a;104(10):2084-2091.
55.
Thompson RH, Webster WS, Cheville JC, et al. B7-H1 glycoprotein blockade: a novel strategy to enhance 
immunotherapy in patients with renal cell carcinoma. Urology. 2005b;66(5 Suppl):10-14.
56.
Tsang M, Shanafelt TD, Call TG, et al. The efficacy of ibrutinib in the treatment of Richter syndrome. Blood. 
2015;125(10):1676-1678.
57.
Tsushima F, Tanaka K, Otsuki N, et al. Predominant expression of B7-H1 and its immunoregulatory roles in 
oral squamous cell carcinoma. Oral Oncol. 2006;42(3):268-274.




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Attachment 2: Modified Diet in Renal Disease (MDRD) Formulas
For creatinine in mg/dL, the estimated glomerular filtration rate (e-GFR) for the modified diet in renal 
disease (MDRD) formulas is: 
e-GFR (MDRD) = 186 x [serum creatinine]-1.154 x [age]-0 203 x [1.212 if Black] x [0.742 if 
female]
For creatinine in µmol/L, the estimated glomerular filtration rate (e-GFR) for the modified diet in renal 
disease (MDRD) formulas is:
e-GFR (MDRD) = 32788 x [serum creatinine]-1.154 x [age]-0 203 x [1.212 if Black] x [0.742 if 
female]
Creatinine levels in µmol/L can be converted to mg/dL by dividing them by 88.4. The 32788 number 
above is equal to 186×88.41.1.






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Attachment 5: Efficacy procedures
Evaluations 
Radiographic Image Assessments
During the study, disease response will be assessed using CT scans with IV contrast of the neck, chest, 
abdomen, and pelvis and any other location where disease was present at Screening or whole body 
FDG-PET scans. Subjects who are intolerant of IV CT contrast agents will have CT scans performed with 
oral contrast. Endoscopy is required to confirm CR for subjects with gastrointestinal (GI) involvement at 
baseline. 
A separate CT scan and PET scan are preferred but, if the only available modality is combined/dual PET/CT 
scanner, then the CT portion of a PET/CT may be submitted in lieu of a dedicated CT; however, the CT 
scanning must be done according to certain imaging requirements provided to the radiologist in the 
radiology manual to ensure that an optimized CT examination is done. Evaluation of other sites of disease 
by radiological imaging, physical examination, or other procedures as necessary (to be performed 
throughout the study using the same method of assessment used to assess disease at baseline), and review 
of hematology and clinical chemistry results may be performed at the site level, as determined by the 
investigator. 
Magnetic resonance imaging may be used to evaluate sites of disease that cannot be adequately imaged 
using CT (in cases where MRI is desirable, the MRI must be obtained at baseline and at all subsequent 
response evaluations). For all other sites of disease, MRI studies do not replace the required neck, chest, 
abdomen, and pelvic CT scans. Brain MRI and lumbar puncture are required, only if clinically indicated.
Radiological assessments will be performed at Screening, every 5 cycles (starting Cycle 5) or approximately 
every 10 weeks up to 15 months after the start of study drug. Thereafter, scans will be performed every 12 
cycles (approximately every 24 weeks) until disease progression, or death, or end of study, whichever 
comes first. A PET scan will be performed at Screening. For subjects who are PET-positive at baseline, 
PET scans will be done at the time of maximal tumor reduction (eg, CR or 2 consecutive CT scans showing 
no further tumor reduction), relapse from CR, and at suspected disease progression if new lesion was 
detected on CT. 
Subjects who discontinue treatment prior to disease progression (for other reasons such as an adverse event) 
must continue to have regularly scheduled CT scans/efficacy assessments every 10 weeks up to 15 months 
after the start of study drug. Thereafter, scan will be performed every 24 weeks until disease progression, 
or death, or the end of the study, whichever occurs first. It is important that instances of progressive disease 
be reported to the sponsor’s medical monitor within 24 hours by means of a form provided by the sponsor 
(see Contact Information pages provided separately).
Definition of Measurable and Assessable Disease
Eligible subjects must have at least 1 measurable site of disease. Measurable sites of disease are defined as 
lymph nodes, lymph node masses, or extranodal sites of lymphoma. Each measurable site of disease must 
be greater than 1.5 cm in the long axis regardless of short axis measurement or greater than 1.0 cm in the 
short axis regardless of long axis measurement, and clearly measurable in 2 perpendicular dimensions. 
Measurement must be determined by imaging evaluation. All other sites of disease are considered 
assessable, but not measurable. 


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Up to 6 measurable sites of disease, clearly measurable in 2 perpendicular dimensions, will be followed for 
each subject. Measurable sites of disease should be chosen such that they are representative of the subject’s 
disease (this includes splenic and extranodal disease). If there are lymph nodes or lymph node masses in 
the mediastinum or retroperitoneum larger than 1.5 cm in 2 perpendicular dimensions, at least 1 lymph 
node mass from each region should always be included. In addition, selection of measurable lesions should 
be from as disparate regions of the body as possible.
All other sites of disease will be considered assessable. Assessable disease includes objective evidence of 
disease that is identified by radiological imaging, physical examination, or other procedures as necessary, 
but is not measurable as defined above. Examples of assessable disease include bone lesions; mucosal 
lesions in the GI tract; effusions; pleural, peritoneal, or bowel wall thickening; disease limited to bone 
marrow; and groups of lymph nodes that are not measurable but are thought to represent lymphoma. In 
addition, if more than 6 sites of disease are measurable, these other sites of measurable disease may be 
included as assessable disease.
Positron Emission Tomography (PET Scan)
PET using [18F]-fluorodeoxyglucose (FDG) is important for the complete assessment of response and 
progression in subjects with DLBCL. Whole body FDG-PET scan (skull base to the proximal femur) is 
recommended at Screening, at the time of maximal tumor reduction (eg, CR or 2 consecutive CT scans 
showing no further tumor reduction), and relapse from CR. For subjects with PET-negative tumors at 
baseline, the response evaluation will be based on the CT scan.
Assessment of PET results is based on published criteria. 
Visual assessment is considered adequate for determining whether a PET scan is positive, and use of the 
standardized uptake value is not necessary. A positive scan is defined as focal or diffuse FDG uptake above 
background in a location incompatible with normal anatomy or physiology, without a specific standardized 
uptake value cutoff. Other causes of false-positive scans should be ruled out. Exceptions include mild and 
diffusely increased FDG uptake at the site of moderate- or large-sized masses with an intensity that is lower 
than or equal to the mediastinal blood pool, hepatic or splenic nodules 1.5 cm with FDG uptake lower than 
the surrounding liver/spleen uptake, and diffusely increased bone marrow uptake within weeks after 
treatment.
Bone Marrow Assessment
Bone marrow aspirate is mandatory and biopsy is optional at Screening (see   Table 1). Subjects with bone 
marrow involvement must have a repeat bone marrow evaluation at the time of CR (preferably within 
30 days of the initial documentation of CR). If bone marrow involvement can be confirmed with 
morphology, IHC or flow cytometry need not be done; 1 bone marrow examination is necessary for 
complete documentation of the CR. 












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a: A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of 
the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two 
diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, 
lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not 
selected as measured, dominant disease and truly assessable disease should be considered not measured. These 
sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not 
meet the requirements for measurability but are still considered abnormal, as well as truly assessable disease, 
which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including 
pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot 
be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone 
marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be 
no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or 
myeloid growth factors). 
b: PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma.


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Attachment 7: Instruction for Concomitant Medications to be Used with Precaution
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong or moderate CYP3A 
inhibitors and consider alternative agents with less CYP3A inhibition. Co-administration of ketoconazole, 
a strong CYP3A inhibitor, in 18 healthy subjects increased dose normalized exposure, Cmax and AUC0-last, 
of ibrutinib by 29- and 24-fold, respectively. The maximal observed ibrutinib exposure (AUC) was ≤ 2-
fold in 37 patients treated with mild and/or moderate CYP3A inhibitors when compared with the ibrutinib 
exposure in 76 patients not treated concomitantly with CYP3A inhibitors. Clinical safety data in 66 patients 
treated with moderate (n=47) or strong CYP3A inhibitors (n=19) did not reveal meaningful increases in 
toxicities. Strong inhibitors of CYP3A (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazadone, and cobicistat) and moderate inhibitors (eg, 
voriconazole, 
erythromycin, 
amprenavir, 
aprepitant, 
atazanavir, 
ciprofloxacin, 
crizotinib, 
darunavir/ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone) 
should be avoided. If the benefit outweighs the risk and a strong CYP3A inhibitor must be used, reduce the 
ibrutinib dose to 140 mg or withhold treatment temporarily (for 7 days or less). If a moderate CYP3A 
inhibitor must be used, reduce ibrutinib to 140 mg for the duration of the inhibitor use. No dose adjustment 
is required in combination with mild inhibitors. Monitor subject closely for toxicity and follow dose 
modification guidance as needed. Avoid grapefruit and Seville oranges during ibrutinib treatment, as these 
contain moderate inhibitors of CYP3A.
Coadministration of ibrutinib with strong inducers of CYP3A decreases ibrutinib plasma concentrations by 
approximately 10-fold. Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, 
phenytoin, and St. John’s Wort). Consider alternative agents with less CYP3A induction.
Examples of inhibitors, inducers, and substrates can be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/
Drugs that may have their plasma concentrations altered by ibrutinib
In vitro studies indicated that ibrutinib is a weak inhibitor toward CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, and CYP3A4/5. The dihydrodiol metabolite of ibrutinib is a weak inhibitor toward CYP2B6, 
CYP2C8, CYP2C9, and CYP2D6. Both ibrutinib and the dihydrodiol metabolite are at most weak inducers 
of CYP450 isoenzymes in vitro. Therefore, it is unlikely that ibrutinib has any clinically relevant drug-drug 
interactions with drugs that may be metabolized by the CYP450 enzymes. 
In vitro studies indicated that ibrutinib is not a substrate of P-gp, but is a mild inhibitor. Ibrutinib is not 
expected to have systemic drug-drug interactions with P-gp substrates. However, it cannot be excluded that 
ibrutinib could inhibit intestinal P-gp after a therapeutic dose. There is no clinical data available; therefore, 
co-administration of narrow therapeutic index P-gp substrates (eg, digoxin) with ibrutinib may increase 
their blood concentration and should be used with caution and monitored closely for toxicity.


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Concomitant Use of Ibrutinib/Placebo and QT Prolonging Agents
Any medications known to cause QT prolongation should be used with caution; periodic monitoring with 
electrocardiograms (ECG) and electrolytes should be considered and, if needed, the medical monitor may 
be contacted.
Concomitant Use of Ibrutinib/Placebo and Antiplatelet Agents and Anticoagulants
Warfarin or other vitamin K antagonists should not be administered concomitantly with ibrutinib. 
Supplements, such as fish oil and vitamin E preparation should be avoided. Use ibrutinib with caution in 
subjects requiring other anticoagulants or medications that inhibit platelet function. Subjects with 
congenital bleeding diathesis have not been studied. Ibrutinib should be held at least 3 to 7 days pre- and 
post-surgery depending upon the type of surgery and the risk of bleeding.
Subjects requiring the initiation of therapeutic anticoagulation therapy (other than warfarin or a vitamin K 
antagonist) during the course of the study should have treatment with ibrutinib/placebo held, the sponsor’s 
medical monitor should be contacted, and ibrutinib/placebo should not be restarted until the subject is 
clinically stable and the re-initiation of ibrutinib/placebo is approved by the sponsor’s medical monitor. 
Subjects should be observed closely for signs and symptoms of bleeding. No dose reduction is required 
when study drug is restarted.


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Attachment 8: Inhibitors and Inducers of CYP3A
Examples of inhibitors and inducers of CYP3A can be found at the following website:
http://medicine.iupui.edu/clinpharm/ddis/main-table/.  The list below reflects information obtained from 
the Indiana University, Division of Clinical Pharmacology, Indianapolis, IN website on 
July 2013. 
Inhibitors of CYP3A
Strong inhibitors:
All other inhibitors:
INDINAVIR
amiodarone
NELFINAVIR
NOT azithromycina
RITONAVIR
chloramphenicol
CLARITHROMYCIN
boceprevir
ITRACONAZOLE
ciprofloxacin
KETOCONAZOLE
delaviridine
NEFAZODONE
diethyl-dithiocarbamate
SAQUINAVIR
fluoxetine-metabolite norfluoxetine
TELITHROMYCIN
fluvoxamine
Moderate inhibitors:
gestodene
aprepitant
imatinib
erythromycin
mibefradil
diltiazem 
mifepristone
fluconazole
norfloxacin
grapefruit juice
norfluoxetine
Seville orange juice
star fruit
verapamil
telaprevir
Weak inhibitors:
troleandomycin
cimetidine
voriconazole
a.
Azithromycin is unique in that it does not inhibit CYP3A
Inducers of CYP3A
efavirenz
phenobarbital
nevirapine
phenytoin
barbiturates
pioglitazone
carbamazepine
rifabutin
glucocorticoids
rifampin
modafinil
St. John's wort
oxcarbazepine
troglitazone 



SAP_001.pdf: 
1 
Approved, Date: 9 August 2017  
 
Janssen Research & Development  
 
 
Statistical Analysis Plan 
 
A Phase 1/2a Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and 
Preliminary Efficacy of the Combination of Ibrutinib with Nivolumab in Subjects with 
Hematologic Malignancies 
 
Protocol PCI-32765LYM1002; Phase 1/2a 
 
JNJ54179060(ibrutinib) 
 
 
 
 
Status: 
Approved  v0.20 
Date: 
9 August 2017 
Prepared by: Janssen Research & Development, LLC   
 
Compliance:  The study described in this report was performed according to the principles of Good Clinical Practice (GCP).  
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information 
is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or confidential. 
NCT02329847


JNJ54179060 (ibrutinib)  
 
 
 
Statistical Analysis Plan PCI-32765LYM1002  
 
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Approved, Date: 9 August 2017  
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
1. 
INTRODUCTION.................................................................................................................................. 5 
1.1. 
Trial Objectives ................................................................................................................................ 5 
1.2. 
Trial Design ...................................................................................................................................... 5 
1.3. 
Statistical Hypotheses for Trial Objectives ....................................................................................... 6 
1.4. 
Sample Size Justification ................................................................................................................. 6 
2. 
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 7 
2.1. 
Analysis Cohorts .............................................................................................................................. 7 
2.2. 
Visit Windows ................................................................................................................................... 7 
2.3. 
Pooling Algorithm for Analysis Centers ............................................................................................ 8 
2.4. 
Analysis Sets .................................................................................................................................... 8 
2.4.1. 
Efficacy Analysis Set(s) ................................................................................................................ 8 
2.4.2. 
Safety Analysis Set ....................................................................................................................... 8 
2.4.3. 
Pharmacokinetics/Pharmacodynamic (PK/PD) Analysis Set ....................................................... 8 
2.5. 
Definition of Subgroups .................................................................................................................... 8 
2.6. 
Imputation of Missing Dates ......................................................................................................... 9 
2.7. 
Other General Definitions ........................................................................................................... 10 
3. 
SUBJECT INFORMATION ................................................................................................................ 11 
3.1. 
Demographics and Baseline Characteristics ................................................................................. 11 
3.2. 
Disposition Information................................................................................................................... 11 
3.3. 
Medical History ............................................................................................................................... 11 
3.4. 
Extent of Exposure ......................................................................................................................... 12 
3.5. 
Protocol Deviations ........................................................................................................................ 12 
3.6. 
Prior and Concomitant Medications ............................................................................................... 13 
4. 
EFFICACY ......................................................................................................................................... 13 
4.1. 
Analysis Specifications................................................................................................................... 13 
4.1.1. 
Level of Significance ................................................................................................................... 13 
4.1.2. 
Data Handling Rules ................................................................................................................... 13 
4.1.3. 
General Analysis Considerations ............................................................................................... 13 
4.2. 
Primary Efficacy Endpoint(s) .......................................................................................................... 13 
4.2.1. 
Definition ..................................................................................................................................... 13 
4.2.2. 
Analysis Methods ........................................................................................................................ 14 
4.3. 
Exploratory Secondary Endpoints .................................................................................................. 14 
4.3.1. 
Duration of Response ................................................................................................................. 14 
4.3.2. 
Duration of Stable Disease or Better .......................................................................................... 14 
4.3.3. 
Progression-free Survival and Overall Survival .......................................................................... 14 
4.3.4. 
Resolution of Lymphoma-related symptoms .............................................................................. 15 
5. 
SAFETY ............................................................................................................................................. 16 
5.1. 
Adverse Events .............................................................................................................................. 16 
5.2. 
Adverse Events of Special ............................................................................................................. 16 
5.3. 
Adverse Events of Clinical Interest ................................................................................................ 16 
5.4. 
Death .............................................................................................................................................. 20 
5.5. 
Clinical Laboratory Tests................................................................................................................ 20 
5.5.1. 
Creatinine Clearance .................................................................................................................. 21 
5.6. 
Other Safety Parameters ............................................................................................................... 21 
6. 
PHARMACOKINETICS ..................................................................................................................... 21 
7. 
BIOMARKER ..................................................................................................................................... 22 
7.1. 
Biomarker Objectives ..................................................................................................................... 22 
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7.2. 
Biomarker Analysis Sets ................................................................................................................ 22 
7.3. 
Biomarker Stratification Groups ..................................................................................................... 22 
7.4. 
Biomarker Tested ............................................................................................................................ 23 
7.5. 
Association Analysis of Biomarkers with Clinical Efficacy Endpoints ......................................... 24 
7.5.1. 
Level of Significance ................................................................................................................... 24 
7.5.2. 
Missing Data Handling ................................................................................................................ 24 
7.5.3. 
Data Transformation and imputation .......................................................................................... 25 
7.5.4. 
Outlier Detection and Handling ................................................................................................... 25 
7.5.5. 
Biomarker Data Analysis Methods ............................................................................................. 25 
REFERENCES ............................................................................................................................................ 26 
APPENDICES ............................................................................................................................................. 26 
1. 
APPENDIX A ..................................................................................................................................... 26 
 
Document No.: 
EDMS-ERI-149261409 
 
 
 
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ABBREVIATIONS 
AE 
adverse event 
ALC 
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
DLBCL 
Diffuse large B-cell lymphoma 
CI 
confidence interval 
CR(s) 
complete response(s) 
CRI(s) 
complete response(s) with incomplete marrow recovery 
CRF 
case report form  
CSR 
clinical study report 
DOR 
duration of response 
DOSD 
duration of stable disease 
ECOG 
Eastern Cooperative Oncology Group 
FL 
follicular lymphoma 
HCV 
hepatitis C virus 
Ig 
immunoglobulin 
IV 
intravenous 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
LDH 
lactic acid dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NCI-ODWG 
National Cancer Institute Organ Dysfunction Working Group 
NPR 
Nodular partial response  
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival  
PK 
pharmacokinetics 
PR(s) 
partial response(s) 
PRL(s) 
partial response(s) with lymphocytosis 
PT 
Preferred Term 
RP2D 
recommended phase 2 dose 
SAP 
statistical analysis plan 
SCT 
stem cell transplant  
SD 
stable disease 
SLL 
Small lymphocyte lymphoma 
SOC 
System Organ Class 
TB 
total bilirubin 
transformed 
DLBCL 
FL transformed to DLBCL 
ULN 
Upper Limit of Normal 
WBC 
white blood cell (count) 
WHODD 
World Health Organization Drug Dictionary 
 
 
 
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1. 
INTRODUCTION 
This is a Phase 1/2a Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and 
Preliminary Efficacy of the Combination of Ibrutinib with Nivolumab in Subjects with 
Hematologic Malignancies. There are two parts of this study. Part A (Dose Optimization Cohorts) 
is to determine whether ibrutinib and nivolumab can be safely combined and to establish the 
recommended Phase 2 dose (RP2D) for this combination in subjects with hematological disorders. 
Part B (Expansion Cohorts) is to determine the preliminary activity of the ibrutinib/nivolumab 
combination regimen in subjects with CLL/SLL with del 17p or 11q (Cohort B1), FL (Cohort B2), 
DLBCL (Cohort B3), and Richter syndrome (Cohort B4) in comparison to historical results. 
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and data 
handling rules, and statistical approaches for the evaluation of safety, preliminary efficacy 
activities, and pharmacokinetics. Biomarker analysis will be included and described in this 
document. 
1.1. 
Trial Objectives  
The preliminary clinical activity of ibrutinib in combination with nivolumab in each disease type 
of part A and B  in the all-treated population will be explored via the following endpoints unless 
otherwise stated: objective response rate [PR(+L) or better], progression-Free Survival (PFS) 
and overall survival (OS), duration of response (DOR) and duration of stable disease (DOSD) 
will be evaluated if there are sufficient data for responders for each disease-specific cohort A1, 
A2, B1, B2, B3 and B4 on the all-treated population. Furthermore, objective response rate 
[PR(+L) or better] will also be explored on the response-evaluable population, if deemed 
necessary. In addition, the safety profile of the ibrutinib and nivolumab combination regimen 
will be evaluated and the pharmacokinetic profile of ibrutinib and nivolumab compared with 
existing single-agent treatment data; and the potential relationships between ibrutinib and 
nivolumab metrics of exposure with relevant clinical or biomarker information will be 
characterized and explored. 
1.2. 
Trial Design  
This is an open-label Phase 1/2a study, which consists of Part A (Dose Optimization Cohorts A1 
and A2) and Part B (Expansion Cohorts B1, B2, B3 and B4). In the context of this study, a 
treatment ‘cycle’ is defined as a course of treatment of 14 days starting with the intravenous 
administration of nivolumab on Day 1 of each cycle along with once daily oral intake of ibrutinib 
on all days.  
It is anticipated that approximately 158 subjects for both Parts A and B would be enrolled. 
Part B (Dose Expansion Cohorts) will be open for enrollment after the RP2D is determined in 
Part A. In Part B, further assessment of the RP2D will be explored in 4 subject populations to 
further evaluate the safety and clinical activity of ibrutinib in combination with nivolumab. 
During the expansion period, subjects with CLL/SLL with del 17p or 11q (Cohort B1), FL 
(Cohort B2), DLBCL including FL transformed into DLBCL (transformed DLBCL) (Cohort 
B3), and Richter syndrome (Cohort B4) will be enrolled. Approximately 35 subjects will be 
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Statistical Analysis Plan PCI-32765LYM1002  
 
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Approved, Date: 9 August 2017  
enrolled in each of the expansion cohorts. The subjects will be treated at the RP2D level selected 
to further assess the safety, pharmacokinetics, pharmacodynamics, pharmacogenomics, and 
activity of the combination. 
The median duration of study therapy is expected to be approximately from 2 (DLBCL) to 15 
(CLL) months. 
The End-of-Treatment Visit will occur within 30 days after the last dose of ibrutinib or 
nivolumab, whichever treatment occurred last. 
During the Follow-up Period, long-term safety, survival status, disease progression, subsequent 
aniticancer therapy, and occurrence of other primary malignancy data will be collected. During 
the Follow-up Period, subjects should be followed for safety up to 30 days after the last dose of 
ibrutinib or 100 days after the last nivolumab infusion, whichever is later. The safety includes 
adverse event reporting and laboratory assessments (at the first follow up). Thereafter Follow-
up visits will be completed approximately every 3 months until death or the end of study. 
Subjects who have developed treatment-related Grade 3 or higher toxicity at the end of treatment 
will be assessed until recovery to Grade ≤1 or baseline, deemed irreversible, or until end of study. 
Adverse events leading to discontinuation will be followed up until resolution or return to 
baseline, or end of study, whichever occur first. 
The primary analysis of the study will be performed 6 months after the last subject has received 
the first dose of study medication, or earlier if that subject discontinues study therapy. After the 
cut off for primary analysis, subjects who are receiving study treatment can continue treatment 
per protocol until progression, unacceptable toxicity, withdrawal of consent, or other reason as 
listed in protocol Section 11.2. End of study will be defined as the time when all subjects have 
completed the End-of-Treatment Visit and have been followed for safety up to 100 days post 
nivolumab as the last study assessment. 
1.3. 
Statistical Hypotheses for Trial Objectives  
This study will evaluate and describe whether ibrutinib combined with nivolumab can result in 
an overall response rate of more than 20% in each cohort of part B (i.e., dose expansion, cohorts 
B1, B2, B3 and B4), respectively.   
1.4. 
Sample Size Justification  
The sample size is calculated based on the following assumptions: 
•The overall response rate under null hypothesis is 20%  
•The overall response rate under alternative hypothesis is at least 38%  
•The probability to mistakenly rejecting the null hypothesis when it is actually true is 0.1 
(one-sided).  
•The probability to correctly rejecting null hypothesis when alternative hypothesis is true 
is at least 0.8 
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Under the above assumptions, the study will enroll approximately 35 subjects to get at least 32 
response evaluable subjects in each cohort of Part B (Cohorts B1, B2, B3, and B4). 
2. 
GENERAL ANALYSIS DEFINITIONS 
2.1. 
Analysis Cohorts 
Disease type cohort is defined as: cohort of patients grouped by disease type of CLL, SLL, 
DLBCL, transformed DLBCL, (i.e., FL transformed to DLBCL), DLBCL overall (include both 
DLBCL and transformed DLBCL) Richter Syndrome from both Part A and B, unless otherwise 
stated.  Study cohort is referring to cohorts A1, A2, B1, B2, B3 and B4.  
2.2. 
Visit Windows 
Visit window will be based on phases and cycles: 
(For the purposes of this study, ‘study drug’ or ‘study therapy’ or “study treatment” refers to both 
ibrutinib and/or nivolumab). 
Screening: Up to 28 days before the start of any study treatment. 
Treatment: Between the date of first administration of study therapy and the date of the last 
dose of study drug. The treatment stage will be subdivided by cycles. Each cycle is 14 days, 
starting from the first dose of study drug.  The end date of the last cycle is the date of the last 
dose of study drug received during the study.  
End of treatment: within 30 days after the last dose of ibrutinib or 100 days after the last 
nivolumab. The assessments performed during the ‘End of treatment visit’ will be included in 
this End of treatment phase.  
Follow-up: After the end of treatment till the last assessment for the last subject in the study 
(e.g. the last follow-up visit or death).  
Baseline assessment is defined as the last non-missing results on or before the first dose of study 
therapy. 
1. 
Cycle-based analysis may be performed for safety parameters during the treatment up to 
date of last dose of ibrutinib + 30 days, and last dose of nivolumab +100 days. For the analysis 
of laboratory measurement by cycle, the mean values within each cycle will be used. For the 
analysis of laboratory grade by cycle, the worst grade within each cycle will be used. 
Assessments will be presented chronologically by cycle day or study day, which are defined as 
the follows: 
Day 1 = date of first dose of study drug / Cycle 1 day -7 (subjects with run-in) 
Study Day (if on or after date of first dose) = assessment date – date of first dose +1  
Study Day (if before date of first dose) = assessment date – date of first dose  
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Cycle Day = assessment date – date of first dose for the cycle +1 
2.3. 
Pooling Algorithm for Analysis Centers 
The data from all investigative sites will be pooled for all analyses. 
2.4. 
Analysis Sets 
2.4.1. 
Efficacy Analysis Set(s) 
The all-treated population is defined as all subjects who have received at least 1 dose of study 
drugs (either ibrutinib or nivolumab). 
The response-evaluable population is defined as all subjects who receive at least 1 dose of both 
study drugs (ibrutinib and nivolumab), and have a pretreatment, and at least 1 posttreatment 
disease assessment; unless no post-baseline scan was performed due to AE possibly related to 
treatment or clinical progression or death.  
ORR, DOR, DOSD, PFS and OS will be analyzed using the all-treated population. In addition, 
ORR will also be analyzed based on response-evaluable, if deemed necessary.  
DOR will be analyzed for subjects who achieve a partial response [PR (+L)] or better.  DOSD 
will be analyzed for subjects who achieve a stable disease (SD) or better. 
 
2.4.2. 
Safety Analysis Set 
The safety population is defined as all subjects who receive at least 1 dose of study drug, which 
is same definition as the all-treated population. 
2.4.3. 
Pharmacokinetics/Pharmacodynamic (PK/PD) Analysis Set 
This population consists of all subjects who receive at least 1 dose of study drug (either 
ibrutinib or nivolumab) and have at least 1 posttreatment sample collected during treatment to 
determine the concentration or pharmacodynamic biomarker response.  
2.5. 
Definition of Subgroups 
Exploratory subgroup analyses will be performed for the primary efficacy endpoint.   
•         Age (<65 vs. 65 years)  
• 
Sex (male vs. female) 
• 
Race (Caucasian vs. Other) 
• 
Prior lines of therapy (1 vs 2 to 4 vs >4)  
• 
Baseline Eastern Cooperative Oncology Group (ECOG) performance status (0 and 
1 vs  2 ) 
• 
Region (United States vs. Non-United States) 
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• 
SLL vs Non-SLL 
• 
Transformed DLBCL vs Non-transformed DLBCL 
 
2.6. 
Imputation of Missing Dates 
In general, missing date of initial diagnosis, date of death and start and end dates of AE, prior, 
concomitant and subsequent therapies will be imputed according to the following rules:  
• General rules 
o If date is completely missing or year is missing, no imputation will be made.  
o If only year is present but month and day are missing, then June 30th will be used. 
o If only day is missing but year and month are available, then the 15th of the month 
will be used  
• Start and end dates rules  
o Start date will be imputed before end date   
o If end date is not missing (i.e., not imputed) and before the imputed start date, then  
end date will be used 
o If end month and year are not missing and before imputed start month and year, 
then  end month and year will be used 
o If imputed end date is before start date, then start date will be used 
However, the above imputation will be modified by the following rules sequentially: 
• For death: if the imputed date is before the last date that the subject is known to be alive, 
the latter date + 1 day will be used. 
• If any imputed date is after date of death, then date of death will be used 
• For initial diagnosis and prior therapies: if imputed date is on or after the first dose date, 
then first dose date - 1 will be used.   
• For AE and concomitant medications: The imputed start date will be adjusted sequentially 
using the following steps 
o If it is in the same month and year but before the first dose date, then the first dose 
date will be used, or if it is in the same month and year but after the last dose date + 
30 days, then the last dose date + 30 days will be used 
o If the end date is not missing and the imputed start date is after the end date, then 
the end date will be used.  
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o If the imputed start date and is after date of death, then date of death will be used. 
o If it is in the same month and year but after the 1st subsequent systemic therapy start 
date, then the 1st subsequent therapy start date will be used. 
o For subsequent therapies: if imputed date is before the treatment discontinuation 
date, then the treatment discontinuation date will be used. 
 
 
2.7. 
Other General Definitions 
Year and Month 
1 year = 365.25 days and 1 month = 30.4375 days.  
Age 
Use Age (year) collected in the case report form (CRF), which is the number of integer years from 
the date of birth to the date of informed consent.  
Date of overall response for each time point 
Date of assessment at that time point. When different assessments for the time point are performed 
on different dates, the date of overall response is the date of the last assessment performed when 
the responses PR(+L) or better [except for biopsies - biopsies of tumor or suspected tumors (such 
as lymph nodes/nodal masses) or extranodal masses (such as GI biopsy, skin lesions, etc.), 
cytology assessments], or the date of earliest assessment showing progression when the response 
is PD or relapse from CR.  
Date of response 
Date of first observed response [PR(+L) or better]. For CLL patients, time to response is calculated 
from onset of PRL. 
Date of best response  
Date of first observed best response [PR(+L) or better].  For instance, for subjects who achieved 
PR followed by CR, PR will be the initial response and CR will be the best response (the date of 
evaluation with first time CR is reported is the date of best response).  Use the ranking below to 
choose the best response.  The response corresponds to the lowest rank of number is the best 
response: 
Rank 
Response 
1 
CR 
2 
CRI 
3 
PR 
4 
NPR 
5 
PR WITH LYMPH (PRL) 
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6 
SD or no response 
7 
PD 
8 
NE 
10 
UNK 
11 
(missing) 
 
Date of progression  
Date of first observed progression. 
3. 
SUBJECT INFORMATION 
3.1. 
Demographics and Baseline Characteristics 
All demographics and baseline characteristic variables will be summarized for the all-treated 
population by disease type and study cohorts. 
 
No formal statistical hypothesis testing is planned. 
• 
Demographic and baseline characteristics data, including age (continuous and grouped as 
<65, or 65 years), sex, race, ethnicity, weight, height, and ECOG performance status will be 
summarized. 
• 
Disease characteristics at baseline including time from initial diagnosis to first dose, 
lymphoma-related symptoms, lactic acid dehydrogenase (LDH), number of lines of prior 
therapies (continuous and grouped as 1 and 2 to 4 and >4) and lymphocyte count (at baseline).  
• 
Chemistry: creatinine, AST, ALT, total bilirubin, lipase and amylase  
• 
Hematology: hemoglobin, white blood cell, absolute neutrophils, absolute lymphocyte 
count, and platelet count 
• 
Beta2-microglobulin, serum immunoglobulin levels (IgG, IgM, IgA). For continuous 
variables, mean, standard deviation, median, minimum, and maximum will be provided. For 
categorical variables, the number and percentage of subjects in each category will be 
summarized. 
3.2. 
Disposition Information 
Disposition will be summarized for the all-treated population by disease type and study cohorts, 
including the number and percentage of subjects who are treated and discontinued treatment as 
well as their reason for discontinuation. Similarly, number of subjects undergoing and 
discontinuing the study as well as their reasons for study discontinuation will be summarized. 
3.3. 
Medical History 
Abnormal medical history findings reported by the investigator will be summarized by body 
system. 
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3.4. 
Extent of Exposure 
Extent of exposure for ibrutinib will be summarized for the safety population by disease type 
and study cohorts.  Descriptive statistics (n, mean, standard deviation, median, and range) will 
be provided for total number of cycles, treatment duration (the interval between date of first dose 
and date of last dose), and ibrutinib dosing information including total dose received (the sum of 
administered doses), dose intensity (the ratio of total dose and treatment duration).  
Dose reduction for ibrutinib is defined as administered planned lower dose level. There is a one 
applicable dose level reduction for CLL/SLL cohort: 280 mg/day (level 1 reduction).  There are 
two applicable dose level reductions in FL, DLBCL or Richter syndrome disease cohorts: 420 
mg/day (level 1 reduction) or 280 mg/day (level 2 reduction). Dose reduction information will 
be summarized for the number of subjects with any dose reduction (at least 1 reported dose 
reduction), as well as the frequency and reason of dose reduction.  Number and percentage of 
subjects with cycle delays will also be presented.  
Dose interruption for ibrutinib is defined as missing/skipped dose for ≥ 7 day. The consecutive 
days of dose interruption are considered as 1 dose interruption.  The number and percentage of 
subjects with dose reduction and dose interruption will be summarized. In addition, subjects with 
dose modifications (i.e., reductions or interruptions) and reasons for dose modifications will be 
summarized. 
Extent of exposure for nivolumab will be summarized for the safety population by disease type 
and study cohorts.  Descriptive statistics (n, mean, standard deviation, median, and range) will 
be provided for total number of infusion, infusion duration (the interval between the start time 
of infusion and the end time of infusion), infusion rate interruption duration (the interval between 
the start time of infusion interruption and the end time of infusion interruption), and nivolumab 
dosing information including, total dose administered/received (the sum of actual dose 
administered), total number of infusions interrupted, total number of infusions skipped, total 
number of infusions discontinued and total number of infusion rate reductions, interval between 
2 consecutive infusions of nivolumab which is defined as end date of prior cycle to first day of 
following cycle.   
Dose modification is defined as at least 1 dose skipped or events occurred during infusion.  The 
frequency and reason of dose skipped or events occurred during infusion will be summarized.   
 
3.5. 
Protocol Deviations 
Subjects with eligibility and major protocol deviations will be summarized and listed, as 
appropriate. Protocol deviations will be based on clinical review for the following aspects, but 
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not limited to: (1) eligibility, (2) treatment compliance, (3) patient safety, and (4) efficacy 
assessment deviation. Protocol deviations will be closely monitored during the execution of the 
study and the final set of protocol deviation criteria will be finalized before database lock. 
3.6. 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarized by the World Health Organization Drug 
Dictionary (WHO-DD) therapeutic class, pharmacological class, and preferred term.   
4. 
EFFICACY 
The primary population for the primary efficacy endpoint, ORR, is the all-treated. Sensitivity 
analysis will be performed on the response-evaluable population, if deemed necessary. Unless 
otherwise specified efficacy analyses will be based on the all-treated population.  
4.1. 
Analysis Specifications 
4.1.1. 
Level of Significance 
If deemed applicable, all tests will be 1-sided. The primary efficacy endpoint will be tested at 
the overall significance level of 0.025. For result presentation purpose, a 2-sided 95% 
confidence interval will be used. 
4.1.2. 
Data Handling Rules 
Unless otherwise specified, missing values will not be imputed. 
4.1.3. 
General Analysis Considerations 
For this study and its CSR, analyses of disease response and disease progression are based on 
investigator assessments.  These assessments are based on IWCLL [International Workshop 
on Chronic Lymphocytic Leukemia (Hallek 2008)] for CLL patients and the Lugano 
Classification by Cheson (2014) for SLL, FL, DLBCL and Richter syndrome and using data 
collected at the clinical cutoff. Detailed criteria for response category can be found in Section 
10.1 of the protocol.  All the additional data collected after the clinical cutoff will be 
summarized in the CSR addendum. 
4.2. 
Primary Efficacy Endpoint(s) 
4.2.1. 
Definition 
The primary endpoint is ORR, defined as the proportion of subjects who achieve partial 
response or better [PR(+L) or better], as assessed by the investigators at or prior to initiation 
of subsequent anti-cancer therapy.  The primary efficacy analysis of ORR will be conducted 
at performed 6 months after the last subject has received the first dose of study medication, or 
earlier if that subject discontinues study therapy. The analysis will be based on the all-treated 
population.  
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4.2.2. 
Analysis Methods 
The response rate and its 95% exact (Clopper-Pearson) CI will be calculated. Subgroup 
analysis will be provided.  Sensitivity analysis will be performed using the response-evaluable 
population. 
A listing of tumor response by assessment visit will be provided. 
4.3. 
Exploratory Secondary Endpoints 
4.3.1. 
Duration of Response 
Definition 
Duration of response is defined as the interval between the date of initial documentation of a 
response [PR(+L) or better] and the date of first documented evidence of PD (or relapse for 
subjects who experience CR during the study) or death, whichever occurs first. Subjects who 
are progression-free and alive, or have unknown status will be censored at the last adequate 
disease assessment.  
Analysis method 
Duration of response will be analyzed for subjects with PR(+L) or better. The distribution of 
duration of response will be estimated using the Kaplan-Meier method. The primary analysis 
will be based on response data by investigator assessment.    
 
4.3.2. 
Duration of Stable Disease or Better 
Definition 
Duration of stable disease or better is measured from the start of the treatment until the criteria 
for progression are met.   
Analysis method 
Duration of SD or better will be analyzed using descriptive summary statistics. Subjects whose 
progression criteria are not met at clinical cut-off will be censored at the last adequate disease 
assessment. 
 
4.3.3. 
Progression-free Survival and Overall Survival 
Definition 
PFS is defined as the interval between the date of first dose of study drug and the date of first 
documented evidence of PD (or relapse for subjects who experience CR during the study) or 
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death, whichever comes first. Subjects who are progression-free and alive, or have unknown 
status will be censored at the last adequate disease assessment. 
OS is defined as the interval between the date of the first dose of study drug and the date of the 
subject’s death from any cause. If the subject is alive at the time of the cut-off, it will be 
censored at the last known alive date (the last date among visit date, AE start and end dates, 
treatment date, disease assessment date, and survival follow up date, and if available, survival 
sweep date, etc.). 
Analysis method 
Similar analyses will be applied to OS and PFS as those used for duration of response. The 
distribution of PFS and OS will be estimated using the Kaplan-Meier method.  
The primary analysis of PFS will be based on assessments by investigator. The reason of 
censoring will be summarized for OS and PFS. The median follow-up duration will be 
provided. Follow-up duration is defined as OS with reversed censoring, i.e., subject who died 
will be censored.    The Kaplan-Meier method will be used to estimate the median follow-up. 
4.3.4. 
Resolution of Lymphoma-related symptoms 
Frequency and percentage of subjects with lymphoma-related symptoms will be summarized 
by cycle. All-treated population will be used.  
For subjects who have reported symptoms at baseline and had at least one time point of 
assessment post baseline (before the start of subsequent therapy), the following summaries will 
be provided for the resolution of symptoms: 
• Frequency and percentage of subjects who have no symptoms reported at least one post 
baseline time point (before the start of subsequent therapy) 
▪ Duration of resolution is defined as the interval between the initial time 
point of assessment when no symptoms was reported and the subsequent 
time point of assessment when symptoms re-occurred before symptoms re-
occurred. Subjects who have no B-symptoms and alive will be censored at 
the last B-symptom assessment prior to subsequent therapy initiated. This 
will be summarized descriptively.   
▪ Time to resolution (applicable to subject with symptom at baseline) is 
defined as the duration from baseline to the first time point when no 
symptom was reported. It will be summarized descriptively for those 
subjects who experienced resolution. 
▪ As an exploratory analysis, subject’s best response, will be summarized for 
those who experienced resolution.  
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5. 
SAFETY 
Safety will be analyzed using the incidence, intensity, and type of adverse events, laboratory tests. 
All safety analyses will be based on the safety analysis set. 
5.1. 
Adverse Events 
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the current Medical Dictionary for Regulatory Activities (MedDRA). The severity of 
adverse events is assessed in NCI common toxicity criteria for adverse events (CTCAE) Version 
4.03. 
Treatment-emergent adverse events are 1) adverse events that occur after the first dose of study 
treatment, and up to + 30 days after last ibrutinib or up to 100 days after last dose of nivolumab 
whichever is last, or the start date of a subsequent systemic anticancer therapy, whichever is 
earlier (including both dates), 2) any adverse event that is considered study treatment - related 
(at least relationship to one drug of combination will be considered related) (i.e., possibly, 
probably, or very likely related to study drug) regardless of the start date of the event, 3) any 
adverse event that is present at baseline but worsens in severity and is subsequently considered 
drug-related by the investigator.  
Treatment-emergent adverse events will be summarized by system organ class (SOC) and 
preferred term (PT), by severity, by relationship to study treatment, and by action taken. For each 
adverse event, the percentage of subjects who experience at least 1 occurrence of the given event 
will be summarized. Tables will be sorted by frequency in incidence (from the highest to lowest 
incidence). The same summary will be provided for drug-related adverse events, serious adverse 
events, and drug-related serious adverse events, immune-related events as well as adverse events 
leading to treatment discontinuation, and death. 
5.2. 
Adverse Events of Special   
Adverse events of special interest to be summarized include the following:  
Major Hemorrhage 
Hemorrhage SMQ without labs will be used to identify bleeding events. Any grade ≥3 
hemorrhage events, any SAE or all grades of CNS hemorrhage (preferred terms are listed in 
Appendix A). Events will be summarized by preferred terms. 
 
5.3. 
Adverse Events of Clinical Interest  
Other Malignancies 
New malignant tumors including solid tumors, skin malignancies and hematologic malignancies 
that occur after study treatment initiated will be identified and summarized by preferred terms 
and toxicity grade. Terms to be extracted are determined through cumulative AE term reviews.  
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Atrial Fibrillation 
Cardiac events – Atrial fibrillation will be extracted by preferred terms. The number and 
percentage of subjects who had events will be summarized by preferred terms.   
Ocular Events 
Ocular events will be extracted and summarized separately by preferred terms. 
Immune-related AEs (irAEs): Endocrine, Gastrointestinal, Hepatic, 
Hypersensitivity/Infusion Reaction, Pulmonary, Renal, Skin, and Visual Events 
Immune-related events will be extracted (as below) and summarized separately by preferred 
terms. 
CATEGORY 
SUBCATEGORY 
PREFERRED TERMS 
ENDOCRINE ADVERSE EVENT 
ADRENAL DISORDER 
ADRENAL UNSUFFICIENCY 
ADRENAL SUPPRESSION 
BLOOD CORTICOTROPHIN DECREASED 
BLOOD CORTICOTROPHIN INCREASED 
HYPOTHALAMIC PITUITARY ADRENAL AXIS SUPPRESSION              
SECONDARY ADRENOCORTICAL INSUFFICIENCY 
DIABETES 
DIABETES MELLITUS 
DIABETIC KETOACIDOSIS 
FULMINANT TYPE 1 DIABETES MELLITUS                           
LATENT AUTOIMMUNE DIABETES IN ADULTS                         
TYPE 1 DIABETES MELLITUS                                     
PITUITARY DISORDER 
HYPOPHYSITIS   
THYROID DISORDER 
AUTOIMMUNE THYROIDITIS                                       
BLOOD THYROID STIMULATING HORMONE DECREASED          
BLOOD THYROID STIMULATING HORMONE INCREASED                  
HYPERTHYROIDISM  
HYPOTHYROIDISM   
PRIMARY HYPERTHYROIDISM                                      
PRIMARY HYPOTHYROIDISM   
THYROID FUNCTION TEST ABNORMAL      
THYROID HORMONES DECREASED                                   
THYROID HORMONES INCREASED                                   
THYROIDITIS   
THYROIDITIS ACUTE                                            
THYROXINE DECREASED                                          
THYROXINE FREE DECREASED 
THYROXINE FREE INCREASED                                     
THYROXINE INCREASED                                          
TRI-IODOTHYRONINE UPTAKE INCREASED                           
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GASTROINTESTINAL 
ADVERSE EVENT 
AUTOIMMUNE COLITIS                                           
COLITIS  
COLITIS ULCERATIVE 
DIARRHOEA   
ENTERITIS  
ENTEROCOLITIS  
FREQUENT BOWEL MOVEMENTS 
GASTROINTESTINAL PERFORATION  
HEPATIC ADVERSE EVENT 
ACUTE HEPATIC FAILURE 
ALANINE AMINOTRANSFERASE INCREASED 
ASPARTATE AMINOTRANSFERASE INCREASED 
AUTOIMMUNE HEPATITIS 
BILIRUBIN CONJUGATED INCREASED 
BLOOD ALKALINE PHOPHATASE INCREASED 
BLOOD BILIRUBIN INCREASED 
DRUG-INDUCED LIVER INJURY 
GAMMA-GLUTAMYLTRANSFERASE INCREASED                          
HEPATIC ENZYME INCREASED  
HEPATIC FAILURE 
HEPATITIS 
HEPATITIS ACUTE 
HEPATOTOXICITY 
HYPERBILIRUBINAEMIA 
LIVER DISORDER  
LIVER FUNCTION TEST ABNORMAL 
LIVER INJURY 
TRANSAMINASES INCREASED  
HYPERSENSITIVITY/INFUSION 
REACTION 
ANAPHYLACTIC REACTION 
ANAPHYLACTIC SHOCK 
BRONCHOSPASM 
HYPERSENSITIVITY  
INFUSION RELATED REACTION 
PULMONARY ADVERSER 
EVENT 
ACUTE RESPIRATORY DISTRESS SYNDROME 
ACUTE RESPIRATORY FAILURE 
INTERSTITIAL LUNG DISEASE 
LUNG INFILTRATION 
PNEUMONITIS 
RENAL ADVERSER EVENT 
ACUTE KIDNEY INJURY  
BLOOD CREATININE INCREASED                                   
BLOOD UREA INCREASED 
CREATININE RENAL CLEARANCE DECREASED                         
HYPERCREATININAEMIA 
NEPHRITIS  
NEPHRITIS ALLERGIC   
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NEPHRITIS AUTOIMMUNE                                         
RENAL FAILURE                                                
RENAL TUBULAR NECROSIS                                       
TUBULOINTERSTITIAL NEPHRITIS                                 
URINE OUTPUT DECREASED                                       
SKIN ADVERSE EVENT 
AUTOIMMUNE DERMATITIS                                        
BLISTER 
DERMATITIS 
DERMATITIS EXFOLIATIVE 
DRUG ERUPTION 
ECZEMA 
ERYTHEMA 
ERYTHEMA MULTIFORME 
EXFOLIATIVE RASH 
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME  
PHOTOSENSITIVITY REACTION 
PRURITUS  
PRURITUS ALLERGIC                                            
PRURITUS GENERALISED  
PSORIASIS  
RASH 
RASH ERYTHEMATOUS                                            
RASH GENERALISED                                             
RASH MACULAR 
RASH MACULO-PAPULAR  
RASH PAPULAR                                                 
RASH PRURITIC                                                
SKIN EXFOLIATION                                             
SKIN HYPOPIGMENTATION 
SKIN IRRITATION  
STEVENS-JOHNSON SYNDROME 
TOXIC EPIDERMAL NECROLYSIS 
URTICARIA 
VITILIGO  
VISUAL AE 
UVEITIS 
VISION BLURRED 
ENDOPHTHALMITIS 
PHOTOSENSITIVITY REACTION 
VISUAL IMPAIRMENT 
PHOTOPSIA 
VISUAL FLOATERS 
PHOTOPHOBIA 
DIPLOPIA 
 
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Adverse events of interest and other safety observations will be summarized by disease type and 
study cohorts. 
5.4. 
Death 
A summary of the number of deaths since first administration of study agent up to + 30 days 
after last ibrutinib or up to 100 days after last dose of nivolumab whichever is last,  will be 
provided, along with the primary cause of death. A death is a study drug-related death if the 
primary cause is a drug-related adverse event.  
5.5. 
Clinical Laboratory Tests 
Laboratory data for hematology and serum chemistry tests, up to the later of the End of Treatment 
visit or up to + 30 days after last ibrutinib or up to 100 days after last dose of nivolumab 
whichever is last, will be reported in SI units. Applicable laboratory results will be graded 
according to NCI-CTCAE Version 4.03. Toxicity grading for creatinine increase is based on the 
NCI-CTCAE v4.03 criteria but limited only to the part based on the ULN, the other part that is 
based on change from baseline is not used for toxicity grading. Toxicity grading for all other lab 
parameters are based on the NCI-CTCAE v4.03 criteria as is. 
The following laboratory tests will be analyzed:  
• 
Hematology: hemoglobin, white blood cell count (WBC), absolute neutrophil count 
(ANC), absolute lymphocyte count (ALC), and platelet count 
• 
Chemistry: sodium, potassium, magnesium, creatinine, creatinine clearance (CrCl), AST, 
ALT, alkaline phosphatase, LDH, total bilirubin, albumin, amylase and lipase. 
• 
Beta2-microglobulin, serum immunoglobulin levels (IgG, IgM, IgA): only for FL and 
CLL/SLL disease cohorts. 
• 
Coagulation panel: PT APTT and INR 
• 
Thyroid function: T3 free T4 and TSH 
Descriptive statistics (mean, standard deviation, median, and range) will be calculated for the 
raw data and for change from baseline at each time point of assessment, as well as for change 
from baseline to the last value. Worst toxicity grade will be summarized for all hematology and 
chemistry parameters except for LDH, which will be summarized by abnormal/normal using 
normal ranges. Change from baseline to the worst grade during the treatment will be provided 
as shift tables for selected parameters. 
Lymphocytosis is defined as ALC increasing ≥ 50% from baseline and achieving level ≥ 5x109 
/L. Descriptive statistics will be provided for time to first lymphocytosis, i.e., time from first 
dose to date of first lymphocytosis. Similar to duration of response, Kaplan-Meier method will 
be used to estimate duration of first lymphocytosis as the time from first lymphocytosis to the 
earliest date of its resolution (i.e., when ALC decreased to the baseline level or lower or 
achieving level of < 5x109 /L) or date of censoring (i.e., date of last non-missing ALC). 
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5.5.1. 
Creatinine Clearance 
Creatinine clearance (CrCl) is calculated using the Cockroft-Gault formula: 
            
 
   for males, the factor is 1 instead of 0.85 
 
5.6. 
Other Safety Parameters 
Change in ECOG scores from baseline to the worst score during the treatment will be provided 
as shift tables.  
Subjects with more than 10% weight loss from baseline will be summarized. 
• Change in ECG (QTcF only) from baseline to the worst score during the treatment will be 
provided as shift tables  
• Listing of transfusion dependency by subject 
• Listing of requirement of gCSF by subject 
6. 
Pharmacokinetics 
The plasma concentration data for ibrutinib and, if possible and judged relevant, PCI-45227 and 
other metabolites, if possible, will be summarized at each time point using descriptive statistics.  
Population pharmacokinetic analysis of plasma concentration-time data will be performed using 
nonlinear mixed-effects modeling. Data may be combined with data from other studies to support 
a relevant structural population-based pharmacokinetic model. Available subject characteristics 
(demographics, laboratory variables, genotypes, etc.) will be tested as potential covariates 
affecting pharmacokinetic parameters. Details will be given in a population pharmacokinetic 
analysis plan and the results of the population pharmacokinetic analysis will be presented in a 
separate report. 
Data will be listed for all subjects with available plasma concentrations. Subjects will be excluded 
from the pharmacokinetic analysis if their data do not allow for accurate assessment of the 
pharmacokinetic (e.g., incomplete administration of the study agent; concentration data not 
sufficient for pharmacokinetic parameter calculation due to missing pharmacokinetic draws at 
multiple visits; or early discontinuation from the study). 
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration data presentation. Concentrations below the lowest quantifiable 
concentration will be treated as zero in the summary statistics. All subjects and samples excluded 
from the analysis will be clearly documented in the study report. 
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For each dosage, descriptive statistics, including arithmetic mean, standard deviation, coefficient 
of variation, geometric mean, median, minimum, and maximum will be calculated for the ibrutinib 
and PCI-45227 plasma concentrations at each sampling time and for all pharmacokinetic 
parameters of ibrutinib. 
7. 
Biomarker 
7.1. 
Biomarker Objectives 
Inhibition of BTK tyrosine phosphorylation by ibrutinib has been shown to abrogate downstream 
survival pathways (eg, ERK1/2, PI3K, NF-kB, and MAPK). Inhibition by ibrutinib also interferes 
with activation of integrins and chemokine networks leading to interference with adhesion, 
migration, and homing of malignant cells. It is anticipated that subjects with alterations in BCR-
signaling components or activation of alternative signaling pathways may have differential 
response to treatment.   
7.2. 
Biomarker Analysis Sets 
This population consists of all subjects who receive at least 1 dose of study drug (either ibrutinib 
or nivolumab). Subjects from this population will be analyzed if they received the treatment, have 
data from at least one of the clinical endpoints and also have data from any biomarkers. The 
biomarker population is defined as having at least one assay among all the results. 
7.3. 
Biomarker Stratification Groups 
Biomarker analysis will be performed with no patient stratification (all patients) and with 
stratification by dose expansion cohort by indication (i.e., biomarker stratification cohort) as 
shown: 
A. CLL 
B. CLL only del 17p 
C. CLL only del 11q 
D. FL 
E. DLBCL 
F. ABC-DLBCL (if available) 
G. GCB-DLBCL (if available) 
H. Richter Syndrome  
I. ABC-like Richter’s (if available) 
J. GCB-like Richter’s (if available) 
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7.4. 
Biomarker Tested 
• IHC of PDL1, NGS and GEP (if available) 
PDL1 protein levels will be examined on tumor cells by Immunohistochemistry (IHC). 
FFPE slides from screening will be examined by IHC for PDL1 Staining. Cut points are 
listed  
Biomarker 
Type 
Biomarker 
Description 
Levels 
(Cutpoints) 
Data column 
IHC 
PDL1 
PDL1 option 1 
Not elevated <5% 
Elevated ≥5% 
PERCENT OF VIABLE TUMOR CELLS 
THAT EXHIBIT PD-L1 MEMBRANE 
STAINING 
IHC 
PDL1 
PDL1 option 2 
Negative = 0  
Positive >0 
PERCENT OF VIABLE TUMOR CELLS 
THAT EXHIBIT PD-L1 MEMBRANE 
STAINING 
NGS 
CARD11 
Mutation 
Positive  
Negative 
 
NGS 
Additional 
genes ~5 
Mutations 
Positive  
Negative 
 
GEP (if 
available) 
Genes ~10 
Expression 
>Median 
<=Median 
calculated within 
disease group 
 
 
• T cell Panel 
The following flow cytometry T-cell panel will determine a percentage and absolute 
numbers of each cell type at multiple time points (C1D1, C1D7, C3D1 and End of 
Treatment (EOT) or Progression (PRO): 
1. Absolute lymphocyte counts 
2. Viable CD3+, % of Single Lymphocytes  
3. Variable CD3+, Counts  
4. CD4% of CD3 
5. CD8% of CD3 
6. TH17, % of CD4+  
7. Treg, % of CD4+  
8. CD4+ICOS+, % of CD4+  
9. CD4+OX40+, % of CD4+  
10. CD4+PD-1+, % of CD4+  
11. CD8+ICOS+, % of CD8+  
12. CD8+OX40+, % of CD8+  
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13. CD8+PD-1+, % of CD8+ 
 
These values need to be calculated: 
14. CD4 Counts  
15. Treg Counts 
16. TH17 Counts 
17. CD4/OX40 Counts  
18. CD4/PD-1 Counts 
19. CD4/ICOS Counts  
20. CD8 Counts 
21. CD*/OX40 Counts  
22. CD8/PD-1 Counts  
23. CD8/ICOS Counts 
 
7.5. 
Association Analysis of Biomarkers with Clinical Efficacy Endpoints 
The primary endpoint is ORR, defined as the proportion of subjects who achieve partial response 
or better [PR(+L) or better], as assessed by the investigators at or prior to initiation of subsequent 
anti-cancer therapy.  The primary efficacy analysis of ORR will be conducted at performed 6 
months after the last subject has received the first dose of study medication, or earlier if that subject 
discontinues study therapy.  The analysis will be based on the response-evaluable or biomarker 
populations, as see appropriate.  
In addition, the following secondary endpoints will be evaluated if there are sufficient events to 
warrant the analysis: 
• Duration of Response. 
• Time to Response. 
• Progression-free Survival and Overall Survival. 
• Best overall Response. 
 
7.5.1. 
Level of Significance 
All tests will be 1-sided. The primary efficacy endpoint will be tested at the overall significance 
level of 0.025.  Nominal p-values will be presented for all statistical analyses, if applicable. 
7.5.2. 
Missing Data Handling 
If >90% of subjects have missing value for a particular biomarker, or if all subjects have the same 
value for a biomarker, then only the frequencies will be summarized and that biomarker will be 
removed from further analysis. 
If a subject has missing data for a clinically defined endpoint, that subject will be excluded from 
that particular association analysis but included in other analyses where data is available. 
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7.5.3. 
Data Transformation and imputation 
No transformation will be performed on any of the clinical data other than what was transformed 
as part of the clinical statistical analysis.  If deemed applicable, biomarker data may be log (base 
2 or 10) transformed if the data distribution is not normal or otherwise skewed.  Shapiro-Wilk’s 
test will be used to determine normality for baseline only. 
7.5.4. 
Outlier Detection and Handling 
No outlier handling will be performed 
7.5.5. 
Biomarker Data Analysis Methods for PDL1, and NGS and GEP (if 
available) 
• Median, mean (SD), and range for continuous variable or N and frequency (%) for 
categorical variables will be reported for all-treated versus the biomarker populations for 
selected demographic and baseline characteristic variables including the biomarker 
stratification cohorts.  
• The number of subjects (N) and the associated percentage (%) will be presented to facilitate 
the evaluation of the response rate. The median duration of response (arising from Kaplan 
-Meier estimate) between 1) PDL1 IHC option 1/2 subgroups (i.e., not elevated/negative 
vs. elevated/positive); 2) NGS subgroups (i.e., negative vs. positive); 3) GEP subgroups 
(i.e., >median vs. <=median) will also be reported.  
 The relationship between 1) PDL1 not elevated (or negative) vs. elevated (or positive) 
subgroups; 2) NGS negative vs. positive subgroups; 3) GEP subgroups >median vs. 
<=median subgroup for duration of response, progression-free survival and overall survival 
will be evaluated by the Kaplan-Meier method. If the number of subjects is ≤7 then Kaplan-
Meier analyses are unnecessary. 
• For each of the biomarker stratification cohort, Fisher exact test will be used to test the 
association on the response between 1) PDL1 subgroups (not elevated and elevated for 
option 1; negative and positive for option 2); 2) NGS subgroups (negative vs. positive); 3) 
GEP subgroups (>median vs. <=median)  
• Descriptive summary statistics [i.e., mean (SD), median and range] will be used to evaluate 
time to initial response and best response of the PDL1, NGS and GEP subgroups for each 
of the biomarker stratification cohort.  
7.5.6. 
Biomarker Data Analysis Methods for Flow Cytometry T-cell Type 
Panel Data 
• Data arisng from T-cell type panel collected over time will be descriptively summarized 
for each biomarker stratification cohorts.  The corresponding mean (± se) over time line 
plot for each biomarker stratification cohorts will be generated. In Addition, mean change 
and percent change from baseline will also be descriptively summarized.  The 
corresponding mean change and percent change from baseline values will be plotted. 
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• Mean values for each T- cell type over times by response group (i.e., non-responder and 
responder) will be reported for the biomarker stratification groups − CLL, FL, DLBCL, 
ABC-DLBCL, GCB-DLBCL and Richter’s. For each cell type, the corresponding mean (± 
se) line and box plots over time by response group for each selected biomarker stratification 
group will be generated. Similarly, the mean (± se) line plot over time by progression group 
(i.e., progressor and non-progressor) for each cell type for selected biomarker stratification 
group will also be generated.    
• Paired t-test will be performed to compare the mean at baseline vs the mean at each post 
baseline time point for each cell type and for each selected biomarker stratification group 
by respond group and progression group, respectively.    
 
REFERENCES 
1. 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 
2007;25(5):579-586. 
2. 
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(12):5446-5456. 
APPENDICES 
1. 
Appendix A 
Preferred terms for CNS hemorrhage are as follows: 
▪ Acute haemorrhagic leukoencephalitis   
▪ Basal ganglia haemorrhage 
▪ Brain stem haemorrhage 
▪ Brain stem haematoma 
▪ Central nervous system haemorrhage 
▪ Cerebellar haematoma 
▪ Cerebellar haemorrhage 
▪ Cerebral arteriovenous malformation haemorrhagic 
▪ Cerebral haematoma 
▪ Cerebral haemorrhage 
▪ Cerebral microhaemorrhage 
▪ Encephalitis haemorrhagic 
▪ Epidural haemorrhage 
▪ Extradural haematoma 
▪ Haemorrhage intracranial 
▪ Haemorrhagic cerebral infarction 
▪ Haemorrhagic stroke 
▪ Haemorrhagic transformation stroke 
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▪ Intracerebral haematoma evacuation 
▪ Intracranial haematoma 
▪ Intracranial tumour haemorrhage 
▪ Intraventricular haemorrhage 
▪ Pituitary haemorrhage 
▪ Putamen haemorrhage 
▪ Ruptured cerebral aneurysm  
▪ Spinal cord haemorrhage 
▪ Spinal epidural haematoma 
▪ Spinal epidural haemorrhage 
▪ Spinal subarachnoid haemorrhage 
▪ Spinal haematoma 
▪ Spinal subdural haematoma 
▪ Spinal subdural haemorrhage 
▪ Subarachnoid haemorrhage 
▪ Subdural haematoma 
▪ Subdural haemorrhage 
▪ Subgaleal haematoma 
▪ Thalamus haemorrhage 
 
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