Clinical trial NCT02077166
Conditions: Relapsed Diffuse Large B-Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma
Keywords: DLBCL
Sponsor: Pharmacyclics LLC.
Start date: 2014-03-13; Completion date: 2020-12-17
Enrollment: 138 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This Phase 1b/2 study is designed to assess the safety and efficacy of ibrutinib in combination with lenalidomide and rituximab in subjects with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not eligible for transplant.

Detailed description:
Phase 1b: In the dose escalation portion of the study, various cohorts with escalating doses of lenalidomide may be explored, using the 3+3+3 principle for dose determination.

Phase 2: This will be conducted as an international, multicenter, open-label study. Eligible subjects will receive ibrutinib, lenalidomide and rituximab.

Arms: arm 1: Ibrutinib 560 mg administered orally (PO) once daily (QD) beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered intravenously (IV) on Day 1 of each 28-day cycle for 6 cycles. arm 2: De-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 10 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. arm 3: Re-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. arm 4: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. arm 5: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. arm 6: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. arm 7: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.
Interventions: intervention 1: Ibrutinib intervention 2: Lenalidomide intervention 3: Rituximab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
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PROTOCOL
TITLE:
A Multicenter Open-Label Phase 1b/2 Study of the Bruton’s 
Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with 
Lenalidomide and Rituximab in Subjects with Relapsed or 
Refractory Diffuse Large B-Cell Lymphoma  
PROTOCOL NUMBER:
PCYC-1123-CA
STUDY DRUG:
Ibrutinib (PCI-32765) 
IND NUMBER:
102,688
EudraCT NUMBER:
2013-004341-17 
SPONSOR MEDICAL 
MONITOR:
Pharmacyclics LLC  
Phone: 
Fax:
Email:
SPONSOR:
Pharmacyclics LLC (An AbbVie Company) 
995 East Arques Avenue  
Sunnyvale, CA 94085-4521
United States of America
DATE FINAL:
21 October 2013 
AMENDMENT 1.0: 
13 January 2014 
AMENDMENT 2.0: 
03 February 2015 
AMENDMENT 3.0:
13 July 2015  
AMENDMENT 4.0: 
10 November 2015 
AMENDMENT 5.0:
01 June 2016  
Confidentiality Statement
This document contains confidential information of Pharmacyclics LLC that must not be disclosed to 
anyone other than the recipient study staff and members of the Institutional Review Board/Independent 
Ethics Committee.  This information cannot be used for any other purpose other than the evaluation 
or conduct of the clinical study without the prior written consent of Pharmacyclics LLC.
NCT02077166




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TABLE OF CONTENTS
PROTOCOL APPROVAL PAGE ...............................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF APPENDICES ...............................................................................................................8 
LIST OF IN-TEXT TABLES AND FIGURES ...........................................................................8 
SYNOPSIS ......................................................................................................................................9 
ABBREVIATIONS ......................................................................................................................18 
1. 
INTRODUCTION............................................................................................................21 
1.1. 
Ibrutinib (PCI-32765) Background .................................................................................21 
1.2. 
Diffuse Large B-Cell Lymphoma ...................................................................................21 
1.2.1. 
ABC (Non-GCB) Subtype ..............................................................................................22 
1.3. 
Standard Treatment and Unmet Medical Need ...............................................................22 
1.4. 
BTK and B cell Lymphoma ............................................................................................25 
1.5. 
Summary of Nonclinical Data ........................................................................................26 
1.5.1. 
Pharmacology .................................................................................................................26 
1.5.2. 
Safety Pharmacology and Toxicology ............................................................................26 
1.6. 
Summary of Clinical Data ..............................................................................................27 
1.6.1. 
Pharmacokinetics and Product Metabolism ....................................................................27 
1.7. 
Summary of Clinical Safety of Ibrutinib ........................................................................27 
1.7.1. 
Monotherapy Studies ......................................................................................................27 
1.7.2. 
Combination Therapy Studies.........................................................................................28 
1.8. 
Risks (Ibrutinib) ..............................................................................................................29 
1.8.1. 
Lymphocytosis and Leukostasis .....................................................................................29 
1.8.2. 
Bleeding-related Events ..................................................................................................29 
1.8.3. 
Rash.................................................................................................................................30 
1.8.4. 
Non-melanoma skin cancer.............................................................................................30 
1.8.5. 
Diarrhea...........................................................................................................................30 
1.8.6. 
Tumor Lysis Syndrome...................................................................................................30 
1.8.7. 
Infections.........................................................................................................................30 
1.8.8. 
Interstitial Lung Disease (ILD) .......................................................................................30 
1.8.9. 
Cytopenias.......................................................................................................................30 
1.8.10. Atrial Fibrillation ............................................................................................................31 
1.9. 
Summary of Clinical Safety for Lenalidomide in Lymphoma .......................................31 
1.9.1. 
Venous Thromboembolism .............................................................................................31 
1.9.2. 
Second New Cancers ......................................................................................................32 
1.10. 
Summary of Clinical Safety for Rituximab ....................................................................32 
1.11. 
Rationale for Combination ..............................................................................................32 
1.12. 
Rationale for Dose ..........................................................................................................33 
1.13. 
Rationale for Implementation of Dose Re-Escalation ....................................................34 
1.13.1. Cohort 1 Findings at Dose Level 1 (15 mg lenalidomide) ..............................................34 
1.13.2. Findings in Study CTEP/A051103 .................................................................................34 
1.13.3. Rationale for Changes in Amendment 2.0 ......................................................................35 
1.14. 
Rationale for Changes in Amendment 3.0 ......................................................................35 
1.14.1. Tumor Lysis Syndrome...................................................................................................35 
1.14.2. Neutropenia .....................................................................................................................36 


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1.14.3. Deep Venous Thrombosis ...............................................................................................37 
1.14.4. Treatment of Subjects with DLTs ...................................................................................37 
1.15. 
Rationale for Changes in Amendment 4.0 ......................................................................38 
1.15.1. Removal of Arm without Rituximab ..............................................................................38 
1.15.2. Proposed Lenalidomide Dose for Phase 2 ......................................................................38 
1.16. 
Rationale for Changes in Amendment 5.0 ......................................................................38 
1.17. 
PCYC-1123-CA Phase 1b Data Summary .....................................................................39 
1.17.1. Preliminary Summary of Safety Data .............................................................................39 
1.17.2. DLRC Meeting Outcome ................................................................................................40 
2. 
STUDY OBJECTIVE ......................................................................................................41 
2.1. 
Primary Objectives..........................................................................................................41 
2.2. 
Secondary Objectives......................................................................................................41 
2.3. 
Exploratory Objectives ...................................................................................................42 
3. 
STUDY DESIGN ..............................................................................................................42 
3.1. 
Overview of Study Design ..............................................................................................42 
3.2. 
Phase 1b Dose Escalation and Expansion Overview ......................................................44 
3.3. 
Phase 2 Efficacy Evaluation Overview ...........................................................................45 
4. 
SUBJECT SELECTION .................................................................................................45 
4.1. 
Inclusion Criteria ............................................................................................................45 
4.2. 
Exclusion Criteria ...........................................................................................................48 
5. 
TREATMENT OF SUBJECTS ......................................................................................49 
5.1. 
Phase 1b Dose Escalation and Stopping Rules ...............................................................49 
5.2. 
Dose Limiting Toxicity (DLT) Definition ......................................................................50 
5.3. 
Treatment Regimens .......................................................................................................52 
5.3.1. 
Phase 1b ..........................................................................................................................52 
5.3.2. 
Phase 2 ............................................................................................................................52 
5.4. 
Ibrutinib...........................................................................................................................52 
5.4.1. 
Formulation, Packaging, and Storage of Ibrutinib ..........................................................53 
5.4.2. 
Dose and Administration of Ibrutinib .............................................................................53 
5.4.3. 
Dose Hold, Reduction or Discontinuation of Ibrutinib ...................................................53 
5.4.4. 
Dose Modification of Ibrutinib .......................................................................................54 
5.4.5. 
Ibrutinib Dose Modification for Hepatic Impaired Subjects ..........................................55 
5.5. 
Lenalidomide ..................................................................................................................56 
5.5.1. 
Formulation, Packaging, and Storage of Lenalidomide..................................................56 
5.5.2. 
Lenalidomide Prescribing Information (applies to US sites only)..................................56 
5.5.3. 
Lenalidomide Drug Dispensing Requirements (applies to ex-US sites only) ................56 
5.5.4. 
Dosage, Preparation and Administration of Lenalidomide .............................................57 
5.5.5. 
Dose Delay, Reduction or Discontinuation of Lenalidomide .........................................58 
5.5.6. 
Dose Modification of Lenalidomide during a Cycle (applies to Days 1-21) ..................59 
5.6. 
Rituximab ........................................................................................................................61 
5.6.1. 
Formulation, Packaging, and Storage of Rituximab .......................................................61 
5.6.2. 
Dosage, Preparation and Administration of Rituximab ..................................................61 
5.6.3. 
Dose Delay of Rituximab................................................................................................62 
5.6.4. 
Dose Interruption of Rituximab ......................................................................................62 
5.6.5. 
Dose Modification of Rituximab ....................................................................................63 
5.7. 
Study Drug Compliance ..................................................................................................63 
5.7.1. 
Ibrutinib and Lenalidomide Compliance ........................................................................63 


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5.7.2. 
Rituximab Compliance ...................................................................................................64 
5.8. 
Overdose Instructions .....................................................................................................64 
5.8.1. 
Ibrutinib...........................................................................................................................64 
5.8.2. 
Lenalidomide ..................................................................................................................64 
5.8.3. 
Rituximab ........................................................................................................................64 
5.9. 
Criteria for Permanent Discontinuation of Study Treatment ..........................................64 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES .................................................65 
6.1. 
Concomitant Medications ...............................................................................................65 
6.1.1. 
Permitted Concomitant Medications ...............................................................................65 
6.1.2. 
Medications to be Used with Caution .............................................................................65 
6.1.3. 
Prohibited Concomitant Medications .............................................................................66 
6.2. 
Guidelines for Ibrutinib Management with Surgeries or Procedures .............................67 
6.2.1. 
Minor Procedures ............................................................................................................67 
6.2.2. 
Major Procedures ............................................................................................................67 
6.3. 
Emergency Procedures....................................................................................................67 
7. 
STUDY EVALUATIONS ................................................................................................67 
7.1. 
Screening / Administrative .............................................................................................67 
7.1.1. 
Informed Consent............................................................................................................67 
7.1.2. 
Confirm Eligibility ..........................................................................................................68 
7.1.3. 
Medical History and Demographics ...............................................................................68 
7.1.4. 
Venous Thromboembolism Risk Assessment ................................................................68 
7.1.5. 
Prior and Concomitant Medications ...............................................................................68 
7.1.6. 
Adverse Events ...............................................................................................................68 
7.2. 
Assessments ....................................................................................................................69 
7.2.1. 
Physical Examination, Height, and Weight ....................................................................69 
7.2.2. 
Eastern Cooperative Oncology Group (ECOG) Performance Status .............................69 
7.2.3. 
Vital Signs .......................................................................................................................69 
7.2.4. 
Electrocardiogram (ECG) ...............................................................................................69 
7.3. 
Efficacy Assessments......................................................................................................69 
7.3.1. 
Radiographic Imaging .....................................................................................................70 
7.3.2. 
Physical Examination......................................................................................................70 
7.3.3. 
Bone Marrow Aspirate and Biopsy .................................................................................71 
7.4. 
Survival and Subsequent Anticancer Therapies .............................................................71 
7.4.1. 
Survival ...........................................................................................................................71 
7.4.2. 
Subsequent Anticancer Therapies ...................................................................................71 
7.5. 
Clinical Laboratory Assessments ....................................................................................72 
7.5.1. 
Hematology .....................................................................................................................72 
7.5.2. 
Serum Chemistry ............................................................................................................72 
7.5.3. 
Creatinine Clearance .......................................................................................................72 
7.5.4. 
Coagulation Studies ........................................................................................................72 
7.5.5. 
Hepatitis Serologies ........................................................................................................72 
7.6. 
Biomarker, Correlative and Special Studies ...................................................................73 
7.6.1. 
Pharmacokinetics ............................................................................................................73 
7.6.2. 
Biomarkers ......................................................................................................................74 
7.6.3. 
Gene Expression Profiling and Immunohistochemistry .................................................75 
7.6.4. 
T/B/NK Cell Count .........................................................................................................75 
7.6.5. 
Serum Immunoglobulins (Phase 2 only).........................................................................75 
7.6.6. 
Tumor Tissue Sample .....................................................................................................75 


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7.7. 
Sample Collection and Handling ....................................................................................76 
8. 
STUDY PROCEDURES .................................................................................................76 
8.1. 
Overview .........................................................................................................................76 
8.2. 
Screening Phase ..............................................................................................................76 
8.2.1. 
Screening Visit ................................................................................................................76 
8.3. 
Treatment Phase ..............................................................................................................77 
8.3.1. 
Cycle 1, Day 1.................................................................................................................78 
8.3.2. 
Cycle 1, Day 8.................................................................................................................78 
8.3.3. 
Cycle 1, Day 15...............................................................................................................79 
8.3.4. 
Cycle 1, Day 22...............................................................................................................79 
8.3.5. 
Cycle 2, Day 1.................................................................................................................80 
8.3.6. 
Cycle 2, Day 15...............................................................................................................81 
8.3.7. 
Cycle 2, Days 22-28 ........................................................................................................81 
8.3.8. 
Cycles 3 and 5, Day 1 .....................................................................................................81 
8.3.9. 
Cycle 3, Day 15...............................................................................................................82 
8.3.10. Cycle 3, Days 22-28 ........................................................................................................82 
8.3.11. Cycle 4, Day 1.................................................................................................................83 
8.3.12. Cycle 4, Days 22-28 ........................................................................................................84 
8.3.13. Cycle 6, Day 1.................................................................................................................84 
8.3.14. Cycle 6, Days 22-28 ........................................................................................................85 
8.3.15. Cycle 7, Day 1 and Beyond ............................................................................................85 
8.3.16. Cycle 7 and 8, Days 22-28 ..............................................................................................86 
8.3.17. Cycle 9 and Beyond, Days 22-28 ...................................................................................86 
8.3.18. Response Evaluation .......................................................................................................86 
8.3.19. End-of-Treatment Visit ...................................................................................................87 
8.4. 
Follow-up Phase..............................................................................................................88 
8.4.1. 
Response Follow-Up .......................................................................................................88 
8.4.2. 
Long-Term Follow-Up....................................................................................................88 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ....................................................89 
9.1. 
Completion ......................................................................................................................89 
9.2. 
Withdrawal from Study Treatment .................................................................................89 
9.3. 
Withdrawal from Study (Study Exit) ..............................................................................89 
10. 
STATISTICAL METHODS AND ANALYSIS ............................................................90 
10.1. 
General Considerations ...................................................................................................90 
10.1.1. Response Assessment .....................................................................................................90 
10.1.2. Safety Monitoring ...........................................................................................................91 
10.2. 
Definition of Analysis Populations .................................................................................91 
10.3. 
Endpoint Data Analysis ..................................................................................................91 
10.3.1. Demographic/Baseline Characteristics and Study Conduct ...........................................91 
10.3.2. Efficacy Endpoints for Phase 1b .....................................................................................91 
10.3.3. Primary Efficacy Endpoint for Phase 2 ..........................................................................92 
10.3.4. Secondary Efficacy Endpoints for Phase 2 .....................................................................92 
10.3.5. Exploratory Analysis (Phase 2 only) ..............................................................................93 
10.3.6. Safety Endpoint ...............................................................................................................93 
10.3.7. Pharmacokinetics ............................................................................................................93 
10.3.8. Biomarkers ......................................................................................................................94 
10.4. 
Determination of Sample Size ........................................................................................94 


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10.5. 
Interim analysis ...............................................................................................................94 
10.6. 
Safety Analysis ...............................................................................................................95 
10.6.1. Adverse Events ...............................................................................................................95 
10.6.2. Clinical Laboratory Tests ................................................................................................96 
10.6.3. Dose Level Review Committee ......................................................................................96 
11. 
ADVERSE EVENT REPORTING ................................................................................96 
11.1. 
Adverse Event Definitions and Classifications...............................................................96 
11.1.1. Adverse Events ...............................................................................................................96 
11.1.2. Serious Adverse Events ..................................................................................................97 
11.1.3. Unexpected Adverse Events ...........................................................................................98 
11.1.4. Severity Criteria (Grade 1-5) ..........................................................................................98 
11.1.5. Causality (Attribution) ....................................................................................................99 
11.2. 
Documenting and Reporting of Adverse Events ............................................................99 
11.2.1. Special Reporting Situations ...........................................................................................99 
11.2.2. Adverse Event Reporting Procedures ...........................................................................100 
11.2.3. Events of Special Interest..............................................................................................101 
11.2.4. Other Malignancies .......................................................................................................101 
11.2.5. Pregnancy ......................................................................................................................102 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ...............102 
12.1. 
Regulatory and Ethical Compliance .............................................................................102 
12.2. 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval................................................................................102 
12.3. 
Informed Consent..........................................................................................................103 
12.4. 
Long-Term Retention of Samples for Additional Future Research ..............................103 
12.5. 
Quality Control and Quality Assurance ........................................................................103 
12.6. 
Protected Subject Health Information Authorization ...................................................104 
12.7. 
Study Files and Record Retention.................................................................................104 
12.8. 
Case Report Forms and Record Maintenance ...............................................................105 
12.9. 
Investigational Study Drug Accountability ..................................................................105 
12.10. 
Study Monitoring/Audit Requirements.........................................................................106 
12.11. 
Investigator Responsibilities .........................................................................................107 
12.12. 
Sponsor Responsibilities ...............................................................................................107 
12.13. 
Financial Disclosure......................................................................................................107 
12.14. 
Liability and Clinical Trial Insurance ...........................................................................108 
12.15. 
Protocol Amendments ...................................................................................................108 
12.16. 
Publication of Study Results .........................................................................................108 
12.17. 
Study Discontinuation ...................................................................................................109 
12.18. 
Study Completion .........................................................................................................109 
13. 
REFERENCES ...............................................................................................................110 
14. 
APPENDICES ................................................................................................................113 


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LIST OF APPENDICES 
Appendix 1.
Schedule of Assessments .....................................................................................114
Appendix 2.
ECOG Status Scores ............................................................................................117
Appendix 3.
Cockcroft-Gault Formula for Estimating Creatinine Clearance ..........................118
Appendix 4.
Inhibitors and Inducers of CYP3A ......................................................................119
Appendix 5.
Revised International Working Group Response Criteria for Malignant 
Lymphoma (Cheson 2007) – Phase 1b Only .......................................................120
Appendix 6.
Revised International Working Group Response Criteria for Malignant 
Lymphoma or Lugano Classification (Cheson 2014) – Phase 2 only .................121
Appendix 7.
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods (for US Sites only) ..........................................................125
Appendix 8.
Lenalidomide Pregnancy Prevention Risk Management Plans  (for ex-US 
sites only) .............................................................................................................128
Appendix 9.
Child-Pugh Score for Subjects with Liver Impairment .......................................141
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1:
Efficacy of Therapies in Relapsed/Refractory NHL Patients ................................23
Table 2:
Efficacy of Select Studies in Relapsed/Refractory NHL Patients .........................24
Table 3:
Dosing Schedule ....................................................................................................44
Table 4:
Phase 1b Dosing Levels .........................................................................................52
Table 5:
Ibrutinib Dose Modifications .................................................................................55
Table 6:
Dose Modification or Interruption for Lenalidomide Toxicity during a 
Cycle ......................................................................................................................59
Table 7:
Dose Reduction of Lenalidomide ..........................................................................61
Table 8:
Dose Modification for Rituximab Toxicity ...........................................................63
Table 9:
Pharmacokinetic Sample Schedule ........................................................................73
Figure 1:
Study Design Schematic ........................................................................................44


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SYNOPSIS
Study Title
A Multicenter Open-Label Phase 1b/2 Study of the Bruton’s Tyrosine 
Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Lenalidomide and 
Rituximab in Subjects with Relapsed or Refractory Diffuse Large B-Cell 
Lymphoma
Protocol Number
PCYC-1123-CA
Study Phase
1b/2
Population
Phase 1b: Relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
Phase 2: Relapsed or refractory de novo DLBCL of non-germinal center 
B-cell like (non-GCB) subtype
Study Drugs
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) 
administration.
Lenalidomide will be supplied as 5 mg hard gelatin capsules for PO 
administration.
Rituximab will be available as 100 mg/10 mL and 500 mg/50 mL solution 
in a single-use vial for intravenous (IV) administration.
Objectives
Phase 1b:
Primary Objectives: 
x
To determine the maximum tolerated doses (MTD) and/or the 
recommended Phase 2 (RP2) dose of ibrutinib in combination with 
lenalidomide and rituximab by dose escalation of lenalidomide in 
subjects with relapsed or refractory DLBCL.
x
To determine the safety and tolerability of ibrutinib in combination 
with lenalidomide and rituximab in subjects with relapsed or 
refractory DLBCL by dose escalating lenalidomide.
Secondary Objective:
x
To evaluate the efficacy of ibrutinib in combination with 
lenalidomide and rituximab by assessing the overall response rate 
(ORR) in subjects with relapsed or refractory DLBCL by 
lenalidomide dose group.
Phase 2:
Primary Objective:
x
To evaluate the efficacy of ibrutinib in combination with 
lenalidomide and rituximab by assessing the overall response rate 
(ORR) in subjects with relapsed or refractory non-GCB DLBCL. 
Secondary Objectives:
x
To determine the efficacy of ibrutinib in combination with 
lenalidomide and rituximab in subjects with relapsed or refractory 
non-GCB DLBCL by assessing the following efficacy parameters:
x
Complete Response (CR)
x
Duration of Response (DOR)
x
Progression Free Survival (PFS)
x
Overall Survival (OS)


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x
To determine the safety and tolerability of ibrutinib in combination 
with lenalidomide and rituximab in subjects with relapsed or 
refractory non-GCB DLBCL.
Exploratory Objectives:
x
Efficacy analysis based on the activated B-cell like (ABC) subtype 
identified by gene expression profiling (GEP) will be performed. 
x
Effect of ibrutinib on peripheral T/B/natural killer (NK) cell counts. 
x
Effect of ibrutinib on serum immunoglobulin levels (IgG, IgM, and 
IgA).
Pharmacokinetics:
x
Plasma pharmacokinetics of ibrutinib and PCI-45227. 
Biomarkers:
x
Identify signaling pathways or biomarkers that predict sensitivity or 
resistance to ibrutinib. 
x
Frequency of tumor mutations (or other molecular markers). 
Study Design
This Phase 1b/2 study is designed to assess the safety and efficacy of 
ibrutinib in combination with lenalidomide and rituximab in subjects with 
relapsed/refractory DLBCL not eligible for transplant.  Phase 2 will 
evaluate only subjects with de novo non-GCB subtype DLBCL.  
Approximately 46 subjects will be enrolled in the Phase 1b portion.  
Phase 2 will enroll approximately 55 subjects to ensure enrollment of at 
least 49 response-evaluable subjects at 20 mg lenalidomide;
approximately 28 additional subjects may be enrolled at 25 mg 
lenalidomide.  
Phase 1b: 
In the dose escalation portion of the study, up to four cohorts may be 
explored and lenalidomide dose escalation will follow the 3+3+3 
principle for MTD determination. Due to the fact that the subject 
population studied is significantly ill and an inability to complete the DLT 
observation period may occur due to progression of disease, additional 
subjects may be screened and enrolled in any cohort. The DLT rules will 
continue to apply whereas if 1 DLT is observed, the cohort will be 
expanded to 6, and if 2 DLTs occur, the cohort will be expanded to 9.   
Ibrutinib will be administered orally daily at 560 mg and will be initiated 
on Day 1 of the first cycle.  Treatment will be continuous (without 
interruption) and will continue until disease progression or unacceptable 
toxicity.  Lenalidomide will be administered orally daily at the dose 
designated by cohort on Days 1-21 of each 28-day cycle and will continue 
until disease progression or unacceptable toxicity.  Rituximab 375 mg/m2
will be administered intravenously (IV) on Day 1 of each 28-day 
(4 weeks) cycle for 6 cycles.  
Ibrutinib 
(PO)
Lenalidomide*
(PO)
Rituximab 
(IV)
Cohort 1 & 1+
560 mg
15 mg
375 mg/m2
Cohort 2
560 mg
20 mg
375 mg/m2
Cohort 3
560 mg
25 mg
375 mg/m2
*If DLT criteria are met in Cohort 1, an additional cohort will be enrolled with 
a lenalidomide dose of 10 mg.


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If 3 subjects in Cohort 1 experience a dose limiting toxicity (DLT), dose 
level -1 (10 mg lenalidomide) was planned to be enrolled. After 
completion of Cohort 1, due to 3 DLTs in 7 evaluable subjects, a cohort at 
Dose Level -1 was opened. After completion of the Dose Level -1 cohort, 
if <33% of subjects experience a DLT, dose re-escalation to higher dose 
levels starting with the lenalidomide dose of 15 mg may occur.  If the 
dose level of 20 mg lenalidomide is determined to be safe and tolerated in 
the Phase 1b, this dose will be considered the recommended Phase 2 dose
(RP2D) and a Phase 2 cohort with 20 mg lenalidomide will be initiated.
Concurrent with the Phase 2 at 20 mg lenalidomide, a Phase 1b cohort 
with 25 mg lenalidomide may be initiated. If the interim analysis of the 20 
mg lenalidomide cohort is negative, the 25 mg lenalidomide dose may be 
used in an additional cohort in the Phase 2, if safe and tolerated in the 
Phase 1b.
Phase 2:
Phase 2 will be conducted as an international, multicenter, open-label 
study.   
Phase 2 will enroll approximately 49 response-evaluable subjects at 20 
mg lenalidomide; approximately 28 additional subjects may be enrolled at 
25 mg lenalidomide.  
Eligible subjects will receive ibrutinib, lenalidomide and rituximab per 
the treatment schedule as shown below.  If determined to be safe and
tolerated in the Phase 1b portion of the trial, the proposed dose of 
lenalidomide for Phase 2 is 20 mg.  Subjects will be treated until disease 
progression or unacceptable toxicity. 
Treatment Schedulea
Cycles 1-6
Cycles 7+
Ibrutinib
PO daily 
PO daily 
Lenalidomide
PO daily Days 1-21
PO daily Days 1-21
Rituximab
IV on Day 1
NA
a
Each cycle will be 28-days in length (4 weeks) and subjects will continue 
until disease progression or unacceptable toxicity. Rituximab will be given 
for the first 6 cycles.
An interim analysis will be performed including approximately 
28 evaluable subjects with adequate tumor response assessment. Details 
of the interim analysis and decision rules will be described in the 
statistical analysis plan (SAP). In addition, if there are safety concerns, a 
cohort with ibrutinib and lenalidomide without rituximab may be 
considered in the Phase 2. 
Immunohistochemistry (IHC) and GEP will be used to assess subject 
status with respect to subtype of DLBCL. The limitations of IHC allow 
only a distinction between subjects as either non-GCB or GCB phenotype 
since within the non-GCB group one may include subjects with a true 
unclassified (intermediate) subtype. With GEP the subjects can be further 
categorized into the following subtypes: ABC, GCB, unclassified, and 
unknown due to tissue limitations.  Throughout the protocol description 
of enrolled subjects as non-GCB is based on IHC testing used at 
screening; and the use of the term ABC subtype refers to subjects who 
have been subsequently profiled by GEP and then classified as the true 
ABC subtype. 


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Inclusion Criteria
Inclusion Criteria:
1.
Pathologically confirmed:
x
Phase 1b: diffuse large B-cell lymphoma
x
Phase 2: de novo non-GCB DLBCL by IHC (Hans method)
Note:  Sufficient tissue sample for evaluation by IHC and GEP is 
required for subjects in Phase 2.  
2.
Relapsed or refractory disease, such as either: 1) recurrence of disease 
after a complete response (CR), or 2) partial response (PR), stable 
disease (SD) or progressive disease (PD) at completion of the 
treatment regimen preceding entry to the study (residual disease).
3.
Subjects must have previously received an appropriate first-line 
treatment regimen.
4.
For subjects having a computed tomography (CT) scan abnormality 
with uncertain interpretation following completion of the most recent 
treatment regimen: biopsy confirmation of residual DLBCL is 
required prior to study entry to confirm residual DLBCL and to rule 
out a non-lymphomatous process (e.g., fibrosis). 
5.
Subjects who have not received HDT/SCT must be ineligible for 
HDT/SCT as defined by meeting any of the following criteria:
a.
$JH\HDUV
b.
Diffuse lung capacity for carbon monoxide <50% by pulmonary 
function test.
c.
Left ventricular ejection fraction <50% by multiple gated 
acquisition/echocardiogram.
d.
Other organ dysfunction or co-morbidities precluding the use of 
HDT/SCT on the basis of unacceptable risk of treatment-related 
morbidity.
e.
Failure to achieve PR or CR with salvage therapy.
f.
Subject refusal of HDT/SCT.
6.
One or more measurable disease sites on CT scan (>1.5 cm in longest 
dimension).  Lesions in anatomical locations (such as extremities or 
soft tissue lesions) that are not well visualized by CT may be 
measured by MRI instead (see Section 7.3.1).
7.
Adequate hematologic function with screening laboratory assessment 
independent of growth factor and transfusion support for at least 
7 days, with the exception of pegylated G-CSF (pegfilgrastim) and 
darbepoetin which require at least 14 days, defined as:
a.
Absolute neutrophil count >1,500 cells/mm3 (1.5 x 109/L).  
b.
Platelet count >75,000 cells/mm3 (75 x 109/L). 
c.
Hemoglobin >8.0 g/dL.
8.
Adequate hepatic and renal function with screening laboratory 
assessment defined as:
a.
Serum aspartate transaminase (AST) or alanine transaminase 
$/7[XSSHUOLPLWRIQRUPDO8/1
b.
Creatinine clearance (Cockcroft-Gault or 24-hour creatinine 
clearance collection) >60 mL/min.


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c.
Bilirubin <1.5 x ULN [unless bilirubin rise is due to Gilbert’s 
syndrome (as defined by >80% unconjugated hyperbilirubinemia) 
or of non-hepatic origin].
9.
PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN.
10. 0HQDQGZRPHQ\HDUVRIDJH
11. Eastern Cooperative Oncology Group performance status of <2.
12. All study participants must be registered into the mandatory Revlimid 
REMS™program, and be willing and able to comply with the 
requirements of the Revlimid REMS™program (US sites only).
13. Female subjects of childbearing potential (FCBP)a must have a 
negative serum or urine pregnancy test with a sensitivity of at least 
25 mIU/mL within 10 – 14 days and again within 24 hours prior to 
prescribing lenalidomide for Cycle 1 (prescriptions must be filled 
within 7 days as required by Revlimid REMS™) and must either 
commit to continued abstinence from heterosexual intercourse or 
begin TWO acceptable methods of birth control, one highly effective 
method and one additional effective method AT THE SAME TIME, 
at least 28 days before she starts taking lenalidomide.  FCBP must 
also agree to ongoing pregnancy testing.  See Appendix 7 (US sites 
only).
14. Female subjects of childbearing potential (FCBP)a must have a 
negative serum or urine pregnancy test with a sensitivity of at least 
25 mIU/mL within 10 – 14 days and again within 24 hours prior to 
starting Cycle 1 of lenalidomide.  FCBP must also agree to ongoing 
pregnancy testing. All subjects must be counseled at a minimum of 
every 28 days about pregnancy precautions and risks of fetal 
exposure.  See Appendix 8 (ex-US sites only).
15. Male subjects must agree to use a latex condom during sexual contact 
with a FCBP even if they have had a successful vasectomy.  See 
Appendix 7 (US sites only).
16. Male subjects must agree to use a latex condom during sexual contact 
with a FCBP even if they have had a successful vasectomy.  All 
subjects must be counseled at a minimum of every 28 days about 
pregnancy precautions and risks of fetal exposure.  See Appendix 8
(ex-US sites only).
17. Female subjects of childbearing potential (FCBP)a and male subjects 
who are sexually active must use TWO acceptable methods of birth 
control, one highly effective method of birth control plus one 
additional effective method of birth control for at least 28 days prior 
to study treatment and during the study treatment period.  For female 
subjects, these birth control requirements must be adhered to for 
12 months after the last dose of rituximab or 30 days after the last 
dose of ibrutinib and lenalidomide, whichever is later.  For male 
subjects, these birth control requirements must be adhered to for 
90 days after the last dose of ibrutinib and lenalidomide, whichever is 
later.  Male subjects must agree to not donate sperm during the study 
a A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in 
the preceding 24 consecutive months).


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treatment period and up to 90 days after the last dose of ibrutinib and 
lenalidomide.
18. Life expectancy of more than 3 months.
Exclusion Criteria:
Exclusion Criteria:
Phase 2 only
1.
Transformed DLBCL, GCB DLBCL or DLBCL with coexistent 
histologies (eg, follicular or mucosa-associated lymphoid tissue 
[MALT] lymphoma).
2.
Primary mediastinal (thymic) large B-cell lymphoma.
Phase 1b/2
3.
Medically apparent central nervous system lymphoma or 
leptomeningeal disease.
4.
History of allogeneic stem-cell (or other organ) transplantation.
5.
Any chemotherapy, external beam radiation therapy, or anticancer 
antibodies within 2 weeks of the first dose of study drug.
6.
Radio- or toxin-immunoconjugates within 10 weeks prior to first dose 
of study drug.
7.
Concurrent enrollment in another therapeutic investigational study or 
have previously taken ibrutinib and/or lenalidomide.
8.
History of other malignancies, except:
a.
Malignancy treated with curative intent and with no known active 
GLVHDVHSUHVHQWIRU\HDUVEHIRUHWKHILUVWGRVHRIVWXG\GUug 
and felt to be at low risk for recurrence by treating physician.
b.
Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease.
c.
Adequately treated carcinoma in situ without evidence of disease.
9.
Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, 
tacrolimus, etc., or chronic administration of >20 mg/day of 
prednisone) within 28 days of the first dose of study drug.
10. Recent infection requiring intravenous anti-infective treatment that 
ZDVFRPSOHWHGGD\VEHIRUHWKHILUVWGRVHRIVWXG\GUXJ
11. Unresolved toxicities from prior anti-cancer therapy, defined as 
having not resolved to Common Terminology Criteria for Adverse
Event (CTCAE, version 4.03*UDGHRUWRWKHOHYHOVGLFWDWHGLQ
the inclusion/exclusion criteria with the exception of alopecia.
12. Known bleeding diathesis (eg, von Willebrand’s disease) or 
hemophilia.
13. Known history of human immunodeficiency virus (HIV), chronic or 
active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection.
14. Major surgery within 4 weeks prior to first dose of study drug.
15. Currently active, clinically significant cardiovascular disease, such as 
uncontrolled arrhythmia or class 3 or 4 congestive heart failure as 
defined by the New York Heart Association Functional 
Classification; or a history of myocardial infarction, unstable angina, 
or acute coronary syndrome within 6 months prior to enrollment.
16. Unable to swallow capsules, malabsorption syndrome, disease 
significantly affecting gastrointestinal function, resection of the 


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stomach or small bowel, symptomatic inflammatory bowel disease or 
ulcerative colitis, or partial or complete bowel obstruction.
17. Concurrent use of warfarin or other Vitamin K antagonists (eg, 
phenprocoumon).
18. Requires treatment with a strong cytochrome P (CYP) 450 3A 
inhibitor.
19. Any life-threatening illness, medical condition including uncontrolled 
Diabetes Mellitus, or organ system dysfunction that, in the opinion of
the investigator, could compromise the subject’s safety or put the 
study outcomes at undue risk
20. Currently active, clinically significant hepatic impairment Child-Pugh 
class B or C according to the Child-Pugh classification 
21. Known hypersensitivity to lenalidomide (or thalidomide) or 
rituximab.
22. Lactating or pregnant.
23. Unwilling or unable to participate in all required study evaluations 
and procedures.
24. Unable to understand the purpose and risks of the study and to 
provide a signed and dated informed consent form (ICF) and 
authorization to use protected health information (in accordance with 
national and local subject privacy regulations).
Safety Monitoring
This study will be monitored in accordance with the Sponsor’s 
Pharmacovigilance Committee procedures.  Adverse events (AEs) and 
serious adverse events (SAEs) will be reviewed by the Sponsor on an 
ongoing basis to identify safety concerns.  The Sponsor may schedule 
periodic conference calls with the Investigators to discuss study progress, 
obtain Investigator feedback and exchange, and discuss study-specific 
issues including AEs and SAEs.  A Dose Level Review Committee will 
evaluate safety data following the completion of each dose observation 
period of the Phase 1b portion.  Members of this committee will include 
the Sponsor (at a minimum: the Medical Monitor or designee, a Drug 
Safety representative and a Biostatistician) as well as participating 
Investigators/designees.
Study Treatment
One cycle of treatment is 28-days in length and consists of daily 
administration of ibrutinib, daily administration of lenalidomide Days 1-
21 each cycle and rituximab once each cycle on Day 1 for 6 cycles.  
Ibrutinib and lenalidomide dosing will continue as long as the subject is 
deriving clinical benefit (CR, PR, or SD) and the subject is not 
experiencing any unacceptable toxicity.
Phase 1b:
Cohort -1 - Ibrutinib 560 mg, lenalidomide 10 mg and rituximab 
375 mg/m2
Cohort 1 & 1+ - Ibrutinib 560 mg, lenalidomide 15 mg and rituximab 
375 mg/m2
Cohort 2 - Ibrutinib 560 mg, lenalidomide 20 mg and rituximab 375 mg/m2
Cohort 3 - Ibrutinib 560 mg, lenalidomide 25 mg and rituximab 375 mg/m2
Phase 2: 


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Treatment: Ibrutinib, lenalidomide and rituximab
Refer to the current rituximab package insert for more details.
Premedication: 
Premedication for rituximab should be administered per the package 
insert.
Dosing/Administration:
The dosage and schedules for the 3 drugs will be administered as follows 
until disease progression or unacceptable toxicity:
x
Ibrutinib 560 mg PO once daily (continuous)
x
Lenalidomide (dose from Phase 1b) mg PO once daily Days 1-21 of a 
28-day cycle
x
Rituximab 375 mg/m2 IV per package insert on Day 1 of each cycle 
for 6 cycles
Concomitant Therapy 
Refer to Section 6.1.1 for permitted concomitant medications.
Refer to Section 6.1.2 for medications to be used with caution.
Refer to Section 6.1.3 for prohibited concomitant medications. 
Statistical Methods and 
Data Analysis
Analysis Methods for Phase 1b
The ORR and its 95% confidence interval (CI) will be calculated using 
the exact binomial distribution. The CR rate and its corresponding 95% 
CI will be calculated likewise. 
Analysis Methods for Phase 2
The primary analysis for all efficacy endpoints will be conducted based 
on the response-evaluable population with de novo non-GCB subtype 
DLBCL.
The ORR and its 95% CI will be calculated using the exact binomial 
distribution.  If the lower bound of the CI around the ORR is greater than 
or equal to 40%, the primary efficacy objective is achieved. 
Duration of response will be analyzed for responders and is defined as the 
interval between the date of initial documentation of a response of CR or 
PR, and the date of first documented evidence of progressive disease, or 
death.  The distribution (median, its 95% CI and Kaplan-Meier curves) of 
DOR will be provided using Kaplan-Meier estimates for responders in the 
all-treated population.  
Progression-free survival will be assessed and defined as the period from 
the date of first dose of study drug until the date of first documented 
evidence of progressive disease or death, whichever occurs earlier.  
Overall survival is measured from the date of first dose of study drug to 
the date of the subject’s death from any cause.  Progression-free survival
and OS will be analyzed by the same Kaplan-Meier analysis method used 
for DOR.
Sample Size Determination
The planned sample size for Phase 2 is approximately 55 subjects to 
ensure enrollment of at least 49 response-evaluable subjects;
approximately 28 additional subjects may be enrolled at 25 mg 
lenalidomide.
The main analysis will be the comparison of the response rate to the ORR 
of a historical control of 40%.  


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An interim analysis will be performed including approximately 
28 evaluable subjects with adequate tumor response assessment. 
Enrollment in the 20 mg lenalidomide cohort will continue while the 
interim analysis is performed. Details of the interim analysis and decision 
rules will be described in the SAP.  At the interim analysis, the review 
committee could recommend
1.
continuation of the study with 20 mg lenalidomide; or
2.
increase of the lenalidomide dose to 25 mg, if determined to be safe
and tolerated in the Phase 1b, including approximately 28 evaluable 
subjects with adequate tumor response assessment followed by an 
interim analysis.
The null hypothesis that the true ORR is 40% will be tested against a 1-
sided alternative that the ORR is 60%. The null hypothesis will be 
rejected if 27 or more responses are observed in the 49 subjects. This 
design yields a 1-sided type I error rate of 0.025 and power of 80% when 
the true ORR is 60%. This statistical design including the number of 
subjects and the number of responders follows the statistical framework 
of Simon’s minmax two-stage design (Simon 1989). 


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ABBREVIATIONS
ABC
activated B-cell like (DLBCL subtype as determined by GEP)
AE
adverse event
ANC
absolute neutrophil count
AUC
area under the curve
BCR
B-cell receptor
BTK
Bruton’s tyrosine kinase 
BUN
blood urea nitrogen
CEPP
cyclophosphamide/etoposide/cisplatin/prednisone
CFR
Code of Federal Regulations
CHOP
cyclophosphamide, doxorubicin, vincristine, prednisone
CI
confidence interval
CLL
chronic lymphocytic leukemia
CTCAE
Common Terminology Criteria for Adverse Events
CR
complete response 
CSR
Clinical Study Report
CT
computed tomography
CYP
cytochrome P
DLBCL
diffuse large B cell lymphoma
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response 
DVT
deep vein thrombosis
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
eCRF
electronic case report form
EOT
End-of-Treatment
EMR
electronic medical records
ESMO
European Society for Medical Oncology
FCBP
female of childbearing potential
FDA
Food and Drug Administration
18F-FDG
18F-fluorodeoxyglucose 
FFPE
formalin-fixed, paraffin-embedded (FFPE) tissues
GCB
germinal-cell B-cell-like (subtype)
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
GDP
gemcitabine/dexamethasone/cisplatin
GEP
gene expression profiling
HBV
hepatitis B virus
HCV
hepatitis C virus
HDT
high dose therapy
HIPAA
Health Insurance Portability and Accountability Act


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HIV
human immunodeficiency virus
ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
,)1ȕ
interferon beta
Ig
Immunoglobulin
IgA
immunoglobulin A
IgG
immunoglobulin G
IgM
immunoglobulin M
IHC
Immunohistochemistry
,ț%Į
inhibitor of kappa B, alpha
ILD
Interstitial Lung Disease 
IPI
International Prognostic Index
IRB
Institutional Review Board
IRC
Independent Review Committee 
IRF4
interferon regulatory factor 4
ITT
intent-to-treat
IUD
intra-uterine device
IV
Intravenous
LDH
lactic acid dehydrogenase
MAD
maximum administered dose
MALT
mucosa-associated lymphoid tissue
MCL
mantle cell lymphoma 
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
MTD
maximum tolerated dose
MRI
magnetic resonance imaging
MYD88
myeloid differentiation factor 88
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NCCN
National Comprehensive Cancer Network
NDC
National Drug Code
NF-țȼ
nuclear factor- țȼ
NHL
non-Hodgkin’s lymphoma
NK
natural killer (cells)
ORR
overall response rate (ORR = CR + PR)
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PE
pulmonary embolism
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PO
per os (oral)


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PPP
Pregnancy Prevention Program
PR
partial response
aPTT
activated prothrombin thromboplastin time
PT
prothrombin time
QTcF
corrected QT interval (Fridericia formula)
RBC
red blood cells
R-CHOP
rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone
REB
Research Ethics Board
REMS™
Risk Evaluation and Mitigation Strategies
R-GEMOX
rituximab/gemcitabine/oxaliplatin
RNA
ribonucleic acid
RP2
recommended Phase 2 
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCT
stem cell transplantation
SD
stable disease
SEER
Surveillance Epidemiology and End Results
SLL
small lymphocytic lymphoma
SOP
standard operating procedures
SPD
sum of the product of the diameters
TLS
tumor lysis syndrome
TSH
thyroid stimulating hormone 
ULN
upper limit of normal
US
United States
VTE
venous thromboembolism
WM
Waldenström's macroglobulinemia


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1.
INTRODUCTION
1.1.
Ibrutinib (PCI-32765) Background
Ibrutinib (IMBRUVICA®) is a first-in-class, potent, orally administered covalently-binding 
inhibitor of Bruton’s tyrosine kinase (BTK) co-developed by Pharmacyclics LLC and Janssen 
Research & Development LLC (collectively referred to as the Sponsor) for the treatment of B-
cell malignancies.
Ibrutinib has been approved in many regions, including the US and EU, for indications covering 
the treatment of patients with mantle cell lymphoma (MCL) who have received at least 1 prior 
therapy, patients with chronic lymphocytic leukemia (CLL), including CLL with a deletion of 
the short arm of chromosome 17 (del17p) or a TP53 mutation, and patients with Waldenström’s 
macroglobulinemia. Ibrutinib is currently under investigation in various indications as a single 
agent and in combinations.
B-cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release.  B-cells express cell surface 
immunoglobulins comprising the B-cell receptor (BCR), which is activated by binding to 
antigen.  Antigen binding induces receptor aggregation and the clustering and activation of 
multiple tyrosine kinases, which in turn activate further downstream signaling pathways 
(Bishop 2003).  
For the most comprehensive nonclinical and clinical information regarding ibrutinib background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to 
the latest version of the ibrutinib Investigator's Brochure (IB).
1.2.
Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common of the aggressive non-Hodgkin 
lymphomas (NHL) in the United States, with an annual incidence that has been rising gradually 
since the 1990s (Fisher 2004). The estimated 2010 prevalence of NHL in the US was 
approximately 509,000 individuals, with over 200,000 of these cases in individuals over the age 
of 70 years (SEER 2010). It is estimated that 30-40% of NHL cases are of the DLBCL category 
(Hans 2004). According to the current SEER data, the median age at diagnosis is 67 years 
(SEER 2010).  While approximately half of the incremental rise in incidence of DLBCL is 
attributable to identifiable factors, such as the increase in the incidence of human 
immunodeficiency virus (HIV)-related DLBCL, the evolution of more specific diagnostic 
techniques, and revisions in lymphoma classification schemes, much of the rising incidence 
remains unexplained (Holford 1992). A very aggressive malignancy in its untreated natural 
history, DLBCL is a potentially curable disease, with a significant proportion of patients cured 
with modern chemoimmunotherapy. Nonetheless, for those patients not cured by standard initial 
therapy, the prognosis remains generally poor (Gisselbrecht 2010) and DLBCL still accounts for 
the highest number of deaths per year of all the NHL histologies.


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1.2.1.
ABC (Non-GCB) Subtype
The major clinical prognostic factors for NHL are well described and have been incorporated 
into the International Prognostic Index (IPI) scoring system.  The specific factors are: age 
>60 years, stage III or IV disease, performance stDWXVDQGHOHYDWHGODFWDWHGHK\GURJHQDVH
(LDH) levels.  These factors are combined in the IPI into 4 categories, with 5-year progression 
free survival (PFS) ranging from 40% to 70% and 5-year OS ranging from 26% to 73% among 
patients treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) 
(Ziepert 2010).  Regarding applicability of the IPI in the era of modern chemoimmunotherapy 
(eg, R-CHOP), a recent report of a large series of patients treated with rituximab-based regimens 
found the IPI remains predictive for disease-free and overall survival (The International 
Non-Hodgkin’s Lymphoma Prognostic Factors Project 1993). 
Diffuse large B cell lymphoma is a heterogeneous disease not only clinically, but also 
morphologically and molecularly.  Recent progress has been made in terms of understanding and 
categorizing the molecular heterogeneity of DLBCL.  In a retrospective analysis of a large series 
of patients with DLBCL, the Leukemia and Lymphoma Molecular Profiling Project used 
deoxyribonucleic acid (DNA) microarray to identify distinct gene-expression profiles on the 
basis of hierarchical clustering (Rosenwald 2002).  Two principal independent gene-expression 
subgroups were identified: germinal-center B-cell-like (GCB) and activated B-cell-like (ABC).  
Following standard chemotherapy, the GCB and ABC subgroups were not only prognostically 
distinct in direct comparison (with superior outcome in the GCB subgroup), but this prognostic 
distinction was also independent of the IPI.  Therefore, it may be possible to distinguish 
prognostic subgroups of DLBCL on a molecular as well as clinical basis.
1.3.
Standard Treatment and Unmet Medical Need
Even with the approval of new agents for the treatment of DLBCL patients, the prognosis for 
those not eligible for high dose therapy (HDT) and stem cell transplant after relapse remains 
poor.  The choice of treatment and intensity is dependent upon patient age, co-morbidities, 
residual treatment related toxicities, and response to previous therapies.  
At this time the standard of care for relapsed and refractory patients with chemosensitive disease 
to second-line therapy is to proceed on to HDT and stem cell transplant (SCT), although no 
preferred regimen has been identified.
For those patients with relapsed and refractory DLBCL not eligible for HDT/SCT, both the U.S. 
National Comprehensive Cancer Network (NCCN) and the European Society for Medical 
Oncology (ESMO) recommend inclusion in a clinical trial whenever possible.  According to the 
NCCN 2013 guidelines, if no appropriate clinical trials are available multiple immunotherapy 
and chemotherapy regimens with or without rituximab can be considered.  Under the same 
circumstances the ESMO treatment guidelines state that multiple salvage chemotherapy 
regimens, including R-GEMOX (rituximab, gemcitabine and oxaliplatin) may be used 
(Tilly 2012).  The reported outcomes for multiple salvage chemotherapy regimens are 
summarized in Table 1.


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Table 1: 
Efficacy of Therapies in Relapsed/Refractory NHL Patients
Study 
Number of 
Patients
ORR
%
CR
%
PFS 
(Months)
OS
(Months)
CEPP +/- B  (Chao 1990)
All patients
DLBCL
69
22
70%
77%
34%
36%
7 
--
12
--
DA-EPOCH + R (Jermann 2004)
All patients
DLBCL 
50
25
68% 
--
28%
--
--
--
17.9
--
GDP +/- R (Crump 2004)
All patients
DLBCL
51
40
53%
--
22%
--
3.1a
--
8.9a
--
GemOx +/- R (Lopez 2008)
All patients
DLBCL 
0 
32
--
43%
--
34%
--
29%b
--
41%b
GemOx +/- R (Corazzelli 2009)
All patients
DLBCL
62
--
57/78%
--
30/50%
--
7/28%
FFS at 42m
7/37%
at 42m
GemOx +/- R (El Gnaoui 2007)
All patients
DLBCL 
46
33
83%
82%
50%
73%
22
24
66%
at 2 years
Bendamustine +/- R (Ohmachi 2013)
All patients 
DLBCL
63
0
62.7%
--
37.3%
--
--
--
--
--
Bendamustine +/- R (Weidmann 2002)
All patients 
DLBCL
18
0
44%
--
17%
--
--
--
--
--
CEPP – cyclophosphamide, etoposide, prednisone, procarbazine; B – bleomycin; DA-EPOCH – dose adjusted 
etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; R – rituximab; GDP – gemcitabine, 
dexamethasone, carboplatin; GemOx – gemcitabine, oxaliplatin; FFS – failure-free survival
a Outcomes for DLBCL patients not eligible for transplant, not reported for those that went on to HDT and SCT
b Calculated as percent of patients at 12 months
It should be noted that the efficacy observed with various chemotherapy regimens with or 
without rituximab is often reported for all B-cell lymphomas, with very few studies reporting
long-term outcomes and/or efficacy in patients specifically with DLBCL histologies (Table 1). 
In addition, we know that the different subtypes of DLBCL can be identified that have 
significant differences in prognosis translating into poor outcomes. 
Although there are currently no approved therapies specifically for the different phenotypic 
subtypes of DLBCL in clinical practice, there is data available for the different subtypes in 
studies evaluating lenalidomide, rituximab and ibrutinib (Table 2).
 
 




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Two Phase 2 trials have evaluated the safety and efficacy of lenalidomide in combination with 
rituximab in relapsed or refractory NHL.  The first study enrolled multiple histologies (n=45) 
and included patients eligible for SCT.  The outcomes for all patients included an ORR of 33% 
with a CR rate of 22% and a median PFS and OS of 3.7 and 10.7 months respectively.  For those 
patients with DLBCL (n=32) the ORR was 28% with a CR rate of 22% and a median PFS of 
2.8 months and OS of 10.2 months.  There were no significant differences in clinical responses 
by DLBCL subtype.  For those patients with transformed large cell lymphoma (n=9), the ORR 
was 56% with a CR rate of 33% and a median PFS of 4.3 and OS of 11.5 months (Wang 2013).  
The second trial evaluated only patients with DLBCL (n=23), and all were elderly and ineligible 
for SCT.  The ORR was 35% and the CR rate was 30%.  Disease free survival at 12 months was 
33% with an OS of 55.1% at 18 months (Zinzani 2011).
Ibrutinib has demonstrated single agent activity in the treatment of relapsed or refractory de novo
DLBCL in Study PCYC-1106-CA.  Study PCYC-1106-CA is an ongoing Phase 2, open-label, 
non-randomized, multicenter study in patients with relapsed or refractory de novo DLBCL 
receiving 560 mg/day of ibrutinib.  Data are currently available on 70 patients from this trial who 
have relapsed or refractory disease with 29 ABC subtype, 20 GCB subtype, 16 Type 3 subtype 
and 5 subjects subtype unknown.  The ORR in these 70 patients was 25% (17/70) with 9% of 
patients achieving a complete response (CR) and 16% of patients achieving a partial response 
(PR).  Of the patients with ABC subtype, the ORR was 41% (12/29) with 17% CR and 24% PR.  
Of the patients with GCB subtype the ORR was 5% (1/20) with the one responder achieving a 
PR.  The median OS was 9.76 months for those with ABC subtype and 3.35 months for those 
with GCB subtype (De Vos 2013).
1.4.
BTK and B cell Lymphoma
BCR signaling is essential for normal B cell differentiation and function. In addition, several 
lines of evidence suggest that signaling through the BCR is necessary to sustain the viability of 
B cell malignancies.  First, expression of a functional BCR is maintained throughout lymphoma 
progression even as the non-expressed immunoglobulin heavy chain is involved in oncogenic 
translocations and despite prolonged treatment of tumor cells with anti idiotype therapies 
(Küppers 2005, Meeker 1985).  Also, selective knockdown of BCR components by RNA 
interference results in apoptosis in multiple B cell lymphoma cell lines (Gururajan 2006).
Recent studies indicate that chronic active BCR signaling is a pathogenic mechanism in ABC 
DLBCL and this chronic activation engages the classic NF-ț%SDWKZD\LQFRQWUDVW*&%
DLBCL pathogenesis is independent of this pathway (Lenz 2010). This difference in the 
molecular mechanism of pathogenesis (ie, constitutive activation of NF-ț%LQ$%&'/%&/
may explain why the ABC subtype is less sensitive to chemotherapy and remains less curable 
than the GCB subtype.
Btk plays an essential role in the chronic active BCR signaling cascade in which engages NF-ț%
activation in wild-type CARD11 ABC DLBCL. In vitro data targeting this pathway in ABC 
DLBCL cells was recently reported by Davis and colleagues (Davis 2010).  Activated B-cell like


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DLBCL cell lines with constitutive BCR signaling undergo cell death when treated with 
ibrutinib, while these drugs had no effect on ABC and GCB DLBCL cell lines that did not rely 
on constitutive BCR signaling.  Clinical evidence that targeting the nuclear factor- țȼ (NF-ț%)
pathway has a favorable response to outcome in ABC versus GCB subtypes was reported by 
Dunleavy and colleagues (Dunleavy 2009).  They showed in a Phase 2 study that bortezomib, 
ZKLFKLQGLUHFWO\WDUJHWVWKH1)ț%SDWKZD\E\LQKLELting proteasome degradation of ,ț%Į, in 
combination with chemotherapy had a response rate of 85% in ABC subtype versus 13% in GCB 
subtype (P=0.0004).  Thus, inhibition of the BCR-NF-ț%SDWKZD\E\blocking Btk activity may 
represent a novel therapeutic strategy in ABC DLBCL.
1.5.
Summary of Nonclinical Data
1.5.1.
Pharmacology
Ibrutinib was designed as a selective and covalent inhibitor of the Btk (Pan 2007).  In vitro, 
ibrutinib is a potent inhibitor of Btk activity (IC50 = 0.39 nM).  The irreversible binding of 
ibrutinib to cysteine-481 in the active site of Btk results in sustained inhibition of Btk catalytic 
activity and enhanced selectivity over other kinases that do not contain a cysteine at this position.  
When added directly to human whole blood, ibrutinib inhibits signal transduction from the BCR 
and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation followed 
by CD69 expression (Herman 2011).
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current ibrutinib IB.
1.5.2.
Safety Pharmacology and Toxicology
No treatment-related effects were observed in the central nervous system or respiratory system in 
rats at any dose tested. Further, no treatment-related corrected QT interval (QTc) prolongation 
effect was observed at any tested dose in a cardiovascular study using telemetry-monitored dogs. 
Based on data from rat and dog including general toxicity studies up to 13 weeks duration, the 
greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation). Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog). In studies in pregnant 
rats and rabbits, ibrutinib administration was associated with malformations (teratogenicity) at 
ibrutinib doses that result in approximately 14 and 2 times the exposure (area under the 
concentration-time curve [AUC]) in patients administered the dose of 560 mg daily, respectively. 
Fetal loss and reduced fetal body weights were also seen in treated pregnant animals. 
Carcinogenicity studies have not been conducted with ibrutinib. In vitro and in vivo genetic 
toxicity studies showed that ibrutinib is not genotoxic. No effects on fertility or reproductive 
capacities were observed in a study in male and female rats.


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For the most comprehensive information regarding nonclinical safety pharmacology and 
toxicology, please refer to the current ibrutinib IB.
1.6.
Summary of Clinical Data
For the most comprehensive clinical information regarding ibrutinib, please refer to the current 
version of the ibrutinib IB.
1.6.1.
Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased proportionally to doses increased with substantial intersubject variability. 
The mean half life (t1/2) of ibrutinib ranged from 4 to 13 hours, with a median time to maximum 
plasma concentration (Tmax) of 2 hours. Taking into account the approximate doubling in mean 
systemic exposure when dosed with food and the favorable safety profile, ibrutinib can be dosed 
with or without food. Ibrutinib is extensively metabolized primarily by cytochrome 
P450 (CYP) 3A4. The on-target effects of metabolite PCI-45227 are not considered clinically 
relevant. Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose 
exposure. Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in 
patients with creatinine clearance (CrCl) >30 mL/min. Patients with severe renal impairment or 
patients on dialysis have not been studied. Following single-dose administration, the AUC of 
ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate 
(Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects 
with normal liver function. A higher proportion of Grade 3 or higher adverse reactions were 
reported in patients with B-cell malignancies (CLL, MCL and WM) with mild hepatic 
impairment based on NCI organ dysfunction working group (NCI-ODWG) criteria for hepatic 
dysfunction compared to patients with normal hepatic function.
For the most comprehensive information regarding pharmacokinetics (PK) and product 
metabolism, please refer to the current version of the ibrutinib IB.
1.7.
Summary of Clinical Safety of Ibrutinib
A brief summary of safety data from monotherapy and combination therapy studies is provided 
below. For more comprehensive safety information please refer to the current version of the 
ibrutinib IB. Additional safety information may be available for approved indications in regional 
prescribing labels where the study is conducted (eg, USPI, SmPC).
1.7.1.
Monotherapy Studies
Pooled safety data for a total of 1071 subjects treated with ibrutinib monotherapy from 9 studies 
in B-cell malignancies, which includes subjects from 2 randomized-control studies who crossed 
over from comparator treatment or placebo to receive ibrutinib monotherapy, are summarized 
below.


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Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1071):
Most frequently reported 
TEAEs >10%  
Most frequently reported 
Grade 3 or 4 TEAEs >2% 
Most frequently reported 
Serious TEAEs >1% 
Diarrhea
Neutropenia
Pneumonia
Fatigue
Pneumonia
Atrial fibrillation
Nausea
Thrombocytopenia
Febrile neutropenia
Cough
Anemia
Pyrexia
Anemia
Hypertension  
Pyrexia
Atrial fibrillation
Neutropenia 
1.7.2.
Combination Therapy Studies
Pooled safety data for a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in B-cell malignancies, which included 1 randomized-control 
study, are summarized below. Therapies used in combination with ibrutinib in these studies, 
included BR (bendamustine and rituximab), FCR (fludarabine, cyclophosphamide, and 
rituximab), ofatumumab, and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, 
and prednisone). 
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib in combination therapy (N=423):
Most frequently reported 
TEAEs >10%  
Most frequently reported 
Grade 3 or 4 TEAEs >2% 
Most frequently reported 
Serious TEAEs >1% 
Neutropenia
Neutropenia
Febrile neutropenia
Diarrhea
Thrombocytopenia
Pneumonia
Nausea
Febrile neutropenia
Atrial fibrillation
Thrombocytopenia
Pneumonia
Pyrexia
Fatigue
Hypertension 


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1.8.
Risks (Ibrutinib)
1.8.1.
Lymphocytosis and Leukostasis
Leukostasis 
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high
number of circulating lymphocytes (>400,000/μL) may confer increased risk. For subject and 
ibrutinib management guidance, refer to Section 5.4.4.
Lymphocytosis
Upon initiation of treatment, a reversible increase in lymphocyte counts (iHLQFUHDVHIURP
baseline and above absolute count 5,000/μL), often associated with reduction of 
lymphadenopathy, has been observed in most subjects with CLL/small lymphocytic lymphoma 
(SLL) treated with ibrutinib. This effect has also been observed in some subjects with MCL 
treated with ibrutinib. This observed lymphocytosis is a pharmacodynamic effect and should not 
be considered progressive disease in the absence of other clinical findings.  In both disease types, 
lymphocytosis typically occurs during the first few weeks of ibrutinib therapy (median time 
1.1 weeks) and typically resolves within a median of 8.0 weeks in subjects with MCL and 
18.7 weeks in subjects with CLL/SLL.
A large increase in the number of circulating lymphocytes (eg, >400,000/μL) has been observed 
in some subjects. Lymphocytosis was not observed in subjects with Waldenström’s 
macroglobulinemia treated with ibrutinib. Lymphocytosis appeared to occur in lower incidence 
and at lesser magnitude in subjects with CLL/SLL receiving ibrutinib in combination with 
chemoimmunotherapy.
For subject and ibrutinib management guidance, refer to Section 5.4.4.
Available data in subjects with DLBCL that have been treated with ibrutinib in multiple Phase 1 
and Phase 2 studies, revealed no evidence of treatment related lymphocytosis.
1.8.2.
Bleeding-related Events
There are reports of hemorrhagic events in subjects treated with ibrutinib, both with and without 
thrombocytopenia. These include minor hemorrhagic events such as contusion, epistaxis, and 
petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria. Use of ibrutinib in subjects requiring other 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding. 
Subjects with congenital bleeding diathesis have not been studied. See Section 6.1.2.3 for 
guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See 
Section 6.2 for guidance on ibrutinib management with surgeries or procedures.  


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1.8.3.
Rash
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. In a randomized Phase 3 study (PCYC-1112-CA), rash 
occurred at a higher rate in the ibrutinib arm than in the control arm. Most rashes were mild to 
moderate in severity.
1.8.4.
Non-melanoma skin cancer
Non-melanoma skin cancers have occurred in patients treated with ibrutinib.  Monitor patients 
for the appearance of non-melanoma skin cancer.
1.8.5.
Diarrhea 
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation. These events are rarely severe. Should symptoms be severe or prolonged 
follow the protocol dose modification guidelines (see Section 5.4.4).
1.8.6.
Tumor Lysis Syndrome
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with 
single-agent ibrutinib or in combination with chemotherapy. Subjects at risk of tumor lysis 
syndrome are those with comorbidities and/or risk factors such as high tumor burden prior to
treatment, increased uric acid (hyperuricemia), elevated LDH, bulky disease at baseline, and 
pre-existing kidney abnormalities.
1.8.7.
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy. At least 25% of subjects 
with MCL and 35% of subjects with CLL had Grade 3 or greater infections per NCI Common 
Terminology Criteria for Adverse Events (CTCAE, v4.03). The most commonly reported 
infections include pneumonia, cellulitis, urinary tract infection and sepsis. Although causality 
has not been established, cases of progressive multifocal leukoencephalopathy (PML) have 
occurred in patients treated with ibrutinib.
1.8.8.
Interstitial Lung Disease (ILD)
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib.
Monitor subjects for pulmonary symptoms indicative of ILD. Should symptoms develop follow 
the protocol dose modification guidelines (see Section 5.4.4).
1.8.9.
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. 


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1.8.10.
Atrial Fibrillation 
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, hypertension, acute infections, and a previous
history of atrial fibrillation. For atrial fibrillation which persists, consider the risks and benefits 
of ibrutinib treatment and follow the protocol dose modification guidelines (see Section 5.4.4).
1.9.
Summary of Clinical Safety for Lenalidomide in Lymphoma
Lenalidomide is currently approved for the treatment of relapsed or refractory mantle cell 
lymphoma at a recommended starting dose of 25 mg orally once daily for 21 days every 28 days. 
The safety data for 134 patients receiving monotherapy for MCL has been evaluated.  The most 
common treatment-emergent adverse events (>15%) were neutropenia (49%), thrombocytopenia 
(36%), fatigue (34%), diarrhea (31%), anemia (31%), nausea (30%), cough (28%), pyrexia 
(23%), rash (22%), dyspnea (18%), pruritis (17%), constipation (16%), and peripheral edema 
(16%).  The most common Grade 3 or 4 adverse events were hematologic in nature: neutropenia 
(43%), thrombocytopenia (28%), and anemia (11%). Pneumonia (9%) was the most frequent 
non-hematologic Grade 3/4 adverse event. 
The median duration of treatment in this patient population was 95 days (1-1002 days).  Seventy-
six patients (57%) required at least one dose interruption for an adverse event, while 51 patients 
(38%) had at least one dose reduction due to toxicity.  Twenty-six patients (19%) discontinued 
treatment due to adverse events.
Lenalidomide has a black box warning for embryo-fetal toxicity, hematologic toxicity and 
venous thromboembolism.
Complete and updated safety information is available in the current Revlimid® Investigator’s 
Brochure.
1.9.1.
Venous Thromboembolism
Venous thromboembolism including deep vein thromobis (DVT) and pulmonary embolism (PE),
has been reported in patients during treatment for NHL generally, occurring at incidences from 
~7% up to 20% (Zhou 2010; Park 2012; Lyman 2013).  In lenalidomide clinical trials, DVT and 
PE were reported in 7 (2.6%) and 6 (2.2%) of 266 subjects with relapsed or refractory NHL 
receiving lenalidomide in clinical studies NHL-002 and NHL-003 (Wiernik 2008; Witzig 2011).  
Anti-thrombotic prophylaxis was not suggested in NHL-002 but was required for subjects 
considered to be at high risk of developing DVT in NHL-003.  In a study evaluating 
lenalidomide plus rituximab versus lenalidomide alone in relapsed follicular lymphoma subjects, 
thrombosis was reported in 2 (4%) of the combination arm versus 7 (16%) in the single agent 
arm (Leonard 2012).  In an additional study evaluating lenalidomide plus rituximab in MCL 
patients 2 (5%) Grade 3 and 1 (5%) Grade 4 thromboembolic events were reported (Wang 2013).


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1.9.2.
Second New Cancers
According to researchers, patients with cancer have a higher risk of developing a second new 
cancer when compared to people without cancer. In clinical studies of newly diagnosed multiple 
myeloma, a higher number of second cancers were reported in patients treated with induction 
therapy (treatment as a first step to reducing the number of cancer cells) and/or bone marrow 
transplant and then with lenalidomide for a long period of time compared to patients treated with 
induction therapy and/or bone marrow transplant and then with placebo (a capsule containing no 
lenalidomide). Patients should make their doctors aware of their medical history and any 
concerns they may have regarding their own increased risk of other cancers. 
For more complete safety information, refer to the current Revlimid® Investigator’s Brochure.
1.10.
Summary of Clinical Safety for Rituximab
Rituximab is currently approved for the treatment of diffuse large B-cell NHL at a recommended 
starting dose of 375 mg/m2 IV on Day 1 of each cycle for up to 8 infusions.
The safety data for 2,783 patients receiving rituximab monotherapy or in combination with 
chemotherapy for lymphoid malignancies has been integrated, and of this population 
927 patients had DLBCL.  The most common treatment-HPHUJHQWDGYHUVHHYHQWVZHUH
infusion reactions, fever, lymphopenia, chills, infection, and asthenia.  The incidence of infusion 
reactions was highest during the first infusion (77%) and could be characterized by fever, 
chills/rigors, nausea, pruritis, angioedema, hypotension, headache, bronchospasm, urticaria, rash, 
vomiting, myalgia, dizziness, or hypertension.  The overall incidence of infection was 31%, with 
serious infections (Grade 3 or 4), including sepsis occurring in <5% in single arm studies.  In 
patients receiving monotherapy, Grade 3 hematologic toxicity was seen in 48% including 
lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%) and thrombocytopenia 
(2%).  Rituximab-induced B-cell depletion occurred in 70-80% of patients with NHL, with 
decreased IgM and IgG serum levels in 14% of these patients.  
Rituximab has a black box warning for fatal infusion reactions, tumor lysis syndrome, severe 
mucocutaneous reactions and progressive multifocal encephalopathy.
For more complete safety information, refer to the prescribing information 
(Rituxan®/MabThera® Prescribing Information and Package Insert).
1.11.
Rationale for Combination 
Preclinical studies document the potential synergy of ibrutinib and lenalidomide in the treatment 
of ABC DLBCL based upon their mechanism of action and specificity for the genetic alterations 
seen in ABC DLBCL (Yang 2012).  Activated B-cell like DLBCL tumors depend upon both the 
BCR and MYD88 signal pathways for survival.  Genetic alterations in the BCR subunits CD79A
and CD79B promote cell survival by activating NF-ț%DQGLQGXFLQJ,5)ZKLFKGHFUHDVHVWKH
F\WRWR[LFHIIHFWVRILQWHUIHURQȕ,)1ȕ0<'PXWDWLRQVLQFUHDVHWKHSURGXFWLRQRILQWHUIHURQ
ȕ,)1ȕZKLFKLVGHWULPHQWDOWRWXPRUFHOOVXUYLYDO,QWHUIHURQUHJXODWRU\ factor 4 (IRF4) 


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expression is also a characteristic of the ABC subtype and appears to be at the center of the cells 
regulatory activities.  Ibrutinib plays a role by blocking chronic BCR signaling leading to a 
decrease in NF-ț%DFWLYLW\ Lenalidomide downmodulates IRF4, leading to an increase LQ,)1ȕ
secretion and a decrease in NF-ț%DFWLYLW\&RPELQLQJLEUXWLQLEDQGOHQDOLGRPLGH therefore 
appears to target key pathways in ABC DLBCL that may lead to synergy in vivo.
It is unclear whether or not the addition of rituximab to the combination of lenalidomide and 
ibrutinib will confer a significant improvement in outcomes.  Although the ORR to lenalidomide 
is similar to that of lenalidomide + rituximab in patients with DLBCL (Table 2), there may be an 
improved depth of response with an increased CR rate when rituximab is added which may 
translate clinically into an improvement in the duration of the response and possible the OS in 
this patient population. For that reason, the 3 drugs in combination were chosen for the Phase 2 
portion of the study. In addition, should safety concerns arise with the 3-drug combination, a 2-
drug combination of ibrutinib with lenalidomide may be considered.
With respect to safety, in the studies evaluating lenalidomide in combination with rituximab the 
overall safety profile is similar to that reported in monotherapy studies with the most common 
Grade 3 and 4 AEs being hematologic in nature.  Based upon the safety profile of ibrutinib 
monotherapy and the lack of significant myelosuppression, the combination of lenalidomide, 
ibrutinib, and rituximab may be well tolerated with the potential to exploit synergistic effects for 
improvement in outcomes in a frail population with minimal therapeutic options and poor 
prognosis.
1.12.
Rationale for Dose 
The rationale for the current dose and schedule of each agent is based not only upon the 
approved dose for these treatments, but also based upon the safety data known regarding the use 
of these therapies for the treatment of NHL in the relapsed and refractory setting.  The 
established dose in monotherapy studies of lenalidomide is 25 mg administered orally once daily 
for 21 days of a 28 day cycle (Witzig 2011).  Rituximab alone or in combination is approved at a 
dose of 375 mg/m2 IV on Day 1 of each cycle for up to 8 doses in patients with DLBCL.  Studies 
combining both lenalidomide and rituximab have followed various dosing schedules for 
rituximab, but the dosing schedule for lenalidomide has remained the same.  For the 
combination, rituximab has been given at a dose of 375 mg/m2 and lenalidomide has been 
administered at 20 mg once daily on the 21/28 day schedule.  The 20 mg dose of lenalidomide 
has been used in studies where rituximab was given weekly for four doses in the first cycle 
(Wang 2013), as well as on days 1 and 21 every 28 days for four cycles (Zinzani 2011).  In this 
trial dose escalation of lenalidomide will proceed above 20 mg to 25 mg since rituximab will be 
administered on a 28 day schedule.
The first escalation cohort will begin lenalidomide at one dose level below that used in the 
lenalidomide and rituximab combination studies with a dose level-1 built in to allow for further 
evaluation of the three drug combination if a lower lenalidomide dose is needed.  Since ibrutinib 
has been studied at the 560 mg dose in several types of NHL on a continuous daily dosing 


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schedule and is well tolerated, it will be administered daily until disease progression or 
unacceptable toxicity.
1.13.
Rationale for Implementation of Dose Re-Escalation
1.13.1.
Cohort 1 Findings at Dose Level 1 (15 mg lenalidomide)
In Cohort 1 at Dose Level 1 (560 mg ibrutinib, 15 mg lenalidomide and 375 mg/m2 rituximab), a 
total of 13 subjects were enrolled.  Seven of 13 subjects were evaluable for DLT observation per 
protocol and 6 subjects were non-evaluable due to >4 missed doses during the DLT observation 
period due to AEs or study drug non-compliance.  In 7 evaluable subjects, 3 DLTs were 
observed, 2 DLTs were Grade 3 rash and 1 DLT was Grade 3 neutropenia lasting longer than 
7 days. 
As of the data cut of 29 Dec 2014, other AEs of interest that occurred during the study were 
2 rashes with onset during Cycle 1: a Grade 2 rash in 1 subject, and a Grade 1 rash on the face 
only in another subject.  Another subject developed a Grade 2 rash related to Augmentin in 
Cycle 3.
Of the 13 subjects in Cohort 1 that were dosed at Dose Level 1, 4 subjects (31%, and in 2 of 
7 evaluable subjects, 29%) experienced an AE of rash with onset during Cycle 1, and 2 of these 
rashes were Grade 3 and considered DLTs; the other 2 rashes were Grade 1 in 1 subject and 
Grade 2 in the other subject. None of the subjects who experienced rash were taking allopurinol.  
One subject with a DLT developed a Grade 3 pruritic rash on Day 10 with a bilateral hand 
edema, all study drugs were permanently withdrawn and the subject was treated with prednisone 
PO for 6 days (60-60-40-40-20-20 mg/day).  The subject responded to the drug hold and 
corticosteroid therapy and is in follow-up observation. The other subject with a DLT developed 
a Grade 1 maculopapular rash on Day 11, which on Day 12 became a Grade 3 rash on chest, 
back and extremities with pruritus, the subject was treated with a permanent hold of all study 
drugs and 40 mg of prednisone PO daily (Days 12-18), benadryl (Days 12-21) and cortisone 
cream. The subject responded to the drug hold and concomitant therapy and is in follow-up
observation.
1.13.2.
Findings in Study CTEP/A051103
In the ongoing investigator (NCI)-sponsored clinical trial CTEP/A051103 (clinicaltrials.gov # 
NCT01829568/since 4/2013, ibrutinib, lenalidomide and rituximab are being administered in 
combination; 22 subjects with follicular lymphoma were enrolled at different dose levels. 
Dose Level
Ibrutinib(mg)
Lenalidomide (mg)
Rituximab (mg/m2)
0
420
15
375
1
560
15
375
2
560
20
375


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Of 22 subjects, 8 developed a Grade 1 or 2 rash, and 8 subjects developed a Grade 3 rash; rash
was not considered a DLT in this study unless the rash did not resolve to < Grade 2 within 
10 days with corticosteroid treatment. In addition, rash was associated with allopurinol in 
several cases and with Bactrim (sulfamethoxazole and trimethoprim) in 1 case.  No cytokine 
storm reactions were seen. As a result of this approach, in the CTEP/A051103 study, no DLTs 
were seen and no MTD was identified. The rashes were manageable with temporary holding of 
ibrutinib and lenalidomide, concomitant therapy with corticosteroids and/or antihistamines, and 
discontinuation of potential contributors such as allopurinol if applicable.  The maximum dose of 
lenalidomide given was the highest planned dose of 20 mg.  Similar DLT rules are implemented 
in the PCYC-1123-CA Protocol Amendment 2.0 with the objective to escalate to 25 mg of 
lenalidomide since DLBCL is a more aggressive lymphoma (than follicular lymphoma) and may 
require higher doses.  A de-escalation cohort (Cohort -1) will be completed prior to re-escalation 
to higher lenalidomide dose cohorts (Cohort 1+, 2 and 3).
1.13.3.
Rationale for Changes in Amendment 2.0
Potential re-escalation to higher doses of lenalidomide after confirmation of safety in Cohort -1
(de-escalation cohort) was included in Protocol Amendment 2.0 to enable a higher and 
potentially more efficacious dose of lenalidomide for the Phase 2 portion of the study. 
Based on the findings in the CTEP/A051103 study and the findings in Cohort 1 at Dose Level 1, 
the DLT rules for rash were modified in this amendment. In both studies, rash was being 
reported frequently mostly early in the treatment period (during the DLT observation period 
[Cycle 1]), the cases were clinically manageable, no cytokine storm reactions were seen, and re-
treatment after a drug hold was clinically permissible if allowed.  Thus, higher and potentially 
more efficacious doses of lenalidomide will be explored in this study.
1.14.
Rationale for Changes in Amendment 3.0
1.14.1.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) is a known possible side effect of antineoplastic treatment and 
usually indicates benefit from treatment. Thus, it was determined between the study 
Investigators and the sponsor that if a TLS occurs during study treatment, only severe forms of 
TLS which require dialysis should result in an event considered a DLT.  This would also be 
consistent with other studies testing the ibrutinib and lenalidomide combination 
(Christian ASH 2014). Since CTCAE grading specifies that if TLS is present, it represents a 
Grade 3 event, the DLT definition has been updated to specify that only a TLS requiring dialysis 
will be considered a DLT.
Patients with bulky tumors have an increased risk of TLS, and sufficient hydration and close 
monitoring of laboratory parameters (eg, a chemistry panel) is recommended for this patient 
population (see Section 5.2). 


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1.14.2.
Neutropenia
Neutropenia is an expected side effect for both lenalidomide and ibrutinib and has also been 
described with rituximab.
In the lenalidomide label (Revlimid® USPI, February 2015) for the indications of multiple 
myeloma and myelosysplastic syndrome, there is a black box warning for hematological toxicity.  
Lenalidomide can cause significant neutropenia and thrombocytopenia and patients may require 
dose interruption and/or dose reduction per label. 
In the pooled multiple myeloma studies, Grade 3 and 4 hematologic toxicities were more 
frequent in patients treated with the combination of lenalidomide and dexamethasone than in 
patients treated with dexamethasone alone.  Grade 3 or 4 neutropenia was seen in 33.4% 
(118/353) of patients with the combination compared to 3.4% (12/350) of patients with 
dexamethasone alone.
In the myelodysplastic syndrome study (N=148), 58.8% (87/148) of patients developed 
neutropenia overall, and 48% developed Grade 3 or 4 neutropenia.  In the 48% of patients who 
developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), 
and the median time to documented recovery was 17 days (range, 2-170 days).  In the 54% of 
patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days 
(range, 8-290 days), and the median time to documented recovery was 22 days 
(range, 5-224 days).
In the ibrutinib label (Imbruvica® USPI, January 2015), neutropenia is among the most common 
DGYHUVHUHDFWLRQVLQSDWLHQWVZLWK%-cell malignancies (MCL, CLL, Waldenström's 
macroglobulinemia [WM]).  Grade 3 or 4 neutropenia occurred in patients treated with ibrutinib 
with a range of 19-29% in clinical studies.  Further, an adverse event of “neutrophils decreased” 
as a laboratory finding was noted in 47% of patients for all grades and in 29% of patients with 
Grade 3 or 4 in the MCL study (N=111).  In the CLL Study 1 (N=48), 54% of patients had an 
adverse event of “neutrophils decreased” (all grades) as a laboratory finding and 23% of patients 
had a Grade 3 or 4 finding. In the CLL Study 2 (N=195), 51% of patients had an adverse event of 
“neutrophils decreased” (all grades) as a laboratory finding and 27% of patients had a Grade 3 or 
4 finding. In the WM study (N=63), 44% of patients had an adverse event of “neutrophils 
decreased” (all grades) as a laboratory finding and 19% of patients had a Grade 3 or 4 finding. 
In the rituximab label (Rituxan® USPI, August 2014) for lymphoid malignancies, neutropenia is 
GHVFULEHGDVDFRPPRQDGYHUVHUHDFWLRQLQFOLQLFDOWULDOV Neutropenia of all grades was 
found in 14% of patients and Grade 3 or 4 neutropenia in 6% of patients with relapsed/refractory 
NHL (N=356) and has been described in other studies with rituximab. 
In summary, neutropenia is a common finding in patients treated with lenalidomide, with 
ibrutinib, and with rituximab, and thus the combination of the 3 agents in this study is expected 
to result in adverse events of neutropenia.  Unless life-threatening, neutropenia is generally 


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easily managed in an oncology setting and the risk-benefit ratio for this study population would 
still be in favor of continued treatment to achieve an anti-tumor response despite episodes of 
neutropenia. In addition, in subsequent treatment cycles beyond the DLT window, dose 
modifications for neutropenia are permitted per Table 6 of the protocol. For these reasons, the 
DLT criteria for neutropenia were updated in this amendment.
1.14.3.
Deep Venous Thrombosis
In the lenalidomide label (Revlimid® USPI, February 2015) for the indication of multiple 
myeloma, there is a black box warning for deep venous thrombosis and pulmonary embolism. In 
patients with multiple myeloma receiving lenalidomide with dexamethasone, there is a 
significantly increased risk of deep venous thrombosis and pulmonary embolism. 
As per the FDA label, venous thromboembolic events (predominantly deep venous thrombosis 
and pulmonary embolism) have occurred in patients with multiple myeloma treated with 
lenalidomide combination therapy and patients with myelodysplastic syndrome treated with 
lenalidomide monotherapy. A significantly increased risk of deep venous thrombosis and 
pulmonary embolism was observed in patients with multiple myeloma who were treated with 
lenalidomide and dexamethasone therapy (see label). It is not known whether prophylactic 
anticoagulation or antiplatelet therapy prescribed in conjunction with lenalidomide may lessen 
the potential for venous thromboembolic events, however thromboprophylaxis is recommended
(see label). The decision to administer prophylactic measures should be done carefully after an 
assessment of an individual patient’s underlying risk factors.
Since deep venous thrombosis can be clinically managed with anticoagulation, and the 
risk-benefit ratio for this study population would still be in favor of continued treatment to 
achieve an anti-tumor response, only deep venous thrombosis that is unresponsive to 
anticoagulation will be considered a DLT. This would also be consistent with other studies 
testing the ibrutinib and lenalidomide combination (Christian ASH 2014).
1.14.4.
Treatment of Subjects with DLTs
In the original protocol subjects who experienced a DLT were required to discontinue study 
treatment. The experience thus far in this study has shown that subjects with a toxicity 
qualifying for a DLT (including 2 subjects with Grade 3 rash, 1 subject each with Grade 3
neutropenia >7 days, 1 subject with TLS, and 1 subject with Grade 4 neutropenia) have 
manageable toxicity despite fitting the criteria for DLT and could benefit from further treatment 
with study drugs. Based on this experience and with input from Investigators, the Sponsor has 
updated the language in the protocol amendment. If clinically warranted and agreed upon by
Investigator and Sponsor, subjects experiencing a DLT may continue with study treatment if the 
treating physician is of the opinion that the subject would benefit from continued therapy and the 
toxicity experienced was manageable.


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1.15.
Rationale for Changes in Amendment 4.0
1.15.1.
Removal of Arm without Rituximab
The use of rituximab in the DLBCL salvage setting is considered standard. To maximize 
potential efficacy in a population with relapsed/refractory and aggressive DLBCL, the arm with 
the 2-drug combination of ibrutinib and lenalidomide has been removed.  Only should safety 
concerns arise with the 3-drug combination, a 2-drug combination of ibrutinib with lenalidomide 
may be considered in this study.
Removing one arm from the study will lead to a smaller overall sample size of the trial. The 
statistical assumptions remain, i.e. to test the null hypothesis (H0) of 60% versus the alternative 
hypothesis (Ha) of 40% for ORR in the remaining arm with the 3-drug combination.
1.15.2.
Proposed Lenalidomide Dose for Phase 2
If the dose level of 20 mg lenalidomide is determined to be safe and tolerated in the Phase 1b, 
this dose will be considered the recommended Phase 2 dose (RP2D) and a Phase 2 cohort with 
20 mg lenalidomide will be initiated.  Concurrent with the Phase 2 at 20 mg lenalidomide, a 
Phase 1b cohort with 25 mg lenalidomide may be initiated. If the interim analysis of the 20 mg 
lenalidomide cohort is negative, the 25 mg lenalidomide dose may be used in an additional 
cohort in the Phase 2, if safe and tolerated in the Phase 1b.
The rationale for initiating the Phase 2 with the lenalidomide dose of 20 mg is based on 
efficacy/toxicity considerations. In the initial cohort with 15 mg lenalidomide (Cohort 1), 3
responses (2 CR and 1 PR) including 2 long-term responses (2 CR subjects with more than 12 
months of response) were observed among 8 subjects who received study drug for more than 1 
cycle and were evaluable for response. Importantly, in the lower dose cohort with 10 mg 
lenalidomide (Cohort -1), there were no responses, implying that higher doses may be more 
efficacious.  In addition, the lower dose cohort appeared better tolerated with fewer DLTs 
reported.  Several other studies have used a maximum dose of 10 mg, 15 mg and 20 mg of 
lenalidomide when combined with ibrutinib due to apparent increased toxicity with increasing 
doses of lenalidomide (eg, CTEP/A051103 [20 mg]; CTEP/9540 [15 mg]; CTEP/9254 [10 mg]).
Thus, the dose of 20 mg lenalidomide was chosen for the Phase 2, representing the best balance 
of safety and efficacy for this study.  However, since higher doses may be more efficacious and 
justified in a population with relapsed/refractory and aggressive DLBCL, if determined to be safe 
and tolerated in the Phase 1b, the 25 mg lenalidomide dose may be explored in the Phase 2.
1.16.
Rationale for Changes in Amendment 5.0
The purpose of Amendment 5 is inclusion of preliminary safety data from the Phase 1b into the 
protocol to support initiation of the Phase 2 portion of the trial.


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1.17.
PCYC-1123-CA Phase 1b Data Summary
As of 25 April 2016, a total of 38 subjects were enrolled (37 treated) in Cohort 1 (13 subjects 
enrolled, 12 treated), Cohort -1 (7 subjects enrolled), Cohort 1+ (9 subjects enrolled) and Cohort 
2 (9 subjects enrolled).
1.17.1.
Preliminary Summary of Safety Data
Cohort 1 (15 mg lenalidomide)
In Cohort 1 (15mg lenalidomide), 13 subjects were enrolled and 12 subjects treated (1 subject 
did not meet dosing criteria on Day 1 and could not be dosed). Seven subjects were evaluable for 
dose-limiting toxicity (DLT) observation purposes. Three DLTs were observed: One subject with 
Grade 3 neutropenia lasting longer than 7 days, and 2 subjects with a Grade 3 rash. Three 
subjects in this cohort experienced SAEs. All SAEs experienced in this cohort were unrelated to 
study drug. One subject experienced 1 SAE of myocardial infarction (unrelated to study drug), 
1 subject experienced 1 SAE of chest pain which was musculoskeletal per exclusion of other 
causes (unrelated to study drug), and 1 subject following disease progression and subsequent 
anticancer therapy experienced 1 SAE of neutropenic sepsis (unrelated to study drug) and 1 SAE 
of cardiac arrest (unrelated to study drug). Two subjects are receiving study treatment as of 
28 Apr 2016, and 10 subjects discontinued treatment (2 subjects are in follow-up, 3 subjects 
withdrew full consent, and 5 subjects expired [1 due to cardiac arrest, 1 due to unknown cause, 
3 due to progressive disease]).  Due to the 3 DLTs of neutropenia and two events of rash 
observed in this cohort, a de-escalation cohort with 10 mg lenalidomide was opened.  In addition, 
the DLT criteria were modified in regards to rash.
Cohort -1 (10 mg lenalidomide)
In Cohort -1 (10mg lenalidomide), 7 subjects were enrolled. Six subjects were evaluable for DLT 
observation purposes. There was 1 DLT of a Grade 4 salmonella sepsis. Two subjects 
experienced SAEs during the DLT observation period. One subject experienced 1 SAE of pleural 
effusion, which was unrelated to study drugs and related to DLBCL, another subject experienced 
1 SAE of salmonella sepsis, and later experienced pancytopenia and pneumonia, all possibly 
related to study drug. Three additional subjects experienced SAEs after the DLT observation
period. One subject experienced cellulitis and folliculitis (possibly related to study drug); 
dehydration, thrombocytopenia, pseudomonas sepsis and Grade 5 pneumonia (all unrelated to 
study drug). Two other subjects experienced Grade 5 SAEs of worsening of DLBCL (not related 
to study drug). As of 28 Apr 2016, all 7 subjects discontinued treatment (2 subjects are in 
follow-up and 5 subjects expired [1 due to pneumonia, 4 due to progressive disease]).  Due to the 
fact that only one DLT was identified during the DLT observation period in this cohort, a dose 
re-escalation cohort with 15 mg lenalidomide was opened.  
Cohort 1+ (15 mg lenalidomide)
In Cohort 1+ (15mg lenalidomide), 9 subjects were enrolled. Seven subjects were evaluable for 
DLT observation purposes, 1 subject was non-evaluable for DLT observation purposes due to 


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death/sepsis while on vacation during and after the DLT observation period (died before 
completion of C2D1) and 1 subject was non-evaluable due to receiving 10 mg lenalidomide 
instead of 15 mg (in error) during the DLT observation period. There was 1 DLT of Grade 4 
neutropenia. Two subjects experienced SAEs during the DLT period, the subject with a DLT of 
neutropenia experienced tumor lysis syndrome (TLS) (possibly related to study drug), as well as 
dehydration (unrelated to study drug), and worsening of DLBCL (unrelated to study drug). The 
subject that was non-evaluable who died during the DLT observation period experienced an SAE 
of sepsis (possibly related to study drug). Three subjects experienced SAEs after the DLT 
observation period, 1 subject experienced a transient ischemic attack (TIA) (possibly related to 
study drug), 1 subject experienced cellulitis (unrelated to study drug) and pneumonia (possibly 
related to study drug), and 1 subject experienced 1 SAE of malignant neoplasm 
progression/lymphoma in the right eye (unrelated to study drug). As of 28 Apr 2016, 4 subjects 
were on study treatment, and 5 subjects discontinued treatment (2 subjects are in follow-up,
1 subject withdrew consent and 2 subjects expired [1 due to sepsis and 1 due to progressive 
disease]).  Due to the fact that with 1 DLT there were less than 33% of subjects experiencing 
DLTs during the re-escalation cohort, dose escalation to 20 mg lenalidomide was pursued.
Cohort 2 (20 mg lenalidomide)
In Cohort 2 (20 mg lenalidomide), 9 subjects were enrolled. Eight subjects were evaluable for 
DLT observation purposes. One subject was non-evaluable due to disease progression and death 
during the DLT observation period. There were no DLTs identified in this dose cohort. Three 
subjects experienced SAEs. During the DLT observation period, one subject with a history of 
vaginal bleeding experienced Grade 3 vaginal bleeding which was related to tumors surrounding 
the vaginal area, unrelated to study drug and therefore not considered a DLT. The same subject 
experienced 3 SAEs that were also unrelated to study drug after the DLT observation period, a 
Grade 3 urinary tract infection, a Grade 3 partial bowel obstruction and a Grade 3 
hydronephrosis; 1 subject experienced Grade 2 fever (possibly related to study drug); 1 subject 
that was non-evaluable experienced Grade 4 hypercalcemia, Grade 4 hypoxic respiratory failure 
and Grade 5 disease progression. Per Investigator, the respiratory failure was thought to be
related to lymphoma; the CT showed worsening lymphadenopathy, suggesting disease 
progression of DLBCL along with diffuse infiltrates in the lung. As of 28 Apr 2016, 6 subjects 
were on study treatment, 3 subjects discontinued treatment (2 subjects are in follow-up and 
1 subject progressed and died during the DLT observation period).
1.17.2.
DLRC Meeting Outcome
Safety and preliminary efficacy data for all enrolled cohorts were reviewed by the DLRC on 
25 April 2016. The voting members (e.g. medical monitors, participating Investigators, safety 
officer, and biostatistician) present during the call and 4 Investigators who voted per e-mail 
unanimously voted to continue the study in Phase 1b with Cohort 3 (dose level of 25 mg of 
lenalidomide in combination with ibrutinib and rituximab) and to repeat safety assessments. In 
addition, the voting members unanimously voted to proceed to Phase 2 with the dose of 20 mg of 


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lenalidomide in parallel with Cohort 3 (25 mg lenalidomide) in the Phase 1b.Based on the DLRC 
recommendation, the Sponsor (Pharmacyclics LLC) is planning to proceed with the 25 mg 
lenalidomide dose level in the Phase 1b of the study. In parallel, the Sponsor is planning to
proceed with the Phase 2 portion of the study with the recommended Phase 2 dose of 20 mg 
lenalidomide, which is the same or similar recommended Phase 2 dose level tested in other trials 
using ibrutinib, lenalidomide and rituximab (Ujjani et al ASH 2015, NCT02160015 [15 and 
20 mg lenalidomide]; NCT02532257 [15 and 20 mg lenalidomide], NCT02446236 [10-25 mg 
lenalidomide], NCT02636322 [25 mg lenalidomide]; Wilson et al ASH 2015, NCT02142049 
[15, 20 and 25 mg lenalidomide].
2.
STUDY OBJECTIVE
2.1.
Primary Objectives
Phase 1b: 
x
To determine the maximum tolerated doses (MTD) and/or the recommended Phase 2 (RP2) 
dose of ibrutinib in combination with lenalidomide and rituximab by dose escalation of 
lenalidomide in subjects with relapsed or refractory DLBCL
x
To determine the safety and tolerability of ibrutinib in combination with lenalidomide and 
rituximab in subjects with relapsed or refractory DLBCL by dose escalating lenalidomide
Phase 2: 
x
To evaluate the efficacy of ibrutinib in combination with lenalidomide and rituximab by 
assessing the overall response rate (ORR) in subjects with relapsed or refractory non-GCB 
DLBCL
2.2.
Secondary Objectives
Phase 1b: 
x
To evaluate the efficacy of ibrutinib in combination with lenalidomide and rituximab by 
assessing the overall response rate (ORR) in subjects with relapsed or refractory DLBCL by 
lenalidomide dose group
Phase 2: 
x
To determine the efficacy of ibrutinib in combination with lenalidomide and rituximab in 
subjects with relapsed or refractory non-GCB DLBCL by assessing the following efficacy 
parameters:
o Complete Response (CR)
o Duration of Response (DOR)
o Progression Free Survival (PFS)
o Overall Survival (OS)


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x
To determine the safety and tolerability of ibrutinib in combination with lenalidomide and 
rituximab in subjects with relapsed or refractory non-GCB DLBCL
2.3.
Exploratory Objectives
Phase 2:
x
Efficacy analysis based on the activated B-cell like (ABC) subtype identified by gene 
expression profiling (GEP) will be performed
x
Effect of ibrutinib on peripheral T/B/NK cell counts
x
Effect of ibrutinib on serum immunoglobulin levels (IgG, IgM and IgA)
Pharmacokinetics:
x
Plasma pharmacokinetics of ibrutinib and PCI-45227
Biomarkers:
x
To identify signaling pathways or biomarkers that predict sensitivity or resistance to 
ibrutinib
x
To determine the frequency of tumor mutations (or other molecular markers) between 
pre and post treatment tissue that predict acquired resistance
3.
STUDY DESIGN
3.1.
Overview of Study Design
The study will be conducted in two Phases.
Phase 1b will be an open-label study.  The dose escalation portion of the study is designed to 
establish the MTD of the ibrutinib, lenalidomide, and rituximab combination.  The dose levels
outlined in (Table 4) may be explored and dose escalation of lenalidomide will follow the 
3+3+3 dose escalation schema. After completion of Cohort 1 at Dose Level 1, due to 3 DLTs in 
7 evaluable subjects, a cohort at Dose Level -1 was opened.  After completion of the Dose Level 
-1 cohort, if <33% of subjects experience a DLT, dose re-escalation to higher dose levels starting 
with the lenalidomide dose of 15 mg may occur. Approximately 46 subjects will be enrolled in 
the Phase 1b portion.
Phase 2 will be an open-label study designed to evaluate the overall response rate of ibrutinib in 
combination with lenalidomide and rituximab, in relapsed or refractory non-GCB DLBCL 
subjects ineligible for transplant. If the dose level of 20 mg lenalidomide is determined to be 
safe and tolerated in the Phase 1b, this dose will be considered the recommended Phase 2 dose 
(RP2D) and a Phase 2 cohort initiated with 20 mg lenalidomide. Concurrent with the Phase 2 at 
20 mg lenalidomide, a Phase 1b cohort with 25 mg lenalidomide may be initiated.
An interim analysis will be performed including approximately 28 evaluable subjects with 
adequate tumor response assessment.  Details of the interim analysis and decision rules will be 


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described in the statistical analysis plan (SAP).  At the interim analysis, the review committee 
could recommend:
1. continuation of the study with 20 mg lenalidomide; or
2. increase of the lenalidomide dose to 25 mg, if determined to be safe and tolerated in the 
Phase 1b, including approximately 28 evaluable subjects with adequate tumor response 
assessment followed by an interim analysis.
In addition, if there are safety concerns, a cohort with ibrutinib and lenalidomide without 
rituximab may be considered.
Phase 2 may enroll approximately 55 subjects to ensure enrollment of at least 49 response-
evaluable subjects. Approximately 129 subjects, inclusive of Phase 1b and Phase 2, will be 
enrolled.  Both Phases will include a Screening Phase, Treatment Phase and a Follow-Up Phase.
The Screening Phase assessments will be performed within 28 days prior to study treatment.  
Eligible subjects will have pathologically confirmed DLBCL, having received at least 1 prior 
therapy, with documented disease that is relapsed or refractory in subjects ineligible for HDT 
and transplant.  For Phase 2, subjects must have pathologically confirmed de novo non-GCB 
DLBCL by Hans method testing using immunohistochemistry (IHC).
The Treatment Phase will extend from the first dose of study treatment until criteria for 
permanent discontinuation of ibrutinib or study treatment are met (Section 9.2), such as disease 
progression, unacceptable toxicity or 2 years after the last subject has been enrolled, whichever 
occurs first.  During the Treatment Phase, efficacy evaluations will be performed every 3 cycles 
(28-day cycle) as specified in Section 7.3.
The Follow-up Phase will begin once a subject discontinues ibrutinib treatment and will continue 
until death, lost to follow up, consent withdrawal, or study end, whichever occurs first.  
x
Subjects who discontinue for reasons other than disease progression (ie, for adverse event or 
Investigator decision) will complete an End-of-Treatment Visit (30 ± 3 days from the last 
dose of ibrutinib, lenalidomide or rituximab, whichever is later), and must continue to have 
disease evaluations (12 weeks ±7 days).  (See Figure 1)
x
Subjects who discontinue due to disease progression will complete an End-of-Treatment 
Visit and be followed for survival and subsequent anticancer therapy (12 weeks ±7 days) 
until study ends. (See Figure 1)
It is imperative that survival status be assessed and that the date of death is documented for each 
subject who has died. The study completion is defined as 3 years from the last study treatment, 
the time point that all subjects have exited the study for any reason, or study termination at the 
Sponsor’s discretion, whichever occurs first.
A Dose Level Review Committee will evaluate safety data following the completion of each 
dose observation period of the Phase 1b portion. Members of this committee will include the 


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Sponsor (at a minimum: the Medical Monitor or designee, a Drug Safety representative and a 
Biostatistician) as well as participating Investigators/designee.  
Table 3: 
Dosing Schedule
Agent
Phase 1b
Phase 2
Cycles 1-6
Cycles 7+
Cycles 1-6
Cycles 7+
Ibrutinib
560 mg PO daily
560 mg PO daily 
Lenalidomide
15-25 mg PO Days 1-21 
RP2 dose = 20 mg PO Days 1-21, 
if determined to be safe and tolerated in the 
Phase 1b portion of the study*  
Rituximab 
375 mg/m2 IV 
Day 1
NA
375 mg/m2 IVDay 1
NA
*25 mg may be explored as outlined in the protocol
Figure 1: 
Study Design Schematic
3.2.
Phase 1b Dose Escalation and Expansion Overview 
Phase 1b will be conducted in the United States (US), with approximately 46 subjects enrolled.  
Additional subjects may be screened and enrolled in any cohort as outlined.  In the dose 
escalation portion, up to four dose levels of lenalidomide will be explored and the dose 
escalation will follow the 3+3+3 principles.  The decision to expand any individual cohort up to 


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9 subjects for the purpose of safety evaluation will be made after review of the dose escalation 
safety data.
During Phase 1b the doses of both ibrutinib and rituximab will remain fixed with up to 4 dose 
levels of lenalidomide to be explored according to cohort (Table 4). After completion of Cohort 
1 at Dose Level 1, due to 3 DLTs in 7 evaluable subjects, a cohort at Dose Level -1 was opened.  
After completion of the Dose Level -1 cohort, if <33% of subjects experience a DLT, dose re-
escalation to higher dose levels starting with the lenalidomide dose of 15 mg may occur. Both 
ibrutinib and lenalidomide will continue until disease progression or unacceptable toxicity, while 
rituximab will be discontinued after 6 cycles.  See Section 5 for study treatment details.
After completion of Phase 1b Cohort 2 at Dose Level 2 (20 mg lenalidomide), enrollment into 
Phase 2 will commence with 20 mg lenalidomide, if determined to be safe and tolerated in the 
Phase 1b portion of the study. Concurrent with the Phase 2 at 20 mg lenalidomide, Phase 1b 
Cohort 3 at Dose Level 3 (25 mg lenalidomide) may be enrolled.
3.3.
Phase 2 Efficacy Evaluation Overview
Phase 2 will be an open-label, international, multi-center study.  This portion of the study will be 
conducted at up to 70 international clinical centers, with approximately 55 subjects enrolled.  
Subjects will be treated with the 20 mg lenalidomide dose, if determined to be safe and tolerated 
in the Phase 1b portion of the trial.
An interim analysis will be performed as outlined in Section 10.
4.
SUBJECT SELECTION
The inclusion and exclusion criteria for enrolling subjects on this study are described below. If 
there are any questions about the entry criteria, the Investigator should consult with the Medical 
Monitor before enrolling a subject in the study. Selected eligibility criteria must be confirmed in 
writing by the Medical Monitor prior to enrollment.
4.1.
Inclusion Criteria
To be enrolled in the study, each potential subject must satisfy all of the following inclusion 
criteria.
Disease Related
1. Pathologically confirmed:
a.
Phase 1b: diffuse large B-cell lymphoma.
b. Phase 2: de novo non-GCB DLBCL by Hans method testing using 
immunohistochemistry
Note: Sufficient tissue sample for evaluation by IHC and GEP is required for subjects in 
Phase 2 (refer to Laboratory Manual for requirements).


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2. Relapsed or refractory disease, such as either: 1) recurrence of disease after a complete 
response (CR), or 2) partial response (PR), stable disease (SD) or progressive disease (PD) at 
completion of the treatment regimen preceding entry to the study (residual disease).
3. Subjects must have previously received an appropriate first-line treatment regimen.
4. For subjects having a computed tomography (CT) scan abnormality with uncertain 
interpretation following completion of the most recent treatment regimen: biopsy 
confirmation of residual DLBCL is required prior to study entry to confirm residual DLBCL 
and to rule out a non-lymphomatous process (eg, fibrosis). 
5. Subjects who have not received HDT/SCT must be ineligible for HDT/SCT as defined by 
meeting any of the following criteria:
a.
$JH\HDUV
b.
Diffuse lung capacity for carbon monoxide <50% by pulmonary function test.
c.
Left ventricular ejection fraction <50% by multiple gated acquisition/echocardiogram.
d.
Other organ dysfunction or co-morbidities precluding the use of HDT/SCT on the basis 
of unacceptable risk of treatment-related morbidity.
e.
Failure to achieve PR or CR with salvage therapy.
f.
Subject refusal of HDT/SCT.
6. One or more measurable disease sites on CT scan (>1.5 cm in longest dimension).  Lesions 
in anatomical locations (such as extremities or soft tissue lesions) that are not well visualized 
by CT may be measured by MRI instead (see Section 7.3.1).
Laboratory
7. Adequate hematologic function with screening laboratory assessment independent of growth 
factor and transfusion support for at least 7 days, with the exception of pegylated G-CSF 
(pegfilgrastim) and darbepoetin which require at least 14 days, defined as:
a.
Absolute neutrophil count (ANC) >1,500 cells/mm3 (1.5 x 109/L).  
b.
Platelet count >75,000 cells/mm3 (75 x 109/L).
c.
Hemoglobin >8.0 g/dL.
8. Adequate hepatic and renal function with screening laboratory assessment defined as:
a.
6HUXPDVSDUWDWHWUDQVDPLQDVH$67RUDODQLQHWUDQVDPLQDVH$/72.5 x upper limit 
of normal (ULN).
b.
Creatinine clearance (Cockcroft-Gault or 24-hour creatinine clearance collection)
>60 mL/min.
c.
Bilirubin <1.5 x ULN [unless bilirubin rise is due to Gilbert’s syndrome (as defined by 
>80% unconjugated hyperbilirubinemia) or of non-hepatic origin].
9. PT/INR <1.5 x ULN and aPTT <1.5 x ULN.


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Demographic
10. 0HQDQGZRPHQ\HDUVRIDge.
11. Eastern Cooperative Oncology Group (ECOG) performance status of <2.
Ethical/Other
12. All study participants must be registered into the mandatory Revlimid REMS™program, 
and be willing and able to comply with the requirements of the Revlimid REMS™program
(for US sites only).
13. Female subjects of childbearing potential (FCBP)a must have a negative serum or urine 
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 – 14 days and again within 
24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 
7 days as required by Revlimid REMS™) and must either commit to continued abstinence 
from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly 
effective method and one additional effective method AT THE SAME TIME, at least 
28 days before she starts taking lenalidomide.  Female subjects of childbearing potential 
(FCBP) must also agree to ongoing pregnancy testing. See Appendix 7 (for US sites only).
14. Female subjects of childbearing potential (FCBP)a must have a negative serum or urine 
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 – 14 days and again within 
24 hours prior to starting Cycle 1 of lenalidomide.  FCBP must also agree to ongoing 
pregnancy testing. All subjects must be counseled at a minimum of every 28 days about 
pregnancy precautions and risks of fetal exposure.  See Appendix 8 (for ex-US sites only).
15. Male subjects must agree to use a latex condom during sexual contact with a FCBP even if 
they have had a successful vasectomy.  See (for US sites only).
16. Male subjects must agree to use a latex condom during sexual contact with a FCBP even if 
they have had a successful vasectomy.  All subjects must be counseled at a minimum of 
every 28 days about pregnancy precautions and risks of fetal exposure.  See Appendix 8
(for ex-US sites only).
17. Female subjects of child bearing potential (FCBP)b and male subjects who are sexually 
active must use TWO acceptable methods of birth control, one highly effective method of 
birth control plus one additional effective method of birth control for at least 28 days prior to 
study treatment and during the study treatment period.  For female subjects, these birth 
control requirements must be adhered to for 12 months after the last dose of rituximab or 30 
days after the last dose of ibrutinib and lenalidomide, whichever is later.  For male subjects, 
these birth control requirements must be adhered to for 90 days after the last dose of ibrutinib 
and lenalidomide, whichever is later.  Male subjects must agree to not donate sperm during 
the study treatment period and up to 90 days after the last dose of ibrutinib and lenalidomide.
18. Life expectancy of more than 3 months.
b A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in 
the preceding 24 consecutive months).


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4.2.
Exclusion Criteria
To be enrolled in the study, potential subjects must not have any of the following exclusion 
criteria:
Disease-Related
Phase 2 Only
1. Transformed DLBCL, germinal center B-cell (GCB) DLBCL or DLBCL with coexistent 
histologies (eg, follicular or mucosa-associated lymphoid tissue [MALT] lymphoma).
2. Primary mediastinal (thymic) large B-cell lymphoma.
Phase 1b/2
3. Medically apparent central nervous system lymphoma or leptomeningeal disease.
4. History of allogeneic stem-cell (or other organ) transplantation.
5. Any chemotherapy, external beam radiation therapy, or anticancer antibodies within 2 weeks 
of the first dose of study drug.
6. Radio- or toxin-immunoconjugates within 10 weeks of the first dose of study drug.
7. Concurrent enrollment in another therapeutic investigational study or have previously taken 
ibrutinib and/or lenalidomide.
Concurrent Conditions
8. History of other malignancies, except:
a.
Malignancy treated with curative intent and with no known active disease present for 
5 years before the first dose of study drug and felt to be at low risk for recurrence by 
treating physician.
b.
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease.
c.
Adequately treated carcinoma in situ without evidence of disease.
9. Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or 
chronic administration of >20 mg/day of prednisone) within 28 days of the first dose of study 
drug.
10. Recent infection requiring intravenous anti-LQIHFWLYHWUHDWPHQWWKDWZDVFRPSOHWHGGD\V
before the first dose of study drug.
11. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), Grade  1 or to 
the levels dictated in the inclusion/exclusion criteria with the exception of alopecia.
12. Known bleeding diathesis (eg, von Willebrand’s disease) or hemophilia.
13. Known history of human immunodeficiency virus (HIV) or chronic or active hepatitis C 
virus (HCV) or hepatitis B virus (HBV) infection.


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14. Major surgery within 4 weeks of first dose of study drug.
15. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable angina, 
or acute coronary syndrome within 6 months prior to enrollment.
16. Unable to swallow capsules, malabsorption syndrome, disease significantly affecting 
gastrointestinal function, resection of the stomach or small bowel, symptomatic inflammatory 
bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
17. Concurrent use of warfarin or other Vitamin K antagonists (eg, phenprocoumon).
18. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see Appendix 4).
19. Any life-threatening illness, medical condition including uncontrolled Diabetes Mellitus, or 
organ system dysfunction that, in the opinion of the Investigator, could compromise the 
subject’s safety or put the study outcomes at undue risk.
20. Currently active, clinically significant hepatic impairment Child-Pugh class B or C according 
to the Child-Pugh classification 
21. Known hypersensitivity to lenalidomide (or thalidomide) or rituximab.
22. Lactating or pregnant.
23. Unwilling or unable to participate in all required study evaluations and procedures.
24. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information 
(in accordance with national and local subject privacy regulations).
5.
TREATMENT OF SUBJECTS
5.1.
Phase 1b Dose Escalation and Stopping Rules
This is an open-label dose escalation study using a 3+3+3 design.  Before applying the dose 
escalation rules, 3 subjects in any given cohort must have completed the DLT observation period 
which is defined as 28 days (1 cycle of therapy followed by laboratory evaluation for toxicity on 
Cycle 2 Day 1, Study Day 29).  The modified 3+3+3 design defines the MTD to have been 
H[FHHGHGZKHQRXWRI subjects in a cohort experience a DLT.  If there are 3 DLTs in Dose 
Level 1, Dose Level -1 will be enrolled. 
After completion of Cohort 1 at Dose Level 1, due to 3 DLTs in 7 evaluable subjects, a cohort at 
Dose Level -1 was opened.  After completion of the Dose Level -1 cohort, if <33% of subjects 
experience a DLT, dose re-escalation to higher dose levels starting with the lenalidomide dose of 
15 mg may occur. Due to the fact that the subject population studied is significantly ill and an 
inability to complete the DLT observation period may occur due to progression of disease, 
additional subjects may be screened and enrolled in each cohort. The DLT rules will continue to 
apply whereas if 1 DLT is observed, the cohort will be expanded to 6, and if 2 DLTs occur, the 
cohort will be expanded to 9.


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Enrollment in a cohort will proceed as follows:
x
If no dose limiting toxicity (DLT) is observed during the DLT observation period in the 
initial 3 subjects of a cohort, dose escalation to the next higher dose level cohort will occur.
x
If 1 DLT is observed, 3 additional subjects will be enrolled at the same dose level for a total 
of at least 6 subjects.  If no further DLT(s) are observed, escalation to the next higher dose 
level cohort will occur.  
x
If a second DLT is observed, 3 additional subjects may be enrolled at the same dose level 
for a total of at least 9 subjects.  If no further DLTs are observed, dose escalation to the next 
higher dose level will occur.  Note: If appropriate, no further expansion of this cohort will 
occur if significant safety concerns are recognized after the first 6 subjects are enrolled.   
x
,I'/7VDUHREVHUYHGLQWKHVXEMHFWVWKHQHQUROOPHQWZLOOVWRSDWWKHWKLUG'/7
observation and enrollment into a cohort at a lower dose level (with the exception of Cohort
-1) will be considered.
x
After enrollment of a cohort at Dose Level -1 (10mg lenalidomide) and if <33% of subjects 
experience a DLT, dose re-escalation to higher dose levels starting with the lenalidomide
dose of 15 mg may occur.
If a subject experiences a DLT during the DLT observation window, the subject may continue
study treatment, if continued clinical benefit from study treatment is expected per the treating 
physician and the toxicity observed is manageable; the Sponsor should be notified in this case.
The decision to proceed to the next dose level will be made in a Dose Level Review Committee
Meeting by the Sponsor in conjunction with the Investigators after careful consideration of all 
available safety and laboratory information.  Safety data from subjects on preceding cohorts that 
remain on continuous dosing will also be considered.
Dose escalation will occur at the planned dose levels until the MTD is determined or until the 
highest dose level is tested.  The MTD is defined as the highest dose at which <33% of the 
subjects enrolled in a cohort experience a DLT.  If all evaluated dose levels demonstrate an 
observed incidence of DLT in <33% of subjects, the MTD of lenalidomide in the combination 
has not been reached.  At least 6 subjects will be treated at the MTD or in any cohort that 
supports the Phase 2. The assessment of DLT will follow the guidelines provided in the Common 
Terminology Criteria for Adverse Events (CTCAE, version 4.03).
5.2.
Dose Limiting Toxicity (DLT) Definition
A DLT is defined as one of the following events that is possibly related to study drug:
Hematologic:
x
Grade 4 neutropenia (ANC <500/mm3) lasting for >7 days 
x
Life-threatening Grade 3 neutropenia (ANC <1,000/mm3ZLWKIHYHU&


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x
Grade 4 thrombocytopenia (<25,000/ mm3) that persists for 7 days, despite holding 
treatment
x
Grade 3 thrombocytopenia associated with Grade 2 bleeding or requiring RBC or platelet 
transfusions 
Non-Hematologic:
Any Grade 3 or higher non-hematologic adverse event with the clarifications noted below: 
(Note: excludes rituximab infusion reactions) 
x
Grade 3 tumor lysis syndrome would be considered a DLT only if it requires dialysis. 
x
Grade 3 deep venous thrombosis would be considered a DLT only if it is unresponsive to 
anticoagulation  
x
Grade 3 rash that has not improved within 10 days to at least Grade 1 using a temporary 
drug hold of all study drugs and administration of up to 100 mg of prednisone PO or 
equivalent (with or without taper) and/or antihistamines PO daily 
x
Grade 3 infection is not a DLT, however an infection with life-threatening consequences or 
requiring urgent intervention (grade 4) will be considered a DLT 
x
*UDGHQDXVHDYRPLWLQJRUGLDUUKHDXQFRQWUROOHGE\PD[LPDOsupportive care and 
persisting greater than 7 days
x
Grade 3 fatigue persisting for greater than 7 days
x
Treatment delay of any drug greater than 7 days for toxicity
In the Dose Escalation Phase, if a subject is non-compliant with the prescribed therapy or ends 
treatment within the first cycle for reasons other than study drug(s) related toxicity, ie, withdraws 
consent, they will be replaced.  In addition, any subject that misses >7 doses of ibrutinib and/or 
lenalidomide for reasons other than AEs of rash will be replaced; subjects with AEs of rash that 
miss >10 doses of ibrutinib and/or lenalidomide will be replaced unless considered a DLT.  Any 
subject that requires rituximab discontinuation during the first cycle per the guidance in 
Section 5.6.4 will be replaced. Subjects with bulky tumors have an increased risk of TLS, and 
sufficient hydration and close monitoring of laboratory parameters (eg, a chemistry panel every 
3 days) is recommended for this patient population.  Investigators are encouraged to monitor 
subjects at high risk for TLS closely. 


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Table 4: 
Phase 1b Dosing Levels 
28-Day Dosing Cycle
Ibrutiniba
Lenalidomideb 
Rituximabc
Dose Level -1d
560 mg once daily 
10 mg 
375 mg/m2
Dose Level 1 = starting dose (Cohort 1 & 1+)
560 mg once daily 
15 mg 
375 mg/m2
Dose Level 2 (Cohort 2) 
560 mg once daily 
20 mg 
375 mg/m2
Dose Level 3 (Cohort 3) 
560 mg once daily 
25 mg 
375 mg/m2
a Ibrutinib will be administered orally daily beginning Cycle 1 Day 1 
a Lenalidomide will be administered orally daily on Days 1-21 of each 28-day cycle 
c Rituximab will be administered IV on Day 1 of each 28-day cycle for 6 cycles 
d If <33% of subjects experience a DLT at Dose Level -1, dose re-escalation to a higher dose level may occur.
5.3.
Treatment Regimens 
All eligible subjects will be treated with rituximab, ibrutinib and lenalidomide. 
5.3.1.
Phase 1b 
Ibrutinib and rituximab will be administered at set doses and lenalidomide will be administered 
according to the assigned dose level (Table 4). 
5.3.2.
Phase 2 
Subjects will be treated with ibrutinib in combination with lenalidomide and rituximab per the 
table below.  If determined to be safe and tolerated in the Phase 1b portion of the trial, the 
proposed dose of lenalidomide is 20 mg.  Additional subjects may receive 25 mg lenalidomide as 
outlined.  
Each cycle is 28 days in length.  Missed doses of ibrutinib, lenalidomide, and rituximab will not 
be made up.  Treatment will continue until disease progression or unacceptable toxicity. 
5.3.2.1.
Treatment
Ibrutinib: 
560 mg (4 capsules) orally administered daily 
Lenalidomide:
Recommended Phase 2 dose = 20 mg* orally administered Days 1-21 in each cycle, 
if determined to be safe and tolerated in the Phase 1b portion of the trial 
*25 mg may be explored as outlined in the protocol
Rituximab: 
375 mg/m2 IV per package insert on Day 1 of cycles 1 – 6 only 
5.4.
Ibrutinib 
All subjects in both phases of this study will receive ibrutinib and will follow guidelines for 
ibrutinib dosing and toxicity management. 


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5.4.1.
Formulation, Packaging, and Storage of Ibrutinib
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib.  All 
formulation excipients are compendial and are commonly used in oral formulations.  Refer to the 
ibrutinib Investigator's Brochure for a list of excipients. 
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies. All study 
drug will be dispensed in child-resistant packaging.  
Refer to the Pharmacy Manual for additional guidance on study drug storage, preparation and 
handling.
5.4.2.
Dose and Administration of Ibrutinib
The first dose of ibrutinib will be administered orally on Cycle 1 Day 1, of the Treatment Phase, 
after which ibrutinib will be self-administered daily by the subjects on an outpatient basis.
Ibrutinib will be dosed 0í30 minutes before the rituximab infusion and at the same time as 
lenalidomide.
Ibrutinib 560 mg (4 x 140-mg capsules) is administered orally once daily with 8 ounces 
(approximately 240 mL) of water at approximately the same time each day.  The capsules should 
be swallowed intact and patients should not attempt to open capsules or dissolve them in water.  
The use of strong CYP3A inhibitors/inducers, and grapefruit and Seville oranges should be 
avoided for the duration of the study (Section 6.1.2.1).
If a dose is missed, it can be taken as soon as possible on the same day with a return to the 
normal schedule the following day.  The subject should not take extra capsules to make up the 
missed dose.
Ibrutinib dosing is continuous (without interruption) throughout the Treatment Phase. Treatment 
will continue until disease progression or other reason for treatment discontinuation as outlined 
in Section 9.
Dose modifications for toxicity are outlined in Section 5.4.4.
Unused ibrutinib capsules dispensed during previous visits must be returned and drug 
accountability records updated at the beginning of the next cycle.  Returned capsules must not be 
re-dispensed to the same subject or to another subject.
5.4.3.
Dose Hold, Reduction or Discontinuation of Ibrutinib
In order to continue ibrutinib at the start of a new cycle, the subject must not meet any of the 
criteria for ibrutinib dose modification (see Section 5.4.4).


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Treatment with ibrutinib should be withheld for any unmanageable, potentially study 
drug-related non-hematological toxicity that is Grade 3 or higher in severity and any hematologic 
toxicity meeting the criteria in Section 5.4.4. 
For Grade 3 rash, hold ibrutinib until rash improves to Grade 1, then resume at original dose 
(for the first episode) or lower dose as clinically indicated.  Treatment with 20 mg prednisone 
PO or equivalent daily for 10 days (with or without taper) and/or antihistamines PO daily is 
recommended; discontinue allopurinol if rash is thought to be at least possibly related to 
allopurinol.  
During the DLT observation period: If Grade 3 rash has not improved to at least Grade 1 using 
a temporary drug hold and administration of  up to 100 mg of prednisone or equivalent (with or 
without taper) and/or antihistamines daily for 10 days, rash is considered a DLT. 
Outside of the DLT observation period: see recommendations for Grade 3 rash above. 
For lenalidomide dose modifications due to rash: see Table 6. 
Subjects who require full-dose of anticoagulant treatment (eg, heparin) should have ibrutinib 
held until stable on anticoagulant therapy (Section 6.1.2.3).  Subjects that require an invasive 
procedure or surgery must have ibrutinib withheld according to the guidance in Section 6.2.  
Any other clinically important events where dose delays may be considered appropriate by the 
Investigator must be discussed with the Medical Monitor. 
Ibrutinib may be withheld for a maximum of 28 consecutive days for toxicity.  Ibrutinib should 
be discontinued in the event of an ibrutinib toxicity lasting more than 28 days, unless reviewed 
and approved by the Medical Monitor. 
5.4.4.
Dose Modification of Ibrutinib 
Recommendations for dose modification of ibrutinib are provided in Table 5 if any of the 
following toxicities occur: 
x
Grade 3 neutropenia (ANC <1,000/μL) with an associated temperature 38.5°C 
x
Grade 4 neutropenia (ANC <500/μL) for more than 7 days.  Refer to Section 6 for 
instruction regarding the use of growth factor support 
x
Grade 3 thrombocytopenia (platelets <50,000/μL) in the presence of Grade 2 bleeding 
events 
x
Grade 4 thrombocytopenia (platelets <25,000/μL) 
x
Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic and/or 
anti-diarrheal therapy  
x
Any other Grade 4 or unmanageable Grade 3 toxicity attributed to ibrutinib 


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For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anti-coagulants or 
anti-platelet agents may be considered for the thromboprophylaxis of atrial fibrillation 
(Section 6.1.2.3). 
If tumor lysis syndrome is diagnosed, follow institutional guidelines for management.
Table 5:
Ibrutinib Dose Modifications
Hematologic Adverse Events
Occurrence
Action to be Taken
First
:LWKKROGLEUXWLQLEXQWLOUHFRYHU\WRDQ$1&/μL or platelets >25,000/μL with no
HYLGHQFHRI*UDGHEOHHGLQJPD\UHVWDUWDWRULJLQDOGRVHOHYHO
Second
:LWKKROGLEUXWLQLEXQWLOUHFRYHU\WRDQ$1&/μL or platelets >25,000/μL with no
HYLGHQFHRI*UDGHEOHHGLQJPD\UHVWDUWDWGRVHOHYHOORZHULHPJGD\
Third
:LWKKROGLEUXWLQLEXQWLOUHFRYHU\WRDQ$1&/μL or platelets >25,000/μL with no
HYLGHQFHRI*UDGHEOHHGLQJPD\UHVWDUWDWGRVHOHYHOORZHULHPJGD\
Fourth
Discontinue ibrutiniba
Non-Hematologic Adverse Events
First
:LWKKROGLEUXWLQLEXQWLOUHFRYHU\WR*UDGHRUEDVHOLQHPD\UHVWDUWDWRULJLQDOGRVHOHYHO
Second
:LWKKROGLEUXWLQLEXQWLOUHFRYHU\WR*UDGHRUEDVHOLQHPD\UHVWDUWDWGRVHOHYHOORZHU
(ie, 420 mg/day)
Third
:LWKKROGLEUXWLQLEXQWLOUHFRYHU\WR*UDGHRUEDVHOLQHPD\UHVWDUWDWGRVHOHYHOORZHU
(ie, 280 mg/day)
Fourth
Discontinue ibrutiniba
a If ibrutinib is discontinued for toxicity, subject will end the Treatment Phase of the study.
Dose changes must be recorded in the Dose Administration eCRF. At the Investigator’s 
discretion, the dose of ibrutinib may be re-escalated after 2 cycles of a dose reduction in the 
absence of a recurrence of the toxicity that led to the reduction.
5.4.5.
Ibrutinib Dose Modification for Hepatic Impaired Subjects
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant hepatic 
impairment at the time of Screening (Child-Pugh class B or C) are excluded from study 
participation. For subjects who develop mild liver impairment while on study (Child-Pugh 
class A), the recommended dose reduction for ibrutinib is to a level of 280 mg daily (two 
capsules). For subjects who develop moderate liver impairment while on study (Child-Pugh 
class B), the recommended dose reduction is to a level of 140 mg daily (one capsule). Subjects 
who develop severe hepatic impairment (Child-Pugh class C) must hold study drug until 
resolved to moderate impairment (Child-Pugh class B) or better. Monitor subjects for signs of 
toxicity and follow dose modification guidance as needed (Refer to Appendix 9).


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5.5.
Lenalidomide
All subjects in both phases of this study will receive lenalidomide and will follow guidelines for 
lenalidomide dosing and toxicity management.
5.5.1.
Formulation, Packaging, and Storage of Lenalidomide
Lenalidomide (Revlimid®) will be supplied as capsules for oral administration by Celgene
Corporation.
Lenalidomide will be shipped to the pharmacy at the study site in individual bottles or blister 
packs.  Bottles or blister packs will contain a sufficient number of capsules to last for one cycle 
of dosing. Lenalidomide must be dispensed in the original packaging with the label clearly 
visible.  Only enough lenalidomide for 1 cycle of therapy may be provided to the subject 
each cycle.
The Investigator or designee is responsible for taking an inventory of each shipment of
lenalidomide received on the drug accountability form.  
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold.
5.5.2.
Lenalidomide Prescribing Information (applies to US sites only)
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this study at no charge to them or their insurance providers.  Lenalidomide will 
be provided in accordance with Celgene Corporation’s Revlimid REMS™program.  Per standard 
Revlimid REMS™program requirements, all physicians who prescribe lenalidomide, and all 
research subjects enrolled into this trial, must be registered in, and must comply with, all 
requirements of the Revlimid REMS™program.  All lenalidomide prescribers must be certified 
to prescribe lenalidomide and included on the Form FDA 1572. Study drug will be shipped on a 
per subject basis by the contract pharmacy (ie, Biologics, Inc.) to the clinical site. All subjects
will be counseled through the Revlimid REMS™program with all pregnancy requirements,
including the use of birth control and pregnancy testing before lenalidomide can be shipped to 
the site investigational pharmacy to dispense to the subjects. Only enough lenalidomide for one 
cycle of therapy will be supplied to the subject each cycle.
Pregnancy Testing
Refer to Appendix 7.
5.5.3.
Lenalidomide Drug Dispensing Requirements (applies to ex-US sites only)
In investigational studies, lenalidomide will be dispensed through a qualified healthcare 
professional (including but not limited to, nurses, pharmacists and physicians) and lenalidomide
prescribers must be included on the Form FDA 1572.  These healthcare professionals will be 
trained by Celgene or designee in requirements specific to counseling of subjects.  Each site is 


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required to have two trained counselors at all times. Once trained, these healthcare staff will 
counsel the subjects prior to medication being dispensed to ensure that the subject has complied 
with all requirements including use of birth control and pregnancy testing (FCBP) and that the 
subject understands the risks associated with lenalidomide.  This step will be documented with a 
completed Education and Counseling Guidance Document (Appendix 8), and no drug will be 
dispensed until this step occurs. Counseling includes verification with the subject that required 
pregnancy testing was preformed and results were negative. A Lenalidomide Information Sheet 
(Appendix 8) will be supplied with each medication dispense.
Pregnancy Testing
Pregnancy tests for females of childbearing potential.  A female of childbearing potential (FCBP) 
is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer 
therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had 
menses at any time in the preceding 24 consecutive months).
Pregnancy tests must occur within 10–14 days and again within 24 hours prior to initiation of 
Cycle 1 of lenalidomide.  FCBP with regular or no menstruation must have a pregnancy test 
weekly for the first 28 days and then every 28 days while on lenalidomide therapy (including 
breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of 
lenalidomide.  A FCBP with irregular menstruation must have a pregnancy test weekly for the 
first 28 days and then every 14 days while on lenalidomide therapy (including breaks in therapy), 
at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide 
(see Appendix 8).
Counseling
All subjects must be counseled about pregnancy precautions, risks of fetal exposure and other 
risks.  The counseling must be done on Day 1 of each cycle (or at a minimum of every 28 days) 
throughout the entire duration of lenalidomide treatment, including dose interruptions, and at 
lenalidomide discontinuation.  The Appendix 8 (Section 3): Education and Counseling Guidance 
Document must be completed by a trained counselor.
5.5.4.
Dosage, Preparation and Administration of Lenalidomide
The first dose of lenalidomide will be administered orally on Cycle 1 Day 1, of the Treatment 
Phase, after which lenalidomide will be self-administered daily by the subjects on Days 1-21 of 
each cycle.
Lenalidomide will be dosed 0-30 minutes before the rituximab infusion and at the same time as 
ibrutinib.
Lenalidomide should be administered with water at approximately the same time each day.  The 
capsule should be swallowed intact and subjects should not attempt to chew capsules, open 


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capsules or dissolve them in water.  Females of childbearing potential should not handle or 
administer lenalidomide unless they are wearing gloves.
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day.  If a
dose is missed for the entire day, it should not be made up.
Lenalidomide dosing during the Treatment Phase occurs on Days 1-21 each cycle followed by a 
mandatory 7-day drug-free interval. If a Day 1 (of any Cycle) is delayed due to scheduling, 
instruct the subject that lenalidomide dosing should not be initiated until Day 1 assessments can 
occur.
Treatment will continue until disease progression or other reason for treatment discontinuation as 
outlined in Section 9.
Dose modifications for toxicity are outlined in Section 5.5, Table 6 and Table 7.
For instructions regarding drug accountability and disposal/return of unused lenalidomide refer 
to the Pharmacy Manual.
5.5.5.
Dose Delay, Reduction or Discontinuation of Lenalidomide
In order to initiate a new cycle of therapy with lenalidomide, the subject must have an ANC 
/DQGDSODWHOHWFRXQW/ and no lenalidomide related Grade 3 toxicity on
Day 1.  If these two criteria are not met, the entire cycle with all drugs is to be delayed and a
repeat assessment is to be performed per the Investigator’s decision. The initiation of 
lenalidomide should be delayed until the subject meets the above criteria at which time the 
subject will initiate drug without dose modification. The initiation of lenalidomide may occur on 
any day of the cycle, but missed doses must be omitted.  Omitted doses should not be made up, 
and lenalidomide dosing must end no later than Day 21 of any given cycle.  Once a cycle has 
initiated, if lenalidomide must be held for toxicity during dosing, except for an AE of rash, 
lenalidomide will not resume until Day 1 of the subsequent cycle, provided the subject meets the 
cycle initiation criteria above, with dose adjustments as per Table 6.
Treatment with lenalidomide should be withheld for any unmanageable, potentially study drug-
related non-hematological toxicity that is Grade 3 or higher in severity and any hematologic 
toxicity as described in Table 6. In the event the subject is diagnosed with a thyroid condition or 
experiences a drop in creatinine clearance to 60 mL/min, refer to Table 6 for further
instructions.
Any other clinically important events where dose delays may be considered appropriate by the 
Investigator must be discussed with the Medical Monitor.
Lenalidomide may be withheld for a maximum of 28 consecutive days for toxicity.  
Lenalidomide treatment should be discontinued in the event of a lenalidomide related toxicity 
lasting more than 28 days, unless approved by the Medical Monitor.


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5.5.6.
Dose Modification of Lenalidomide during a Cycle (applies to Days 1-21)  
The dose of lenalidomide should be modified according to the dose modification guidelines in 
Table 6 if any of the following toxicities occur:  
Table 6: 
Dose Modification or Interruption for Lenalidomide Toxicity during a Cycle
Toxicity
Intervention
Thrombocytopenia: 
x
Grade 3 (decrease to <50,000/μL) 
associated with Grade 2 bleeding, 
OR
x
Grade 4 (decrease to <25,000/μL) 
x
Interrupt lenalidomide treatment for the remainder of the 
cycle 
x
Reduce the dose of lenalidomide by one dose level (5 mg) 
at the start of the next cycle.  Do not initiate a new cycle 
until the subject meets cycle initiation criteria (see 
Section 5.5.5).  Do not dose below 5 mg daily. 
Neutropenia:
x
ANC <1,000/μL for > 7 days, OR
x
ANC <1,000/μL with an associated 
WHPSHUDWXUH&25
x
ANC <500/μL 
x
Interrupt lenalidomide treatment for the remainder of the 
cycle
x
Reduce the dose of lenalidomide by one dose level (5 mg) 
at the start of the next cycle.  Do not initiate a new cycle 
until the subject meets cycle initiation criteria (see 
Section 5.5.5).  Do not dose below 5 mg daily. 
Rash:
x
Any Grade desquamating 
(blistering) 
x
Grade 4 non-blistering
x
Grade 
x
For any Grade desquamating or Grade 4, discontinue 
lenalidomide permanently
x
)RU*UDGHUDVKKROGOHQDOLGRPLGHXQWLOUDVKLPSURYHV
to  Grade 1, then resume at original dose (for first 
episode) or lower dose as clinically indicated. Treatment 
with 20 mg prednisone PO or equivalent daily for 10 days 
(with or without taper) and/or antihistamines PO daily is 
recommended; discontinue allopurinol if rash is thought 
to be at least possibly related to allopurinol. 
x
During DLT observation period: If  Grade 3 rash has 
not improved to at least Grade 1 within 10 days using a 
temporary hold of study drugs and administration of up to 
100 mg of prednisone or equivalent (with or without taper)
and/or antihistamines daily, rash is considered a DLT. 
x
Outside of DLT observation period: see 
UHFRPPHQGDWLRQVIRU*UDGHUDsh above
Venous thromboembolism Grade 3 
x
Interrupt lenalidomide treatment for the remainder of the 
cycle
x
Initiate therapeutic anticoagulation – see Section 6.1.2.3.
x
Resume lenalidomide without dose modification at the 
start of the next cycle if the benefit of therapy on this 
study outweighs the risk for bleeding.
Hyperthyroidism or hypothyroidism 
x
Interrupt lenalidomide treatment for the remainder of the 
cycle


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Toxicity
Intervention
x
Evaluate etiology and initiate appropriate therapy
x
Reduce the dose of lenalidomide by one dose level (5 mg) 
at the start of the next cycle.  Do not initiate a new cycle 
until the subject meets cycle initiation criteria 
(see Section 5.5.5).  Do not dose below 5 mg daily.
Creatinine Clearance 60 mL/min 
(Cockcroft-Gault or 24-hour creatinine 
clearance collection) 
x
Interrupt lenalidomide treatment for the remainder of the 
cycle
x
Reduce the dose of lenalidomide according to the 
recommendations below based upon creatinine clearance 
at the start of the next cycle.  Do not initiate a new cycle 
until the patient meets cycle initiation criteria 
(see Section 5.5.5).  Do not dose below 5 mg daily. 
o
CrCl 30-60 mL/min:  

If the dose for subjects with CrCl >60 mL/min is 
25 or 20 mg of lenalidomide, the starting dose is 
10 mg every 24 hours. 

If the dose for subjects with CrCl >60 mL/min is 
15 or 10 mg of lenalidomide, the starting dose is 
5 mg.
o
CrCl <30 mL/min (not requiring dialysis): 15 mg 
every 48 hours 
x
At Investigator discretion, subjects started with a reduced 
OHQDOLGRPLGHGRVHGXHWREDVHOLQH&U&OP/PLQEXW
<60mL/min may have the lenalidomide dose gradually 
increased in a step-wise manner at the start of Cycle 2 or 
at the start of subsequent treatment cycles, if they tolerated 
the prior treatment cycle without requiring dose 
modifications, dose interruptions or delays due to toxicity.  
Lenalidomide dose titrations are permitted in 5 mg 
increments on the same dosing schedule up to the 
maximum allowable target dose.  
x
The lenalidomide dose may only be increased once every 
28 days (or less frequently), and may only be increased if 
the prior treatment cycle was completed without requiring 
dose modifications, interruptions or delays due to toxicity.  
x
If creatinine clearance becomes >60mL/min for a 
minimum of 2 cycles then one may re-escalate to the dose 
prior to reduction for renal dysfunction at the discretion 
of theInvestigator.
Any other Grade 3/4 non-hematologic 
toxicities attributed to lenalidomide 
x
Interrupt lenalidomide treatment for the remainder of the 
cycle.
x
Reduce the dose of lenalidomide by one dose level (5 mg) 
at the start of the next cycle.  Do not initiate a new cycle 
until the patient meets cycle initiation criteria 
(see Section 5.5.5).  Do not dose below 5 mg daily. 


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Table 7: 
Dose Reduction of Lenalidomide 
Current Dose Level 
10 mg 
15 mg 
20 mg 
25 mg 
Dose Reduction 1 
5 mg  
10 mg 
15 mg 
20 mg 
Dose Reduction 2 
Discontinue 
5 mg 
10 mg 
15 mg 
Dose Reduction 3 
NA 
Discontinue 
5 mg 
10 mg 
Dose Reduction 4 
NA
NA 
Discontinue 
5 mg 
Dose Reduction 5 
NA
NA
NA 
Discontinue 
5.6.
Rituximab 
All subjects will receive rituximab and will follow guidelines for rituximab dosing and toxicity 
management. 
5.6.1.
Formulation, Packaging, and Storage of Rituximab 
Rituximab will be available in either 100 mg/10 mL single-use vials or 500 mg/50 mL single-use 
vials.  The active ingredient is rituximab and the inactive ingredients are sodium chloride, 
sodium citrate dihydrate, polysorbate 80, and water for injection.
Rituximab vials are stable at 2°C to 8°C (36°F to 46°F) and should not be used beyond 
expiration date stamped on carton.  Rituximab vials should be protected from direct sunlight.  
Do not freeze or shake.
For more information regarding stability and storage refer to the Pharmacy Manual. 
5.6.2.
Dosage, Preparation and Administration of Rituximab 
The first dose of rituximab will be administered IV on Cycle 1 Day 1, of the Treatment Phase, 
and will continue to be administered at the clinical site on Day 1 of each cycle through Cycle 6. 
Rituximab will be administered IV by clinic staff according to the prescribing information.  
Both ibrutinib and lenalidomide will be administered 0-30 minutes prior to rituximab infusion.  
Rituximab will be administered as an IV infusion.  Premedication will be given prior to each 
administration. 
Premedication: Prior to each infusion administer acetaminophen (or equivalent) and an 
antihistamine. 
x
First Infusion: Initiate infusion at a rate of 50 mg/hr.  In the absence of infusion toxicity, 
increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 
400 mg/hr. 
x
Subsequent Infusions: If no infusion reactions occur during the first infusion, initiate 
infusion at a rate of 100 mg/hr.  In the absence of infusion toxicity, increase rate by 
100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr. 


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In the event of an infusion reaction, institute medical management (eg, glucocorticoids, 
epinephrine, bronchodilators, or oxygen) as appropriate.  Depending on the severity of the 
infusion reaction and the required interventions, temporarily or permanently discontinue. See 
Section 5.6.3 for further instructions.
If a dose is missed in Cycle 2 or beyond due to scheduling conflicts, it can be delayed up to 
2 days after the scheduled time. If dosing must be delayed for more than 2 days for reasons other 
than toxicity, contact the Medical Monitor. 
Rituximab dosing during the Treatment Phase occurs on Day 1 of each cycle. Treatment will 
continue for 6 cycles unless disease progression or other reason for treatment discontinuation as 
outlined in Section 9.2 occurs before the completion of Cycle 6. 
Dose modifications for toxicity are outlined in Section 5.6.5.
Unused rituximab must be disposed of according to the sites drug disposal policy and drug 
accountability records updated.  
5.6.3.
Dose Delay of Rituximab
In order to initiate a new cycle of therapy with rituximab, the subject must not have any 
unmanageable, potentially rituximab-related non-hematological toxicity that is Grade 3 or higher 
in severity.  
Any other clinically important events where dose delays may be considered appropriate by the 
Investigator must be discussed with the Medical Monitor. 
Rituximab may be withheld for a maximum of 28 consecutive days for toxicity.  Rituximab 
should be discontinued in the event of a rituximab toxicity lasting more than 28 days, unless 
reviewed and approved by the Medical Monitor.
5.6.4.
Dose Interruption of Rituximab
Modify administration of rituximab for infusion-related reactions of any severity.  
x
For Grade 1 and 2 infusion-related reactions, slow the infusion rate by a minimum of 50% 
and monitor subject closely.  Provide medical intervention as indicated.  If symptoms 
resolve, complete the infusion at the decreased rate.  If symptoms do not improve, or 
worsen, discontinue the infusion.
x
For Grade 3 infusion-related reactions, interrupt the infusion, provide medical intervention 
as appropriate.  Monitor subject closely and if symptoms resolve resume the infusion at 50% 
or less of the previous rate.  If there is no return of symptoms complete the infusion at the 
decreased rate.  If symptoms do not improve, or worsen, discontinue the infusion. May 
resume at next scheduled dose per Table 8 guidelines.


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x
For Grade 4 infusion-related reactions, stop the infusion.  Provide appropriate medical 
intervention.  Contact the medical monitor prior to re-challenge or if permanent 
discontinuation of rituximab is necessary. 
Note: A Grade 4 infusion reaction on Cycle 1 Day 1 of Phase 1b will not be considered a DLT 
and the subject will be replaced.
5.6.5.
Dose Modification of Rituximab 
The dose of rituximab should be modified according to the dose modification guidelines in 
Table 8 if any of the following toxicities occur: 
x
Any Grade 4 or unmanageable Grade 3 non-hematologic toxicity attributed to rituximab.
Note: For guidance on management of rituximab in relation to infusion reactions see 
Section 5.6.4.
Table 8: 
Dose Modification for Rituximab Toxicity 
Occurrence
Action to be Taken
1st-3rd  
:LWKKROGULWX[LPDEXQWLOUHFRYHU\WR*UDGHRUEDVHOLQHPD\UHVWDUWDWRULJLQDO
dose level
Fourth 
Discontinue rituximab
5.7.
Study Drug Compliance 
5.7.1.
Ibrutinib and Lenalidomide Compliance
The study drugs (ibrutinib and lenalidomide) are to be prescribed only by the principal 
Investigator or a qualified physician listed as a Sub-Investigator on the Form FDA 1572.  The
study site personnel must maintain all study drug records in the study file, and record all study 
drugs dispensing and returning on the drug accountability form and in the subject’s source 
documents.  The study drugs must not be used for any purpose other than that outlined in this 
protocol, including other human studies, animal investigations, or in vitro testing.  The 
Interactive Web Response System (IWRS) will be used to assign study drug kits for each subject 
enrolled with each cohort assignment. 
Drug supplies for each subject will be inventoried and accounted for throughout the study by the 
site personnel.  Subjects will be provided with a subject diary card at the beginning of Day 1 of 
each cycle to record daily dosing. The site personnel must instruct the subjects to bring the 
completed subject diary card along with any used and unused study drugs to each study visit.
The site personnel must reconcile and document the returned capsules from the study subjects at 
each study visit to ensure ibrutinib and lenalidomide dosing compliance.  Instructions for 
self-administration and storage conditions of ibrutinib and lenalidomide will be provided to the 
subjects by the site personnel. Precautions associated with the use of study drugs and prohibited 
concomitant medications must be reviewed with the study subjects by the Investigator or 


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qualified study site personnel. The site staff will provide additional instruction to re-educate any
subject who is not compliant with the study drug dosing schedule.
5.7.2.
Rituximab Compliance
Rituximab treatment will be administered by qualified study-site personnel. The site pharmacist 
or designee must document all rituximab treatment and premedications prepared for the infusion 
and administration in the subject’s source documents. Drug supplies for each subject will be 
inventoried and accounted for throughout the study by the site personnel as appropriate. The
infusion will be administered to the study subjects according to the approved prescribing 
information per protocol and/or institutional guidelines.
5.8.
Overdose Instructions
Any dose of study drug administered in excess of that specified in this protocol is considered to 
be an overdose. Signs and symptoms of an overdose of any of the study drugs that meet any 
Serious Adverse Event (SAE) criterion must be reported as an SAE in the appropriate time frame 
and documented as clinical sequelae to an overdose.  
5.8.1.
Ibrutinib
There is no specific experience in the management of ibrutinib overdose in patients. No 
maximum tolerated dose (MTD) was reached in the Phase 1 study in which subjects received up 
to 12.5 mg/kg/day (1400 mg/day). Healthy subjects were exposed up to single dose of 1680 mg. 
One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) 
after a dose of 1680 mg. Subjects who ingested more than the recommended dosage should be 
closely monitored and given appropriate supportive treatment.
Refer to Section 11 for further information regarding AE reporting.
5.8.2.
Lenalidomide
There is no specific experience in the management of lenalidomide overdose in patients; 
although in dose-ranging studies, some patients were exposed to up to 150 mg and in single-dose 
studies, some patients were exposed to up to 400 mg.  
Patients who take more than the prescribed dose of lenalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately.
5.8.3.
Rituximab
There has been no experience with overdose in human clinical trials.  Single doses of up to 
500 mg/m2 have been administered in clinical trials.
5.9.
Criteria for Permanent Discontinuation of Study Treatment
Investigators are encouraged to keep a subject who is experiencing clinical benefit in the study 
unless significant toxicity puts the subject at risk or routine noncompliance puts the study 


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outcomes at risk.  For a complete list of criteria for permanent discontinuation of study treatment 
refer to Section 9.2.
An End-of-Treatment Visit (Section 8.3.19) is required for all subjects except for those subjects 
who have withdrawn full consent (see Section 9.3).
6.
CONCOMITANT MEDICATIONS/PROCEDURES
6.1.
Concomitant Medications
6.1.1.
Permitted Concomitant Medications
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted. 
Erythropoietic growth factors (eg, erythropoietin) and hematopoietic growth factors are allowed 
per institutional policy and in accordance with the ASCO guidelines (Smith 2006).  
Transfusional support (packed red blood cells and platelets) may be given in accordance with 
institutional policy.
6KRUWFRXUVHVGD\VRIcorticosteroid treatment for non-cancer-related medical reasons 
(eg, joint inflammation, asthma exacerbation, rash, antiemetic use, autoimmune cytopenias and 
infusion reactions) at doses that do not exceed 100 mg per day of prednisone or equivalent are 
permitted.  For purposes of premedication or management of rituximab infusion reactions only, 
100 mg of corticosteroid treatment per day may be exceeded.
For rash management, please see Sections 5.4.3 and 5.5.6 (Table 6).
Prophylaxis for hepatitis is permitted as per local guidelines provided no contraindicated 
antiviral medications are used.
6.1.2.
Medications to be Used with Caution
6.1.2.1.
CYP3A Inhibitors/Inducers
Ibrutinib is metabolized primarily by CYP3A4. Avoid co-administration with strong CYP3A4 
or moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.
x
If a strong CYP3A inhibitor (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazadone, or cobicistat) must be used, reduce
the ibrutinib dose to 140 mg or withhold treatment for the duration of the inhibitor use.
Subjects should be monitored for signs of ibrutinib toxicity. 
x
If a moderate CYP3A inhibitor (eg, voriconazole, erythromycin, amprenavir, aprepitant, 
atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, 
fosamprenavir, imatinib, verapamil, amiodarone, or dronedarone) must be used, reduce 
ibrutinib to 140 mg for the duration of the inhibitor use. Avoid grapefruit and Seville 


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oranges during ibrutinib/placebo treatment, as these contain moderate inhibitors of CYP3A 
(see Section 5.4.2).
x
No dose adjustment is required in combination with mild inhibitors. 
Avoid grapefruit and Seville oranges during ibrutinib treatment, as these contain moderate 
inhibitors of CYP3A (see Appendix 4).
Avoid use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and St. John’s 
Wort). Consider alternative agents with less CYP3A induction.
A list of common CYP3A inhibitors and inducers is provided in Appendix 4. For further 
information, please refer to the current version of the ibrutinib IB and examples of inhibitors, 
inducers, and substrates may be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/.
This website is continually revised and should be checked frequently for updates.
6.1.2.2.
Drugs that may Have Their Plasma Concentrations Altered by Ibrutinib
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor. Ibrutinib is not expected to have systemic drug-drug interactions with P-gp substrates. 
However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp after a therapeutic 
dose.  There are no clinical data available. Therefore, to avoid a potential interaction in the GI 
tract, narrow therapeutic range P-gp substrates such as digoxin should be taken at least 6 hours 
before or after ibrutinib. 
6.1.2.3.
Concomitant Use of Antiplatelet Agents and Anticoagulants
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib.
Supplements such as fish oil and vitamin E preparations should be avoided. Use ibrutinib with 
caution in subjects requiring other anticoagulants or medications that inhibit platelet function. 
Subjects with congenital bleeding diathesis have not been studied.  For guidance on ibrutinib and 
the use of anticoagulants during procedures/surgeries see Section 6.2.
For subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), 
consider the risks and benefits of continuing ibrutinib treatment.  If therapeutic anticoagulation is 
clinically indicated, treatment with ibrutinib should be held and not be restarted until the subject
is clinically stable and has no signs of bleeding.  Subjects should be observed closely for signs 
and symptoms of bleeding.  No dose reduction is required when study drug is restarted.
6.1.3.
Prohibited Concomitant Medications
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy is
prohibited while the subject is receiving study treatment.
Corticosteroids for the treatment of the underlying disease is prohibited.  Corticosteroids for the 
treatment of non-cancer related reasons for longer than 14 days and/or at doses >100 mg of 


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prednisone or equivalent are prohibited except when given for an AE of rash, where the
corticosteroid treatment may exceed 14 days.  See Section 6.1.1 for permitted uses.
The Sponsor should be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
6.2.
Guidelines for Ibrutinib Management with Surgeries or Procedures
Ibrutinib may increase risk of bleeding with invasive procedures or surgery. The following 
guidance should be applied to the use of ibrutinib in the peri-operative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib:  
6.2.1.
Minor Procedures
For minor procedures (such as a central line placement, needle biopsy, lumbar puncture [other 
than shunt reservoir access], thoracentesis, or paracentesis) ibrutinib should be held for at least 
3 days prior to the procedure and should not be restarted for at least 3 days after the procedure.  
For bone marrow biopsies that are performed while the subject is on ibrutinib, it is not necessary 
to hold ibrutinib.
6.2.2.
Major Procedures
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib should be 
held at least 7 days prior to the intervention and should be held at least 7 days after the procedure 
and restarted at the discretion of the Investigator when the surgical site is reasonably healed 
without serosanguineous drainage or the need for drainage tubes.
6.3.
Emergency Procedures
For emergency procedures, ibrutinib should be held as soon as possible and until the surgical site 
is reasonably healed or for at least 7 days after the urgent surgical procedure, whichever is 
longer.  
7.
STUDY EVALUATIONS
7.1.
Screening / Administrative
All clinical screening assessments and routine laboratory must be performed within 28 days of 
the first administration of study drug.
7.1.1.
Informed Consent
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved informed consent form (ICF)
confirming his or her willingness to participate in this study before any study-specific screening 
procedures are performed. In addition, subjects must sign all approved ICF amendments per the 
site IRB/REB/IEC guidelines during the course of the study.


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7.1.2.
Confirm Eligibility
All necessary procedures and evaluations must be performed to document that the subject meets 
all of the inclusion criteria and none of the exclusion criteria (Section 4) including prior to the 
first dose on Day 1.  Measurable disease documented by radiographic imaging is required at the 
time of study entry.  Confirmation of non-GCB phenotype by IHC according to the central 
laboratory is required prior to enrollment to confirm eligibility for Phase 2 only.
7.1.3.
Medical History and Demographics
The subject’s complete history through review of medical records and by interview will be 
collected and recorded. Concurrent medical signs and symptoms must be documented to 
establish baseline severities. A disease history, including the date of initial diagnosis and list of 
all prior anticancer treatments, dates administered, and responses and DOR to these treatments, 
also will be recorded. 
7.1.4.
Venous Thromboembolism Risk Assessment
The subject’s risk for development of venous thromboembolism (VTE) will be assessed.
General risk factors for subjects with cancer include, but are not limited to: underlying disease, 
family history, age, obesity, immobilization, hormonal therapy, central venous catheter, recent 
DVT, gender, renal dysfunction and certain chemotherapy-based regimens.  It is not known 
whether prophylactic anticoagulation or anti-platelet therapy prescribed in conjunction with 
lenalidomide may lessen the potential for venous thromboembolism.  It is up to the discretion of 
the Investigator after consideration of the subject’s individual risk/benefit profile whether to 
institute VTE prophylaxis using a permitted concomitant medication (see Section 6.1.2.3). It is 
recommended that protocol-appropriate VTE prophylaxis be used in subjects considered at 
high-risk for thrombosis.  This assessment must be performed at the Screening Visit and may be 
performed anytime thereafter as appropriate. Refer to Table 6 for dose modification in the event 
a VTE occurs while on treatment.
7.1.5.
Prior and Concomitant Medications
All medications from 14 days before Cycle 1, Day 1 through 30 days after the last dose of study 
treatment will be documented. After a subject discontinues study treatment, subsequent 
anticancer therapies will be collected.
7.1.6.
Adverse Events
The accepted regulatory definition for an adverse event is provided in Section 11.1. The 
occurrence of adverse events from the time the ICF is signed until the first dose should be 
recorded under medical history in the eCRF form. All medical occurrences after the first dose 
with study drug until 30 days after the last dose of study drug that meet the adverse event 
definition must be recorded as AEs in the eCRF. Laboratory abnormalities designated clinically 
significant by the Investigator will also be documented as adverse events.  Additional important 
requirements for adverse event and serious adverse event reporting are explained in 
Section 11.2.2.


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7.2.
Assessments
7.2.1.
Physical Examination, Height, and Weight
The physical examination will include, at a minimum, the general appearance of the subject, 
height (Screening Visit only) and weight, and examination of the skin, eyes, ears, nose, throat, 
lungs, heart, abdomen, extremities, and if indicated, musculoskeletal system, nervous system, 
and lymphatic system.
A limited symptom-directed physical examination is performed at all other time points.  A
limited physical examination will include all organ systems previously abnormal or involved 
with disease and documentation of any clinically relevant organ abnormalities. Lymphoma
symptoms reported at Screening should be reviewed and noted in the subject source documents
during the limited physical examination. Refer to Schedule of Assessments (Appendix 1).
7.2.2.
Eastern Cooperative Oncology Group (ECOG) Performance Status
The ECOG performance index is found in Appendix 2. The ECOG performance status will be 
assessed at time points specified in the Schedule of Assessments (Appendix 1).  
7.2.3.
Vital Signs
Vital signs will include blood pressure, heart rate, respiratory rate, and body temperature and will 
be assessed at time points specified in the Schedule of Assessments (Appendix 1).  Blood 
pressure should be obtained after the subject has been resting in the sitting position for at least 
3 minutes. 
7.2.4.
Electrocardiogram (ECG)
A 12-lead ECG will be taken at Screening and at the End-of-Treatment Visit.  Subjects should be 
in a supine position and resting for at least 10 minutes prior to the ECG.  The ECG is
recommended to be performed prior to any blood samples being collected.  Any clinically 
significant abnormality noted at Screening should be included in the medical history or noted 
post-Screening should be recorded as an adverse event as appropriate.
An ECG should be performed at any time during the study at the Investigator’s discretion, 
particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness, atrial 
fibrillation) or new onset dyspnea.
7.3.
Efficacy Assessments
Efficacy assessments (response evaluations) will be performed every 3 cycles up to Cycle 25 and 
then every 6 cycles thereafter.  For Phase 1b, refer to Appendix 5 for the Revised International 
Working Group Response Criteria (Cheson 2007).  For Phase 2, refer to Appendix 6 for the 
Revised International Working Group Response Criteria or Lugano Classification 
(Cheson 2014).


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7.3.1.
Radiographic Imaging
Pretreatment tumor assessment will be performed within 28 days before the first dose of study 
drug.  Lesions that have been irradiated cannot be included in the tumor assessment unless 
unequivocal tumor progression has been documented in these lesions after radiation therapy.  A 
CT scan (with contrast unless contraindicated) of the neck, chest, abdomen, and pelvis and any 
other disease sites and a positron emission tomography (PET) scan are required for the 
pretreatment tumor assessment.  Thereafter, a PET scan is to be performed to confirm CR if the 
PET result was positive at Screening or may be performed at any time if clinically indicated.
Information on extranodal involvement (eg, gastric or ocular disease) will also be obtained.
Lesions in anatomical locations that are not well visualized by CT may be measured at baseline 
by MRI instead and should continue to be measured by MRI until disease progression.  
In the case where CT with contrast is contraindicated, an alternative would be MRI of the 
abdomen and pelvis with contrast and CT of the chest and neck without contrast.  In this case, 
neck nodes cannot be used as target lesions.
During treatment, CT/MRI scans will be done for tumor assessments within 7 days of Day 1 of 
Cycle 4 and Cycle 7 and then every 3 cycles up to Cycle 25, and then every 6 cycles thereafter, 
until PD or use of alternative anticancer therapy.
NOTE: PET/CT hybrid scanners may be used to acquire the required CT images only if the CT 
produced by the scanner is of diagnostic quality, adheres to the specified slice thickness/scan 
parameters, and includes the use of intravenous (IV) contrast.  Additionally, the CT images must 
be separated from the PET data prior to submitting the data, and cannot be transmitted as fused 
CT/PET images. 
If using a hybrid machine to acquire both PET and CT, the PET must be performed prior to the 
CT with IV contrast as to not compromise PET results. 
If independent CT and PET scanners are used, and the subject is receiving both scans on the 
same day, the PET must be performed prior to the CT with IV contrast.
De-identified copies of all scans and radiology reports (including those from screening) must be 
provided to the Sponsor or designee (eg – central imaging vendor).  At the Sponsor’s discretion, 
the Sponsor or designee may conduct an independent review of the Investigator responses.
7.3.2.
Physical Examination
Physical examination findings should be used at the time of response evaluation to assess both 
response and/or progression.  Abdominal examination to assess for enlarged liver and/or spleen 
should be performed and documented, with verification of findings by radiographic imaging 
preferred.  Non-palpable liver and spleen is required for CR response category.


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Any new or enlarged palpable masses suspected to be disease progression should be verified by 
radiographic imaging when possible.
7.3.3.
Bone Marrow Aspirate and Biopsy
A unilateral bone marrow aspirate and biopsy will be done at Screening or up to 28 days before 
the first dose of study drug.
For Phase 1b: Follow-up bone marrow aspirate and biopsy will only be required to confirm CR if 
result was positive at Screening.
For Phase 2: If the baseline PET result is positive for bone marrow involvement, a baseline bone 
marrow aspirate and biopsy is no longer required (Cheson 2014). [For clinical trial purposes and 
to ensure eligibility, baseline bone marrow samples/results will be collected.]
For CR in Phase 2:
If the PET result is positive for bone marrow involvement at baseline and confirmed negative at 
CR, a follow-up bone marrow aspirate and biopsy is not required to confirm CR; if the PET 
result is negative at baseline and the bone marrow aspirate and biopsy (which is then required at
baseline) is positive at baseline, a confirmatory follow-up bone marrow aspirate and biopsy to 
confirm CR is required (Cheson 2014).
Subjects who have a bone marrow aspirate and biopsy result since completion of their last 
therapy for DLBCL may use those bone marrow results in lieu of the baseline bone marrow 
aspirate and biopsy required for this study provided the biopsy and aspirate were done within 
28 days of first dose of study drug.
Additional samples may be collected for biomarkers and other exploratory evaluations.
7.4.
Survival and Subsequent Anticancer Therapies
7.4.1.
Survival
After disease progression or study treatment discontinuation, subjects will be contacted to assess 
survival status every 12 weeks (±14 days) from End-of-Treatment Visit until death, subject 
withdrawal of full consent, lost to follow-up, or study completion, whichever comes first.  At the 
time of the analysis and at study completion, a survival sweep will be conducted.  All subjects 
who are not known to have died or withdrawn consent prior to survival sweep will be contacted 
at that time.
7.4.2.
Subsequent Anticancer Therapies
After study treatment is complete, the following information on subsequent anticancer therapies
will be collected every 12 weeks (±14 days) from End-of-Treatment Visit to death, subject 
withdrawal of full consent, loss to follow-up, or study completion, whichever comes first:


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x
Receipt of subsequent anticancer therapies
x
Indication for subsequent anticancer therapies
7.5.
Clinical Laboratory Assessments
7.5.1.
Hematology
Hematology parameters will include a complete blood count: white blood cells, red blood cells, 
hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils 
and bands (if reported). See time points specified in the Schedule of Assessments (Appendix 1).
7.5.2.
Serum Chemistry
Serum chemistry parameters will include sodium, potassium, chloride, blood urea nitrogen 
(BUN), creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline phosphatase, 
total bilirubin, lactate dehydrogenase (LDH), phosphate, uric acid, magnesium and bicarbonate.  
See time points specified in the Schedule of Assessments (Appendix 1).
7.5.3.
Creatinine Clearance
Creatinine clearance will be calculated using the Cockcroft-Gault method (Appendix 3) or 
24-hour creatinine clearance collection.  See time points specified in the Schedule of 
Assessments (Appendix 1).
7.5.4.
Coagulation Studies
Measurement of prothrombin time (PT)/INR, and activated partial thromboplastin time (aPTT) 
will be performed at Screening and End-of-Treatment Visit.
7.5.5.
Hepatitis Serologies
Hepatitis serologies include hepatitis C antibody, hepatitis B surface antigen, hepatitis B surface 
antibody, and hepatitis B core antibody.  PCR must be confirmed negative prior to enrollment for 
subjects who are hepatitis B core antibody positive, hepatitis B surface antigen positive or 
hepatitis C antibody positive.
7.5.5.1.
Thyroid Function 
Thyroid stimulating hormone (TSH) will be used to evaluate thyroid function.  If abnormal, 
further testing should be performed as clinically appropriate.  Testing will be performed at 
Screening, pre-dose Day 1 of every 3 cycles for the first year, then every 6 cycles thereafter, and 
at the End-of-Treatment Visit. Testing at additional time points may be performed at the 
Investigator’s discretion.
7.5.5.2.
Urinalysis
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  Testing 
will be performed at Screening and the End-of-Treatment Visit.


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7.5.5.3.
Pregnancy Test
A pregnancy test (urine or serum) with a sensitivity of 25 mIU/mL must be done in accordance 
with Celgene Corporation’s Revlimid REMS™or global Pregnancy Prevention Program (PPP) 
guidelines for females of childbearing potential (FCBP) only.  If the pregnancy test is positive at 
Screening, the subject is not eligible.  
A FCBP is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer 
therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had 
menses at any time in the preceding 24 consecutive months).   
Pregnancy tests must occur within 10–14 days and again within 24 hours prior to initiation of 
Cycle 1 of lenalidomide.  A FCBP with regular or no menstruation must have a pregnancy test 
weekly for the first 28 days and then every 28 days while on lenalidomide therapy (including 
breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of 
lenalidomide.  A FCBP with irregular menstruation must have a pregnancy test weekly for the 
first 28 days and then every 14 days while on lenalidomide therapy (including breaks in therapy), 
at discontinuation of lenalidomide and at Day 14 and Day 28 following lenalidomide 
discontinuation.  
In order to allow for drug delivery in the US, pregnancy testing can be performed on Days 22-28 
of each cycle.  A pregnancy test may be performed more frequently if required by local and 
national requirements.  
7.6.
Biomarker, Correlative and Special Studies
7.6.1.
Pharmacokinetics  
Plasma concentrations of ibrutinib and its metabolite PCI-45227 will be determined using a 
validated analytical method in Phase 2 in up to 25 subjects on 20 mg lenalidomide and up to 
25 subjects on 25 mg lenalidomide. Other potential metabolites of ibrutinib may be explored.  
Refer to the Schedule of Assessments (Appendix 1) and the Pharmacokinetic Sample Schedule 
(Table 9). 
Table 9: 
Pharmacokinetic Sample Schedule
Cycle
Day
Predose
Time Point Postdosea
1h ± 
15 min
2 h ± 
15 min
4 h ± 
30 min
6 h ± 
1 h
1
22
X
X
X
X
X
2
1
X
X
X
X
X
a Record actual time of sample collection


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Refer to the Laboratory Manual/Flow Chart for instructions on collecting and processing PK 
samples.  On the day of the sampling visit, the clinical staff will instruct the subject to not take 
either ibrutinib or lenalidomide before arrival at the clinic.  Study drug intake will be observed 
by clinic staff.  The actual time (versus requested time) that each PK sample is drawn must be 
recorded in the using a 24 hour format.
7.6.1.1.
Pharmacokinetics Sample Collection for Subjects who Received Ibrutinib
and Concomitant CYP3A Inhibitors
For subjects in Phase 2 who must take strong or moderate CYP3A inhibitors while on treatment 
with ibrutinib, the PK blood samples for evaluation of ibrutinib exposure should be collected at 
the next scheduled visit (preferably after the CYP3A inhibitor has started and when it is in use).
Pharmacokinetic samples will be collected at the following time points: 
x
Predose:  If possible, the sample should be obtained 22-24 hours post the previous day’s 
dose of ibrutinib and before dosing on the day of the scheduled visit)
x
1 hour postdose ± 15 min
x
2 hours postdose ± 15 min
x
4 hours postdose ± 30 min
Refer to the Laboratory Manual/Flow Chart for instructions on collecting and processing PK
samples.  On the day of the sampling visit, the clinical staff will instruct the subject to not take 
either ibrutinib or lenalidomide (if applicable) before arrival at the clinic.  Study drug intake will 
be observed by clinic staff.  The actual time (versus requested time) that each sample is drawn 
must be entered in the eCRF using a 24-hour format.  
7.6.2.
Biomarkers
Identification of signaling pathways or biomarkers that predict sensitivity or resistance to 
ibrutinib will be explored in this study. 
A pre-dose blood sample will be collected at the following visits: Cycle 1 Day 1, Cycle 2 Day 1, 
Cycle 3 Day 1; at response evaluation visits (eg, Cycle 4, 7, 10, etc.); and End-of-Treatment
(EOT) Visit. These samples will be sent to a central laboratory for testing.
If a subject progresses and returns to clinic within 24 hours after his or her last dose of ibrutinib, 
then an additional post-progression blood sample will be collected.  If this post-progression 
blood sample is collected, then the biomarker blood sample collection at the EOT Visit is not 
required.
Samples collected may be used for pharmacodynamic and biomarker assessments including BTK 
and other kinase activity and signaling, expression analysis, sequencing, flow cytometry and
secreted protein analyses.  Fluids including blood collected during the course of the study may be 
used for, but not limited to, pharmacodynamics and biomarker assessments as noted above.


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7.6.3.
Gene Expression Profiling and Immunohistochemistry
Immunohistochemistry testing for determination of DLBCL subtype (GCB/non-GCB) will be 
performed at a central laboratory.  DNA and RNA extracted from the tumor samples will be used 
for GEP and sequencing assays.  An adequate amount of tissue must be available for both IHC 
and GEP to be eligible for the Phase 2 portion.  Tumor tissue will also be required for the Phase 
1b study to determine the DLBCL subtype. (Local laboratory results for DLBCL subtype for 
subjects in the Phase 1b may be collected). The sample can be archival tissue from original 
diagnosis, from relapsed or refractory disease or fresh in order to meet the requirement (see 
Laboratory Manual/Flow Chart for more details).  These samples will be used for 
ABC/GCB/Type 3 DLBCL subtyping by GEP and may be used to identify biomarkers that may 
predict response or resistance to ibrutinib.  Proteomic analyses to examine BCR-related signaling 
pathways or activation of BTK or related kinases may also be performed on remaining material 
from these samples.
The concordance of the central GEP and central IHC classifiers may be assessed with estimates 
of sensitivity and specificity of the IHC classifier given the central GEP subtype classification.  
The SAP will provide additional analysis details.
Tissue samples collected during the course of the study may be used for, but not limited to, 
biomarker assessments as noted above.  In addition, samples collected from non-eligible subjects 
may be retained for purposes of validation of a diagnostic assay.
Refer to the Laboratory Manual/Flow Chart for detailed information on the required amount and 
acceptable preparations of sample and sample handling specifications and shipment to the central 
laboratory.
7.6.4.
T/B/NK Cell Count
The blood sample(s) for T/B/NK cell count (CD3+, CD4+, CD8+, CD19+, CD16/56+) must be 
collected predose at the time points specified in the Schedule of Assessments (Appendix 1).
These samples will be sent to a central laboratory for testing.
7.6.5.
Serum Immunoglobulins (Phase 2 only)
Blood samples will be collected for analysis of serum immunoglobulins in the Phase 2 portion of 
the study. The blood sample(s) for serum immunoglobulins (IgG, IgM and IgA) must be 
collected predose at the time points specified in the Schedule of Assessments (Appendix 1).
These samples will be sent to a central laboratory for testing.
7.6.6.
Tumor Tissue Sample
Material from either of the optional biopsy samples may be used for exploratory analysis 
including gene expression profiling, sequencing to identify mutations in BTK, related kinases or 
other critical genes, and determination of Btk active-site occupancy.  Molecular characterization 


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of this sample may identify altered signaling patterns that associate with response or resistance to 
ibrutinib treatment.
For a subject who consents to participate in the optional pre-treatment lymph node biopsy, the 
sample must be collected since the completion of the most recent treatment regimen.  For a 
subject who consents to participate in the optional post-progression lymph node biopsy, the 
sample must be collected within 30 (±7) days after the last dose of ibrutinib or prior to the start 
of a new anticancer treatment and as early as possible on or before the End-of-Treatment Visit.
All samples must be sent to the central laboratory for processing. Refer to the Study Manual for 
more information regarding sample submission.
7.7.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in source documents for 
transcription to the eCRF or laboratory requisition form.  Refer to the Schedule of Assessments 
(Appendix 1) for the timing and frequency of all sample collections.
Instructions for the collection, handling, and shipment of samples are found in the Laboratory 
Manual/Flow Chart.
8.
STUDY PROCEDURES
8.1.
Overview
The study is divided into a Screening Phase, a Treatment Phase, and a Follow-up Phase.  The 
Schedule of Assessments (Appendix 1) summarizes the frequency and timing of efficacy, PK, 
biomarker, and safety measurements applicable to this study.  
8.2.
Screening Phase
Screening procedures will be performed up to 28 days before Cycle 1, Day 1.  All subjects must 
first read, understand, and sign the IRB/IEC-approved ICF before any study-specific screening 
procedures are performed.  A subject may be re-screened up to 2 times if the subject does not 
meet eligibility criteria within the 28-Day Screening Phase and has not been enrolled nor 
received any study drug treatment.
8.2.1.
Screening Visit
The following procedures will be performed at the Screening Visit within 28 days prior to 
treatment unless otherwise noted:
x
Obtain signed, written informed consent
x
Medical history including demographic information
x
Perform a complete physical examination, including height and weight 
x
Evaluation of ECOG performance status


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x
Obtain vital signs (including blood pressure, heart rate, respiratory rate, and body 
temperature) after the subject has rested LQWKHVLWWLQJSRVLWLRQIRUPLQXWHV
x
Obtain a 12-lead ECG after the subject has been in a supine position and resting for at least 
10 minutes.
x
Record concomitant medication history including over-the-counter drugs, vitamins and 
herbs
x
Imaging by CT/MRI and positron emission tomography (PET) (if not performed within
28 days prior to first dose of study drug)
x
Obtain a bone marrow aspirate and biopsy (if not performed within 28 days prior to first 
dose of study drug)
x
Venous thromboembolism assessment
x
Obtain blood specimens for the following laboratory tests:
o Hematology
o Serum chemistry
o Coagulation studies (PT/INR, aPTT)
o Hepatitis serologies
o Thyroid function (TSH)
x
Obtain urinalysis
x
Obtain urine or serum pregnancy test for women of childbearing potential within 10–14 days 
prior to initiation of Cycle 1 of lenalidomide according to Section 7.5.5.3.
x
Collection of archival or fresh tumor tissue from a lymph node biopsy for determination of 
DLBCL subtype by IHC using the Hans method
o Note: Sufficient tissue sample for evaluation by IHC and GEP is required for subjects in 
Phase 2 (refer to Laboratory Manual/Flow Chart for requirements).
x
Calculate creatinine clearance
x
Review AEs
x
Review inclusion and exclusion criteria to confirm subject eligibility
x
Lenalidomide counseling
8.3.
Treatment Phase
Subjects must continue to meet eligibility criteria pre-dose on Day 1 Cycle 1 in order to enroll 
into the study.  Safety laboratory assessments performed within 48 hours prior to Day 1 of any 
cycle of study drug may be used for dosing.  


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8.3.1.
Cycle 1, Day 1
Pre-dose
x
Complete physical exam including weight
x
ECOG performance status
x
Vitals signs including blood pressure, heart rate, respiratory rate, and body temperature
x
Collect blood samples for the following laboratory tests:
o Hematology
o Serum chemistry 
o T/B/NK
o Biomarkers
o Serum immunoglobulins (Phase 2 only)
x
Calculate creatinine clearance
x
Review of AEs and concomitant medications
x
Obtain urine or serum pregnancy test for women of childbearing potential within 24 hours
prior to initiation of Cycle 1 of lenalidomide according to Section 7.5.5.3.
x
Review inclusion and exclusion criteria to confirm subject eligibility prior to dosing
x
Lenalidomide counseling
Dosing and Postdose
x
Dispense ibrutinib and lenalidomide
x
Review study drug compliance instructions
x
Administration of ibrutinib, lenalidomide and rituximab 
x
Review of AEs and concomitant medications 
8.3.2.
Cycle 1, Day 8
Predose 
x
Symptom directed physical exam including weight
x
ECOG performance status
x
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature)
x
Collect blood samples for the following laboratory tests:
o Hematology
o Serum chemistry
x
Review study drug compliance
x
Review of AEs and concomitant medications 


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x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3.
Dosing and Postdose
x
Administration of ibrutinib and lenalidomide
8.3.3.
Cycle 1, Day 15
Predose 
x
Symptom directed physical exam including weight
x
ECOG performance status
x
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature)
x
Collect blood samples for the following laboratory tests:
o Hematology
o Serum chemistry
x
Review study drug compliance
x
Review of AEs and concomitant medications 
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3.
Dosing and Postdose
x
Administration of ibrutinib and lenalidomide
8.3.4.
Cycle 1, Day 22
Predose 
x
Symptom directed physical exam including weight
x
ECOG performance status
x
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature)
x
Collect blood samples for the following laboratory tests:
o Hematology
o Serum chemistry
x
Review study drug compliance
x
Review of AEs and concomitant medications 
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3.
x
Collect predose PK sample (Phase 2 only)


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Dosing and Postdose
x
Administration of ibrutinib 
x
Collect PK samples (Phase 2 only) at 1 hour (± 15 minutes), 2 hours (± 15 minutes), 
4 hours (±30 minutes), and 6 hours (± 1 hour) postdose
8.3.5.
Cycle 2, Day 1
Predose 
x
Complete physical exam including weight
x
ECOG performance status
x
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature)
x
Collect blood samples for the following laboratory tests:
o Hematology
o Serum chemistry
o T/B/NK
o Biomarkers
x
Collect pre-dose PK sample (Phase 2 only)
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3
o FCBP with regular or no menstruation must have a pregnancy test weekly for the first 
28 days and then every 28 days while on lenalidomide therapy (including breaks in 
therapy).  
o FCBP with irregular menstruation must have a pregnancy test weekly for the first 28 days 
and then every 14 days while on lenalidomide therapy (including breaks in therapy).
x
Calculate creatinine clearance
x
Review study drug compliance
x
Review of AEs and concomitant medications
x
Lenalidomide counseling
Dosing and Postdose
x
Administration of ibrutinib, lenalidomide and rituximab  
x
Collect PK samples (Phase 2 only) at 1 hour (±15 minutes), 2 hours (±15 minutes), 
4 hours (±30 minutes), and 6 hours (±1 hour) post-dose


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8.3.6.
Cycle 2, Day 15
Predose 
x
Symptom directed physical exam including weight
x
ECOG performance status
x
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature)
x
Collect a blood sample for the following laboratory test:
o Hematology
o Serum Chemistry
x
Review study drug compliance
x
Review of AEs and concomitant medications
x
Females with irregular menstruation must have a pregnancy test every 14 days while on 
lenalidomide therapy (including breaks in therapy).
Dosing and Postdose
x
Administration of ibrutinib and lenalidomide.  
8.3.7.
Cycle 2, Days 22-28
x
Review study drug compliance
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3
o FCBP with regular or no menstruation must have a pregnancy test every 28 days while on 
lenalidomide therapy (including breaks in therapy).
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on lenalidomide therapy (including breaks in therapy).
o In order to allow for drug delivery in the US, pregnancy testing can be done on 
Days 22-28 of each cycle.
8.3.8.
Cycles 3 and 5, Day 1
Predose 
x
Complete physical exam including weight
x
ECOG performance status
x
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature)
x
Collect blood samples for the following laboratory tests:
o Hematology
o Serum chemistry
o Thyroid function (TSH) (Cycle 3, Day 1 only)


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o T/B/NK (Cycle 3, Day 1 only)
o Biomarkers (Cycle 3, Day 1 only)
x
Calculate creatinine clearance
x
Review study drug compliance
x
Review of AEs and concomitant medications 
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3
o FCBP with regular or no menstruation must have a pregnancy test every 28 days while on 
lenalidomide therapy (including breaks in therapy).
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on lenalidomide therapy (including breaks in therapy).
o In order to allow for drug delivery in the US, pregnancy testing can be done on 
Days 22-28 of each cycle.
x
Lenalidomide counseling
Dosing and Postdose
x
Administration of ibrutinib, lenalidomide and rituximab 
8.3.9.
Cycle 3, Day 15
Predose 
x
Collect a blood sample for the following laboratory test:
o Hematology
o Serum Chemistry
x
Review study drug compliance
x
Review of AEs and concomitant medications
x
FCBP with irregular menstruation must have a pregnancy test weekly every 14 days while 
on lenalidomide therapy (including breaks in therapy).
Dosing and Postdose
x
Administration of ibrutinib and lenalidomide.  
8.3.10.
Cycle 3, Days 22-28
x
Review study drug compliance
x
Imaging by CT/MRI and PET if applicable within 7 days of Cycle 4 Day 1
x
Obtain urine or serum pregnancy test for women of childbearing potential according to
Section 7.5.5.3


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o FCBP with regular or no menstruation must have a pregnancy test every 28 days while on 
lenalidomide therapy (including breaks in therapy).
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on lenalidomide therapy (including breaks in therapy).
o In order to allow for drug delivery in the US, pregnancy testing can be done on 
Days 22-28 of each cycle.
x
Administration of ibrutinib
8.3.11.
Cycle 4, Day 1
The following procedures will be performed on Cycle 4, Day 1:
Predose 
x
Complete physical exam including weight
x
ECOG performance status
x
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature)
x
Collect blood samples for the following laboratory tests:
o Hematology
o Serum chemistry 
o Serum immunoglobulins (Phase 2 only)
o T/B/NK 
o Biomarkers 
x
Calculate creatinine clearance
x
Review study drug compliance
x
Review of AEs and concomitant medications 
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3
o FCBP with regular or no menstruation must have a pregnancy test every 28 days while on 
lenalidomide therapy (including breaks in therapy).
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on lenalidomide therapy (including breaks in therapy).
o In order to allow for drug delivery in the US, pregnancy testing can be done on 
Days 22-28 of each cycle.
x
Lenalidomide counseling
Dosing and Postdose
x
Administration of ibrutinib, lenalidomide and rituximab   


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8.3.12.
Cycle 4, Days 22-28
x
Review study drug compliance
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3
o FCBP with regular or no menstruation must have a pregnancy test every 28 days while on 
lenalidomide therapy (including breaks in therapy).  
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on lenalidomide therapy (including breaks in therapy).  
o In order to allow for drug delivery in the US, pregnancy testing can be done on 
Days 22-28 of each cycle.
x
Administration of ibrutinib
8.3.13.
Cycle 6, Day 1
Predose 
x
Complete physical exam including weight
x
ECOG performance status
x
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature)
x
Collect blood samples for the following laboratory tests:
o Hematology
o Serum chemistry
o Thyroid function (TSH will be tested pre-dose Day 1 every 3 cycles for the first year and 
every 6 cycles thereafter)
x
Calculate creatinine clearance
x
Review study drug compliance
x
Review of AEs and concomitant medications 
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3
o FCBP with regular or no menstruation must have a pregnancy test every 28 days while on 
lenalidomide therapy (including breaks in therapy).
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on lenalidomide therapy (including breaks in therapy).
o In order to allow for drug delivery in the US, pregnancy testing can be done on 
Days 22-28 of each cycle.
x
Lenalidomide counseling


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Dosing and Postdose
x
Administration of ibrutinib, lenalidomide and rituximab  
8.3.14.
Cycle 6, Days 22-28
x
Imaging by CT/MRI and PET if applicable within 7 days of Cycle 7, Day 1, then every 
3 cycles up to Cycle 25, and every 6 cycles thereafter, until PD or use of alternative
anticancer therapy.
x
Administration of ibrutinib
8.3.15.
Cycle 7, Day 1 and Beyond
Predose 
x
Complete physical exam including weight
x
ECOG performance status
x
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature)
x
Collect blood samples for the following laboratory tests:
o Hematology
o Serum chemistry
o Serum immunoglobulins (Phase 2 only)
o T/B/NK (i.e, every 3 cycles up to Cycle 25, and then every 6 cycles thereafter)
o Biomarkers (i.e, every 3 cycles up to Cycle 25, and then every 6 cycles thereafter)
x
Calculate creatinine clearance
x
Review study drug compliance
x
Review of AEs and concomitant medications 
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3
o FCBP with regular or no menstruation must have a pregnancy test every 28 days while on 
lenalidomide therapy (including breaks in therapy).
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on lenalidomide therapy (including breaks in therapy).
o In order to allow for drug delivery in the US, pregnancy testing can be done on 
Days 22-28 of each cycle.
x
Lenalidomide counseling
Dosing and Postdose
x
Administration of ibrutinib and lenalidomide.


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8.3.16.
Cycle 7 and 8, Days 22-28
x
Review study drug compliance
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3
o FCBP with regular or no menstruation must have a pregnancy test every 28 days while on
lenalidomide therapy (including breaks in therapy).  
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on lenalidomide therapy (including breaks in therapy).  
o In order to allow for drug delivery in the US, pregnancy testing can be done on 
Days 22-28 of each cycle.
x
Administration of ibrutinib
8.3.17.
Cycle 9 and Beyond, Days 22-28
x
Review study drug compliance
x
Imaging by CT/MRI and PET if applicable within 7 days of Cycle 10, Day 1
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3.
o FCBP with regular or no menstruation must have a pregnancy test every 28 days while on 
lenalidomide therapy (including breaks in therapy).
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on lenalidomide therapy (including breaks in therapy).
o In order to allow for drug delivery in the US, pregnancy testing can be done on 
Days 22-28 of each cycle.
x
Administration of ibrutinib
8.3.18.
Response Evaluation 
The Response Evaluation should be performed in alignment with the CT/MRI and/or PET scans
schedules.  The Response Evaluation is to be performed within 7 days of Day 1 of Cycle 4 and 
Cycle 7, then every 3 cycles up to Cycle 25, and every 6 cycles thereafter, or at any time during 
the study if indicated per the Investigator.  If possible, the visit should be performed within 4 to 
24 hours after the subject’s most recent dose.  The following procedures are required to assess 
response:
x
Imaging by CT/MRI; and PET if applicable
x
Bone marrow aspirate and biopsy if applicable
For Phase 1b (Cheson 2007):

If bone marrow biopsy result is positive at Screening, a follow-up bone marrow 
biopsy is required to confirm CR.


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For Phase 2 (Cheson 2014):

If the baseline PET result is positive for bone marrow involvement, the follow-up
PET has to be negative to confirm CR.

If the baseline PET result is negative for bone marrow involvement, a bone marrow 
biopsy should be performed:
o
If the bone marrow biopsy result is negative at baseline, a follow-up bone 
marrow biopsy is not required to confirm CR.
o
If the bone marrow biopsy result is positive at baseline, a follow-up bone 
marrow biopsy is required to confirm CR, unless a follow-up PET result is 
available and positive for bone marrow involvement.  
x
Complete physical exam including weight
x
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature)
x
Collect blood samples for the following laboratory tests:
o Hematology
o Serum chemistry
o T/B/NK
o Biomarkers 
o Serum immunoglobulins (Phase 2 only)
x
Review study drug compliance
x
Review of AEs and concomitant medications
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3.
o FCBP with regular or no menstruation must have a pregnancy test every 28 days while on 
lenalidomide therapy (including breaks in therapy).
o FCBP with irregular menstruation must have a pregnancy test weekly every 14 days 
while on lenalidomide therapy (including breaks in therapy).
o In order to allow for drug delivery in the US, pregnancy testing can be done on 
Days 22-28 of each cycle.
8.3.19.
End-of-Treatment Visit
An End-of-Treatment Visit should occur 30 days (±7 days) from the last dose of study drug or 
prior to the start of a new anticancer treatment.  If a subject starts a new anticancer treatment less 
than 7 days after the last visit with a response assessment, only those procedures not conducted 
at the last visit should be performed at the End-of-Treatment Visit. 


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The following procedures will be performed at the End-of-Treatment Visit:
x
Complete physical exam including weight
x
ECOG performance status
x
Vitals signs (including blood pressure, heart rate, respiratory rate, and body temperature)
x
12-lead ECG
x
Collect blood samples for the following laboratory tests:
o Hematology
o Serum chemistry
o Coagulation studies (PT/INR, aPTT)
o Thyroid function (TSH)
o T/B/NK
o Biomarkers
o Serum immunoglobulins (Phase 2 only)
x
Obtain urinalysis
x
Obtain urine or serum pregnancy test for women of childbearing potential according to 
Section 7.5.5.3
FCBP with regular or no menstruation must have a pregnancy test weekly at discontinuation 
of lenalidomide (EOT Visit) and at Day 28 post the last dose of lenalidomide  
FCBP with irregular menstruation must have a pregnancy test at discontinuation of 
lenalidomide (EOT visit) and at Day 14 and Day 28 after last dose of lenalidomide
x
Optional tumor tissue biopsy
x
Review of AEs and concomitant medications
8.4.
Follow-up Phase
Once a subject has completed the End-of-Treatment Visit, he/she will enter the Follow-Up 
Phase.  Subjects that withdraw from treatment for reasons other than PD will participate in 
ongoing Response Follow-Up.
8.4.1.
Response Follow-Up
Subjects who discontinue the study treatment for reasons other than PD will be followed every 
3 months (±14 days) until PD or use of alternative anticancer therapies.  During this period, 
CT/MRI and PET scans will be done per the Investigator’s discretion.
8.4.2.
Long-Term Follow-Up
Once subjects progress (for subjects who have not withdrawn consent), they will be contacted 
approximately every 3 months (±14 days) by clinic visit or telephone to assess survival.  


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Subsequent anticancer therapies and information about second malignancies will be collected.  
Subjects will be contacted until death, subject withdrawal, lost to follow-up, or study completion,
whichever occurs first.
9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Completion
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost to follow up, or has not withdrawn consent before the end of study.
9.2.
Withdrawal from Study Treatment
Study treatment will be discontinued in the event of any of the following events:
x
Progressive disease 
x
Unacceptable toxicity: an intercurrent illness or an AE that prevents further ibrutinib 
administration 
x
Dose limiting toxicity (DLT)
x
Withdrawal of consent for treatment by subject
x
Investigator decision (such as chronic noncompliance, significant protocol deviation, or best 
interest of the subject)
x
Study termination by Sponsor
x
Subject becomes pregnant
All subjects, regardless of reason for discontinuation of study treatment will undergo an End-of-
Treatment Visit and be followed for progression and survival. 
The Investigator should notify the Sponsor within 24 hours if a subject discontinues ibrutinib 
treatment due to disease progression. If a subject shows signs of disease progression on physical 
examination or laboratory assessment, the subject may continue study treatment until disease 
progression is confirmed. These subjects should stay in the study to be followed for survival. 
9.3.
Withdrawal from Study (Study Exit)
Withdrawal from study (including all follow-up) will occur under the following circumstances:
x
Withdrawal of consent for follow-up observation by the subject
x
Lost to follow-up
x
Study termination by Sponsor
x
Death


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If a subject is lost to follow-up, every reasonable effort should be made by the study site 
personnel to contact the subject. The measures taken to follow up should be documented.
When a subject withdraws before completing the study, the following information should be 
documented in the source documents:
x
Reason for withdrawal
x
Whether the subject withdraws full consent (ie, withdraws consent to treatment and all 
further contact) or partial consent (ie, withdraws consent to treatment but agrees to 
participate in follow-up visits)
10.
STATISTICAL METHODS AND ANALYSIS
Statistical analysis will be performed by the Sponsor or under the authority of the Sponsor.  A 
general description of the statistical methods for the analysis of the efficacy and safety data is 
outlined below.  Specific details will be provided in the SAP.
10.1.
General Considerations
The Phase 1b part of this study is a dose escalation study.  All safety and efficacy assessments 
will be summarized by dose group.
The Phase 2 part of this study is designed to assess the efficacy and safety of ibrutinib in 
combination with lenalidomide and rituximab in subjects with relapsed or refractory de novo 
non-GCB DLBCL.  
An analysis will occur approximately 12 months after the last subject initiates study treatment or 
when all subjects have discontinued from the study treatment, whichever occurs first, and will be 
reported in the Clinical Study Report (CSR).  A final follow-up analysis will occur 2 years after 
the last subject has been enrolled and will be reported in the CSR addendum. The study 
completion is defined as 3 years from the last study treatment, the time point all subjects have 
exited the study due to any reason, or study termination at the Sponsor’s discretion, whichever 
occurs first.
10.1.1.
Response Assessment
Response assessments will be made by the Investigator.  Tumor response will be assessed by the 
Investigator using the revised International Working Group Response Criteria for NHL 
(Cheson 2007) for Phase 1b and the revised International Working Group Response Criteria for 
NHL or Lugano Classification (Cheson 2014) for Phase 2.
Confirmation of Investigator-assessed responses by an independent review committee (IRC) may 
be done as a supportive assessment.  The method of independent review will be governed by an 
IRC charter.


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10.1.2.
Safety Monitoring
This study will be monitored in accordance with the Sponsor’s Pharmacovigilance Committee
procedures.  Adverse events (AEs) and Serious Adverse Events (SAEs) will be reviewed by the 
Sponsor on an ongoing basis to identify safety concerns.  
The Sponsor may schedule periodic conference calls with the Investigators to discuss study 
progress, obtain Investigator feedback and exchange, and discuss study-specific topics including 
AEs and SAEs.  
10.2.
Definition of Analysis Populations
The following definitions will be used for the efficacy and safety analysis sets.
x
All-treated analysis population (Phase 1b/2): will include subjects who have enrolled in 
the study and received any dose of study drug(s) in each study phase respectively. This is 
the primary analysis population for all efficacy endpoints (ie, PFS, OS) except ORR and CR
rate for the Phase 1b and Phase 2. This is also the sensitivity analysis population for ORR
and CR rate.
x
Response-evaluable population (Phase 1b/2): is defined as subjects in the all-treated 
population who have measurable disease at baseline and have at least 1 adequate post-
treatment disease assessment by the Investigator before the start of a subsequent anti-cancer 
therapy.  This is the primary analysis population for ORR and CR rate.
x
Safety analysis population (Phase 1b/2): consists of all enrolled subjects who have 
received any dose of study drug(s). All safety and dose administration analyses will be 
performed using the safety population. 
10.3.
Endpoint Data Analysis
10.3.1.
Demographic/Baseline Characteristics and Study Conduct
Subject demographics (including age, sex, and race/ethnicity) and other baseline characteristics 
(including ECOG performance status, disease status, and number of prior therapies) will be 
summarized. Summary statistics will include means, standard deviations, and medians for 
continuous variables and proportions for categorical variables.
Further, compliance parameters (including number of doses taken compared with number of 
doses that should have been taken), the reason for discontinuation, and concurrent treatments 
will also be similarly summarized.  
10.3.2.
Efficacy Endpoints for Phase 1b
The efficacy endpoints for the Phase 1b of this study are ORR and CR rate. The ORR of Phase 
1b and its 95% 2-sided exact confidence interval will be calculated for the response-evaluable 
population and the all-treated population of Phase 1b. The CR rate of Phase 1b will be analyzed 
likewise.


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10.3.3.
Primary Efficacy Endpoint for Phase 2
The primary efficacy endpoint for Phase 2 is the overall response rate (ORR). The ORR is 
defined as the rate of subjects who achieve either a PR or CR, according to the revised 
International Working Group Response Criteria for NHL, as assessed by the Investigator 
(Cheson 2014).  The ORR will be calculated for the response-evaluable population of Phase 2.  
The corresponding 95% 2-sided exact CI will be derived.  If the lower bound of the CI around 
the ORR is greater than or equal to 40%, then the hypothesis that the ORR of the ibrutinib 
combination treatment is equal to or lower than 40% will be rejected.  The ORR will also be 
calculated for the all-treated population of Phase 2.
10.3.4.
Secondary Efficacy Endpoints for Phase 2
The secondary efficacy endpoints for Phase 2 of this study are CR, DOR, PFS and OS.
10.3.4.1.
Complete Response
Complete response rate will be analyzed by the same method used for the analysis of ORR.
10.3.4.2.
Duration of Response
For subjects achieving an overall response as assessed by the Investigator, their DOR as assessed 
by the Investigator will be calculated to determine durability.  Duration of response will be 
measured from the time by which the measurement criteria are met for CR or PR, whichever is 
recorded first, until death or the first date by which recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  For subjects without disease progression or death, DOR will be 
censored at the date of the last tumor assessment.
The distribution (median, its 95% CI and Kaplan-Meier curves) of DOR will be provided using 
Kaplan-Meier estimates for responders in the all-treated analysis population.
10.3.4.3.
Progression-Free Survival
Progression-free survival will be measured as time from first study drug administration to 
lymphoma progression or death from any cause.  Data for subjects without disease progression 
or death will be censored at the date of the last tumor assessment. 
Progression-free survival will be calculated using assessments by the Investigator.  Kaplan-Meier 
methodology will be used to estimate event-free curves and corresponding quartiles (including 
the median). The distribution (median, its 95% CI and Kaplan-Meier curves) of PFS will be 
provided using Kaplan-Meier estimates in the all-treated analysis population.
10.3.4.4.
Overall Survival
The duration of OS will be measured from the time of first study drug administration until the 
date of death. Kaplan-Meier methodology will be used to estimate overall survival curves and 
corresponding quartiles (including the median).  Data for subjects who have not died will be 


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censored at the date last known to be alive (on site or phone contact) or study completion 
whichever comes first. 
The distribution (median, its 95% CI and Kaplan-Meier curves) of OS will be provided using 
Kaplan-Meier estimates in the all-treated analysis population.
10.3.5.
Exploratory Analysis (Phase 2 only)
The ORR will be analyzed by ABC vs. non-ABC subtype identified by gene expression profiling 
(GEP).
The absolute cell counts on peripheral T/B/NK will be summarized by scheduled visits.
The serum immunoglobulin levels (IgG, IgM, and IgA) will be summarized by scheduled visits.
10.3.6.
Safety Endpoint
Safety summaries will include tabulations in the form of tables and listings. The frequency 
(number and percentage) of treatment-emergent AEs will be reported by MedDRA® System 
Organ Class and Preferred Term.  Additional AE summaries will include AE frequency by AE 
severity and by relationship to study drug.
Adverse events requiring discontinuation of study drug will be summarized separately, both 
overall and by AE severity and by relationship to study drug.
Clinically significant abnormal laboratory values will be summarized.  Laboratory shift tables 
containing counts and percentages will be prepared by laboratory parameter and time. Summary 
tables will be prepared for each laboratory parameter.  Figures of changes in laboratory 
parameters over time will be generated.
Safety: Missing or partial start and end dates for AEs and concomitant medications will be 
imputed according to pre-specified, conservative imputation rules.  No other imputation of 
values for missing data will be performed.
10.3.7.
Pharmacokinetics
The PK evaluation in the Phase 2 of the study is to obtain the PK parameters of ibrutinib in 
subjects with relapsed or refractory DLBCL after administration of ibrutinib in combination with 
lenalidomide and rituximab. The PK samples will be collected and analyzed in a subset of 
subjects in Phase 2 (approximately 25 subjects). Although not based on statistical 
considerations, the number of subjects for PK collections in this study is consistent with the 
number of subjects collected in other Phase 1 and Phase 2 studies with various histologies and 
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Plasma concentrations of ibrutinib and a major metabolite (PCI-45227) will be determined using 
a validated analytical method. Other potential metabolites of ibrutinib may be explored.
Bioanalytical data from this study will be used in noncompartmental PK analysis and also may 
be combined with data from other studies performed with ibrutinib in subjects with hematologic 
malignancies as part of a population PK analysis using nonlinear mixed effects models.  For the 
population PK analysis, covariates that could potentially correlate with plasma PK parameters 
will be evaluated.  Pharmacokinetic relationships to pharmacodynamic measures of efficacy or 
toxicity may also be explored. The results of the population PK analyses will be presented in a 
separate report. For subjects who received CYP3A inhibitors, as data permits, a comparison of 
ibrutinib and PCI-45227 plasma concentrations after ibrutinib administration alone and in 
combination with CYP3A inhibitors will be explored.
10.3.8.
Biomarkers
x
Identification of signaling pathways or biomarkers that predict sensitivity or resistance to 
ibrutinib. 
x
Frequency of tumor mutations (or other molecular markers) between pre and post treatment 
tissue that predict acquired resistance.
The concordance of the central GEP and central IHC classifiers may be assessed with estimates 
of sensitivity and specificity of the IHC classifier given the central GEP subtype classification.  
The SAP will provide additional analysis details.
10.4.
Determination of Sample Size
The planned sample size for Phase 2 is approximately 55 subjects to ensure enrollment of at least 
49 response-evaluable subjects at 20 mg lenalidomide; approximately 28 additional subjects may 
be enrolled at 25 mg lenalidomide. The main analysis will be the comparison of response rate to 
the ORR of a historical control of 40%.  The null hypothesis that the true ORR is 40% will be 
tested against a one-sided alternative that the ORR is 60%. The null hypothesis will be rejected, 
if 27 or more responses are observed in the 49 subjects. This design yields a 1-sided type I error 
rate of 0.025 and power of 80% when the true ORR is 60%. This statistical design including 
number of subjects and number of responders follows the statistical framework of Simon’s 
minmax two-stage design (Simon 1989). Enrollment will continue while the interim analysis is 
being performed.
10.5.
Interim analysis
An interim analysis will be performed including approximately 28 evaluable subjects with 
adequate tumor response assessment.  Enrollment in the 20 mg lenalidomide cohort will continue 
while the interim analysis is performed. Details of the interim analysis and decision rules will be 
described in the SAP.  At the interim analysis, the review committee could recommend


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1. continuation of the study with 20 mg lenalidomide; or
2. increase of the lenalidomide dose to 25 mg, if determined to be safe and tolerated in the 
Phase 1b, including approximately 28 evaluable subjects with adequate tumor response 
assessment followed by an interim analysis.
The decisions based on the interim analysis will be made by the Sponsor (at a minimum: the 
Medical Monitor or designee, a Drug Safety representative and a Biostatistician).
10.6.
Safety Analysis
Analysis of safety data will be conducted on the safety analysis population. The baseline value 
for safety assessments will be defined as the last value on or before the day of the first dose of 
study drugs if we do not specify. The further details for selecting the baseline value of safety 
parameters will be described in the SAP. The safety analyses will be based on the monitoring of 
adverse events, deaths, vital signs measurements, and clinical laboratory results.
The safety variables to be analyzed include adverse events, clinical laboratory test results 
(hematology and chemistry), physical examination findings, and vital signs measurements.
Overall exposure to ibrutinib and the drug combination, and reasons for discontinuation from 
study treatment will be tabulated. In general, continuous variables will be summarized using 
descriptive statistics (n, mean, median, standard deviation, standard error and range).  
Categorical variables will be summarized using frequencies and percentages.  No formal 
statistical testing is planned. 
10.6.1.
Adverse Events
Adverse event parameters to be evaluated are the type, incidence, and intensity of AEs; the 
relationship of AEs to ibrutinib; and the action taken with respect to ibrutinib treatment due to 
AEs.
The verbatim terms used in the eCRF by the Investigator to identify non-hematological adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®). 
Treatment-emergent AEs are those AEs events occurring after the first dose of study drugs and 
within 30 days following the last dose of study drug; any AE that is considered study drug-
related regardless of the start date of the event; or any AE that is present at baseline but worsens 
after the first administration of study drug in severity or is subsequently considered drug-related 
by the Investigator. All treatment-emergent AEs will be included in the analysis. For each AE,
the percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized. The number and percent of subjects with treatment-emergent adverse events will 
be summarized according to intensity (NCI CTCAE, Version 4.03) and drug relationship as well 
as categorized by system organ class and preferred term. Summaries, listings, datasets, or 
subject narratives may be provided, as appropriate, for those subjects who die, who discontinue 
treatment due to an AE, or who experience a SAE.


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10.6.2.
Clinical Laboratory Tests
Laboratory tests will be summarized separately for hematology and serum chemistry.  Local 
laboratory results will be converted based on the normal ranges and standardized using the SI 
unit.  Selected hematologic and chemistry laboratory parameters are detailed in Section 7.5.
Descriptive statistics will be provided for the values of selected clinical laboratory tests at each 
scheduled on-treatment evaluation including the final value. Percent change from baseline to 
each scheduled on-treatment evaluation and to the final value will also be summarized. For 
selected variables, the mean value and mean percent change over time will be presented 
graphically.
A summary of the shifts in selected laboratory hematology and serum chemistry parameters from 
baseline to the worst toxicity grade during the study will be provided. The worst toxicity grade 
during the study will be tabulated.
All laboratory values will be converted to standard international units and will be graded using 
the NCI CTCAE Version 4.03. Standard methods for summarizing laboratory variables will be 
used, including the use of summary statistics and shift tables.
10.6.3.
Dose Level Review Committee
A Dose Level Review Committee will evaluate safety data following the completion of each 
dose observation period of the Phase 1b portion. The same committee will review safety data in 
the event that an interim analysis for Phase 2 will be performed. Members of this committee will 
include the Sponsor (at a minimum: the Medical Monitor or designee, a Drug Safety 
representative and a Biostatistician) as well as participating Investigators/designees.
11.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of subjects, Investigators, and the Sponsor, and are mandated by 
regulatory agencies worldwide. The Sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the Sponsor or its affiliates will be conducted in 
accordance with those procedures.
11.1.
Adverse Event Definitions and Classifications
11.1.1.
Adverse Events
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (ICH-E2A 1995).


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For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions.
Disease progression is not an adverse event; rather it may be the cause of an adverse event.  The
clinical diagnosis that is associated with disease progression must be reported as all other adverse 
events.  “Disease progression” should never be used as an adverse event term.
Adverse events may include, but are not limited to:
x
Subjective or objective symptoms spontaneously offered by the subject and/or observed by 
the Investigator or study staff including laboratory abnormalities of clinical significance.
x
Any AEs experienced by the subject through the completion of final study procedures.
x
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with DLBCL that were not present 
before the AE reporting period 
x
Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies).
The following are NOT considered AEs:
x
Pre-existing condition: A pre-existing condition (documented on the medical history 
eCRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period.
x
Pre-planned or elective hospitalization: A hospitalization planned before signing the 
informed consent form is not considered an SAE, but rather a therapeutic intervention.  
However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE.  
Surgeries or interventions that were under consideration, but not performed before 
enrollment in the study, will not be considered serious if they are performed after enrollment 
in the study for a condition that has not changed from its baseline level.  Elective 
hospitalizations for social reasons, solely for the administration of chemotherapy, or due to 
long travel distances are also not SAEs.
x
Diagnostic Testing and Procedures: Testing and procedures should not to be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported.
x
Asymptomatic Treatment Related Lymphocytosis: This event should not be considered 
an AE.  Patients with treatment-related lymphocytosis should remain on study treatment and 
continue with all study-related procedures.
11.1.2.
Serious Adverse Events
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:
x
Results in death (ie, the AE actually causes or leads to death).


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x
Is life-threatening.  Life-threatening is defined as an AE in which the patient was at risk of 
death at the time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe.  If either the Investigator or the Sponsor believes that an 
AE meets the definition of life-threatening, it will be considered life-threatening.
x
Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization.
x
Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions).
x
Is a congenital anomaly/birth defect.
x
Is an important medical event that may not result in death, be immediately life-threatening 
or require hospitalization, but may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the patient or patient may require intervention 
to prevent one of the other outcomes listed in this definition.  Examples of such events are 
intensive treatment in an emergency department or at home for allergic bronchospasm, 
blood dyscrasias, or convulsion that does not result in hospitalization; or development of 
drug dependency or drug abuse.
Given that the Investigator’s perspective may be informed by having actually observed the event, 
and the Sponsor is likely to have broader knowledge of the drug and its effects to inform its 
evaluation of the significance of the event, if either the Sponsor or the Investigator believes that 
the event is serious, the event will be considered serious.
11.1.3.
Unexpected Adverse Events
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is 
not listed at the specificity or severity that has been observed.  For example, hepatic necrosis 
would be “unexpected” (by virtue of greater severity) if the Investigator's Brochure referred only 
to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator's Brochure/
package insert listed only cerebral vascular accidents.  "Unexpected" also refers to AEs that are 
mentioned in the Investigator's Brochure as occurring with a class of drugs or as anticipated from 
the pharmacological properties of the drug, but are not specifically mentioned as occurring with 
the study drug under investigation.
11.1.4.
Severity Criteria (Grade 1-5)
Definitions found in the Common Terminology Criteria for Adverse Events version 4.03
(CTCAE v4.03) will be used for grading the severity (intensity) AEs.  The CTCAE v4.03
displays Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE.  
Should a subject experience any AE not listed in the CTCAE v4.03, the following grading 
system should be used to assess severity:
x
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, 
and not interfering with the subject’s daily activities


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x
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures
x
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment
x
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death
x
Grade 5 (Death related to AE) – experiences which result in subject death
11.1.5.
Causality (Attribution)
The Investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study drug caused the event) using the following definitions:
Not Related:
Another cause of the AE is more plausible; a temporal sequence 
cannot be established with the onset of the AE and administration of 
the investigational product; or, a causal relationship is considered 
biologically implausible.
Unlikely:
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely.
Possibly Related:
There is a clinically plausible time sequence between onset of the 
AE and administration of the investigational product, but the AE 
could also be attributed to concurrent or underlying disease, or the 
use of other drugs or procedures.  Possibly related should be used 
when the investigational product is one of several biologically 
plausible AE causes.
Related:
The AE is clearly related to use of the investigational product.
11.2.
Documenting and Reporting of Adverse Events
The Investigator is responsible for ensuring that all AEs and SAEs observed or reported during 
the study, as outlined in the prior sections, are recorded on the eCRF.  All SAEs must also be 
reported on the Serious Adverse Event Report Form and submitted to the Sponsor (see 
Section 11.2.2.2).
11.2.1.
Special Reporting Situations
Safety events of interest on a Sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:
x
Overdose of a study drug
x
Suspected abuse/misuse of a study drug


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x
Inadvertent or accidental exposure to a study drug
x
Medication error involving a product (with or without subject/patient exposure to the study 
drug, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a SAE should be recorded on the AE eCRF.
11.2.2.
Adverse Event Reporting Procedures
11.2.2.1.
All Adverse Events
All subjects who receive at least one dose of study drug(s) will be considered evaluable for
safety assessments. All AEs whether serious or non-serious, will be recorded in the source 
documents from the time signed and dated ICF is obtained until 30 days following the last dose 
of study drug. Starting from the time of first dose of study drug, all AEs and SAEs will be 
entered in the eCRF until 30 days after the date of last dose of study drug.  Serious Adverse 
Events that occur during study conduct including the screening period must be reported to the 
Sponsor. Serious adverse events occurring more than 30 days following the last dose of study 
drug should also be reported if considered related to any of the study drugs. Resolution 
information after 30 days should be provided.
Progressive disease should NOT be reported as an AE, but instead symptoms/clinical signs of 
disease progression may be reported. Otherwise, all events that meet the definition of a SAE will
be reported as SAEs, regardless of whether they are protocol-specific assessments.
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document. All records will need to capture the 
details of the duration and the severity of each episode, the action taken with respect to the study 
drug, Investigator’s evaluation of its relationship to the study drug, and the event outcome. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
"upper respiratory infection"). Investigators must record in the eCRF their opinion concerning 
the relationship of the 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.
11.2.2.2.
Reporting Criteria for Serious Adverse Events
All SAEs occurring during the study must be reported to the Sponsor by the study-site within 
24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to Pharmacyclics using the Serious Adverse 
Event Report Form, which must be completed by a study physician from the study site, and 
submitted to Pharmacyclics within 24 hours of the study site becoming aware of the event. 


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All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs:
x
The event resolves
x
The event stabilizes
x
The event returns to baseline, if a baseline value/status is available
x
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct
x
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)
11.2.3.
Events of Special Interest
Specific AEs or groups of AEs will be followed as part of standard safety monitoring activities 
by the Sponsor. These events will be reported to Pharmacyclics within 24 hours of awareness 
irrespective of seriousness (ie, serious and non-serious adverse events) following the procedure 
described above for SAEs and will require enhanced data collection.
11.2.3.1.
Major Hemorrhage
Major hemorrhage is defined as any of the following: 
1. Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*.  
2. Any treatment-emergent serious adverse events of bleeding of any grade
3. Any treatment-emergent central nervous system hemorrhage/hematoma of any grade
*All hemorrhagic events requiring transfusion of red blood cells should be reported as grade 3 or higher AE per 
CTCAE, v4.03.
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 11.2.3 above.
11.2.4.
Other Malignancies
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported as SAEs. This includes any second primary malignancy, 
regardless of causal relationship to study drug[s], occurring at any time for the duration of the 
study, from the time of signing the informed consent to 3 years after the last study drug 
treatment.
Events of second primary malignancy are to be reported using the SAE form; these events must 
also be documented in the appropriate page(s) of the eCRF and in the subject’s source 
documents. Documentation of the diagnosis of the second primary malignancy must be provided 


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at the time of reporting as an SAE (eg, any confirmatory histology or cytology results, X-rays, 
CT scans, etc.).
11.2.5.
Pregnancy
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 
However, should a pregnancy occur in a female study subject, consent to provide follow-up
information regarding the outcome of the pregnancy and the health of the infant (until 30 days 
old) will be requested.
A female subject must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 30 days after the last dose of study drug. A male subject must immediately 
inform the Investigator if his partner becomes pregnant from the time of his consent to 90 days 
after the last dose of study drug. Any female subjects receiving study drug(s) who become 
pregnant must immediately discontinue study treatment. The Investigator should counsel the 
subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus.
11.2.5.1.
Pregnancy Reporting
Although pregnancy itself is not regarded as an adverse event, the outcome will need to be 
documented. Any pregnancy occurring in a subject or subject’s partner from the time of consent 
to 30 days after the last dose of study drug must be reported.  Any occurrence of pregnancy must 
be recorded on the Pregnancy Report Form Part I and submitted to Pharmacyclics Drug Safety, 
or designee, within 24 hours of learning of the event.  All pregnancies will be followed for 
outcome, which is defined as elective termination of the pregnancy, miscarriage, or delivery of 
the fetus. For pregnancies with an outcome of live birth, the newborn infant will be followed 
until 30 days old by completing the Pregnancy Report Form Part II. Any congenital 
anomaly/birth defect noted in the infant must be reported as a serious adverse event.
12.
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS
12.1.
Regulatory and Ethical Compliance
This clinical study was designed and will be implemented in accordance with the protocol, the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local 
regulations (including US Code of Federal Regulations [CFR] Title 21 and European Directive 
2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki.
12.2.
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval
The Investigator will submit this protocol, the ICF, IB, and any other relevant supporting 
information (eg, all advertising materials or materials given to the subject during the study) to the 
appropriate IRB/REB/IEC for review and approval before study initiation.  Amendments to the 
protocol and informed consent form must also be approved by the IRB/REB/IEC before the 
implementation of changes in this study.


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The Investigator is responsible for providing the IRB/REB/IEC with any required information 
before or during the study, such as SAE expedited reports or study progress reports.
The IRB/REB/IEC must comply with current United States (US) regulations (§21 CFR 56) as 
well as country-specific national regulations and/or local laws.
The following documents must be provided to Pharmacyclics or its authorized representative 
before entering subjects in this study: (1) a copy of the IRB/REB/IEC letter that grants formal 
approval; and (2) a copy of the IRB/REB/IEC-approved ICF.
12.3.
Informed Consent
The ICF and process must comply with the US regulations (§ 21 CFR Part 50) as well as country 
specific national regulations and/or local laws.  The ICF will document the study-specific 
information the Investigator or his/her designee provides to the subject and the subject’s 
agreement to participate.  
The Investigator or designee (designee must be listed on the Delegation of Authority log), must 
explain in terms understandable to the subject the purpose and nature of the study, study 
procedures, anticipated benefits, potential risks, possible AEs, and any discomfort participation 
in the study may entail.  This process must be documented in the subject’s source record.  Each 
subject must provide a signed and dated ICF before any study-related (nonstandard of care) 
activities are performed.  The original and any amended signed and dated consent forms must 
remain in each subject’s study file at the study site and be available for verification by study 
monitors at any time.  A copy of each signed consent form must be given to the subject at the 
time that it is signed by the subject. 
12.4.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored at a central lab for up to 10 years (or according to 
local regulations) for additional research.  Samples will only be used to better understand the 
effects of ibrutinib and lenalidomide, to understand DLBCL, to understand sensitivity or 
resistance to the investigational products tested in this study, and to develop tests/assays related 
to ibrutinib/lenalidomide and DLBCL.  The research may begin at any time during the study or 
the post-study storage period.  Stored samples will be coded throughout the sample storage and 
analysis process and will not be labeled with personal identifiers. 
12.5.
Quality Control and Quality Assurance 
Sponsor shall implement and maintain quality control and quality assurance procedures to ensure 
that the study is conducted and data are generated, documented and reported in compliance with 
the protocol, GCP, and applicable regulatory requirements.  This study shall be conducted in 
accordance with the provisions of the Declaration of Helsinki (October 2008) and all revisions 
thereof, and in accordance with FDA regulations (21 CFR Parts 11, 50, 54, 56, and 312, 
Subpart D – Responsibilities of Sponsors and Investigators) and with the ICH guidelines on GCP 
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12.6.
Protected Subject Health Information Authorization
Information on maintaining subject confidentiality in accordance to individual local and national 
subject privacy regulations must be provided to each subject as part of the informed consent 
process (refer to Section 12.3), either as part of the ICF or as a separate signed document (for 
example, in the US, a site-specific HIPAA consent may be used).  The Investigator or designee 
must explain to each subject that for the evaluation of study results, the subject’s protected health 
information obtained during the study may be shared with Pharmacyclics and its designees, 
regulatory agencies, and IRBs/REBs/IECs.  As the study Sponsor, Pharmacyclics will not use the 
subject’s protected health information or disclose it to a third party without applicable subject
authorization.  It is the Investigator’s or designee’s responsibility to obtain written permission to 
use protected health information from each subject.  If a subject withdraws permission to use 
protected health information, it is the Investigator’s responsibility to obtain the withdrawal 
request in writing from the subject and to ensure that no further data will be collected from the 
subject.  Any data collected on the subject before withdrawal will be used in the analysis of study 
results.
During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations.
12.7.
Study Files and Record Retention
The Investigator must keep a record of all subjects who have consented to enroll in the study.  
For those subjects subsequently excluded from enrollment, the reason(s) for exclusion is to be 
recorded.
The Investigator/study staff must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified.  Essential 
documentation includes, but is not limited to, the IB, signed protocols and amendments, 
IRB/REB/IEC approval letters (dated), signed Form FDA 1572 and Financial Disclosures, 
signed ICFs (including subject confidentiality information), drug dispensing and accountability 
records, shipping records of investigational product and study-related materials, signed 
(electronically), dated and completed eCRFs, and documentation of eCRF corrections, SAE 
forms transmitted to Pharmacyclics and notification of SAEs and related reports, source 
documentation, normal laboratory values, decoding procedures for blinded studies, curricula 
vitae for study staff, and all relevant correspondence and other documents pertaining to the 
conduct of the study.
All essential documentation will be retained by the Investigator for at least 2 years after the date 
the last marketing application is approved for the drug for the indication for which it is being 
investigated and until there are no pending or contemplated marketing applications; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years 
after formal discontinuation of clinical development of the drug. 


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The Investigator must notify Pharmacyclics and obtain written approval from Pharmacyclics 
before destroying any clinical study documents or images (eg, scan, radiograph, ECG tracing) at 
any time.  Should an Investigator wish to assign the study records to another party or move them 
to another location, advance written notice will be given to Pharmacyclics.  Pharmacyclics will 
inform the Investigator of the date that study records may be destroyed or returned to 
Pharmacyclics.
Pharmacyclics must be notified in advance of, and Pharmacyclics must provide express written 
approval of, any change in the maintenance of the foregoing documents if the Investigator 
wishes to move study records to another location or assign responsibility for record retention to 
another party.  If the Investigator cannot guarantee the archiving requirements set forth herein at 
his or her study site for all such documents, special arrangements must be made between the 
Investigator and Pharmacyclics to store such documents in sealed containers away from the 
study site so that they can be returned sealed to the Investigator for audit purposes.
12.8.
Case Report Forms and Record Maintenance
Electronic CRFs will be used to collect the clinical study data and must be completed for each 
enrolled subject with all required study data accurately recorded such that the information 
matches the data contained in medical records (eg, physicians’ notes, nurses’ notes, clinic charts 
and other study-specific source documents).  Authorized study site personnel (ie, listed on the 
Delegation of Authority log) will complete eCRFs designed for this study according to the 
completion guidelines that will be provided.  The Investigator will ensure that the eCRFs are 
accurate, complete, legible, and completed within a reasonable amount of time.  At all times, the 
Investigator has final responsibility for the accuracy and authenticity of all clinical data.
The eCRFs exists within an electronic data capture (EDC) system with controlled access 
managed by Pharmacyclics or its authorized representative for this study.  Study staff will be 
appropriately trained in the use of eCRFs and application of electronic signatures before the start 
of the study and before being given access to the EDC system.  Original data and any changes of 
data will be recorded using the EDC system, with all changes tracked by the system and recorded 
in an electronic audit trail.  The Investigator attests that the information contained in the eCRFs 
is true by providing electronic signature within the EDC system.  After database lock, the 
Investigator will receive a copy of the subject data (eg, paper, CD, or other appropriate media) 
for archiving at the study site.
12.9.
Investigational Study Drug Accountability
Study drug(s) must be kept in a locked limited access room and must not be used outside the 
context of the protocol.  Under no circumstances should the Investigator or other site personnel 
supply ibrutinib, lenalidomide or rituximab to other Investigators, subjects, or clinics or allow 
supplies to be used other than as directed by this protocol without prior authorization from 
Pharmacyclics.


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Accountability records for ibrutinib, lenalidomide and rituximab must be maintained and readily 
available for inspection by representatives of Pharmacyclics and are open to inspections by 
regulatory authorities at any time. 
An Investigational Drug Accountability Log must be used for drug accountability.  For accurate 
accountability, the following information must be noted when drug supplies are used during the 
study:
x
Study identification number (PCYC-1123-CA)
x
Subject identification number
x
Lot number(s) of study drug (s) dispensed for that subject
x
Date and quantity of drug dispensed
x
Any unused drug returned by the subject
For additional details on investigational product management, please refer to the Pharmacy 
Manual.
12.10.
Study Monitoring/Audit Requirements
Representatives of Pharmacyclics or its designee will monitor this study until study completion.  
Monitoring will be conducted through personal visits with the Investigator and site staff, remote 
monitoring, as well as any appropriate communications by mail, fax, email, or telephone.  The 
purpose of monitoring is to ensure that the study is conducted in compliance with the protocol, 
Standard Operating Procedures (SOPs), and other written instructions and regulatory guidelines, 
and to ensure the quality and integrity of the data.  This study is also subject to reviews or audits.
To assure the accuracy of data collected in the eCRFs, it is mandatory that the monitor/auditor 
have access to all original source documents, including all Electronic Medical Records (EMR) at 
reasonable times and upon reasonable notice.  If access to the EMR cannot be granted to the 
monitor, the site must ensure that certified copies of all documents are made available during 
monitoring visits for all screened and enrolled subjects. During the review of source documents, 
every effort will be made to maintain the anonymity and confidentiality of all subjects during 
this clinical study.  However, because of the experimental nature of this treatment, the 
Investigator agrees to allow the IRB/REB/IEC, representatives of Pharmacyclics, its affiliates, 
designated agents and authorized employees of the appropriate Regulatory Authority to inspect 
the facilities used in this study and, for purposes of verification, allow direct access to the 
hospital or clinic records of all subjects enrolled into this study.  A statement to this effect will be 
included in the informed consent and permission form authorizing the use of protected health 
information.
Pharmacyclics or its authorized representative may perform an audit at any time during or after 
completion of this study.  All study-related documentation must be made available to the 
designated auditor.  In addition, a representative of the FDA or other Regulatory Agencies may 


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choose to inspect a study site at any time before, during, or after completion of the clinical study.  
In the event of such an inspection, Pharmacyclics will be available to assist in the preparation.  
All pertinent study data should be made available as requested to the Regulatory Authority for 
verification, audit, or inspection purposes.
12.11.
Investigator Responsibilities
A complete list of Investigator responsibilities are outlined in the clinical trial research 
agreement and the Statement of Investigator Form FDA 1572, both of which are signed by the 
Investigator before commencement of the study.  In summary, the Investigator will conduct the 
study according to the current protocol; will read and understand the IB; will obtain 
IRB/REB/IEC approval to conduct the study; will obtain informed consent from each study 
participant; will maintain and supply to the Sponsor or designee, auditors and regulatory 
agencies adequate and accurate records of study activity and drug accountability for study-
related monitoring, audits, IRB/REB/IEC reviews and regulatory inspections; will report SAEs
to the Sponsor or designee and IRB/ REB/IEC according to the specifics outlined in this 
protocol; will personally conduct or supervise the study; and will ensure that colleagues 
participating in the study are informed about their obligations in meeting the above 
commitments.
12.12.
Sponsor Responsibilities
A complete list of the Sponsor responsibilities is outlined in the clinical trial research agreement 
and in the laws and regulation of the country in which the research is conducted.  In summary, 
the Sponsor will select qualified Investigators, provide them with the information they need to 
properly conduct the study, ensure adequate monitoring of the study, conduct the study in 
accordance with the general investigational plan and protocols and promptly inform 
Investigators, health and regulatory agencies/authorities as appropriate of significant new 
adverse effects or risks with respect to the drug.
12.13.
Financial Disclosure
A separate financial agreement will be made between each Principal Investigator and 
Pharmacyclics or its authorized representative before the study drug is delivered.
For this study, each Investigator and Sub-Investigator (as designated on the Form FDA1572) will 
provide a signed Financial Disclosure Form in accordance with § 21 CFR 54.  Each Investigator 
will notify Pharmacyclics or its authorized representative of any relevant changes during the 
conduct of the study and for 1 year after study completion.


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12.14.
Liability and Clinical Trial Insurance
In the event of a side effect or injury, appropriate medical care as determined by the 
Investigator/Designee will be provided.
The ICF will include a description of treatment in the event of a study related injury and 
handling of the costs associated therewith, incorporating country-specific national regulations 
and/or local laws.  Financial compensation for lost wages, disability or discomfort due to the 
study is not available.
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted.  An insurance certificate will be made available to the participating sites 
at the time of study initiation.
12.15.
Protocol Amendments
Only Pharmacyclics can initiate any change to the protocol in a protocol amendment document.  
The amendment will be submitted to the IRB/REB/IEC together with, if applicable, a revised 
model ICF.  Written documentation of IRB/REB/IEC and required site approval must be 
received by Pharmacyclics before the amendment may take effect at each site.  Additionally 
under this circumstance, information on the increased risk and/or change in scope must be 
provided to subjects already actively participating in the study, and they must read, understand 
and sign any revised ICF confirming willingness to remain in the trial.
No other significant or consistent change in the study procedures, except to eliminate an 
immediate hazard, shall be implemented without the mutual agreement of the Investigator and 
Pharmacyclics.
12.16.
Publication of Study Results
Pharmacyclics may use the results of this clinical study in registration documents for Regulatory 
Authorities in the US or abroad.  The results may also be used for papers, abstracts, posters, or 
other material presented at scientific meetings or published in professional journals or as part of 
an academic thesis by an Investigator.  In all cases, to avoid disclosures that could jeopardize 
proprietary rights and to ensure accuracy of the data, Pharmacyclics reserves the right to preview 
all manuscripts and abstracts related to this study, allowing Pharmacyclics sufficient time to 
make appropriate comments before submission for publication.
In most cases, the Investigators at the sites with the highest accruals of eligible subjects shall be 
listed as lead authors on manuscripts and reports of study results.  The Medical Monitor, Study 
Director and/or Lead Statistician may also be included in the list of authors.  This custom can be 
adjusted upon mutual agreement of the authors and Pharmacyclics.


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12.17.
Study Discontinuation
The Sponsor reserves the right to terminate the study at any time.  Should this be necessary, both 
the Sponsor and the Investigator will arrange discontinuation procedures.  In terminating the 
study, the Sponsor and the Investigator will assure that adequate consideration is given to the 
protection of the subjects’ interests.
12.18.
Study Completion
The study is expected to be completed 3 years from the last study treatment, the time point all 
subjects have exited the study for any reason, or study termination at the Sponsor’s discretion,
whichever occurs first.  


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13.
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15. El Gnaoui T, Dupuis J, Belhadj K, et al. Rituximab, gemcitabine and oxaliplatin: an effective salvage 
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16. Fisher SG, Fisher RI. The epidemiology of non-Hodgkin's lymphoma. Oncogene. 
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17. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for 
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18. Gururajan M, Jennings CD, Bondada S. Cutting edge: Constitutive B cell receptor signaling is critical 
for basal growth of B lymphoma. Journal of Immunology 2006;176:5715-5719.
19. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of 
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20. Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic 
target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765.  Blood 
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21. Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, et al. Higher Response to Lenalidomide in Relapsed/
Refractory Diffuse Large B-Cell Lymphoma in Non-germinal Center B-Cell-Like Than in Germinal 
Center B-Cell-Like Phenotype. Cancer 2011;117:5058-5066.
22. Holford TR, Zheng T, Mayne ST, McKay LA. Time trends of non-Hodgkin's lymphoma: are they 
real? What do they mean? Cancer Res 1992;52 (19 Suppl):5443s–5446s.
23. IMBRUVICA® [ibrutinib package insert]. Sunnyvale, CA: Pharmacyclics LLC; Janssen Biotech Inc.;
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24. Investigator's Brochure. Ibrutinib. Version 9: 30June 2015. Pharmacyclics LLC; Janssen Research & 
Development, LLC.
25. Investigator's Brochure. Revlimid®. Edition 17:  31 Jan 2014. Celgene Corporation; 2014
26. Jermann M, Jost LM, Taverna Ch, et al. Rituximab-EPOCH, an effective salvage therapy for 
relapsed, refractory or transformed B-cell lymphomas: results of a phase II study. Annals of 
Oncology 2004;15:511-516.
27. Küppers R. Mechanisms of B cell lymphoma pathogenesis. Nature Reviews Cancer 2005;5:251-262.
28. Lenz G, Staudt LM Aggressive lymphomas. N Engl J Med 2010;362:1417-1429.
29. Leonard J, Jung S, Johnson JL, et al. CALGB 50401: A randomized trial of lenalidomide alone versus 
lenalidomide plus rituximab in patients with recurrent follicular lymphoma. [abstract]. 2012 ASCO 
Annual Meeting. J Clin Oncol 2012;30(suppl); abstr 8000.
30. Lopez A, Gutierrez A, Palacios A, et al. GEMOX-R regimen is a highly effective salvage regimen in 
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31. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in 
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32. MabThera® [EU SmPC]. Welwyn Garden City, United Kingdom: Roche Registration Limited; 2014.
33. Meeker T, Lowder J, Cleary ML, et al. Emergence of idiotype variants during treatment of B-cell 
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34. National Cancer Comprehensive Network (NCCN). NCCN Clinical Practice Guidelines in Oncology 
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36. Ohmachi K, Niitsu N, Uchida T, et al. Multicenter Phase II Study of Bendamustine Plus Rituximab in 
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37. Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine 
kinase. ChemMedChem 2007;2:58-61.
38. Park LC, Woo SY, Kim S, et al. Incidence, risk factors and clinical features of venous 
thromboembolism in newly diagnosed lymphoma patients: results from a prospective cohort study 
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40. REVLIMID® [lenalidomide package insert]. Summit, NJ: Celgene Corporation; 2015.
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42. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after 
chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002;346:1937 47.
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44. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1-10.
45. Smith TJ, Khatcheressian J, Lyman GH, et al.  2006 Update of Recommendations for the Use of 
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Clinical Oncology. 2006:24: 3187-205.
46. US Food & Drug Administration. Guidance for Industry: Clinical Safety Data Management: 
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47. Tilly H, Vitolo U, Walewski J, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical 
Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 
2012;23(s7):vii78-vii82.
48. Wang M, Fowler N, Wagner-Bartak N, et al. Oral Lenalidomide with rituximab in relapsed or 
refractory diffuse large cell, follicular, and transformed lymphoma: a phase II clinical trial. Leukemia 
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49. Weidmann E, Kim SZ, Rost A, et al. Bendamustine is effective in relapsed or refractory aggressive 
non-Hodgkin’s lymphoma. Annals of Oncology 2002;13:1285-1289.
50. Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide Monotherapy in Relapsed or Refractory 
Aggressive Non-Hodgkin’s Lymphoma. JCO 2008;26:4962-4957.
51. Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of single-agent lenalidomide for 
relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Annals of Oncology 
2011;22:1622-1627.
52. Yang Y, Shaffer AL, Tolga Emre NC, et al. Exploiting Synthetic Lethality for the Therapy of ABC 
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53. Zhou X, Teegala S, Huen A, et al. Incidence and risk factors of venous thromboembolic events in 
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54. Ziepert M, Hasenclever D, Kuhnt E, et al. Standard International prognostic index remains a valid 
predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J 
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55. Zinzani PL, Pellegrini C, Gandolfi L, et al. Combination of Lenalidomide and Rituximab in Elderly 
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14.
APPENDICES




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Cycle
C1
C2
C3
C4
C5
C6
C7 & 
Beyond
C9 & 
Beyond
Response 
Evaluationo
Assessment 
Until Disease
EOT
RFUa
LTFU
Day
1
8
15
22
1
15
1
15 22-28
1
1
1
22-28
1
22-28
Laboratory Assessment
Hematologyg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine clearance
X
X
X
X
X
X
X
X
Coagulation (PT, INR, aPTT)
X
X
Thyroid Function Test (TSH)h
X
X
X
Xh
X
Hepatitis Serologiesi
X
Urinalysis
X
X
Pregnancy Test (serum or urine)j
X
X
X
X
X
X
X j
X
X j
X
X
X
X
X
X j
T/B/NK Cell Countk
X
X
X
X
Xk
Xk
X
Serum Immunoglobulins (Ig)l
(Phase 2)
X
Xl
Xl
X
X
Biomarker Blood Samplek
X
X
X
X
Xk
Xk
X
PK Blood Samplingm (Phase 2)
Xm
Xm
Radiologic Tumor Assessment
CT Neck, Chest, Abdomen, Pelvisn
X
X
X
X
Xn,o
X
PET or PET/CTn
X
Xn,o
X
Other
Survival Statusp
Xp
Subsequent Anticancer Therapy
X
Xp
Abbreviations:  C=cycle; CT=computed tomography; D=day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=End-of-Treatment Visit; 
LTFU=Long-Term Follow Up; RE=Response Evaluation; PD=progressive disease; PET=positron emission tomography; PO=oral; RFU=Response Follow Up
Footnotes for PCYC-1123-CA Schedule of Assessments:
a
CT/MRI and PET scans may be done per the Investigator’s discretion during the response follow-up period. 
b
Study Drug diary must be provided to the subjects at the beginning of each Day 1 visit to record daily dosing.  Site personnel must instruct the subjects to bring the 
completed diary card with any used and unused study drugs at each study visit.  Site personnel must reconcile and document the returned capsules from the subjects 
at each visit to ensure compliance.
c
Phase 2 only: A fresh tissue sample, archived unstained slides or an archived paraffin block must be sent to central lab for determination of DLBCL subtype by GEP 
and IHC using the Hans method at Screening to confirm eligibility for enrollment. For subjects in Phase 1b, available tissue (archived or fresh) will be sent to 
central lab at Screening for DLBCL subtyping. (Local laboratory results for DLBCL subtype for subjects in the Phase 1b may be collected).The tumor sample(s) can be 
archival tissue from original diagnosis, from relapsed or refractory disease, or a fresh (recent) biopsy, if done to confirm eligibility for this study.  


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d
A subject who consents to participate in the optional pre-treatment lymph node biopsy, the sample must be collected since the completion of the most recent 
treatment regimen.  A subject who is discontinued from study treatment due to disease progression may consent to an optional post-progression tumor tissue sample
(see Section 7.6.5). For a subject who consents to participate in the optional tumor tissue sample assessment, the lymph node biopsy must be collected within 
30 (±7) days after the last dose of ibrutinib or prior to the start of a new anticancer treatment and as early as possible on or before the EOT visit.  See Laboratory 
Manual/Flow Chart for details regarding specimen collection and processing.
e
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be assessed after the subject hDVUHVWHGLQWKHVLWWLQJSRVLWLRQIRUPLQXWHV
f
A unilateral bone marrow aspirate and biopsy will be done at Screening or up to 28 days before the first administration of study drug.  If a bone marrow biopsy and 
aspirate were done within 28 days of the first dose of study drug, the sample may be used.  Thereafter, a bone marrow aspirate and biopsy will only be required to 
confirm CR if result was positive at Screening. (See Section 8.3.18) 
g
Hematology includes complete blood count with differential and platelet counts.
h
TSH will be performed at Screening, on pre-dose Day 1 of every 3 cycles for the first year, then every 6 cycles thereafter and at the EOT Visit.
i
Hepatitis C antibody, hepatitis B surface antigen and antibody and hepatitis B core antibody will be evaluated.  If hepatitis B core antibody or hepatitis B surface 
antigen is positive, then hepatitis B PCR to quantitate hepatitis B DNA must be performed.  DNA PCR needs to be confirmed negative prior to enrollment  in 
subjects who are hepatitis B core antibody or hepatitis B surface antigen positive.  For subjects who are hepatitis C antibody positive, hepatitis C PCR needs to be 
confirmed negative prior to enrollment.  
j
Must be done in accordance with Celgene Revlimid REMS™ program (US Sites) or global Pregnancy Prevention Program (PPP) guidelines (Ex-US Sites) for 
females of childbearing potential (FCBP).  Day 15 of each Cycle only applies if a subject’s menstruation is irregular.  Serum or urine depending on site standard 
method.  If positive at Screening Visit, the subject is not eligible to enroll.  See Appendix 7 and Appendix 8 for pregnancy testing frequency requirements.
k
T/B/NK cell count and biomarkers should be done at pre-dose on Day 1 of Cycles 1, 2, 3, at response evaluation (ie, Day 1 Cycles 4, 7, 10, 13, 16, 19, 22, 25, and
then every 6 cycles thereafter) and EOT Visits.  
l
Phase 2 only: Serum Ig will be taken pre-dose Day 1 Cycle 1.  Samples will also be taken at all response evaluation visits (eg, Cycle 4, 7, 10, etc.) and EOT Visit.
m
Phase 2 only: PK samples will be drawn according to the schedule Table 9.  For subjects who must take strong or moderate CYP3A inhibitors while on treatment 
with ibrutinib, additional PK blood samples for evaluation of ibrutinib exposure is requested. 
n
Pretreatment tumor assessment should be performed within 28 days before the first dose.  A CT scan (with contrast unless contraindicated) of the neck, chest, 
abdomen, and pelvis and any other disease sites and a PET or PET/CT scan are required for the pretreatment tumor assessment. Thereafter, a PET scan is to be 
performed to confirm CR if PET result was positive at Screening or may be performed at anytime if clinically indicated.  During treatment, CT/MRI scans will be 
done for tumor assessments within 7 days prior to Day 1 of Cycle 4 and Cycle 7, then every 3 cycles up to Cycle 25, and then every 6 cycles thereafter, until PD or 
use of alternative anticancer therapy.  In the event that CT contrast is contraindicated, MRI of the abdomen and pelvis with contrast and CT of the chest and neck 
may be performed as an alternative. Lesions in anatomical locations that are not well visualized by CT may be measured at baseline from MRI instead and should 
continue to be measured from MRI until disease progression. Follow the Cheson 2007 (Phase 1b) Appendix 5 and Cheson 2014 (Phase 2) Appendix 6. 
o
Response evaluation (RE) should be performed in alignment with the CT/MRI and/or PET scans schedules. The RE is to be performed within 7 days of Day 1 of 
Cycle 4 and Cycle 7, then every 3 cycles up to Cycle 25, and then every 6 cycles thereafter, or at any time during the study if indicated per the Investigator. 
p
Subjects will be contacted about every 3 months to assess subsequent anticancer therapies, information about second malignancies & survival status. 


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Appendix 2. ECOG Status Scores
Status
Eastern Cooperative Oncology Group (ECOG) Performance Status**
0
Fully active, able to carry on all pre-disease performance without restriction. 
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light housework, office work. 
2
Ambulatory and capable of all self-care, but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5
Dead.
**Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.:  Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
Available at: http://www.ecog.org/general/perf_stat html.  Accessed January 4, 2008.


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Appendix 3.
Cockcroft-Gault Formula for Estimating Creatinine Clearance
Ccr =
(140 – age) x Body Weight (kg)
(Serum creatinine mg/dL) x 72
Note:
x
Multiply by 0.85 for women
x
Use with caution in cirrhosis and muscle wasting
x
To convert μmol (micromoles)/L of creatinine to mg/dL, divide by 88.4.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.


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Appendix 4.
Inhibitors and Inducers of CYP3A
Inhibitors and inducers of CYP3A enzymes are defined as follows. Refer to Section 6.1.2.1 on
instructions for concomitant use of CYP3A inhibitors and inducers with ibrutinib. Further information 
can be found at the following website: http://medicine.iupui.edu/clinpharm/ddis/main-table/.
Inhibitors of CYP3A
Inducers of CYP3A
Strong inhibitors:
carbamazepine
indinavir
efavirenz
nelfinavir
nevirapine
ritonavir
barbiturates
clarithromycin
glucocorticoids
itraconazole
modafinil
ketoconazole
oxcarbarzepine
nefazodone
phenobarbital
saquinavir
phenytoin
suboxone
pioglitazone
telithromycin
rifabutin
cobicistat
rifampin
boceprevir
St. John’s Wort
mibefradil
troglitazone
telaprevir
troleandomycin
posaconazole
Moderate inhibitors:
aprepitant
amprenavir
amiodarone
atazanavir
ciprofloxacin
crizotinib
darunavir/ritonavir
dronedarone
erythromycin
diltiazem
fluconazole
fosamprenavir
grapefruit juice
Seville orange juice
verapamil
voriconazole
imatinib
Weak inhibitors:
cimetidine
fluvoxamine
All other inhibitors:
chloramphenicol
delaviridine
diethyl-dithiocarbamate
gestodene
mifepristone
norfloxacin
norfluoxetine
star fruit


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Appendix 5.
Revised International Working Group Response Criteria for Malignant 
Lymphoma (Cheson 2007) – Phase 1b Only
Response Categories
Response
Definition
Nodal Masses
Spleen, Liver
Bone Marrow
CR
Disappearance 
of all evidence 
of disease
a) FDG-avid or PET 
positive prior to 
therapy; mass of any 
size permitted if PET 
negative
b) Variably FDG-avid or 
PET negative; 
regression to normal 
size on CT
Not palpable, nodules 
disappeared
Infiltrate cleared on repeat 
biopsy; if indeterminate by 
morphology, 
immunohistochemistry should
be negative
PR
Regression of 
measurable 
disease and no 
new sites
GHFUHDVHLQ63'RI
up to 6 largest dominant 
masses; no increase in size 
of other nodes
a) FDG-avid or PET 
positive prior to 
therapy; one or more 
PET positive at 
previously involved 
sites
b) Variably FDG-avid or 
PET negative; 
regression on CT
GHFUHDVHLn
SPD of nodules (for 
single nodule in 
greatest transverse 
diameter); no 
increase in size of 
liver or spleen
Irrelevant if positive prior to 
therapy; cell type should be 
specific
SD
Failure to 
attain CR/PR 
or PD
a) FDG-avid or PET 
positive prior to 
therapy; PET positive 
at prior sites of disease 
and no new sites on CT 
or PET
b) Variably FDG-avid or 
PET negative; no 
change in size of 
previous lesions on CT
Relapsed 
disease or 
PD
Any new 
lesion or 
LQFUHDVHE\
50% of 
previously 
involved sites 
from nadir
Appearance of a new 
lesion(s) >1.5 cm in any 
D[LVLQFUHDVHLQ
SPD of more than one 
node, or 50% increase in 
longest diameter of a 
previously identified node 
> 1cm in short axis
Lesions PET positive if 
FDG-avid lymphoma or 
PET positive prior to 
therapy
>50% increase from 
nadir in the SPD of 
any previous lesions
New or recurrent involvement
Abbreviations: CR, complete remission; FDG, (18F) fluorodeoxyglucose; PET, positron emission tomography; CT, 
computerized tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; 
PD, progressive disease


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Appendix 6.
Revised International Working Group Response Criteria for Malignant 
Lymphoma or Lugano Classification (Cheson 2014) – Phase 2 only
Evaluation, Staging, and Response Assessment for Non-Hodgkin Lymphoma: The Lugano 
Classification (according to Cheson 2014)
Evaluation, staging, and response criteria are summarized in 3 Tables below.
Table 1:
Criteria for Involvement of Site
Tissue Site
Clinical
FDG Avidity
Test
Positive Finding
Lymph nodes
Palpable
FDG-avid 
histologies
PET-CT
Increased FDG uptake
Non avid disease
CT
Unexplained node enlargement
Spleen
Palpable
FDG-avid 
histologies
PET-CT
Diffuse uptake, solitary mass, 
miliary lesions, nodules
Non avid disease
CT
>13 cm in vertical length, mass, 
nodules 
Liver
Palpable
FDG-avid 
histologies
PET-CT
Diffuse uptake, mass
Non avid disease
CT
Nodules
CNS
Signs, 
symptoms
CT
Mass lesion(s)
MRI
Leptomeningeal infiltration, mass 
lesions
CSF assessment
Cytology, flow cytometry
Other (eg, skin, 
lung, GI tract, 
bone, bone 
marrow)
Site 
dependent
PET-CTa, biopsy
Lymphoma involvement
Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; FDG, fluorodeoxyglucose; MRI, magnetic 
resonance imaging; PET, positron emission tomography. 
a: PET-CT is adequate for determination of bone marrow involvement and can be considered highly suggestive for 
involvement of other extralymphatic sites. Biopsy confirmation of those sites can be considered if necessary. 
Table 2:
Staging System for Primary Nodal Lymphomas
Stage
Involvement
Extranodal (E) Status
Limited
I
One node or a group of adjacent nodes
Single extranodal lesions without nodal 
involvement
II
Two or more nodal groups on the same side of 
the diaphragm
Stage I or II by nodal extent with limited 
contiguous extranodal involvement
II bulkya
II as above with “bulky” disease
Not applicable
Advanced
III
Nodes on both sides of the diaphragm; nodes 
above the diaphragm with spleen involvement
Not applicable
IV
Additional noncontiguous extralymphatic 
involvement
Not applicable
NOTE: Extent of disease is determined by positron emission tomography–computed tomography for avid 
lymphomas and computed tomography for nonavid histologies. Tonsils, Waldeyer's ring, and spleen are considered 
nodal tissue. 
a Whether stage II bulky disease is treated as limited or advanced disease may be determined by histology and a 
number of prognostic factors.


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Table 3:
Criteria for Response Assessment of Non-Hodgkin’s Lymphoma
Response
Site
PET-CT-Based Response
CT-Based Response
Complete
Lymph nodes 
and 
extralymphatic 
sites
Complete metabolic response
Complete radiologic response 
(all of the following)
Score 1, 2, or 3a with or without a residual 
mass on 5PS2
It is recognized that in Waldeyer's ring or 
extranodal sites with high physiologic 
uptake or with activation within spleen or 
marrow (eg, with chemotherapy or myeloid 
colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or 
liver. In this circumstance, complete 
metabolic response may be inferred if uptake 
at sites of initial involvement is no greater 
than surrounding normal tissue even if the 
tissue has high physiologic uptake
Target nodes/nodal masses 
PXVWUHJUHVVWRFPLQ/'L
No extralymphatic sites of 
disease
Non measured 
lesion
Not applicable
Absent
Organ 
enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if 
determinate, IHC negative
Partial
Lymph nodes 
and 
extralymphatic 
sites
Partial metabolic response
Partial remission (all of the 
following)
Score 4 or 5b with reduced uptake compared 
with baseline and residual mass(es) of any 
size
At interim, these findings suggest 
responding disease
At end of treatment, these findings indicate 
residual disease
GHFUHDVHLQ63'RIXSWR
6 target measurable nodes and 
extranodal sites
When a lesion is too small to 
measure on CT, assign 5 mm × 
5 mm as the default value
When no longer visible, 0 × 0 
mm
For a node >5 mm × 5 mm, but 
smaller than normal, use actual
measurement for calculation
Nonmeasured 
lesion
Not applicable
Absent/normal, regressed, but 
no increase
Organ 
enlargement
Not applicable
Spleen must have regressed by 
>50% in length beyond normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in 
normal marrow but reduced compared with 
baseline (diffuse uptake compatible with 
reactive changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consideration should be 
given to further evaluation with MRI or 
biopsy or an interval scan
Not applicable


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Response
Site
PET-CT-Based Response
CT-Based Response
No response 
or 
stable disease
Lymph nodes 
and 
extralymphatic 
sites
No metabolic response
Stable disease
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or end 
of treatment
<50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met
Non measured 
lesion
Not applicable
No increase consistent with 
progression
Organ 
enlargement
Not applicable
No increase consistent with 
progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive 
disease
Individual target 
nodes/nodal 
masses
Extranodal 
lesions
Progressive metabolic disease
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or
New FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment
Progressive disease requires at 
least 1 of the following:
PPD progression:
An individual node/lesion must 
be abnormal with:
LDi >1.5 cm and
,QFUHDVHE\50% from PPD 
nadir and
An increase in LDi or SDi from 
nadir.
FPIRUOHVLRQVFP
1.0 cm for lesions >2 cm
In the setting of splenomegaly, 
the splenic length must increase 
by >50% of the extent of its 
prior increase beyond baseline 
(eg, a 15-cm spleen must 
increase to >16 cm). If no prior 
splenomegaly, must increase by 
at least 2 cm from baseline
New or recurrent splenomegaly
Non measured 
lesions
None
New or clear progression of 
preexisting nonmeasured 
lesions
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another etiology (eg, 
infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy or 
interval scan may be considered
Regrowth of previously 
resolved lesions
A new node >1.5 cm in any 
axis
A new extranodal site >1.0 cm 
in any axis; if <1.0 cm in any 
axis, its presence must be 
unequivocal and must be 
attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, 
positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis 
perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions.


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a A score of 3 in many subjects 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 3(736QRXSWDNHDERYHEDFNJURXQGXSWDNHPHGLDVWLQXPXSWDNH!PHGLDVWLQXPEXWOLYHUXSWDNH
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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Appendix 7.
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods (for US Sites only)
Risks Associated with Pregnancy
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has 
the effect of the lenalidomide on human eggs and sperm.  Lenalidomide is structurally related to 
thalidomide.  Thalidomide is a known human teratogenic active substance that causes severe life-
threatening birth defects.  An embryofetal development study in animals indicates that 
lenalidomide produced malformations in the offspring of female monkeys who received the drug 
during pregnancy.  The teratogenic effect of lenalidomide in humans cannot be ruled out.  
Therefore, a risk minimization plan to prevent pregnancy must be observed.
All study participants must be registered into the mandatory Revlimid REMS™program, and be 
willing and able to comply with the requirements of Revlimid REMS™. (for US sites only)
Criteria for females of childbearing potential (FCBP)
This protocol defines a female of childbearing potential as a sexually mature female who: 1) has
not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the 
preceding 24 consecutive months).
The Investigator must ensure that:
x
Females of childbearing potential comply with the conditions for pregnancy risk 
minimization, including confirmation that she has an adequate level of understanding
x
Females NOT of childbearing potential acknowledge that she understands the hazards 
and necessary precautions associated with the use of lenalidomide
x
Male patients taking lenalidomide acknowledge that he understands that traces of 
lenalidomide have been found in semen, that he understands the potential teratogenic 
risk if engaged in sexual activity with a female of childbearing potential or pregnant 
female, and that he understands the need for the use of a condom even if he has had a 
vasectomy, if engaged in sexual activity with a female of childbearing potential or 
pregnant female.  
Contraception
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable 
forms of contraception simultaneously or to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this study: 1) for at least 28 days before 
starting lenalidomide; 2) throughout the entire duration of lenalidomide treatment; 3) during dose 
interruptions; and 4) for at least 28 days after lenalidomide discontinuation.


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The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and additional 
effective methods of contraception:  
x
Highly effective methods:
Intrauterine device (IUD)
Hormonal (birth control pills, injections, implants)
Tubal ligation
Partner’s vasectomy
x
Additional effective methods:
Male condom
Diaphragm
Cervical Cap
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk 
of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics 
should be considered particularly in patients with neutropenia.
Pregnancy testing
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence, as outlined below.
Before starting lenalidomide
Female Patients:
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to 
prescribing lenalidomide.  The first pregnancy test must be performed within 10-14 days prior to 
prescribing lenalidomide and the second pregnancy test must be performed within 24 hours prior 
to prescribing lenalidomide.  The patient may not receive lenalidomide until the Investigator has 
verified that the results of these pregnancy tests are negative.
Male Patients:
Must agree to practice complete abstinence or agree to use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire duration of 
lenalidomide treatment, during dose interruptions and for at least 90 days following lenalidomide 
discontinuation, even if he has undergone a successful vasectomy.


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During study participation and for 28 days following lenalidomide discontinuation.
Female Patients:
x
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly 
for the first 28 days of lenalidomide treatment, including dose interruptions and then 
every 28 days throughout the remaining duration of lenalidomide treatment, including 
dose interruptions, at lenalidomide discontinuation, and at Day 28 following 
lenalidomide discontinuation.  If menstrual cycles are irregular, the pregnancy testing 
must occur weekly for the first 28 days of lenalidomide treatment, including dose 
interruptions, and then every 14 days throughout the remaining duration of lenalidomide 
treatment, including dose interruptions, at lenalidomide discontinuation, and at Day 14 
and Day 28 following lenalidomide discontinuation.  
x
At each visit, the Investigator must confirm with the FCBP that she is continuing to use 
two reliable methods of birth control at each visit during the time that birth control is 
required.  
x
If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide 
must be immediately discontinued.
x
Pregnancy testing and counseling must be performed if a patient misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide treatment must 
be temporarily discontinued during this evaluation.
x
Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after lenalidomide discontinuation.
Male Patients:
x
Must practice complete abstinence or use a condom during sexual contact with pregnant 
females or females of childbearing potential throughout the entire duration of 
lenalidomide treatment, during dose interruptions and for at least 90 days following 
lenalidomide discontinuation, even if he has undergone a successful vasectomy.  
x
If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the Investigator must be notified immediately.
x
Male patients should not donate semen or sperm during therapy or for at least 90 days 
following discontinuation of lenalidomide.
Additional Precautions
x
Patients should be instructed never to give lenalidomide to another person.
x
Patients should not donate blood during therapy and for at least 28 days following
discontinuation of lenalidomide (90 days for male subjects).
x
Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle 
of therapy. 
x
Any unused lenalidomide must be returned as instructed through the Revlimid REMS™
program (for US sites only).


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Appendix 8.
Lenalidomide Pregnancy Prevention Risk Management Plans 
(for ex-US sites only)
1.
LENALIDOMIDE PREGNANCY PREVENTION PLAN FOR SUBJECTS IN 
CELGENE CLINICAL TRIALS
The Pregnancy Prevention Plan (PPP) applies to all subjects receiving lenalidomide within a 
clinical trial. The following PPP documents are included:
1. The Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods document (Section 2) provides the following 
information:
x
Potential risks to the fetus associated with lenalidomide exposure
x
Definition of female of childbearing potential (FCBP)/female not of childbearing 
potential (FNCBP)
x
Requirements for counseling of all subjects receiving lenalidomide about pregnancy 
precautions and the potential risks of fetal exposure to lenalidomide
x
Acceptable birth control methods for both female subjects of childbearing potential 
and male subjects receiving lenalidomide in the study
x
Pregnancy testing requirements for subjects receiving lenalidomide who are FCBP
2. The Lenalidomide Education and Counseling Guidance Document for each gender 
(female and male; Section 3 and Section 4 respectively) must be completed and signed by
a trained counselor at the participating clinical center prior to each dispensing of 
lenalidomide. A copy of this document must be maintained in the subject’s records for 
each dispense.
3. The Lenalidomide Information Sheet (Section 5) will be given to each subject receiving 
lenalidomide. The subject must read this document prior to starting lenalidomide and 
each time the subject receives a new supply of lenalidomide.


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2.
LENALIDOMIDE RISKS OF FETAL EXPOSURE, PREGNANCY TESTING 
GUIDELINES AND ACCEPTABLE BIRTH CONTROL METHODS
2.1.
Risks Associated with Pregnancy
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic 
active substance that causes severe life-threatening birth defects. An embryofetal development 
study in animals indicates that lenalidomide produced malformations in the offspring of female 
monkeys who received the drug during pregnancy. A teratogenic effect of lenalidomide in 
humans cannot be ruled out. Therefore, a pregnancy prevention program must be followed.
2.1.1.
Definition of Females of Childbearing Potential
A FCBP is a female who: 1) has achieved menarche at some point; or 2) has not undergone a 
hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 
consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
2.1.2.
Definition of Females Not of Childbearing Potential
Females who do not meet the above definition of FCBP should be classified as FNCBP.
2.2.
Counseling
2.2.1.
Females of Childbearing Potential
For a FCBP, lenalidomide is contraindicated unless all of the following are met (ie, all FCBP
must be counseled concerning the following risks and requirements prior to the start of 
lenalidomide): 
x
She understands the potential teratogenic risk to the unborn child
x
She understands the need for effective contraception, without interruption, 28 days before 
starting lenalidomide, throughout the entire duration of lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide
x
She understands and agrees to inform the Investigator if a change or stop of method of 
contraception is needed
x
She must be capable of complying with effective contraceptive measures
x
She is informed and understands the potential consequences of pregnancy and the need to 
notify her study doctor immediately if there is a risk of pregnancy
x
She understands the need to commence lenalidomide as soon as it is dispensed following 
a negative pregnancy test
x
She understands and accepts the need to undergo pregnancy testing based on the 
frequency outlined in this plan (Section 2.4) and in the Informed Consent
x
She acknowledges that she understands the hazards lenalidomide can cause to an unborn 
fetus and the necessary precautions associated with the use of lenalidomide.


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The Investigator must ensure that a FCBP:
x
Complies with the conditions of the pregnancy prevention plan, including confirmation 
that she has an adequate level of understanding
x
Acknowledges the aforementioned requirements.
2.2.2.
Females Not of Childbearing Potential
For a FNCBP, lenalidomide is contraindicated unless all of the following are met (ie, all FNCBP
must be counseled concerning the following risks and requirements prior to the start of 
lenalidomide): 
x
She acknowledges she understands the hazards lenalidomide can cause to an unborn fetus 
and the necessary precautions associated with the use of lenalidomide.
2.2.3.
Males
Traces of lenalidomide have been found in semen. Male subjects taking lenalidomide must meet 
the following conditions (ie, all males must be counseled concerning the following risks and 
requirements prior to the start of lenalidomide):
x
Understand the potential teratogenic risk if engaged in sexual activity with a pregnant 
female or a FCBP
x
Understand the need for the use of a condom even if he has had a vasectomy, if engaged 
in sexual activity with a pregnant female or a FCBP
x
Understand the potential teratogenic risk if the subject donates semen or sperm.
2.3.
Contraception
2.3.1.
Female Subjects of Childbearing Potential
Females of childbearing potential enrolled in this protocol must agree to use two reliable forms 
of contraception simultaneously or to practice complete abstinence (True abstinence is 
acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence [eg calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal 
are not acceptable methods of contraception.) from heterosexual contact during the following 
time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while 
taking lenalidomide; 3) during dose interruptions; and 4) for at least 28 days after the last dose of 
lenalidomide.
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. If the below contraception methods are not appropriate for 
the FCBP, she must be referred to a qualified provider of contraception methods to determine the 
medically effective contraception method appropriate to the subject. The following are examples 
of highly effective and additional effective methods of contraception:


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x
Examples of highly effective methods:

Intrauterine device (IUD)

Hormonal (birth control pills, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, ovulation 
inhibitory progesterone-only pills [eg, desogestrel])

Tubal ligation

Partner’s vasectomy
x
Examples of additional effective methods:

Male condom

Diaphragm

Cervical Cap
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk 
of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics 
should be considered particularly in subjects with neutropenia. 
2.3.2.
Male Subjects
Male subjects must practice complete abstinence (True abstinence is acceptable when this is in 
line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable methods 
of contraception.) or agree to use a condom during sexual contact with a pregnant female or a 
FCBP while taking lenalidomide, during dose interruptions and for at least 90 days after the last 
dose of lenalidomide, even if he has undergone a successful vasectomy. 
2.4.
Pregnancy Testing
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for FCBP.
Females of childbearing potential must have two negative pregnancy tests (sensitivity of at least 
25 mIU/mL) prior to starting lenalidomide. The first pregnancy test must be performed within 
10 to 14 days prior to the start of lenalidomide and the second pregnancy test must be performed 
within 24 hours prior to the start of lenalidomide. The subject may not receive lenalidomide until 
the study doctor has verified that the results of these pregnancy tests are negative.
Females of childbearing potential with regular or no menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 28 days while 
taking lenalidomide, at study discontinuation, and at Day 28 following the last dose of 
lenalidomide. 
Females of childbearing potential with irregular menstrual cycles must agree to have pregnancy 
tests weekly for the first 28 days of study participation and then every 14 days while taking 
lenalidomide, at study discontinuation, and at Days 14 and 28 following the last dose of 
lenalidomide.


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2.5.
Pregnancy Precautions for Lenalidomide Use
2.5.1.
Before Starting Lenalidomide
2.5.1.1.
Female Subjects of Childbearing Potential
Females of childbearing potential must have two negative pregnancy tests (sensitivity of at least 
25 mIU/mL) prior to starting lenalidomide. The first pregnancy test must be performed within 
10 to 14 days prior to the start of lenalidomide and the second pregnancy test must be performed 
within 24 hours prior to the start of lenalidomide. The subject may not receive lenalidomide until 
the study doctor has verified that the results of these pregnancy tests are negative.
Females of childbearing potential must use two reliable forms of contraception simultaneously, 
or practice complete abstinence (True abstinence is acceptable when this is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, ovulation, 
symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.) from heterosexual contact for at least 28 days before starting lenalidomide.
2.5.1.2.
Male Subjects
Male subjects must agree to practice complete abstinence (True abstinence is acceptable when 
this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg 
calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) or agree to use a condom during sexual contact with a 
pregnant female or a FCBP while taking lenalidomide, during dose interruptions and for at least 
90 days after the last dose of lenalidomide, even if he has undergone a successful vasectomy. 
2.5.2.
During and After Study Participation
2.5.2.1.
Female Subjects
x
Females of childbearing potential with regular or no menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 28 days 
while taking lenalidomide, at study discontinuation, and at Day 28 following the last dose 
of lenalidomide.
x
Females of childbearing potential with irregular menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 14 days 
while taking lenalidomide, at study discontinuation, and at Days 14 and 28 following the 
last dose of lenalidomide.
x
At each visit, the Investigator must confirm with the FCBP that she is continuing to use 
two reliable methods of birth control if not committing to complete abstinence, or 
confirm commitment to complete abstinence.
x
If a FCBP considers the need to change or to stop a method of contraception, the 
Investigator must be notified immediately.
x
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days. 


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x
If pregnancy or a positive pregnancy test does occur in a subject, lenalidomide must be 
immediately discontinued.
x
Pregnancy testing and counseling must be performed if a subject misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal. Lenalidomide must be 
discontinued during this evaluation.
x
Females must agree to abstain from breastfeeding while taking lenalidomide and for at 
least 28 days after the last dose of lenalidomide.
2.5.2.2.
Male Subjects
x
Must practice complete abstinence (True abstinence is acceptable when this is in line 
with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) or use a condom during sexual contact with a pregnant female 
or a FCBP while taking lenalidomide, during dose interruptions and for at least 90 days
after the last dose of lenalidomide, even if he has undergone a successful vasectomy.
x
Must not donate semen or sperm while receiving lenalidomide, during dose interruptions 
or for at least 90 days after the last dose of lenalidomide.
x
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days.
x
If pregnancy or a positive pregnancy test does occur in the partner of a male subject while 
taking lenalidomide, the Investigator must be notified immediately.
2.5.3.
Additional Precautions
x
Subjects should be instructed to never give lenalidomide to another person.
x
Subjects should be instructed to return any unused capsules to the study doctor.
x
Subjects should not donate blood while receiving lenalidomide, during dose interruptions
and for at least 28 days after the last dose of lenalidomide (90 days for male subjects).
x
No more than a 28-day lenalidomide supply may be dispensed with each cycle of 
lenalidomide.


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3.
LENALIDOMIDE EDUCATION AND COUNSELING GUIDANCE DOCUMENT 
FOR FEMALE SUBJECTS
To be completed prior to each dispensing of lenalidomide.
Protocol Number: ____________________________________________
Subject Name (Print): __________________ DOB: _____/_____/_____ (dd/mmm/yyyy)
Check one risk category:
 FCBP (Female of childbearing potential): a female who: 1) has achieved menarche 
(first menstrual cycle) at some point, 2) has not undergone a hysterectomy (the 
surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of 
both ovaries) or 3) has not been naturally postmenopausal (amenorrhea following 
cancer therapy does not rule out childbearing potential) for at least 24 consecutive 
months (ie, has had menses at any time during the preceding 24 consecutive months)
 NOT FCBP
3.1.
Female of Childbearing Potential:
1. I have verified and counseled the subject regarding the following:
 Potential risk of fetal exposure to lenalidomide: A teratogenic potential of 
lenalidomide in humans cannot be ruled out. If lenalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby. Females are 
advised to avoid pregnancy while taking lenalidomide. Females of childbearing 
potential must agree not to become pregnant while taking lenalidomide.
 That the required pregnancy tests performed are negative.
 The subject confirmed that she is using TWO reliable methods of birth control at the 
same time, or complete abstinence (True abstinence is acceptable when this is in line 
with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) from heterosexual contact (at least 28 days 
prior to receiving lenalidomide, while receiving lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide). 
One highly effective method and one additional method of birth control must be used
AT THE SAME TIME. The following are examples of highly effective and 
additional effective methods of contraception:

Examples of highly effective methods:
o
Intrauterine device (IUD)
o
Hormonal (birth control pills, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, 
ovulation inhibitory progesterone-only pills [eg, desogestrel])
o
Tubal ligation


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o
Partner’s vasectomy

Examples of additional effective methods:
o
Male condom
o
Diaphragm
o
Cervical Cap
 The subject confirmed that even if she has amenorrhea she must comply with advice 
on contraception.
 Pregnancy tests before, during administration of lenalidomide and at the last dose of 
lenalidomide, even if the subject agrees not to have reproductive heterosexual 
contact.
 Frequency of pregnancy tests to be done:

Two pregnancy tests will be performed prior to receiving lenalidomide, one 
within 10 to 14 days, and a second within 24 hours of the start of lenalidomide.

Every week during the first 28 days of this study and a pregnancy test every 
28 days while the subject is taking lenalidomide if menstrual cycles are regular.

Every week during the first 28 days of this study and a pregnancy test every 
14 days while the subject is taking lenalidomide if menstrual cycles are irregular.

If the subject missed a period or has unusual menstrual bleeding.

When the subject is discontinued from the study and at Day 28 after the last dose 
of lenalidomide if menstrual cycles are regular. If menstrual cycles are irregular, 
pregnancy tests will be done at discontinuation from the study and at Days 14 and 
28 after the last dose of lenalidomide.
 The subject confirmed that she will stop taking lenalidomide immediately in the event 
of becoming pregnant and to call her study doctor as soon as possible. 
 The subject confirmed that she has not and will not breastfeed a baby while taking 
lenalidomide and for at least 28 days after the last dose of lenalidomide.
 The subject has not and will never share lenalidomide with anyone else.
 The subject has not and will not donate blood while taking lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide.
 The subject has not and will not break, chew, or open lenalidomide capsules at any 
point.
 The subject confirmed that she will return unused lenalidomide capsules to the study 
doctor.
2. I have provided the Lenalidomide Information Sheet to the subject.


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3.2.
Female Not of Childbearing Potential (Natural Menopause for at Least 24 
Consecutive Months, a Hysterectomy, or Bilateral Oophorectomy):
3. I have verified and counseled the subject regarding the following:
 Potential risk of fetal exposure to lenalidomide: A teratogenic potential of 
lenalidomide in humans cannot be ruled out. If lenalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby.
 The subject has not and will never share lenalidomide with anyone else.
 The subject has not and will not donate blood while taking lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide.
 The subject has not and will not break, chew, or open lenalidomide capsules at any 
point.
 The subject confirmed that she will return unused lenalidomide capsules to the study 
doctor.
4. I have provided the Lenalidomide Information Sheet to the subject.
Do Not Dispense Lenalidomide if:
x
The subject is pregnant.
x
No pregnancy tests were conducted for a FCBP.
x
The subject states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence from heterosexual contact) at least 28 days prior 
to receiving lenalidomide, while receiving lenalidomide and during dose 
interruptions.
x
The subject stated that she has or does not want to adhere to pregnancy 
precautions outlined within this PPP.
Counselor Name (Print): ____________________
Counselor Signature: _______________________ Date: _____/_____/_____(dd/mmm/yyyy)
**Maintain a copy of the Education and Counseling Guidance Document in the subject’s records.**


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4.
LENALIDOMIDE EDUCATION AND COUNSELING GUIDANCE DOCUMENT 
FOR MALE SUBJECTS
To be completed prior to each dispensing of lenalidomide.
Protocol Number: ____________________________________________
Subject Name (Print): __________________ DOB: _____/_____/_____ (dd/mmm/yyyy)
1. I have verified and counseled the subject regarding the following:
 Potential risk of fetal exposure to lenalidomide: A teratogenic potential of 
lenalidomide in humans cannot be ruled out. If lenalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby.
 The subject confirmed that he has practiced complete abstinence (True abstinence is 
acceptable when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence [eg calendar, ovulation, symptothermal or post-ovulation 
methods] and withdrawal are not acceptable methods of contraception.) or used a 
condom when engaging in sexual contact (including those who have had a 
vasectomy) with a pregnant female or FCBP, while taking lenalidomide, during dose 
interruptions and for at least 90 days after the last dose of lenalidomide.
 The subject confirmed that he has not impregnated his female partner while in the 
study.
 The subject confirmed that he will notify his study doctor if his female partner 
becomes pregnant and the female partner of a male subject taking lenalidomide 
confirmed that she will call her healthcare provider immediately if she becomes 
pregnant.
 The subject has not and will never share lenalidomide with anyone else.
 The subject confirmed that he has not donated and will not donate semen or sperm 
while taking lenalidomide or during dose interruptions and that he will not donate 
semen or sperm for at least 90 days after the last dose of lenalidomide.
 The subject has not and will not donate blood while taking lenalidomide, during dose 
interruptions and for at least 90 days after the last dose of lenalidomide.
 The subject has not and will not break, chew, or open lenalidomide capsules at any 
point.
 The subject confirmed that he will return unused lenalidomide capsules to the study 
doctor.
2. I have provided the Lenalidomide Information Sheet to the subject.


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Do Not Dispense Lenalidomide if:
x
The subject stated that he has or does not want to adhere to pregnancy 
precautions outlined within this PPP.
Counselor Name (Print): ____________________
Counselor Signature: _______________________ Date: _____/_____/_____(dd/mmm/yyyy)
**Maintain a copy of the Education and Counseling Guidance Document in the subject’s records.**


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5.
LENALIDOMIDE INFORMATION SHEET 
For subjects enrolled in clinical research studies 
Please read this Lenalidomide Information Sheet before you start taking lenalidomide and each 
time you get a new supply. This Lenalidomide Information Sheet does not take the place of an 
informed consent to participate in clinical research or talking to your study doctor or healthcare 
provider about your medical condition or your treatment.
What is the most important information I should know about lenalidomide?
1. Lenalidomide may cause birth defects (deformed babies) or death of an unborn 
baby. Lenalidomide is similar to the medicine thalidomide. It is known that thalidomide 
causes life-threatening birth defects.
If you are a female who is able to become pregnant:
x
Do not take lenalidomide if you are pregnant or plan to become pregnant
x
You must practice complete abstinence from sexual contact with a male or use 
two reliable, separate forms of effective birth control at the same time: 

for 28 days before starting lenalidomide

while taking lenalidomide

during breaks (dose interruptions) of lenalidomide

for at least 28 days after the last dose of lenalidomide
x
You must have pregnancy testing done at the following times:

within 10 to 14 days prior to the first dose of lenalidomide

24 hours prior to the first dose of lenalidomide

weekly for the first 28 days

if you have regular menstrual periods: every 28 days after the first month 

if you have irregular menstrual periods: every 14 days after the first month

if you miss your period or have unusual menstrual bleeding

28 days after the last dose of lenalidomide (14 and 28 days after the last dose if 
menstrual periods are irregular)
x
Stop taking lenalidomide if you become pregnant while taking lenalidomide

If you suspect you are pregnant at any time during the study, you must stop 
lenalidomide immediately and immediately inform your study doctor. Your study 
doctor will report all cases of pregnancy to Celgene Corporation.
x
Do not breastfeed while taking lenalidomide and for at least 28 days after the 
last dose of lenalidomide
x
The study doctor will be able to advise you where to get additional advice on 
contraception.


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If you are a female not able to become pregnant:
In order to ensure that an unborn baby is not exposed to lenalidomide, your study doctor 
will confirm that you are not able to become pregnant.
If you are a male:
A small amount of lenalidomide is found in human semen. The risk to an unborn baby in 
females whose male partner is receiving lenalidomide is unknown at this time.  
x
Male subjects (including those who have had a vasectomy) must practice complete 
abstinence or must use a condom during sexual contact with a pregnant female or a 
female that can become pregnant:

While you are taking lenalidomide

During breaks (dose interruptions) of lenalidomide

For at least 90 days after the last dose of lenalidomide
x
Male subjects should not donate sperm or semen while taking lenalidomide, 
during breaks (dose interruptions) and for at least 90 days after the last dose of 
lenalidomide.
x
If you suspect that your partner is pregnant any time during the study, you must 
immediately inform your study doctor. The study doctor will report all cases of 
pregnancy to Celgene Corporation. Your partner should call their healthcare 
provider immediately if they become pregnant.
2. All subjects:
x
Do not share lenalidomide with other people. It must be kept out of the reach of 
children and should never be given to any other person.
x
Do not donate blood while you take lenalidomide, during breaks (dose interruptions)
and for at least 28 days after the last dose of lenalidomide (90 days for male subjects).
x
Do not break, chew, or open lenalidomide capsules at any point.
x
You will get no more than a 28-day supply of lenalidomide at one time.
x
Return unused lenalidomide capsules to your study doctor.
Additional information is provided in the informed consent form and you can ask your 
study doctor for more information.


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Appendix 9. Child-Pugh Score for Subjects with Liver Impairment
Measure
1 point
2 points
3 points
7RWDOELOLUXELQȝPROL (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL)
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT/INR
<1.7 
1.71-2.30 
>2.30 
Ascites
None 
Mild
Moderate to Severe
Hepatic encephalopathy
None
Grade I-II (or suppressed 
with medication) 
Grade III-IV 
(or refractory)
Points
Class
5-6 
A 
7-9 
B 
10-15 
C 
Source: 
1.
Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia:Saunders. 1964. pp. 50-64.  
2.
Pugh RN, Murray-Lyon IM, Dawson L, et al . “Transection of the oesophagus for bleeding oesophageal 
varices”.  The British journal of surgery, 1973;60: 646-9.

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
A Multicenter Open-Label, Phase 1b/2 Study of the Bruton’s Tyrosine Kinase (BTK) 
Inhibitor, Ibrutinib, in Combination with Lenalidomide and Rituximab in Subjects with 
Relapsed or Refractory Diffuse Large B-Cell Lymphoma 
 
Protocol PCYC-1123-CA; Phase 1b/2 
 
Prepared by:  
 
 
 
                                                      Date: 20 April 2020 
 
 
 
 
 
The information in this document is considered privileged and confidential by Pharmacyclics 
LLC (PCYC), and may not be disclosed to anyone other than the recipient and as requested 
to the members of the Institutional Review Board/Independent Ethics Committee, or as 
required by Federal and State Laws.  Persons to whom this information is disclosed must be 
informed that this information is privileged and confidential and that it should not be further 
disclosed. 
 
   
	 
9970) 3&<&&$ 6WDWLVWLFDO $QDO\VLV 3ODQ 6$3   $SU   )LQDO &RS\ NCT02077166


Statistical Analysis Plan 
PCYC-1123-CA 
20APR2020 
 
1 
 
TABLE OF CONTENTS 
1 Introduction 4 
1.1 Study Design ...............................................................................................................4 
1.1.1 
Phase 1b .........................................................................................................4 
1.1.2 
Phase 2 ...........................................................................................................5 
1.2 Endpoints ....................................................................................................................6 
1.2.1 
Phase 1b .........................................................................................................6 
1.2.2 
Phase 2 ...........................................................................................................6 
1.3 Statistical Hypotheses .................................................................................................7 
1.4 Sample Size Determination .........................................................................................7 
1.5 Planned Analyses ........................................................................................................8 
1.5.1 
Timing of Analyses .......................................................................................8 
1.5.2 
Interim Analysis ............................................................................................8 
1.6 Testing Procedure and Level of Significance .............................................................9 
1.7 Blinding and Randomization Methods (if applicable) ................................................9 
1.7.1 
Blinding Method ............................................................................................9 
1.7.2 
Randomization Method .................................................................................9 
2 General Analysis Consideration ..........................................................................................9 
2.1 Analysis Sets ...............................................................................................................9 
2.2 Definitions of Subgroups ..........................................................................................10 
3 Subject information ............................................................................................................10 
3.1 Subject disposition ....................................................................................................10 
3.2 Demographics and Baseline characteristics ..............................................................11 
3.3 Prior, Concomitant, and Subsequent Medications/Procedures .................................11 
3.4 Subsequent Anti-Cancer Treatment ..........................................................................11 
3.5 Extent of Exposure to Study Drug ............................................................................11 
4 Efficacy Evaluations ..........................................................................................................12 
5 Safety Evaluation ...............................................................................................................14 
6 Changes in Protocol Planned Analysis ..............................................................................16 
7 References 
17 
   
	 
9970) 3&<&&$ 6WDWLVWLFDO $QDO\VLV 3ODQ 6$3   $SU   )LQDO &RS\


Statistical Analysis Plan 
PCYC-1123-CA 
20APR2020 
 
2 
 
LIST OF ABBREVIATIONS 
ABC 
activated B-cell like (DLBCL subtype as determined by GEP) 
 
AE 
adverse event 
 
ANC 
absolute neutrophil count 
 
BTK 
Bruton’s tyrosine kinase  
 
CFR 
Code of Federal Regulations 
 
CI 
confidence interval 
 
CR 
complete response  
 
CT 
computed tomography 
 
CYP 
cytochrome P 
 
DLBCL 
diffuse large B cell lymphoma 
 
DLT 
dose limiting toxicity 
 
DOR 
duration of response  
 
ECG 
electrocardiogram 
 
ECOG 
Eastern Cooperative Oncology Group 
 
EDC 
electronic data capture 
 
eCRF 
electronic case report form 
 
FDA 
Food and Drug Administration 
 
GCB 
germinal-cell B-cell-like (subtype) 
 
GEP 
gene expression profiling 
 
IV 
intravenous 
 
MAD 
maximum administered dose 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
MTD 
maximum tolerated dose 
 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
 
NHL 
non-Hodgkin’s lymphoma 
 
ORR 
overall response rate 
 
OS 
PCYC 
overall survival 
Pharmacyclics Inc. (Sponsor) 
 
PD 
progressive disease 
 
PFS 
progression-free survival 
 
PK 
pharmacokinetic(s) 
 
PO 
per os (oral) 
 
PR 
partial response 
 
   
	 
9970) 3&<&&$ 6WDWLVWLFDO $QDO\VLV 3ODQ 6$3   $SU   )LQDO &RS\


Statistical Analysis Plan 
PCYC-1123-CA 
20APR2020 
 
3 
 
RP2D 
Recommended Phase 2 Dose 
 
SAE 
serious adverse event 
 
SAP 
Statistical Analysis Plan 
 
SD 
stable disease 
 
SPD 
sum of the product of the diameters 
 
 
 
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Statistical Analysis Plan 
PCYC-1123-CA 
20APR2020 
 
4 
 
1 
INTRODUCTION 
This statistical analysis plan (SAP) is based on Protocol Amendment 5, dated on 01JUN2016, 
and is to define key elements including variable definitions, and statistical methods for analysis 
of data in the evaluation of efficacy and safety of the study PCYC-1123-CA. Analyses of 
biomarker and pharmacokinetics data will be addressed in separate documents.  
Analysis methods specified in this document take precedence over those described in the 
protocol, should there be any difference. 
1.1 
Study Design  
This Phase 1b/2 study is designed to assess the safety and efficacy of ibrutinib in 
combination with lenalidomide and rituximab in subjects with relapsed/refractory diffuse 
large B-cell lymphoma (DLBCL) ineligible for a stem cell transplant.  Phase 2 will evaluate 
only subjects with the non-GCB subtype of de novo DLBCL.  Approximately 46 subjects 
will be enrolled in the Phase 1b portion.  Phase 2 will enroll approximately 55 subjects to 
ensure enrollment of at least 49 response-evaluable subjects at 20 mg lenalidomide; 
approximately 28 additional subjects may be enrolled at 25 mg lenalidomide. 
1.1.1 Phase 1b  
In the dose escalation portion of the study, up to four cohorts may be explored, and the 
lenalidomide dose escalation will follow the 3+3+3 principle for the maximum tolerated dose 
(MTD) determination.  Due to the fact that the subject population studied is significantly ill, 
and an inability to complete the dose-limiting toxicity (DLT) observation period may occur 
due to progression of disease, additional subjects may be screened and enrolled in each 
cohort.  The DLT rules will continue to apply whereas if 1 DLT is observed, the cohort will 
be expanded to 6, and if 2 DLTs occur, the cohort will be expanded to 9.   
Ibrutinib will be administered orally once daily at 560 mg and will be initiated on Day 1 of 
the first cycle.  Treatment will be continuous (without interruption) and will continue until 
disease progression or unacceptable toxicity.  Lenalidomide will be administered orally once 
daily at the dose designated by cohort on Days 1-21 of each 28-day cycle and will continue 
until disease progression or unacceptable toxicity.  Rituximab 375 mg/m2 will be 
administered intravenously (IV) on Day 1 of each 28-day (4-week) cycle for 6 cycles.   
If 3 subjects in Cohort 1 experience a DLT, dose level -1 was planned to be enrolled 
(Table 1). After completion of Cohort 1, due to 3 DLTs in 7 evaluable subjects, a cohort at 
Dose Level -1 was opened. After completion of the Dose Level -1 cohort, if <33% of 
subjects experience a DLT, dose re-escalation to higher dose levels starting with the 
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Statistical Analysis Plan 
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20APR2020 
 
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lenalidomide dose of 15 mg may occur.  If the dose level of 20 mg lenalidomide is 
determined to be safe and tolerated in the Phase 1b, this dose will be considered the 
recommended Phase 2 dose (RP2D), and a Phase 2 cohort with 20 mg lenalidomide will be 
initiated.  Concurrent with the Phase 2 at 20 mg lenalidomide, a Phase 1b cohort with 25 mg 
lenalidomide may be initiated. If the interim analysis of the 20 mg lenalidomide cohort is 
negative, the 25 mg lenalidomide dose may be used in an additional cohort in the Phase 2, if 
safe and tolerated in the Phase 1b. 
Table 1: Phase 1b Dose Levels 
28-Day Dosing Cycle  
Ibrutiniba 
Lenalidomideb 
Rituximabc 
Dose Level -1d 
560 mg once daily 
10 mg 
375 mg/m2 
Dose Level 1 = starting dose (Cohort 1 & 
1+) 
560 mg once daily 
15 mg 
375 mg/m2 
Dose Level 2 (Cohort 2) 
560 mg once daily 
20 mg 
375 mg/m2 
Dose Level 3 (Cohort 3) 
560 mg once daily 
25 mg 
375 mg/m2 
a. 
Ibrutinib will be administered orally once daily beginning Cycle 1 Day 1 
b. Lenalidomide will be administered orally once daily on Days 1-21 of each 28-day cycle 
c. 
Rituximab will be administered IV on Day 1 of each 28-day cycle for 6 cycles 
d. If <33% of subjects experience a DLT at Dose Level -1, dose re-escalation to a higher dose level may 
occur. 
At least 6 subjects will be treated at the MTD or in any cohort defined as the RP2D that supports 
the Phase 2. 
1.1.2 Phase 2  
The Phase 2 part of this study will be conducted as an international, multicenter, open-label 
study.  Phase 2 will enroll approximately 49 response-evaluable subjects at 20 mg 
lenalidomide; approximately 28 additional subjects may be enrolled at 25 mg lenalidomide.  
Eligible subjects will receive ibrutinib, lenalidomide and rituximab per the treatment 
schedule as shown below (Table 2).  If determined to be safe and tolerated in the Phase 1b 
portion of the trial, the proposed dose of lenalidomide for Phase 2 is 20 mg.  Subjects will be 
treated until disease progression or unacceptable toxicity. 
 
 
 
 
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20APR2020 
 
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Table 2: Treatment Schedulea 
 
Cycles 1-6 
Cycles 7+ 
Ibrutinib 
PO daily  
PO daily  
Lenalidomide 
PO daily Days 1-21 
PO daily Days 1-21 
Rituximab 
IV on Day 1 
NA 
a  Each cycle will be 28-days in length (4 weeks) and subjects will continue 
until disease progression or unacceptable toxicity.  Rituximab will be given 
for the first 6 cycles. 
An interim analysis might be performed including approximately 28 evaluable subjects with 
adequate tumor response assessments. Details of the interim analysis and decision rules will 
be described in Section 1.5.  In addition, if there are safety concerns, a cohort with ibrutinib 
and lenalidomide without rituximab may be considered in the Phase 2 part of the study. 
Immunohistochemistry (IHC) and gene expression profiling (GEP) will be used to assess 
subject status with respect to the subtype of DLBCL.  The limitations of IHC allow only a 
distinction between subjects as either non-germinal center B cell-like (non-GCB) or GCB 
phenotype, since within the non-GCB group, one may include subjects with a true 
unclassified (intermediate) subtype.  With GEP, the subjects can be further categorized into 
the following subtypes: ABC, GCB, unclassified, and unknown due to tissue limitations.  
Throughout the protocol, the description of enrolled subjects as non-GCB is based on IHC 
testing used at screening; and the use of the term ABC subtype refers to subjects who have 
been subsequently profiled by GEP and then classified as the true ABC subtype. 
1.2 
Endpoints 
1.2.1 Phase 1b 
Primary Endpoints:  
x MTD or RP2D 
x Safety and tolerability of ibrutinib in combination with lenalidomide and rituximab in 
subjects with relapsed or refractory DLBCL   
Secondary Endpoints:  
x Overall response rate (ORR) and complete response (CR) rate 
 
1.2.2 Phase 2 
Primary Endpoint: 
x ORR  
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Statistical Analysis Plan 
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20APR2020 
 
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Secondary Endpoints: 
Efficacy: 
x CR rate  
x Duration of response (DOR)  
x Progression-free survival (PFS)  
x Overall survival (OS)  
Safety: 
x Frequency, severity, and relationship (to study drug) of AEs  
x Frequency of AEs requiring discontinuation of study drug or dose reductions 
Exploratory Analyses: 
x Efficacy endpoints by DLBCL subtype per GEP  
x Change in peripheral T/B/NK counts 
x Change in serum immunoglobulin levels (IgG, IgM, and IgA)  
1.3 
Statistical Hypotheses 
The main analysis for the Phase 2 part of this study will be the comparison of the response 
rate to the ORR of a historical control of 40%.  The null hypothesis that the true ORR is 40% 
will be tested against a one-sided alternative that the ORR is 60%. 
 
1.4 
Sample Size Determination 
The planned sample size for the Phase 2 part of this study is approximately 55 subjects to 
ensure enrollment of at least 49 response-evaluable subjects at 20 mg lenalidomide.   
An interim analysis might be performed including approximately 28 evaluable subjects with 
adequate tumor response assessments.  If only 11 or fewer responders (11/28) are observed, 
the Sponsor may consider discontinuation of the study; however, if there is evidence for 
clinical benefit from biomarker data or tumor measurements (showing clinically relevant tumor 
reductions, e.g. 40%, that fit the criteria for the response of SD), continued enrollment may be 
supported.  
The main analysis will be the comparison of the response rate to the ORR of a historical control 
of 40%.  The null hypothesis that the true ORR is 40% will be tested against a one-sided 
alternative that the ORR is 60%.  The null hypothesis will be rejected if 27 or more responses 
are observed in the 49 subjects. 
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Statistical Analysis Plan 
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This design yields a 1-sided type I error rate of 0.025 and power of 80% when the true ORR is 
60%.  This statistical design including the number of subjects and the number of responders 
follows the statistical framework of Simon’s minimax two-stage design (Simon 1989).  
Enrollment will continue while the interim analysis is being performed. 
Approximately 28 additional subjects may be enrolled at 25 mg lenalidomide to explore the 
efficacy and safety at this higher dose of lenalidomide in Phase 2. 
1.5 
Planned Analyses  
1.5.1 Timing of Analyses 
An analysis will occur approximately 12 months after the last subject initiates study treatment 
or when all subjects have discontinued from the study treatment, whichever occurs first.  A 
final analysis will occur 2 years after the last subject has been enrolled and will be reported in 
the CSR.  The study completion is defined as 3 years from the last study treatment, the time 
point all subjects have exited the study due to any reason, or study termination at the Sponsor’s 
discretion, whichever occurs first. 
 
1.5.2 Interim Analysis 
An interim analysis for Phase 2 at the 20 mg lenalidomide dose might be performed including 
approximately 28 evaluable subjects with adequate tumor response assessment.  If only 11 or 
fewer responders ( 11/28) are observed, the Sponsor may consider discontinuation of the 
study; however, if there is evidence for clinical benefit from biomarker data or tumor 
measurements (showing clinically relevant tumor reductions, e.g. 40%, that fit the criteria for 
SD), continued enrollment may be supported.  
At the interim analysis, the review committee could recommend: 
x Continuation or discontinuation of the study with 20 mg lenalidomide; or  
x Increase of the lenalidomide dose to 25 mg, if determined to be safe and tolerated in the 
Phase 1b, including approximately 28 evaluable subjects with adequate tumor response 
assessment followed by an interim analysis. 
In addition, if there are safety concerns, a cohort with ibrutinib and lenalidomide without 
rituximab may be considered in the Phase 2.  The decisions based on the interim analysis will 
be made by the Sponsor (at a minimum: the Medical Monitor or designee, a Drug Safety 
representative and a Biostatistician).  Enrollment in the 20 mg lenalidomide cohort will 
continue while the interim analysis is being performed.  
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Statistical Analysis Plan 
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1.6 
Testing Procedure and Level of Significance  
The null hypothesis that the true ORR is 40% will be tested at a 2-sided alpha of 0.05 for Part 
2 at the 20 mg lenalidomide dose.  If the lower bound of the 95% CI is greater than 40%, the 
study will be claimed as positive for Part 2 at the 20 mg lenalidomide dose. 
1.7 
Blinding and Randomization Methods (if applicable) 
1.7.1 Blinding Method 
This is an open-label study.  Blinding does not apply. 
1.7.2 Randomization Method 
This is not a randomized study.  Subjects are enrolled according to the order of Phase 1b to 
Phase 2 and low dose to high dose cohorts.  Note: The Phase 2 was started at a 20 mg 
lenalidomide dose while the Phase 1b was still ongoing with a 25 mg lenalidomide cohort. 
2 
GENERAL ANALYSIS CONSIDERATION 
The Phase 1b part of this study is a dose escalation study.  All safety and efficacy assessments 
will be summarized by dose group.  The Phase 2 part of this study is designed to assess the 
efficacy and safety of ibrutinib in combination with lenalidomide and rituximab in subjects 
with relapsed or refractory de novo non-GCB DLBCL.   
In general, continuous variables will be summarized with descriptive statistics (mean, 
standard error or standard deviation, median, quartiles, minimum, and maximum).  For 
categorical variables, the number and percentage of subjects in each applicable category will 
be provided.  Time-to-event or duration-of-event endpoints will be based on the event and 
censoring dates.  
All statistical analyses will be performed using SAS® version 9.3 or higher. 
2.1 
Analysis Sets 
All-treated analysis population (Phase 1b/2) 
The all-treated analysis population will include subjects who have been enrolled in the study 
and received any dose of study drug(s) in each study phase, respectively.  This is the primary 
analysis population for all efficacy endpoints (i.e., PFS, OS), except ORR and the CR rate for 
the Phase 1b and Phase 2. This is also the sensitivity analysis population for ORR and CR. 
Response-evaluable Population (Phase 1b/2) 
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Statistical Analysis Plan 
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The response-evaluable population in the Phase 1b/2 study is defined as subjects in the all-
treated population who have measurable disease at baseline and have at least 1 adequate post-
treatment disease assessment by the investigator before the start of a subsequent anti-cancer 
therapy.  This is the primary analysis population for ORR and the CR rate. 
Safety Population (Phase 1b/2) 
The safety population consists of all enrolled subjects who received at least one dose of study 
drug.  The safety population will be used for the analysis of all safety and dosing data.  For this 
study, this population is equivalent to the all-treated analysis population. They are 
interchangeably used. 
2.2 
Definitions of Subgroups 
Analyses for the baseline subgroups (hereafter referred as “subgroup” or “subgroups”) will 
be performed for the selected primary and secondary endpoint variables analyses for 
Phases 1a and 2 except where noted in Table 3. 
Table 3: Baseline Subgroups 
Baseliner Characteristics 
Subgroup 
Analysis Type 
DLBCL subtype by GEP  
ABC, GCB and Unclassified 
E 
DBLC subtype by IHC  
GCB and Non-GCB 
E 
Transformed DLBCL (Phase 1b only) 
Yes 
E 
Subjects with refractory disease  
Yes 
ORR and Baseline 
Subjects with relapsed disease  
Yes 
ORR and Baseline 
Subjects with primary refractory disease  Yes 
ORR and Baseline 
  Analysis type:  E = Efficacy (ORR, CR, PFS and OS). 
 
3 
SUBJECT INFORMATION 
3.1 
Subject disposition 
Subject enrollment will be summarized by dose cohort in Phase 1b and in Phase 2, 
respectively.  The disposition of all enrolled subjects will be summarized by study phase.  
The disposition tables will include the following summaries. 
x Analysis population (all-treated subjects) 
x Enrollment by region, country and investigator  
x Study treatment disposition and discontinuation  
x Study status and the time on study  
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Statistical Analysis Plan 
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The Kaplan-Meier estimates will be calculated to estimate the time on study using reversed 
censoring from the OS analysis. 
3.2 
Demographics and Baseline characteristics 
Subject demographics (including age, sex, and race/ethnicity), general baseline characteristics 
(including ECOG performance status, weight and height), and baseline disease characteristics 
(including Ann Arbor staging, bulky disease, DLBCL category and number of prior therapies) 
will be summarized.  Summary statistics will include means, standard deviations, and medians 
for continuous variables and proportions for categorical variables. 
Concordance is summarized for the all-treated population between the DLBCL subtypes per 
GEP test by central lab and per IHC test by local lab.   
3.3 
Prior, Concomitant, and Subsequent Medications/Procedures 
Medications will be coded to preferred term and Anatomical Therapeutic Chemical (ATC) 
class according to World Health Organization (WHO) Drug dictionary. 
Prior medications are defined as medications that started prior to the first dose date of study 
drug.  Prior anti-neoplastic therapies will be summarized separately.   
Concomitant medications are defined as medications that were taken at any time on treatment 
(i.e. from the date of the first dose of study drug through the date of the last dose of study drug) 
and will be summarized separately.  Concomitant use of CYP3A inhibitors (strong, moderate, 
and weak) and CYP3A4 inducers will be listed and summarized separately.  
3.4 
Subsequent Anti-Cancer Treatment 
Subsequent anticancer therapies are anti-DLBCL treatments that started after discontinuation 
of study treatment (i.e. started after the last dose of study drug) will be summarized for the 
all-treated population by type (e.g. radiotherapy, systemic therapy, bone marrow or stem cell 
transplant). 
3.5 
Extent of Exposure to Study Drug 
For each study treatment, the number of treatment cycles each subject received will be 
summarized for the all-treated population. Subjects with any dose interruption or dose 
reduction due to AEs will be summarized.   
Summary tables for ibrutinib, lenalidomide, and rituximab will present duration of treatment, 
the number of doses received, the total amount of study drug received, the average dose per 
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administration, the relative dose intensity, and subjects with at least 1 dose modification 
(interruption or reduction) due to AE.   
For rituximab, the average dose per administration, relative dose intensity, the number and 
percentage of subjects with infusion interruption, duration of interruption, and at least 1 dose 
modification will be summarized.  
4 
EFFICACY EVALUATIONS 
The Response-evaluable population (Phase 1b/2) is the primary analysis population for ORR 
and the CR rate.  The ORR and the CR rate will be calculated for the all-treated population as 
well.  The all-treated population is the primary analysis population for all other efficacy 
endpoints (i.e. PFS, OS).  The analysis of endpoints is presented in Table 4. 
The scanned images will be centrally stored for a possible future independent review of 
overall response.  In case PCYC decides to implement an independent review of tumor 
response data, the overall response as assessed independently will become the primary 
analysis set for ORR, CR, DOR and PFS, and the previous analyses by investigators’ 
assessments will become a secondary analysis set. 
Table 4: Definitions and Analyses for Efficacy Endpoints 
Endpoint 
Definition 
Analysis Method 
Phase 1b: 
 
 
Secondary Endpoints (for all subtypes of DLBCL): 
 
ORR  
The ORR is defined as the rate of 
subjects who achieve either a PR 
or CR, according to the revised 
International 
Working 
Group 
Response 
Criteria 
for 
NHL 
(Cheson 2007), as assessed by the 
Investigator. 
ORR and its corresponding exact binomial 2-sided 
95% CI, based on the response-evaluable population 
enrolled in Phase 1b. 
Sensitivity 
Analysis based on the all-treated population 
enrolled in Phase 1b. 
 
In addition, waterfall plot for maximum percent 
reduction in tumor size and time to response will be 
summarized. 
 
CR rate 
The ORR is defined as the rate of 
subjects who achieve a CR, 
according 
to 
the 
revised 
International 
Working 
Group 
Response 
Criteria 
for 
NHL 
(Cheson 2007), as assessed by the 
Investigator. 
The same as for ORR 
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Endpoint 
Definition 
Analysis Method 
Phase 2: 
 
 
Primary Endpoint: 
 
ORR  
The ORR is defined as the rate of 
subjects who achieve either a PR 
or CR, according to the revised 
International 
Working 
Group 
Response 
Criteria 
for 
NHL 
(Cheson 2014), as assessed by the 
Investigator. 
ORR and its corresponding exact binomial 2-sided 
95% CI, based on the response-evaluable population 
enrolled in Phase 2. 
Sensitivity 
Analysis based on all-treated population enrolled in 
Phase 2. 
 
In addition, a waterfall plot for maximum percent 
reduction in tumor size and time to response will be 
summarized.   
Secondary Endpoints: 
 
CR rate 
The ORR is defined as the rate of 
subjects who achieve a CR, 
according 
to 
the 
revised 
International 
Working 
Group 
Response 
Criteria 
for 
NHL 
(Cheson 2014), as assessed by the 
Investigator 
The same as for ORR 
DOR 
Time from the date of the first 
documented response (CR or PR) 
to the first documented evidence of 
PD or death from any cause.  
For subjects who have achieved an 
overall response but did not die or 
progress at the time of analysis, 
DOR will be censored on the date 
of the last adequate post-baseline 
disease assessment, or on the date 
of the first occurrence of response 
(CR or PR) if there is no disease 
assessment afterwards. 
Analysis of DOR will be based on the subjects who 
have achieved a response (CR or PR) prior to 
initiation of the next line of anticancer therapy in the 
all-treated population enrolled in Phase 2. The 
median DOR and its 2-sided 95% CI will be 
obtained using the same method described for PFS. 
 
Similar analysis for duration of CR, as defined as 
time from the date of the initial CR to the first 
documented evidence of PD or death from any 
cause, will be performed for all treated subjects who 
have achieved a response of CR prior to initiation of 
the next line of anticancer therapy in Phase 2. 
 
 
PFS 
Time from the date of the first dose 
of study drug to confirmed PD or 
death from any cause, whichever 
occurred first. 
For 
subjects 
without 
disease 
progression or death, PFS data will 
Kaplan-Meier method based on the all-treated 
population by dose level enrolled in Phase 2. The 
median PFS and its 2-sided 95% CI will be 
provided. PFS at landmark time points (e.g., 3, 6, 9, 
12 months from the first study drug dose date) will 
also be obtained by the Kaplan-Meier method; 95% 
CI for the landmark PFS rates will be calculated. 
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Endpoint 
Definition 
Analysis Method 
be censored at the date of the last 
tumor assessment. 
 
 
OS 
Overall survival (OS) is defined as 
the time from the date of the first 
dose of study drug to the date of 
death due to any cause.  
For subjects who are not known to 
have died at or prior to the 
database lock date, OS data will be 
censored at the date last known 
alive.  Subjects who withdraw 
consent prior to study closure will 
be censored on the date of the 
consent withdrawal. 
Kaplan-Meier method based on the all-treated 
population by dose level enrolled in Phase 2. The 
median OS and its 2-sided 95% CI will be provided. 
OS at landmark time points (e.g., 3, 6, 9, 12 months 
from the first study drug dose date) will also be 
obtained by the Kaplan-Meier method; 95% CI for 
the landmark OS rates will be calculated. 
 
Exploratory Analysis: 
 
Peripheral 
T/B/NK counts 
The absolute cell counts on 
peripheral T/B/NK 
Summary statistics will be calculated for the 
measured values and for their changes from baseline 
at each scheduled visit of assessment. 
Serum 
immunoglobulin 
levels 
The serum immunoglobulin levels 
(IgG, IgM, and IgA) 
Summary statistics will be calculated for the 
measured values and for their changes from baseline 
at each scheduled visit of assessment. 
Efficacy 
endpoints (DOR, 
PFS, and OS) by 
DLBCL subtype 
per GEP 
See definitions above for DOR, 
PFS, and OS 
Subgroup analyses will be performed as defined in 
Table 3. See analysis methods above for DOR, PFS, 
and OS. 
ABC: Activated B cell-like; CI: confidence interval; CR: complete response; DLBCL: diffuse large B-cell 
lymphoma; ECOG PS: Eastern Cooperative Oncology Group Performance Status; GCB: germinal center B 
cell-like; GEP: gene expression profile; IHC: immunohistochemistry; KM: Kaplan-Meier; ORR: overall 
response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; PR: partial 
response; RP2D: recommended phase 2 dose. 
 
5 
SAFETY EVALUATION 
Safety data for the all-treated population will be summarized for Phase 1b by the dose for 
Phase 2, unless otherwise indicated.  Table 5 summarizes the safety analyses to be conducted.  
Adverse events will be coded in accordance with the Medical Dictionary for Regulatory 
Activities (MedDRA).  Severity of AEs will be graded by the investigator according the NCI 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) (version 22.1 or higher).  
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Statistical Analysis Plan 
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20APR2020 
 
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In general, the treatment-emergent period is defined as the period from the date of the first 
dose of study treatment up to 30 days after the date of the last dose of study treatment or the 
day before initiation of subsequent anticancer therapy, whichever comes first.  Treatment-
emergent AEs are those events that occur or worsen during the treatment-emergent period or 
that are related to the study treatment or events with a complete missing onset date but with a 
resolution date during the treatment phase.  
All laboratory values will be converted to and reported as international standard (SI) units.  In 
general, only data from the central laboratory will be summarized and analyzed.  Laboratory 
parameters will be graded using the NCI CTCAE (version 4.03 or higher).  Unless otherwise 
specified, only baseline and post-baseline values collected during the treatment-emergent 
period will be included in the safety analysis. 
Table 5: Summary of Safety Assessments 
Assessment Type 
Definition   
Analysis Methods 
AE 
TEAEs, SAEs, grade 3 or higher TEAEs, 
study treatment-related TEAEs, TEAEs as the 
primary reason for treatment discontinuation, 
TEAEs leading to treatment discontinuation, 
TEAEs leading to dose reduction, TEAEs 
leading to death, protocol-defined events of 
special interest and other safety observations 
Descriptive summary 
statistics and/or listings 
Lab 
Worst post-baseline toxicity grade for selected 
CTCAE gradable hematology and chemistry.  
Abnormalities in creatinine clearance, uric 
acid, and liver function.  
Descriptive summary 
statistics and/or listings. 
For gradable lab results, 
the worst toxicity grade 
during the study will be 
tabulated and the 
summary of treatment-
emergent abnormal 
laboratory results with 2 
or more grade worsening 
will be provided. 
Vital Signs and other 
Observations Related to Safety 
SBP, DBP, heart rate, body temperature, 
weight, and ECOG PS 
The baseline and the 
change from baseline will 
be summarized by 
scheduled visits. 
DLT 
DLT 
Listing   
CTCAE= Common Terminology Criteria for Adverse Events; DLT: dose limiting toxicity; ECOG: Eastern 
Cooperative Oncology Group; TEAE: treatment-emergent adverse event; SAE= serious adverse event; SBP: 
systolic blood pressure; DBP: diastolic blood pressure 
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6 
CHANGES IN PROTOCOL PLANNED ANALYSIS 
Per protocol, an analysis will occur approximately 12 months after the last subject initiates 
study treatment or when all subjects have discontinued from the study treatment, whichever 
occurs first, and will be reported in the Clinical Study Report (CSR).  Since the study results 
were summarized and presented at the American Society of Hematology Annual Meeting 
2019, which was close to the time for that planned analysis, a decision was made to delay the 
clinical study report, which will be prepared at the final follow-up analysis, which will occur 
24 months or 2 years after the last subject has been enrolled. 
 
 
 
 
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Statistical Analysis Plan 
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7 
REFERENCES 
Brookmeyer R., and Crowley J., A Confidence Interval for the Median Survival Time.  
Biometrics, March 1982: 29-41. 
Cheson B.D, Pfistner B, Juweid ME, et al.  Revised Response Criteria for Malignant 
Lymphoma, Journal of Clinical Oncology 2007; 25: 579-586. 
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. 
JCO 2014; 32:3059-3067. 
Collett D. Modeling Survival Data in Medical Research, 2nd Edition, Chapman & Hall CRC, 
2003. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989; 
10:1-10. 
 
 
 
 
 
 
 
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