A Multicenter, Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination With Rituximab Versus Placebo in Combination With Rituximab in Treatment Naïve Subjects With Follicular Lymphoma (PERSPECTIVE)
Phase: PHASE3
Conditions: Follicular Lymphoma
Sponsor: Pharmacyclics LLC.

IMBRUVICA® (ibrutinib) 
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PROTOCOL 
 
TITLE: 
A Multicenter, Randomized, Double-blind, Placebo-controlled 
Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, 
Ibrutinib, in Combination with Rituximab versus Placebo in 
Combination with Rituximab in Treatment Naïve Subjects with 
Follicular Lymphoma 
PROTOCOL NUMBER: 
PCYC-1141-CA 
STUDY DRUG: 
Ibrutinib (PCI-32765) 
IND NUMBER: 
102,688 
EU CT NUMBER: 
2023-507271-21-00 
SPONSOR MEDICAL 
MONITOR: 
 MD 
AbbVie  
Phone: 
 
Email: 
 
SPONSOR: 
Pharmacyclics LLC, an AbbVie company  
1000 Gateway Boulevard 
South San Francisco, CA 94080 
United States of America 
DATE FINAL: 
04 August 2016 
Amendment 1: 
30 January 2018 
Amendment 2: 
10 March 2021 
Amendment 3: 
10 October 2022 
Amendment 4: 
07 February 2023 
Amendment 5: 
10 May 2024 
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/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. 
 
 
 
 
NCT02947347

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PROTOCOL APPROVAL PAGE 
Study Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Phase 
3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in 
Combination with Rituximab versus Placebo in Combination with 
Rituximab in Treatment Naïve Subjects with Follicular Lymphoma 
Study Number: PCYC-1141-CA 
Protocol Date: 04 August 2016 
Amendment 1: 30 January 2018 
Amendment 2:  10 March 2021 
Amendment 3: 10 October 2022 
Amendment 4: 07 February 2023 
Amendment 5: 10 May 2024 
 
I have carefully read Protocol PCYC-1141-CA entitled "A Multicenter, Randomized, Double-
blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, 
Ibrutinib, in Combination with Rituximab versus Placebo in Combination with Rituximab in 
Treatment Naïve Subjects with Follicular Lymphoma.” I agree to conduct this study as outlined 
herein and in compliance with Good Clinical Practices (GCP) and all applicable regulatory 
requirements. Furthermore, I understand that the Sponsor, Pharmacyclics, and the Institutional 
Review Board/Research Ethics Board/Independent Ethics Committee (IRB/REB/IEC) must 
approve any changes to the protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or methods 
of Pharmacyclics. All data pertaining to this study will be provided to Pharmacyclics. The policy 
of Pharmacyclics LLC requires that any presentation or publication of study data by clinical 
Investigators be reviewed by Pharmacyclics, before release, as specified in the protocol. 
 
Principal Investigator's Signature 
Date 
Print Name 
The following Pharmacyclics LLC representative is authorized to sign the protocol and any 
amendments: 
Medical Monitor's Signature 
Date 
 MD  
Imbruvica Global Development, AbbVie 

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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ........................................................................................... 2 
TABLE OF CONTENTS .......................................................................................................... 3 
LIST OF APPENDICES ........................................................................................................... 7 
LIST OF IN-TEXT TABLES AND FIGURES ........................................................................ 8 
SYNOPSIS ................................................................................................................................. 9 
ABBREVIATIONS ................................................................................................................. 18 
1. 
BACKGROUND .................................................................................................... 22 
1.1. 
Follicular Lymphoma............................................................................................... 22 
1.1.1. 
Current Treatment Options....................................................................................... 23 
1.2. 
Ibrutinib Overview................................................................................................... 23 
1.2.1. 
Summary of Nonclinical Data .................................................................................. 24 
1.2.1.1. 
Pharmacology .......................................................................................................... 24 
1.2.1.2. 
Safety Pharmacology and Toxicology ...................................................................... 24 
1.2.2. 
Summary of Clinical Data ........................................................................................ 25 
1.2.2.1. 
Pharmacokinetics and Product Metabolism .............................................................. 25 
1.2.3. 
Summary of Clinical Safety ..................................................................................... 25 
1.2.4. 
Ibrutinib Risks ......................................................................................................... 25 
1.2.4.1. 
Bleeding-related Events ........................................................................................... 25 
1.2.4.2. 
Cardiac Arrhythmias ................................................................................................ 26 
1.2.4.3. 
Cytopenias ............................................................................................................... 26 
1.2.4.4. 
Diarrhea ................................................................................................................... 26 
1.2.4.5. 
Infections ................................................................................................................. 26 
1.2.4.6. 
Interstitial Lung Disease (ILD) ................................................................................ 26 
1.2.4.7. 
Non-Melanoma Skin Cancer .................................................................................... 27 
1.2.4.8. 
Rash ........................................................................................................................ 27 
1.2.4.9. 
Tumor Lysis Syndrome ............................................................................................ 27 
1.3. 
Rituximab Overview ................................................................................................ 27 
1.3.1. 
Summary of Nonclinical Data .................................................................................. 27 
1.3.2. 
Summary of Clinical Safety ..................................................................................... 27 
1.3.2.1. 
Infusion Reactions ................................................................................................... 28 
1.3.2.2. 
Mucocutaneous Reactions ........................................................................................ 28 
1.3.2.3. 
Hepatitis B Reactivation with Fulminant Hepatitis ................................................... 28 
1.3.2.4. 
Progressive Multifocal Leukoencephalopathy .......................................................... 28 
1.3.2.5. 
Tumor Lysis Syndrome ............................................................................................ 29 
1.3.2.6. 
Infections ................................................................................................................. 29 
1.3.2.7. 
Cardiac Disorders .................................................................................................... 29 
1.3.2.8. 
Renal Toxicity ......................................................................................................... 29 
1.3.2.9. 
Bowel Obstruction and Perforation .......................................................................... 29 
1.4. 
Study Rationale ....................................................................................................... 29 
1.4.1. 
Preclinical ................................................................................................................ 29 
1.4.2. 
Study PCYC-04753 ................................................................................................. 30 
1.4.3. 
Study PCYC-1125-CA............................................................................................. 30 
1.4.4. 
Overall Rationale for Study PCYC-1141-CA ........................................................... 31 

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1.4.4.1. 
Study Population and Treatment Rationale ............................................................... 31 
1.4.4.2. 
Dose Selection Rationale ......................................................................................... 33 
2. 
STUDY OBJECTIVE ............................................................................................ 34 
2.1. 
Primary Objective .................................................................................................... 34 
2.2. 
Secondary Objective(s) ............................................................................................ 34 
2.3. 
Exploratory Objective(s) .......................................................................................... 34 
3. 
STUDY DESIGN ................................................................................................... 35 
3.1. 
Overview of Study Design ....................................................................................... 35 
3.2. 
Study Schema .......................................................................................................... 37 
4. 
SUBJECT SELECTION ....................................................................................... 38 
4.1. 
Inclusion Criteria ..................................................................................................... 38 
4.2. 
Exclusion Criteria .................................................................................................... 40 
5. 
TREATMENT OF SUBJECTS ............................................................................. 42 
5.1. 
Treatment Allocation and Blinding .......................................................................... 42 
5.1.1. 
Randomization, Stratification and Placebo Control .................................................. 42 
5.1.2. 
Blinding ................................................................................................................... 43 
5.2. 
Study Treatment ...................................................................................................... 44 
5.2.1. 
Route and Schedule ................................................................................................. 44 
5.3. 
Study Medications ................................................................................................... 44 
5.3.1. 
Ibrutinib/Placebo (Study Drug) ................................................................................ 44 
5.3.1.1. 
Ibrutinib/Placebo: Formulation/Packaging/Storage................................................... 45 
5.3.1.2. 
Ibrutinib/Placebo: Dose and Administration ............................................................. 45 
5.3.1.3. 
Ibrutinib/Placebo: Overdose ..................................................................................... 47 
5.3.1.4. 
Ibrutinib/Placebo: Dose Modification for Ibrutinib/Placebo-Related Adverse 
Reactions ................................................................................................................. 47 
5.3.1.5. 
Ibrutinib/Placebo: Dose Modification for Hepatic Impaired Subjects ....................... 49 
5.3.2. 
Rituximab ................................................................................................................ 49 
5.3.2.1. 
Rituximab: Formulation/Package/Storage ................................................................ 50 
5.3.2.2. 
Rituximab: Dose and Administration ....................................................................... 50 
5.3.2.3. 
Rituximab: Overdose ............................................................................................... 51 
5.3.2.4. 
Rituximab: Dose Modification for Rituximab-Related Adverse Reactions ............... 51 
5.3.2.5. 
Rituximab: Dose Interruption for Infusion-Related Reactions .................................. 53 
5.3.2.6. 
Rituximab: Dose Reduction ..................................................................................... 53 
5.3.2.7. 
Rituximab: Dose Discontinuation ............................................................................ 53 
5.4. 
Study Treatment Compliance ................................................................................... 53 
5.4.1. 
Study Drug (Ibrutinib/Placebo) Compliance............................................................. 53 
5.4.2. 
Rituximab Compliance ............................................................................................ 54 
5.5. 
Criteria for Permanent Discontinuation of Study Treatment ..................................... 54 
5.6. 
Replacement of Subjects .......................................................................................... 54 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES.......................................... 54 
6.1. 
Permitted Concomitant Medications ........................................................................ 54 
6.2. 
Medications to be Used with Caution ....................................................................... 55 
6.2.1. 
CYP3A Inhibitors/Inducers ...................................................................................... 55 
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib ................ 57 
6.2.3. 
Antiplatelet Agents and Anticoagulants ................................................................... 57 

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6.3. 
Prohibited Concomitant Medications ....................................................................... 57 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures ......................... 57 
6.4.1. 
Minor Surgical Procedures ....................................................................................... 58 
6.4.2. 
Major Surgical Procedures ....................................................................................... 58 
6.4.3. 
Emergency Procedures ............................................................................................. 58 
7. 
STUDY EVALUATIONS ...................................................................................... 58 
7.1. 
Description of Procedures ........................................................................................ 58 
7.1.1. 
Assessments ............................................................................................................ 58 
7.1.1.1. 
Informed Consent .................................................................................................... 58 
7.1.1.2. 
Confirm Eligibility................................................................................................... 58 
7.1.1.3. 
Medical History and Demographics ......................................................................... 59 
7.1.1.4. 
Follicular Lymphoma International Prognostic Index-1 (FLIPI-1) ............................ 59 
7.1.1.5. 
Diagnostic Tissue Block(s) or Slides ........................................................................ 59 
7.1.1.6. 
Prior and Concomitant Medications ......................................................................... 59 
7.1.1.7. 
Adverse Events ........................................................................................................ 59 
7.1.1.8. 
Physical Examination............................................................................................... 60 
7.1.1.9. 
Eye-related Symptom Assessment ........................................................................... 60 
7.1.1.10. B-Symptoms ............................................................................................................ 60 
7.1.1.11. ECOG ...................................................................................................................... 60 
7.1.1.12. Vital Signs ............................................................................................................... 61 
7.1.1.13. Patient Reported Outcomes (PRO) ........................................................................... 61 
7.1.2. 
Laboratory ............................................................................................................... 61 
7.1.2.1. 
Hematology ............................................................................................................. 61 
7.1.2.2. 
Chemistry (Serum)................................................................................................... 61 
7.1.2.3. 
Coagulation Studies ................................................................................................. 62 
7.1.2.4. 
Hepatitis Serologies ................................................................................................. 62 
7.1.2.5. 
Urinalysis ................................................................................................................ 62 
7.1.2.6. 
Pregnancy Test ........................................................................................................ 62 
7.1.3. 
Diagnostics/Procedures ............................................................................................ 62 
7.1.3.1. 
Electrocardiograms (ECGs) ..................................................................................... 62 
7.1.3.2. 
Radiographic Imaging Assessments (CT/MRI) ........................................................ 63 
7.1.3.3. 
Positron Emission Tomography (PET) Scan ............................................................ 63 
7.1.3.4. 
Tumor Tissue Biopsy (Optional) .............................................................................. 64 
7.1.3.5. 
Bone Marrow Biopsies and Aspirate for Bone Marrow Involvement ........................ 64 
7.1.3.6. 
Bone Marrow Aspirate and Blood Samples for Minimal Residual Disease 
(MRD) ..................................................................................................................... 64 
7.1.4. 
Pharmacokinetics/Biomarkers .................................................................................. 65 
7.1.4.1. 
Pharmacokinetics ..................................................................................................... 65 
7.1.4.2. 
Exploratory Genetic and Molecular Biomarkers ....................................................... 66 
7.2. 
Efficacy Evaluations ................................................................................................ 66 
7.3. 
Sample Collection and Handling .............................................................................. 67 
7.4. 
COVID-19 Pandemic and Geo-Political Conflict in Ukraine and Surrounding 
Impacted Countries Provisions ................................................................................. 68 
8. 
STUDY PROCEDURES ........................................................................................ 69 
8.1. 
Screening/Consenting Visit ...................................................................................... 69 
8.2. 
Treatment Phase ...................................................................................................... 70 

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8.2.1. 
Treatment Visits ...................................................................................................... 70 
8.2.1.1. 
Cycle 1, Day 1 ......................................................................................................... 70 
8.2.1.2. 
Cycle 1, Day 8 ......................................................................................................... 71 
8.2.1.3. 
Cycle 1, Day 15 ....................................................................................................... 72 
8.2.1.4. 
Cycle 1, Day 22 ....................................................................................................... 72 
8.2.1.5. 
Cycle 2, Day 1 ......................................................................................................... 73 
8.2.1.6. 
Cycle 3, Day 1 ......................................................................................................... 73 
8.2.1.7. 
Cycle 5, Day 1: First Response Evaluation Visit ...................................................... 74 
8.2.1.8. 
Cycles 7  25 (odd cycles only), Day 1 .................................................................... 75 
8.2.1.9. 
Cycles 27 until Treatment Termination (odd cycles only), Day 1 ............................. 75 
8.2.1.10. Response Evaluation Visits ...................................................................................... 76 
8.2.2. 
Suspected PD and/or Treatment Termination Visit ................................................... 77 
8.2.3. 
End of Treatment Safety Follow-up Visit ................................................................. 78 
8.3. 
Follow-up Phase ...................................................................................................... 78 
8.3.1. 
Response Follow-up ................................................................................................ 78 
8.3.2. 
Survival Follow-Up, Subsequent Anticancer Therapy Collection, and Long-term 
Surveillance of Other Malignancies ......................................................................... 79 
8.3.3. 
Missed Evaluations .................................................................................................. 79 
9. 
SUBJECT COMPLETION AND WITHDRAWAL............................................. 79 
9.1. 
Completion .............................................................................................................. 79 
9.2. 
Withdrawal from Study Treatment ........................................................................... 79 
9.3. 
Withdrawal from Study ............................................................................................ 80 
10. 
STATISTICAL METHODS AND ANALYSIS .................................................... 80 
10.1. 
Subject Information ................................................................................................. 80 
10.1.1. 
Intent-to-Treat (ITT) Population .............................................................................. 80 
10.1.2. 
Safety Population ..................................................................................................... 81 
10.1.3. 
Pharmacokinetic Population ..................................................................................... 81 
10.2. 
Endpoints................................................................................................................. 81 
10.2.1. 
Primary Endpoint ..................................................................................................... 81 
10.2.2. 
Secondary Endpoints ............................................................................................... 81 
10.2.3. 
Exploratory Endpoints ............................................................................................. 81 
10.3. 
Sample Size Determination ...................................................................................... 81 
10.4. 
Efficacy Analysis Methods for Primary and Secondary Endpoints ........................... 83 
10.4.1. 
Analysis Study ......................................................................................................... 83 
10.4.1.1. Primary Endpoint PFS ............................................................................................. 83 
10.4.1.2. Secondary Endpoints ORR and OS .......................................................................... 83 
10.5. 
Safety Analysis ........................................................................................................ 84 
10.5.1. 
Adverse Events ........................................................................................................ 84 
10.5.2. 
Clinical Laboratory Tests ......................................................................................... 85 
10.6. 
Analysis Methods for Selected Exploratory Endpoints ............................................. 85 
10.6.1. 
Pharmacokinetic Analysis ........................................................................................ 85 
10.6.2. 
Biomarker Analyses ................................................................................................. 86 
10.6.3. 
Patient-reported Outcomes (PRO) as Measured by FACT-Lym ............................... 86 
10.7. 
Data Monitoring Committee (DMC) ........................................................................ 86 
11. 
ADVERSE EVENT REPORTING ....................................................................... 87 
11.1. 
Definitions ............................................................................................................... 87 

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11.1.1. 
Adverse Events ........................................................................................................ 87 
11.1.2. 
Serious Adverse Events ........................................................................................... 88 
11.1.3. 
Severity Criteria (Grade 1-5) .................................................................................... 88 
11.1.4. 
Causality (Attribution) ............................................................................................. 89 
11.1.5. 
Serious Adverse Reactions and Suspected Unexpected Serious Adverse Reactions .. 89 
11.2. 
Unexpected Adverse Events ..................................................................................... 90 
11.3. 
Special Reporting Situations .................................................................................... 90 
11.4. 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators ............................................................................................................ 90 
11.4.1. 
Assessment of Adverse Events ................................................................................. 90 
11.4.2. 
Adverse Event Reporting Period .............................................................................. 91 
11.4.3. 
Reporting Requirements for Serious Adverse Events ............................................... 91 
11.4.4. 
Pregnancy ................................................................................................................ 92 
11.4.5. 
Other Malignancies .................................................................................................. 93 
11.4.6. 
Eye-Related Adverse Events .................................................................................... 93 
11.4.7. 
Adverse Events of Special Interest (AESI) ............................................................... 93 
11.4.8. 
Major Hemorrhage................................................................................................... 93 
11.4.9. 
COVID-19 Pandemic-Related Provisions for Adverse Event Reporting ................... 94 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ........... 94 
12.1. 
Regulatory and Ethical Compliance ......................................................................... 94 
12.2. 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval ........................................................................... 94 
12.3. 
Informed Consent .................................................................................................... 95 
12.4. 
Quality Control and Quality Assurance .................................................................... 95 
12.5. 
Protected Subject Health Information Authorization ................................................ 95 
12.6. 
Study Files and Record Retention ............................................................................ 96 
12.7. 
Case Report Forms and Record Maintenance ........................................................... 97 
12.8. 
Investigational Study Treatment Accountability ....................................................... 98 
12.9. 
Study Monitoring/Audit Requirements..................................................................... 98 
12.10. 
Investigator Responsibilities .................................................................................... 99 
12.11. 
Sponsor Responsibilities ........................................................................................ 100 
12.12. 
Financial Disclosure .............................................................................................. 100 
12.13. 
Liability and Clinical Trial Insurance ..................................................................... 100 
12.14. 
Protocol Amendments ............................................................................................ 100 
12.15. 
Publication of Study Results .................................................................................. 101 
12.16. 
Study Discontinuation ............................................................................................ 101 
12.17. 
Start-of-Study, End-of-Study, and Study Completion ............................................. 101 
13. 
REFERENCES .................................................................................................... 103 
14. 
APPENDICES ...................................................................................................... 107 
LIST OF APPENDICES 
Appendix A. Schedule of Assessments.................................................................................. 108 
Appendix B. ECOG Performance Status Scores .................................................................... 112 
Appendix C. Inhibitors and Inducers of CYP3A ................................................................... 113 

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Appendix D. Follicular Lymphoma International Prognostic Index-1 .................................... 114 
Appendix E. New York Heart Association (NYHA) Functional Classification ..................... 115 
Appendix F. Child-Pugh Score for Subjects with Liver Impairment...................................... 116 
Appendix G. Revised Criteria for Response Assessment of Malignant Lymphoma 
(Cheson 2014) .................................................................................................. 117 
Appendix H. FACT-Lym (Version 4) ................................................................................... 120 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1. 
The Groupe pour l'Etude de Lymphome Folliculaire (GELF) Criteria ................ 23 
Table 2. 
Treatment, Dose, and Schedule of Administration for Study Treatment .............. 44 
Table 3. 
Study Drug (Ibrutinib/Placebo) Administration .................................................. 46 
Table 4. 
Ibrutinib/Placebo: Study Drug Dose Modifications for Events not Specified 
in Table 5 ........................................................................................................... 48 
Table 5. 
Ibrutinib Dose Modifications for Cardiac Failure or Cardiac Arrhythmias .......... 49 
Table 6. 
Rituximab: Dose Modification for Toxicity ........................................................ 52 
Table 7. 
Pharmacokinetic Sample Schedule for Study Drug (Ibrutinib/Placebo)............... 65 
Table 8. 
Pharmacokinetic Sample Schedule for Rituximab .............................................. 66 
Table 9. 
Futility and Efficacy Boundaries for Interim Analysis for PFS ........................... 82 
Table 10. 
FLIPI-1 Criteria ............................................................................................... 114 
Table 11. 
Criteria for Response Assessment of Non-Hodgkin's Lymphoma ..................... 117 
 
Figures 
Figure 1. 
Study Design...................................................................................................... 35 
 

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SYNOPSIS 
Title: 
A Multicenter, Randomized, Double-blind, Placebo-controlled Phase 3 Study of the 
Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with 
Rituximab versus Placebo in Combination with Rituximab in Treatment Naïve 
Subjects with Follicular Lymphoma 
Protocol 
number: 
PCYC-1141-CA 
Phase: 
3 
Subject 
population: 
Treatment naïve subjects with follicular lymphoma (Grade 1-3A) meeting Groupe 
d'Etude des Lymphomes Folliculaire (GELF) criteria for therapy and are: 70 years 
of age or older or 60-69 years of age with comorbidities (see Inclusion/Exclusion 
criteria for additional details) 
Study drug and 
comparator: 
Study drug: ibrutinib PO hard gelatin capsule in combination with rituximab 
Comparator: placebo PO hard gelatin capsule in combination with rituximab 
Primary 
objective: 
To evaluate whether the addition of ibrutinib to rituximab will result in 
prolongation of progression-free survival (PFS) when compared with rituximab 
alone in treatment naïve subjects with follicular lymphoma. 
Study design: 
This is a randomized, double-blind, placebo-controlled Phase 3 study designed to 
assess the efficacy and safety of ibrutinib in combination with rituximab compared 
to placebo in combination with rituximab in treatment naïve subjects with follicular 
lymphoma. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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Approximately 440 subjects will be enrolled (estimate based on an accrual 
assumption of 30 months). Subjects will be randomized at a 3:1 (Arm A: Arm B) 
ratio. Subjects will be stratified on the basis of: 
• 
Age (60-69 vs. ≥70 years) 
• 
Follicular Lymphoma-specific International Prognostic Index 
(FLIPI)-1 (low vs. intermediate/high), and 
• 
Eastern Cooperative Oncology Group (ECOG) performance 
status score (0/1 vs. 2) 
Subjects randomized to the investigational arm (Arm A) will receive ibrutinib 
560 mg by mouth (PO) (4 capsules) daily until disease progression or unacceptable 
toxicity. Subjects randomized to the control arm (Arm B) will receive placebo PO 
(4 capsules) daily until disease progression or unacceptable toxicity. Primary 
analysis for PFS will be conducted when 200 PFS events are observed, or if pre-
specified boundaries are crossed at an interim analysis. The final analysis for OS 
will be conducted when 165 OS events are observed or five years after enrollment 
of the last subject, whichever is earlier. 
 
Subjects in both arms (Arms A and B) will also receive rituximab 375 mg/m2 
intravenous (IV) once weekly for the first 4 weeks of study treatment (Cycle 1: 
Days 1, 8, 15, and 22). Beginning with Cycle 3, Day 1, rituximab will be given as 
maintenance therapy administered as a single 375 mg/m2 IV dose every 8 weeks for 
up to 12 additional doses (approximately 2 years) or until disease progression or 
unacceptable toxicity, whichever comes first. 
 
A Response Evaluation Visit including local imaging assessments will be 
performed every 16 weeks through Cycle 37 and then every 24 weeks thereafter and 
copies of the images will be stored at a central location for independent review-
based assessment. The details of the analyses will be specified in a separate 
document. Blinded study treatment administration will continue until disease 
progression, unacceptable toxicity or study termination. Subjects who discontinue 
study treatment due to any reason will be followed for OS every 24 weeks. 
Subsequent anticancer therapies, best response to therapy, and information about 
other malignancies will be collected. 

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Inclusion/ 
Exclusion 
Criteria: 
Inclusion Criteria 
Disease-Related 
1. Subjects with histologically documented follicular lymphoma (Grade 1, 2 or 3a) 
according to World Health Organization (WHO) criteria and Ann Arbor 
Stage II, III or IV disease. 
2. At least one two-dimensionally measurable lesion ≥2.0 cm in the longest 
diameter (LDi) by contrast-enhanced CT scan. Lesions in anatomical locations 
(such as extremities or soft tissue lesions) that are not well visualized by CT 
may be measured by MRI instead. 
3. Subjects 70 years of age or older; OR subjects 60-69 years of age who have one 
or more comorbidities that make them a candidate to receive single -agent 
rituximab therapy: 
• 
Creatinine clearance 30-59 mL/min (by Cockcroft-Gault or creatinine 
clearance calculated based on 24-hour urine collection). 
• 
ECOG performance status score of 2 
4. In need of systemic therapy as evidenced by meeting one or more of the 
following Groupe d'Etude des Lymphomes Folliculaire (GELF) criteria 
(Solal-Céligny 1998, Chen 2012): 
• 
Involvement of ≥3 nodal sites, each with a diameter of >3 cm 
• 
Any nodal or extranodal tumor mass with a diameter of >7 cm or risk 
of local compressive symptoms that may result in organ compromise 
• 
B symptoms (ie, fever, night sweats or weight loss) 
• 
Splenomegaly 
• 
Pleural effusions or peritoneal ascites 
• 
Thrombocytopenia (platelet count <100 x 109/L) 
• 
Peripheral blood involvement (>5.0 x 109/L malignant cells) 
Laboratory 
5. Adequate hematologic function defined as: 
• 
Hemoglobin ≥8.0 g/dL  
• 
Platelet count ≥50 x 109/L (50,000 cells/mm3) 
• 
Absolute neutrophil count ≥1.0 x 109/L (1,000 cells/mm3) 
6. Adequate renal and hepatic function defined as: 
• 
Estimated creatinine clearance ≥30 mL/min (Cockcroft-Gault) 
• 
Serum aspartate transaminase (AST) and alanine transaminase (ALT) 
≤3.0 x upper limit of normal (ULN) 
• 
Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome 
such that bilirubin ≤3 x ULN or is of non-hepatic origin) 
7. PT/ INR <1.5 x ULN (unless treated with warfarin or other vitamin K 
antagonists such that INR ≤3.0) and PTT (aPTT) <1.5 x ULN. 
Demographic 
8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2. 

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Ethical/Other 
9. Female subjects of reproductive potential must have a negative urine/serum 
pregnancy test upon study entry. Female subjects who are of nonreproductive 
potential (ie, post-menopausal by history - no menses for ≥1 year; OR history of 
hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral 
oophorectomy) are exempt from pregnancy testing. 
10. Male and female subjects of reproductive potential who agree to use both a 
highly effective method of birth control (eg, implants, injectables, combined 
oral contraceptives, some intrauterine devices [IUDs], complete abstinence1, or 
sterilized partner) and a barrier method (eg, condoms, cervical ring, sponge, etc) 
during the period of therapy. For female subjects, these birth control 
requirements must be adhered to for 90 days after the last dose of 
ibrutinib/placebo and 12 months after the last dose of rituximab, whichever is 
later. For male subjects, these birth control requirements must be adhered to for 
90 days after the last dose of ibrutinib/placebo. 
11. Subjects must not be incarcerated and must be freely willing and able to provide 
informed consent (e.g., adults under legal protection measure [e.g., under 
guardianship/curatorship] or unable to express their consent and select adults 
under psychiatric care). Investigator discretion should be applied.  
Exclusion criteria 
Any potential subject who meets any of the following criteria will be excluded from 
participating in the study. 
Disease-Related 
1. 
Transformed lymphoma; if clinical evidence of transformed lymphoma is 
present (high lactate dehydrogenase [LDH] and/or high maximum standard 
uptake value [SUVmax] of a lymph node/lesion on positron emission 
tomography [PET] scanning, LDH and SUVmax level cut off per investigator's 
clinical judgement), transformation should be ruled out by biopsy of the 
suspicious lymph node/lesion. 
2. Prior treatment for follicular lymphoma (eg, systemic anti-cancer therapy or 
involved site radiotherapy). 
3. Medically apparent central nervous system lymphoma or leptomeningeal 
disease. 
Concurrent conditions 
4. History of other malignancies, except: 
• 
Malignancy treated with curative intent and with no known active disease 
present for ≥3 years before the first dose of study treatment and felt to be at 
low risk for recurrence by treating physician. 
• 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
• 
Adequately treated carcinoma in situ without evidence of disease. 
                                                   
 
1 Complete abstinence is a highly effective method only if defined as refining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and 
the preferred and usual lifestyle of the subject. http://www.hma.eu/fileadmin/dateien/Human Medicines/01 
About HMA/Working Groups/CTFG/2014 09 HMA CTFG Contraception.pdf 

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5. Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, 
tacrolimus, etc., or chronic administration of >20 mg/day of prednisone or 
equivalent) within 28 days of the first dose of study treatment. For indications 
other than lymphoma or management of lymphoma-related symptoms, the 
following are exceptions to this criterion: 
• 
Intranasal, inhaled, topical corticosteroids or local corticosteroid 
injections (eg, intra-articular injection) 
• 
Systemic corticosteroids at doses not to exceed 20 mg/day of 
prednisone or its equivalent 
• 
Corticosteroids as pre-medication for hypersensitivity reactions 
(eg, computed tomography [CT] scan pre-medication) 
6. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of 
study treatment. 
7. Known bleeding disorders (eg, von Willebrand's disease or hemophilia). 
8. History of stroke or intracranial hemorrhage within 6 months prior to 
enrollment. 
9. Known history of human immunodeficiency virus (HIV) or active infection 
with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are 
positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C 
antibody must have a negative polymerase chain reaction (PCR) result before 
enrollment. Those who are PCR positive will be excluded. In equivocal cases, 
hepatitis B or C PCR may be performed and must be negative for enrollment. 
10. Any uncontrolled active systemic infection or recent infection requiring 
intravenous antibiotic treatment that was completed ≤14 days before the first 
dose of study treatment. 
11. Major surgery within 4 weeks of first dose of study treatment. 
12. Any life-threatening illness, medical condition, or organ system dysfunction 
that, in the investigator's opinion, could compromise the subject's safety or put 
the study outcomes at undue risk. 
13. 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 randomization. 

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14. Unable to swallow capsules or malabsorption syndrome, disease significantly 
affecting gastrointestinal function, or resection of the stomach or small bowel, 
symptomatic inflammatory bowel disease or ulcerative colitis, or partial or 
complete bowel obstruction. 
15. Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to 
any component of rituximab.  
16. Prior use of an anti-CD20 agent or an inhibitor of Bruton's tyrosine kinase 
(BTK) (eg, rituximab, ibrutinib). (NOTE: use of any prior treatment for 
follicular lymphoma is not permitted per protocol) 
17. Any investigational drug within 4 weeks prior to randomization or concurrent 
enrollment in another therapeutic investigational clinical treatment study. 
18. Subject who received systemic administration of a strong cytochrome 
P-450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or 
subject who requires continuous treatment with a strong CYP3A inhibitor 
(see Appendix D). 
19. Currently active, clinically significant hepatic impairment Child-Pugh class B 
or C according to the Child Pugh classification (see Appendix G). 
20. Lactating or pregnant. 
21. Unwilling or unable to participate in all required study evaluations and 
procedures.  
22. 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). 
Endpoints: 
Primary Endpoint 
• 
Progression-free survival (PFS)  
Secondary Endpoints 
• 
Overall response rate (ORR) (Cheson 2014) 
• 
Overall Survival (OS) 
• 
Infusion-related reaction rate (Arm A vs. Arm B) 
• 
Duration of response (DOR) as assessed by investigator 
• 
Frequency, severity, seriousness, and relatedness of adverse events (AEs)  
Exploratory Endpoints 
• 
Health-related quality of life (QOL) as measured by the Functional Assessment of 
Cancer Therapy- Lymphoma (FACT- Lym)  
• 
Pharmacokinetic parameters or metrics of systemic exposure of ibrutinib and rituximab 
• 
Evaluation and/or identification of relevant patient populations defined by biomarker(s)  
Minimal residual disease (MRD)-negative rate defined as the proportion of follicular 
lymphoma subjects who achieve a CR and who reach MRD-negative disease status 
• 
Complete response rate at 30 months (CR30) as defined by the International Working 
Group (IWG) Revised Response Criteria for Malignant Lymphoma (Cheson 2014) 

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Study 
treatment: 
Subjects randomized to the investigational arm (Arm A) will receive ibrutinib 
560 mg PO daily continuously in combination with rituximab 375 mg/m2 IV once 
weekly for the first 4 weeks of study treatment (Cycle 1: Days 1, 8, 15, and 22) and 
as maintenance therapy beginning Cycle 3, Day 1 given as a single dose of 
375 mg/m2 IV every 8 weeks for up to 12 additional doses (approximately 2 years). 
In the control arm (Arm B) subjects will receive placebo PO daily continuously in 
combination with rituximab 375 mg/m2 IV once weekly for the first 4 weeks of 
study treatment (Cycle 1: Days 1, 8, 15, and 22), and as maintenance therapy 
beginning with Cycle 3, Day 1 given as a single dose of 375 mg/m2 IV every 
8 weeks up to 12 additional doses (approximately 2 years). Rituximab is not given 
in Arms A and B in Cycle 2 unless as specified in Section 5.3.2. 
Administration of study treatment will continue until disease progression or 
unacceptable toxicity. Subjects who discontinue study treatment in the absence of 
disease progression will continue to be followed for response. Subjects who 
discontinue study treatment, due to any reason and have not withdrawn consent for 
follow up, will be followed for overall survival. Subsequent anticancer therapies, 
best response to therapy, and information about other malignancies will be 
collected. 
Select 
Concomitant 
therapy: 
Permitted Concomitant Therapy 
Antiemetics are permitted if clinically indicated. Standard supportive care 
medications are permitted including prophylaxis for infusion-related reactions. 
Corticosteroids for non-cancer-related medical reasons at doses equivalent to 
≤ 20 mg per day or its equivalent are permitted. Corticosteroids as pre-medication 
for hypersensitivity reactions (eg, CT scan pre-medication) are also permitted. Short 
courses (< 14 days) of corticosteroid treatment for non-cancer-related medical 
reasons (eg, asthma, rash, etc.) at doses that do not exceed 100 mg per day of 
prednisone or equivalent are permitted. Corticosteroid treatment courses of 14 days 
or more may be considered after consultation with the Medical Monitor. For 
purposes of premedication or management of rituximab infusion reactions only, 
100 mg of prednisone (or its equivalent) treatment per day may be exceeded. 
Prohibited Concomitant Therapy 
Any chemotherapy, anti-cancer immunotherapy, corticosteroids (used for cancer-
related medical reasons) or corticosteroids for non–cancer-related medical reasons 
at doses >20 mg/day of prednisone or equivalent for 14 days or more, (unless 
approved by Medical Monitor), experimental therapy, and radiotherapy are 
prohibited while the subject is receiving ibrutinib/placebo. 

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Statistical 
methods: 
This study evaluates ibrutinib + rituximab (Arm A) vs. placebo + rituximab 
(Arm B) with 2 interim analyses planned and a primary analysis for PFS when the 
study observes 200 PFS events, or if pre-specified boundaries are crossed at an 
interim analysis. The final analysis for OS is planned when 165 OS events are 
observed or five years after enrollment of the last subject, whichever is earlier. 
Statistical Analysis: 
Primary Analysis of PFS 
Progression Free Survival, as assessed by the investigator, will be analyzed in the 
intent-to-treat (ITT) population, comparing the 2 treatment arms at an overall 
1-sided 0.025 significance level using a log-rank test stratified by the randomization 
factors including age (60-69, ≥70 years), FLIPI-1 score and ECOG performance 
status score. Two interim analyses are planned. First interim analysis will be 
conducted for futility when approximately 55% of the 200 PFS events have 
occurred. The second interim analysis will be carried out for efficacy when 
approximately 75% of the PFS events have occurred and after the last subject has 
been enrolled, with approximately 90% of the subjects reaching at least 1 year of 
study follow-up. Kaplan-Meier (KM) estimates for PFS will be summarized by 
treatment arm. The estimate of the hazard ratio and its corresponding 95% 
confidence interval (CI) will be computed using a Cox proportional hazards model 
stratified by the age group, FLIPI-1 score, and ECOG performance status score. 
ORR and OS: 
These two secondary endpoints will be tested sequentially with ORR ranked first 
followed by OS, once the primary analysis of PFS has demonstrated statistical 
significance. Details will be specified in the SAP. ORR in the two treatment arms 
will be compared using the Cochran-Mantel-Haenszel (CMH) chi-square test, 
stratified by the age group, FLIPI-1 score, and ECOG performance status score. The 
OS analysis will use the same statistical method as defined for PFS. 
 
Safety Analysis: 
Details of safety data (AEs, clinical laboratory tests and other safety endpoints) will 
be summarized by treatments that subjects in the Safety population actually receive. 
Safety plan: 
This study will be monitored by an independent Data Monitoring Committee 
(DMC) and in accordance with the Sponsor's Pharmacovigilance procedures. 
An independent DMC of at least 2 medical experts in the relevant therapeutic area 
and at least 1 statistician will be established to monitor unblinded data on an 
ongoing basis to ensure the safety of the subjects enrolled in this study. At least 
three safety review meetings are planned that will occur approximately 1 month 
after 88 subjects have been randomized (20% of expected enrollment), 1 month 
after 220 subjects have been randomized (50% of expected enrollment), and 
1 month after all subjects have been randomized. The safety review will focus on 
deaths, treatment discontinuations, serious adverse events, Grade ≥3 events, and 
events of special interest. Based on the results from these scheduled safety review 
meetings, the DMC chair may request additional safety interim analyses and more 
frequent monitoring. Two interim analyses are planned and both will be performed 
by the DMC as described below. The plan for monitoring subject safety and the 
roles and responsibilities of the DMC will be detailed in the DMC Charter.  

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Interim 
analysis: 
An interim futility analysis will be conducted when approximately 55% of the 
200 PFS events have occurred., An interim efficacy analysis will be carried out for 
PFS with a separate futility assessment for OS when approximately 75% of the 
200 PFS events have occurred and after the last subject has been enrolled with 
approximately 90% of the subjects reaching at least 1 year of study follow-up. An 
interim efficacy analysis for OS will be conducted when 200 PFS events have 
occurred. 
Sample size 
determination: 
Approximately 440 subjects will be randomized into 2 groups (Arms A, and B) at a 
3:1 (Arm A: Arm B) ratio. 
A sample size of approximately 440 subjects will be randomized to Arms A and B 
to evaluate whether Arm A will result in prolongation of PFS when compared to 
Arm B in treatment naïve subjects with follicular lymphoma. The sample size is 
determined according to the Group Sequential Design. For this calculation, the 
references used for the assumptions were Hainsworth 2002, Ghielmini 2004, 
Zucca 2019, and Fowler 2020. Assuming exponential survival distribution for the 
PFS events and 66.7% improvement in median PFS of Arm A over Arm B (a 
hazard ratio [HR] of 0.60), the study has ~ 87% power with 200 observed PFS 
events using an overall 1-sided significance level of 0.025. 
Two interim analyses are planned. The first interim analysis (IA1) of futility will be 
conducted when approximately 55% of the 200 PFS events have occurred. The 
second interim analysis (IA2) for efficacy is planned after approximately 75% of 
the 200 events (150 PFS events) are observed and after the last subject has been 
enrolled. The futility boundary is based on a Rho parameter of 5 and the efficacy 
boundary is based on the unequally weighted Bonferroni method allocating 1-sided 
alpha of 0.001 to IA2 and 0.024 to primary analysis (PA). 
 

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ABBREVIATIONS 
AE  
adverse event  
AESI 
Adverse Events of Special Interest 
ALT  
alanine aminotransferase  
ANC 
absolute neutrophil count  
anti-HBc 
antibody to hepatitis B core antigen 
anti-HBs 
antibody to hepatitis B surface antigen 
ASCO 
American Society of Clinical Oncology 
AST  
aspartate aminotransferase  
AUC 
area under the concentration-time curve 
BCL-2 
B-cell lymphoma 
BCR  
B-cell receptor  
BTK  
Bruton's tyrosine kinase  
BR 
bendamustine and rituximab 
BUN 
blood urea nitrogen 
CLL 
chronic lymphocytic leukemia  
CMH 
Cochran-Mantel-Haenszel 
COVID–19 
Coronavirus Disease – 2019 
CR  
complete response  
CR30 
complete response rate at 30 months 
CrCl 
creatinine clearance 
CRF 
case report form (paper or electronic as appropriate for this study) 
CT 
computed tomography 
CTCAE 
NCI Common Terminology Criteria for Adverse Events  
CYP  
cytochrome P450 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
DSUR 
Development safety update report 
DTP 
Direct-to-patient 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMR 
electronic medical record 
ESMO 
European Society of Medical Oncology 
EU 
European Union 
FACT-G 
Functional Assessment of Cancer Therapy - General 
FACT-Lym 
Functional Assessment of Cancer Therapy - Lymphoma 

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FDA 
Food and Drug Administration 
FCR 
fludarabine, cyclophosphamide, and rituximab 
FDG 
fluorodeoxyglucose 
FFPE 
formalin-fixed, paraffin-embedded 
FL 
follicular lymphoma 
FLIPI 
Follicular Lymphoma International Prognostic Index 
GCP 
Good Clinical Practice 
GELA 
Group d'Etude des Lymphomes de l'Adulte  
GELF 
Group d'Etude des Lymphomes Folliculaire 
GI 
gastrointestinal 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV  
hepatitis C virus 
HIV 
human immunodeficiency virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
IB 
Investigator's Brochure 
IBR 
ibrutinib 
IC50  
concentration that inhibits a process by 50% 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IIA 
Investigator Information and Agreement 
ILD 
interstitial lung disease 
IMP 
Investigational medicinal product 
INR 
International normal ratio 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IUD 
intrauterine device 
IV 
intravenous 
IWG 
International Working Group 
IXRS 
interactive voice and web response system 
KM 
Kaplan-Meier  
LDH 
lactate dehydrogenase 
LDi 
longest diameter 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 

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MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin's lymphoma 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression free survival 
P-gp 
P-glycoprotein 
PI 
prescribing information 
PK 
pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy 
PO 
per os; by mouth 
PR  
partial response  
PRO 
patient-reported outcome(s) 
(a)PTT 
(activated) partial thromboplastin time 
PT 
prothrombin time  
QOL 
Quality of life 
R-CHOP 
rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone 
SAE  
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
REB 
Research Ethics Board 
SAR 
Serious Adverse Reaction 
SLL 
small lymphocytic lymphoma  
SmPC 
Summary of Product Characteristics 
SPD 
sum of the product of the greatest diameters 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUVmax 
maximum standard uptake value 
t1/2 
half-life 
Tmax 
time to maximum plasma concentration  
TEAE 
treatment-emergent adverse event 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
US  
United States 

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USPI 
United States Prescribing Information 
WHO 
World Health Organization 
 

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1. 
BACKGROUND 
1.1. 
Follicular Lymphoma 
Follicular lymphoma (FL) is one of the most common types of Non-Hodgkin's Lymphoma 
(NHL) accounting for approximately 22% of cases and for about 70% of indolent lymphomas 
(Dreyling 2014). Follicular lymphoma is characterized by an indolent clinical course, typical 
morphology, and the presence of a chromosomal translocation, t(14;18)(q32;q21) or variant in 
85% of patients (Relander 2010), which can result in the overexpression of the BCL-2 protein, a 
member of a family of proteins that blocks apoptosis. The overall incidence of B-cell lymphoid 
neoplasms in the United States (US) is estimated at 26.13/100,000 person-years (Morton 2006), 
with FL accounting for 3.18 new cases per 100,000 persons each year in the US and 5 to 7 new 
cases per 100,000 persons each year in the European Union (EU) (Dreyling 2014). The 
neoplastic lymphocytes in FL express pan-B markers CD19, CD20, CD22, and CD79a; as well 
as antigens of the germinal center (including CD10 and BCL-6). Histologically, the follicular 
form of NHL is composed mainly of centrocytes with an admixture of centroblasts. Grading is 
based on the number of large transformed cells in 10 malignant follicles viewed at high power 
(Martinez 2007). Follicular lymphoma is generally subdivided into 3 grades (Freedman 2014). 
However, Grade 3 is often further divided into 2 subgroups, 3a and 3b; with 3b considered more 
aggressive (Hans 2003). 
Follicular lymphoma is diagnosed at a median age of 60 years with the majority of patients 
diagnosed at advanced stages of III and IV (Freedman 2014). Since FL is slow growing, it may 
take years for the disease to progress, during which time treatment may not be necessary. The 
indications for treatment often include the presence of symptomatic disease including 
B symptoms (fevers, night sweats, and weight loss), bulky lymphadenopathy or splenomegaly or 
both, compromise of normal organ function, the presence of cytopenias resulting from bone 
marrow involvement, or rapid disease progression (Freedman 2014; Gribben 2007). 
The Groupe pour l'Etude de Lymphome Folliculaire (GELF) criteria have been developed from 
studies of the Groupe d'Etude des Lymphomes de l'Adulte (GELA) (Solal-Céligny 1998, 
Solal-Céligny 1993, Chen 2012) to evaluate risk factors and determine indications for initiating 
therapy in patients with treatment naïve FL Grade 1, 2 or 3a. The GELF criteria consider the 
number of involved nodal sites, diameter of nodal or extranodal tumor mass, presence of 
B symptoms, splenomegaly, pleural effusions/ascites, cytopenias, and presence of malignant 
cells in the peripheral blood. The presence of just one of the criteria (Table 1) justifies initiation 
of therapy (Férme 2005) since these factors are thought to represent clinically significant disease 
burden. 

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Table 1. 
The Groupe pour l'Etude de Lymphome Folliculaire (GELF) Criteria 
GELF criteria 
Involvement of ≥ 3 nodal sites, each with a diameter of >3 cm 
Any nodal or extranodal tumor mass with a diameter of >7 cm or risk of local compressive symptoms 
that may result in organ compromise 
B symptoms 
Splenomegaly 
Pleural effusions or peritoneal ascites 
Cytopenias (leukocytes <1.0 x 109/L and/or platelets <100 x 109/L) 
Leukemia (>5.0 x 109/L circulating malignant cells) 
From: GELF criteria: A guide for the need for treatment of indolent lymphoma (Solal Céligny 1993, Chen 2012). 
 
While the indications for treatment are based on GELF criteria, the choice of agent(s) depends on 
stage of disease as well as age and co-morbidities. Notably, the introduction of monoclonal 
antibodies, and of rituximab in particular, into FL therapy has resulted in substantial 
improvement in clinical outcomes (NCCN 2020, Dreyling 2014, Salles 2010). 
1.1.1. 
Current Treatment Options 
Treatment guidelines provided by both the National Comprehensive Cancer Network (NCCN) 
(NCCN 2020) and the European Society for Medical Oncology (ESMO) (Dreyling 2014) 
provide similar evidence-based recommendations for standard first-line and consolidation 
therapy for patients with advanced stage FL. These recommendations include rituximab with or 
without chemotherapy or radioimmunotherapy (NCCN 2020; Dreyling 2014). For additional 
information on treatments, tolerability, and clinical outcomes in FL please refer to Section 1.4. 
1.2. 
Ibrutinib Overview 
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 including 
treatment of patients with mantle cell lymphoma (MCL) who have received at least 1 prior 
therapy, patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma 
(SLL), including CLL with a deletion of the short arm of chromosome 17 (del17p), patients with 
Waldenström's macroglobulinemia, patients with Marginal Zone Lymphoma (MZL) who require 
systemic therapy and have received at least one prior anti-CD20-based therapy and for patients 

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with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic 
therapy.  
For the most up to date and comprehensive nonclinical and clinical information regarding 
ibrutinib background, safety, in vitro and in vivo preclinical activity, and toxicology of ibrutinib, 
refer to the latest version of the ibrutinib Investigator's Brochure (IB) and/or the applicable 
regional labeling information. 
1.2.1. 
Summary of Nonclinical Data  
1.2.1.1. 
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. 
1.2.1.2. 
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. 
For the most comprehensive information regarding nonclinical safety pharmacology and 
toxicology, please refer to the current ibrutinib IB. 

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1.2.2. 
Summary of Clinical Data 
For the most comprehensive clinical information regarding ibrutinib, please refer to the current 
version of the ibrutinib IB. 
1.2.2.1. 
Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased proportionally to increasing doses 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 on pharmacokinetics (PK) and ibrutinib metabolism, please refer to the current 
version of the ibrutinib IB. 
1.2.3. 
Summary of Clinical Safety 
For 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, Imbruvica® US Prescribing Information [USPI], 
Imbruvica® Summary of Product Characteristics [SmPC]). 
1.2.4. 
Ibrutinib Risks  
For more comprehensive risk information please refer to the current version of the ibrutinib IB 
and/or the applicable regional labeling information. 
1.2.4.1. 
Bleeding-related Events 
There have been reports of hemorrhagic events in patients treated with ibrutinib, both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, epistaxis, 
and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria. Use of ibrutinib in patients requiring other 

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anticoagulants or medications that inhibit platelet function may increase the risk of bleeding. 
Patients with congenital bleeding diathesis have not been studied. See Section 6.2.3 for guidance 
on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See Section 6.4 
for guidance on ibrutinib management with surgeries or procedures.  
1.2.4.2. 
Cardiac Arrhythmias 
Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia including some fatal 
events, have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac 
risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmia. 
Periodically monitor subjects clinically for cardiac arrhythmia. Subjects who develop arrhythmic 
symptoms (eg, palpitations, lightheadedness, syncope, chest discomfort or new onset of dyspnea) 
should be evaluated clinically and, if indicated, have an ECG performed. For cardiac arrhythmias 
which persist, consider the risks and benefits of ibrutinib treatment and follow the dose 
modification guidelines (see Section 5.3.1.4). 
1.2.4.3. 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in patients treated with ibrutinib.  
1.2.4.4. 
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 5.3.1.4). 
1.2.4.5. 
Infections  
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects 
treated with ibrutinib therapy. Some of these infections have been associated with hospitalization 
and death. Consider prophylaxis according to standard of care in subjects who are at increased 
risk for opportunistic infections. Although causality has not been established, cases of 
progressive multifocal leukoencephalopathy and hepatitis B reactivation have occurred in 
subjects treated with ibrutinib. Cases of hepatitis E, which may be chronic, have occurred in 
patients treated with ibrutinib. Subjects should be monitored for signs and symptoms (such as 
fever, chills, weakness, confusion, vomiting and jaundice, and abnormal liver function tests) and 
appropriate therapy should be instituted as indicated. 
1.2.4.6. 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in patients treated with ibrutinib. 
Monitor patients for pulmonary symptoms indicative of ILD. Should symptoms develop follow 
the protocol dose modification guidelines (see Section 5.3.1.4). 

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1.2.4.7. 
Non-Melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in patients treated with ibrutinib. Monitor subjects 
for the appearance of non-melanoma skin cancer. 
1.2.4.8. 
Rash 
Rash has been commonly reported in patients 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. 
1.2.4.9. 
Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in patients treated with single- 
agent ibrutinib or in combination with chemotherapy. Patients at risk of TLS are those with 
comorbidities and/or risk factors such as high tumor burden prior to treatment, increased uric 
acid (hyperuricemia), elevated lactate dehydrogenase (LDH), bulky disease at baseline, and pre-
existing kidney abnormalities.  
1.3. 
Rituximab Overview 
1.3.1. 
Summary of Nonclinical Data 
Rituximab (Rituxan®, Mabthera®) is a chimeric murine/human monoclonal antibody that is 
directed specifically against the B-cell antigen CD20 (Tedder and Engel 1994). In preclinical 
studies, rituximab was shown to induce both complement-mediated and antibody-dependent, cell 
mediated lysis of CD20+ cells (Reff 1994). Rituximab also induces apoptosis in vitro and 
sensitizes drug-resistant human B-cell lymphoma cell lines to the cytotoxic effects of some 
chemotherapeutic agents (Maloney 1996, Demidem 1996). 
1.3.2. 
Summary of Clinical Safety 
In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias 
were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), 
leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of 
lymphopenia was 14 days (range, 1-588 days) and of neutropenia was 13 days (range,  
2-116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two 
occurrences of hemolytic anemia following rituximab therapy occurred during the single-arm 
studies. In studies of monotherapy, rituximab-induced B-cell depletion occurred in 70% to 80% 
of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients 
(Rituxan® USPI 2021). 
Specific safety considerations regarding the use of rituximab detailed in the rituximab regional 
prescribing information are described below (MabThera® SmPC 2023, Rituxan® USPI 2021). 

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1.3.2.1. 
Infusion Reactions 
Rituximab can cause severe, including fatal, infusion reactions. Severe reactions typically 
occurred during the first infusion with time to onset of 30-120 minutes. Rituximab-induced 
infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, 
bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, 
ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate patients 
with an antihistamine and acetaminophen prior to dosing. 
In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, 
pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, 
dizziness, or hypertension occurred during the first rituximab infusion. Infusion reactions 
typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with 
slowing or interruption of the rituximab infusion and with supportive care (diphenhydramine, 
acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during 
the first infusion (77%) and decreased with each subsequent infusion. 
1.3.2.2. 
Mucocutaneous Reactions 
Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab.  
These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid 
dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these 
reactions has been variable and includes reports with onset on the first day of rituximab exposure. 
1.3.2.3. 
Hepatitis B Reactivation with Fulminant Hepatitis 
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic 
failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic 
antibodies, including rituximab. Cases have been reported in patients who are hepatitis B surface 
antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core 
antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have 
resolved hepatitis B infection (ie, HBsAg negative, anti-HBc positive and hepatitis B surface 
antibody [anti-HBs] positive). 
1.3.2.4. 
Progressive Multifocal Leukoencephalopathy 
John Cunningham virus (JCV) infection resulting in PML and death can occur in rituximab-
treated patients with hematologic malignancies or with autoimmune diseases. The majority of 
patients with hematologic malignancies diagnosed with PML received rituximab in combination 
with chemotherapy or as part of a hematopoietic stem cell transplant. 

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1.3.2.5. 
Tumor Lysis Syndrome 
Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from 
tumor lysis, some fatal, can occur within 12-24 hours after the first infusion of rituximab in 
patients with NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor 
burden confers a greater risk of TLS. 
1.3.2.6. 
Infections 
Serious infections, including fatalities, can occur during therapy with rituximab. Serious 
infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with 
NHL in the single-arm studies.  
1.3.2.7. 
Cardiac Disorders 
Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac 
monitoring during and after all infusions of rituximab for patients who develop clinically 
significant arrhythmias, or who have a history of arrhythmia or angina. 
1.3.2.8. 
Renal Toxicity 
Severe, including fatal, renal toxicity can occur after rituximab administration in patients with 
NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in 
patients with NHL administered concomitant cisplatin therapy during clinical trials. Monitor 
closely for signs of renal failure and discontinue rituximab in patients with a rising serum 
creatinine or oliguria. 
1.3.2.9. 
Bowel Obstruction and Perforation 
Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in 
patients receiving rituximab in combination with chemotherapy. In postmarketing reports, the 
mean time to documented gastrointestinal perforation was 6 (range 1-77) days in patients with 
NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur. 
For additional clinical safety information for rituximab, please refer to the current regional 
prescribing information.  
1.4. 
Study Rationale 
1.4.1. 
Preclinical  
Bruton's Tyrosine Kinase is a central mediator of BCR signaling and is essential for normal 
B-cell development. Aberrant signaling of the B-cell receptor pathway has been linked to the 
development and maintenance of B-cell malignancies. Subtypes of NHL may be dependent on 
chronic activation of the BCR pathway and primary FL cells have been found to maintain 
enhanced signaling when compared to normal B-cells (Irish 2006). 

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1.4.2. 
Study PCYC-04753 
Because of the central role of BCR signaling, the restricted expression of BTK within 
B lymphocytes, and promising preclinical activity, ibrutinib was evaluated in study 
PCYC-04753, a first-in-human, Phase 1, dose-escalating study of ibrutinib in subjects with 
recurrent B-cell lymphoma including NHL, CLL, FL, MCL, and WM (Advani 2013). 
Five sequential cohorts of subjects received ibrutinib from 1.25 to 12.5 mg/kg/day for 28 days of 
a 35-day cycle and 2 additional cohorts received a continuous ibrutinib dose of 8.3 mg/kg/day or 
a 560-mg fixed dose. Sixty-six (66) subjects were enrolled including 16 subjects with FL. Of the 
16 subjects with FL, 13 (81.5%) were evaluable for response. The ORR for these 13 subjects was 
46%, with 3 complete responses (CR, 23.1%) and 3 partial responses (PR, 23.1%). Four (30.8%) 
of the seven remaining subjects had stable disease (SD). The most common AEs (>20% of 
subjects) in this population were diarrhea, nausea/vomiting, fatigue, muscle spasms/myalgia, 
cough, decreased appetite and pyrexia (Advani 2013). Subjects with stable disease or better, who 
received therapy for 6 months, continued ibrutinib at a fixed dose of 560 mg/day in the extension 
study (PCYC-1103-CA) until progression or unacceptable toxicity.  
1.4.3. 
Study PCYC-1125-CA 
Study PCYC-1125-CA was an open-label, multicenter Phase 2 study designed to assess the 
efficacy and safety of ibrutinib combined with rituximab in treatment naïve subjects with FL 
(ClinicalTrials.gov identifier NCT01980654). The study was fully enrolled with 80 subjects in 
two separate treatment arms with 61 subjects in the main clinical study arm (Arm 1) (60 received 
study drug) and 20 subjects in the exploratory biomarker study arm (Arm 2) (Fowler 2020). Arm 
2 used a different dosing regimen than the main study arm and was designed to explore 
biomarkers that may predict sensitivity or resistance to ibrutinib.  
This phase 2 study evaluated the activity and safety of ibrutinib plus rituximab in adults with 
previously untreated FL. Patients received once-daily ibrutinib 560 mg continuously plus once-
weekly rituximab 375 mg/m2 for 4 weeks beginning Week 1 (Arm 1, n  60) or Week 9 
(following an 8-week ibrutinib lead-in) to explore biomarkers (Arm 2, n  20). The primary 
endpoint was the best overall response rate (ORR). The median age was 58 years; most had an 
ECOG Performance Status of 0 (74%) and Stage III/IV disease (84%). At a median study follow-
up of 34 months in Arm 1 and 29 months in Arm 2, ORRs were 85% [95% confidence interval 
(CI) 73 93] and 75% (95% CI 51 91), respectively, with complete responses in 40% and 50%. 
The median duration of response was not reached in either arm; 30-month progression-free and 
overall survival rates were 67% and 97% (Arm 1) and 65% and 100% (Arm 2). The most 
common adverse events were fatigue, diarrhoea and nausea. Higher grade (Grade 3 or 4) 
haematological, haemorrhagic and cardiac events occurred infrequently. Ibrutinib plus rituximab 
was active and tolerable in first-line follicular lymphoma (Fowler 2020). 
In conclusion, the combination of ibrutinib with four weekly infusions of rituximab 
demonstrated clinical activity and durable responses in first-line FL. This combination was well 

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tolerated, with a manageable overall safety profile consistent with those of single-agent ibrutinib 
or rituximab (Fowler 2020).  
1.4.4. 
Overall Rationale for Study PCYC-1141-CA 
Despite the improvements in the treatment of FL, the disease remains incurable; thus, there is a 
continued need to optimize treatment outcomes. Given the toxicity seen with standard 
combination treatment regimens in patients who are elderly or infirm, an initial chemotherapy-
free regimen such as rituximab and ibrutinib may be an attractive treatment option if found to be 
well tolerated and to have significant anti-tumor activity. Data from clinical trials in high-risk 
CLL and MCL have shown that the combination of ibrutinib and rituximab has a favorable 
safety profile with enhanced efficacy (Burger 2014, Wang 2014). The clinical efficacy and 
tolerability observed in the Phase 2 study of ibrutinib in combination with rituximab in treatment 
naïve FL (PCYC-1125-CA) serves as the basis for study PCYC-1141-CA, a randomized, double-
blind, placebo-controlled, multicenter Phase 3 study to evaluate the efficacy and safety of 
ibrutinib in combination with rituximab versus placebo in combination with rituximab in 
treatment naïve subjects with FL. 
To date, ibrutinib administration in an indolent lymphoma setting has been daily treatment until 
disease progression.  
1.4.4.1. 
Study Population and Treatment Rationale 
Treatment guidelines provided by both the National Comprehensive Cancer Network (NCCN) 
(NCCN 2020) and the European Society for Medical Oncology (ESMO) (Dreyling 2014) 
provide similar evidence-based recommendations for standard first-line and maintenance therapy 
for patients with advanced-stage FL. These recommendations include rituximab with or without 
chemotherapy, or radio-immunotherapy (NCCN 2020; Dreyling 2014). In the treatment naïve 
population, rituximab-based chemo-immunotherapy regimens have demonstrated overall 
response rates in excess of 85% with complete remissions in the range of 20-60% with 
subsequent periods of median progression-free survival exceeding 4 to 5 years (Rummel 2012, 
Marcus 2007, Czuczman 2005, Hiddemann 2005, Peterson 2003) when administered to a 
population with a median age less than 65 years with good performance status (Flinn 2014, 
Rummel 2013, Salles 2010). To date, no comparative randomized studies have shown superiority 
of one chemo-immunotherapy regimen over another with regards to overall survival outcomes. 
Addition of rituximab as maintenance treatment improves the response rate and disease-free 
interval (Salles 2010; Hainsworth 2003, Colombat 2001). 
Data are available to support a comparable survival advantage for older patients whose initial 
therapy is less intense, such as with rituximab monotherapy (Casulo 2015). Age-defined, risk-
factor adjusted, subgroup analyses conducted using a prospective, multicenter registry that 
enrolled 2,652 FL patients from 2004 to 2007 (the National LymphoCare Study) have shown no 
difference in overall survival (OS) among patients 71-80 and >80 years of age who received 
rituximab monotherapy compared to those who received rituximab plus chemotherapy 

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(Casulo 2015). In the cohort of patients 61-70 years of age, representing approximately 25% of 
the study population (Nabhan 2012), the overall survival appears to favor rituximab 
monotherapy in the front-line setting (Casulo 2015).  
PFS was similar between the cohorts of patients 71-80 and >80 years of age who received 
rituximab plus chemotherapy compared to rituximab monotherapy. Among the cohort of patients 
61-70 years of age, there was a trend toward improved PFS outcomes with rituximab plus 
chemotherapy compared to rituximab monotherapy (Casulo 2015). Overall, the efficacy findings 
in this study regarding PFS and OS support the use of rituximab monotherapy followed by 
maintenance as a reasonable treatment option for patients 60 years of age and older. 
Clinical practice guidelines acknowledge that chemo-immunotherapy regimens may not be 
tolerable for all patients. Patients 60-69 years of age with diminished performance status 
(eg, ECOG 2) or decreased renal function are at risk of toxicity and have inferior outcomes on 
standard chemo-immunotherapy regimens (Beumer 2016, Fischer 2012, Hurria 2005). For 
elderly or infirm (for whom the aforementioned regimens are not expected to be tolerable in the 
opinion of the treating physician), rituximab monotherapy is a preferred choice over single-agent 
alkylators with or without rituximab in part due to the lower rates of nonhematologic and 
hematologic toxicity (NCCN 2020). Rituximab monotherapy has significant clinical activity in 
treatment naïve patients with indolent NHL with response rates of 47-73% in newly diagnosed 
FL following four weekly doses of 375 mg/m2 (Hainsworth 2002, Colombat 2001). Additional 
exposure to rituximab as maintenance therapy given at a dose of 375 mg/m2 weekly for four 
weeks every six months, further improves response rates and complete remission rates with a 
median PFS following the addition of maintenance rituximab dosing reaching 34 months 
(Hainsworth 2002). Similarly, rituximab maintenance given at a dose of 375 mg/m2 every 
2 months for four doses resulted in a median event-free survival of 36 months (Ghielmini 2004).  
Treatment with maintenance rituximab after a response to induction therapy appears to be an 
effective and tolerable approach for extending the duration of disease remission including event-
free and progression-free survival. Various dosing schedules for maintenance treatment have 
been investigated including a single dose given every 2 or 3 months and once-weekly dosing for 
4 weeks every 6 months for up to 2 years following induction therapy. In a meta-analysis of all 
randomized trials, similar improvements in response were seen regardless of the maintenance 
schedule used with no one regimen being clearly superior (Vidal 2011, Vidal 2009).  
While there are a number of available therapies for patients with previously untreated FL, these 
regimens are typically chemo-immunotherapy, which may not be well-tolerated by all patients 
and none of these are curative, highlighting the need for novel, effective treatment options with a 
favorable toxicity profile. Thus, there is a medical need for treatments that can be combined with 
existing therapies to provide durable clinical benefit without added toxicities.  
A new, chemotherapy-free treatment combination was tested by SAKK 35/10 (Swiss Group for 
Clinical Cancer Research) and the Nordic Lymphoma Group (NLG) comparing single-agent 

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rituximab and rituximab plus lenalidomide as first-line treatment for symptomatic grade 1 3a FL 
patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2 IV on 
day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same 
schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end 
point was complete response (CR)/un-conﬁrmed CR (CRu) rate at 6 months. In total, 77 patients 
were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular 
Lymphoma International Index score in each arm). A signiﬁcantly higher CR/CRu rate at 
6 months was documented in the combination arm by the investigators (36%; 95% conﬁdence 
interval [CI],26%-48% vs 25%; 95% CI, 16%-36%) and conﬁrmed by an independent response 
review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% 
CI, 26%-48%). After a median follow-up of 4 years, signiﬁcantly higher 30-month CR/CRu rates 
and longer progression-free survival (PFS) (5.0 vs 2.3 years; HR, 0.60 [95% CI: 0.38-0.97], 
p  0.035) and time to next treatment (TTNT) were observed for the patients in the combination 
arm. Overall survival (OS) rates were similar in both arms (≥ 90%). Toxicity grade ≥ 3 was more 
common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia 
(23% vs 7%). Addition of lenalidomide to rituximab signiﬁcantly improved CR/CRu rates, PFS, 
and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms 
suggests that chemotherapy-free strategies should be further explored (Zucca 2019). 
The choice of rituximab as background therapy in the frontline treatment of FL is based on the 
recommendations in the NCCN and ESMO guidelines (NCCN 2020, Dreyling 2014). In these 
guidelines, rituximab is considered the treatment of choice for patients who are elderly or infirm 
(NCCN 2020, Dreyling 2014). In addition, the previously described Phase 2 study 
(PCYC-1125-CA) adding rituximab to ibrutinib demonstrates robust clinical activity with a high 
overall response rate in treatment naïve patients with FL; here the combination was well 
tolerated for the eligible population (Fowler 2020). 
1.4.4.2. 
Dose Selection Rationale 
The dose for ibrutinib in study PCYC-1141-CA is 560 mg (4 x 140-mg capsules) administered 
once daily without interruption. The 560 mg daily dose of ibrutinib was selected as the 
recommended dose in combination with rituximab based on clinical data. In the Phase 1 study 
(PCYC-04753 including similar mg/kg/day doses), the extension study (PCYC-1103-CA), and 
Phase 2 study (PCYC-1125-CA), the 560 mg dose administered once daily appeared safe and led 
to favorable responses in subjects with FL (Advani 2013, Fowler 2020). The dose for rituximab 
in cycle 1 is 375 mg/m2 administered intravenously once weekly for 4 weeks. This dose was 
given in two single-arm studies that form the basis for the NCCN guidelines for rituximab in the 
first-line setting (Hainsworth 2002, Colombat 2001). Beginning with cycle 3, rituximab 
maintenance is given as a 375 mg/m2 intravenous dose every 8 weeks up to 12 doses 
(approximately 2 years) or until disease progression. This dose and frequency is consistent with 
the FDA and EMA-approved labeling (MabThera® SmPC 2023, Rituxan® USPI 2021). 

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The assessment of pharmacokinetics is important in understanding both safety and efficacy in 
this patient population. The study includes a sparse pharmacokinetic sampling strategy for 
population pharmacokinetic purposes, which will serve as a means to derive the individual 
subject's ibrutinib exposure. In addition to determination of subject-covariates that influence the 
pharmacokinetics of ibrutinib, this may provide supportive evidence for the efficacy and safety 
analyses, and identify at-risk subjects who require a dose-adaptation. Furthermore, rituximab 
exposure with or without ibrutinib combination treatment will also be examined. 
2. 
STUDY OBJECTIVE 
2.1. 
Primary Objective 
• To evaluate whether the addition of ibrutinib to rituximab will result in prolongation of 
progression-free survival (PFS) when compared with rituximab alone in treatment naïve 
subjects with follicular lymphoma 
2.2. 
Secondary Objective(s) 
• Evaluate whether the addition of ibrutinib to rituximab will result in improvement in 
investigator-assessed ORR when compared with rituximab alone in treatment naïve 
subjects with follicular lymphoma 
• To evaluate whether the addition of ibrutinib to rituximab will result in a reduction in 
infusion-related reactions 
• To evaluate whether the addition of ibrutinib to rituximab will result in prolongation of 
OS  
• To evaluate whether the addition of ibrutinib to rituximab will result in prolongation of 
duration of response (DOR) 
• To evaluate the safety and tolerability of ibrutinib combined with rituximab compared to 
rituximab alone in treatment naïve subjects with follicular lymphoma 
2.3. 
Exploratory Objective(s) 
• To compare treatment groups with regards to patient reported lymphoma symptoms and 
health-related QOL as measured by the Functional Assessment of Cancer Therapy-
Lymphoma (FACT-Lym) 
• To characterize the pharmacokinetics of ibrutinib and rituximab and explore the potential 
relationships between ibrutinib metrics of exposure with relevant clinical or biomarker 
information 
• To evaluate and/or identify patient populations defined by relevant biomarker(s)  
• To evaluate the minimal residual disease (MRD)-negative rate defined as the proportion 
of follicular lymphoma subjects who achieve a CR and who reach MRD-negative disease 
status 

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• To evaluate whether the addition of ibrutinib to rituximab will result in improvement of 
the investigator-assessed CR30 when compared with rituximab alone in treatment naïve 
subjects with follicular lymphoma 
The statistical analysis methods and final set of exploratory endpoints are detailed in the 
Statistical Analysis Plan (SAP); if there are any variances between both documents the SAP 
takes precedence. 
3. 
STUDY DESIGN 
3.1. 
Overview of Study Design 
The rationale for the study concept is provided in Section 1.4. 
This is a randomized, double-blind, placebo-controlled Phase 3 study designed to assess the 
efficacy and safety of ibrutinib in combination with rituximab compared to placebo in 
combination with rituximab in treatment naïve subjects with follicular lymphoma. The 
methodology used for these analyses is outlined in the Statistical methods (Section 10). 
Figure 1. 
Study Design 
 
 
Approximately 440 subjects will be enrolled (estimate based on an accrual assumption of 
30 months). Subjects will be randomized at a 3:1 ratio to Arm A and B, respectively. Subjects 
will be stratified on the basis of: (a) age (60-69 vs. ≥70 years), (b) Follicular Lymphoma-specific 
International Prognostic Index (FLIPI)-1 score (low vs. intermediate/high) and (c) ECOG 
performance status score (0/1 vs. 2). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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Subjects randomized to the investigational arm (Arm A) will receive ibrutinib 560 mg PO daily 
until disease progression or unacceptable toxicity. Subjects randomized to the control arm 
(Arm B) will receive placebo PO (4 capsules) daily until disease progression or unacceptable 
toxicity.  
Subjects in both arms (Arm A and B) will also receive rituximab 375 mg/m2 IV once weekly for 
the first 4 weeks of study treatment (Cycle 1: Days 1, 8, 15, and 22). Beginning with Cycle 3, 
Day 1, rituximab will be given as maintenance therapy administered as a single dose of 
375 mg/m2 IV every 8 weeks up to 12 additional doses (approximately 2 years) or until disease 
progression or unacceptable toxicity, whichever comes first. Two interim analyses are planned: 
the first interim analysis (IA1) is for futility and is planned at approximately 55% information; 
and the second interim analysis (IA2) is for efficacy and is planned after approximately 75% 
information (150 PFS events) is observed and after the last subject has been enrolled. 
Primary analysis for PFS will be conducted when 200 PFS events are observed, or if 
pre-specified boundaries are crossed at an interim analysis. The final analysis for OS is planned 
when 165 OS events are observed or five years after enrollment of the last subject, whichever is 
earlier. 
A Response Evaluation Visit including local imaging assessments will be performed every 
16 weeks through Cycle 37 and then every 24 weeks thereafter and copies of the images will be 
stored at a central location for independent review-based assessment. The detail of the analyses 
will be specified in a separate document. Blinded study treatment administration will continue 
until disease progression, unacceptable toxicity, withdrawal of consent or study termination. 
Subjects who discontinue study treatment due to any reason other than withdrawal of consent for 
follow-up will be followed for overall survival every 24 weeks. Subsequent anticancer therapies, 
best response to therapy, and information about other malignancies will also be collected. 
Assessment of tumor response and progression, safety and tolerability, and pharmacokinetics and 
biomarkers will be evaluated at time points throughout the study. Please refer to Section 7 
and Section 8 and the Schedule of Assessments (Appendix A) for details. 

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3.2. 
Study Schema 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
Screening Phase 
(within 28 days before randomization) 
Assess Eligibility Criteria 
Randomization 
Subjects must start study treatment within 72 hours after randomization 
Treatment Arm A 
Background Therapy:  
Rituximab 375 mg/m2 IV Cycle 1, Day 1, 8, 15 and 22 
(induction) and 
Cycles 3  25, Day 1 (odd cycles only) (maintenance) 
 
Study Drug:  
Ibrutinib 560 mg PO once daily continuously 
starting on Cycle 1, Day 1 until disease progression or 
unacceptable toxicity 
Treatment Arm B 
 Background Therapy:  
Rituximab 375 mg/m2 IV Cycle 1, Day 1, 8, 15 and 22 
(induction) and  
Cycles 3  25, Day 1 (odd cycles only) (maintenance) 
 
Study Drug:  
Placebo PO once daily continuously 
starting on Cycle 1, Day 1 until disease progression or 
unacceptable toxicity 
 
Double Blind Treatment Phase 
Treatment Termination 
End of Treatment Safety Follow up 
Post Treatment Survival Follow Up 
Prior to Disease Progression (if applicable): Continue disease evaluations 
Following Disease Progression: Follow up for survival status 
 
  
 

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4. 
SUBJECT SELECTION 
Screening for eligible subjects will be performed within 28 days before randomization. 
Computed tomography/magnetic resonance imaging (CT/MRI) and PET may be performed up 
to 60 days before randomization. Bone marrow aspirate and biopsy may be performed up to 
60 days before randomization, at the latest prior to the first dose of study treatment.  
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. Investigators must ensure that all inclusion and exclusion criteria have 
been satisfied at Screening. Retesting during the Screening Period is allowed. A subject is 
considered eligible if the last observation before randomization and first study treatment dose 
satisfies the inclusion and exclusion criteria. If a subject's status changes (including 
laboratory results or receipt of additional medical records) after Screening but before 
randomization or first study treatment dose such that he or she no longer meets all 
eligibility criteria, then the subject should be excluded from participation in the study. If there is 
a question about the inclusion or exclusion criteria below, the investigator should consult with 
the appropriate sponsor representative before obtaining randomization for a subject in the study. 
The eligibility in question will be confirmed by the appropriate sponsor representative prior to 
randomization. 
Minimum criteria for the availability of documentation supporting the eligibility criteria are 
described in Section 12.6, Study Files and Record Retention. 
4.1. 
Inclusion Criteria 
Prior to randomization each potential subject must satisfy all of the following inclusion criteria. 
Disease-Related 
1. Subjects with histologically documented follicular lymphoma CD20+ (Grade 1, 2 or 3a) 
according to World Health Organization (WHO) criteria; Ann Arbor Stage II, III or IV 
disease.  
• Prior to randomization, diagnosis must be confirmed by local pathology report stating 
a diagnosis of follicular lymphoma. If the report from the local laboratory is not 
available or insufficient (if not including all the following information: FL diagnosis, 
CD20+ and Grade), the diagnosis must be confirmed by the central pathology 
laboratory (Section 7.1.1.5). 
2. At least one two-dimensionally measurable lesion ≥2.0 cm in longest diameter (LDi) by 
contrast-enhanced CT scan. Lesions in anatomical locations (such as extremities or soft 
tissue lesions) that are not well visualized by CT may be measured by MRI instead.  
3. Subjects 70 years of age or older; OR subjects 60-69 years of age who have one or 
more comorbidities that make them a candidate to receive single-agent rituximab 
therapy:  

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• Creatinine clearance 30-59 mL/min (by Cockcroft-Gault). Alternatively, creatinine 
clearance may be calculated based on a 24-hour urine collection. 
• ECOG performance status score of 2 
4. In need of systemic therapy as evidenced by meeting one or more of the following 
Groupe d'Etude des Lymphomes Folliculaire (GELF) criteria (Solal-Céligny 1998, 
Chen 2012): 
• Involvement of ≥3 nodal sites, each with a diameter of >3 cm 
• Any nodal or extranodal tumor mass with a diameter of >7 cm or risk of local 
compressive symptoms that may result in organ compromise 
• B symptoms (ie, fever, night sweats or weight loss) 
• Splenomegaly 
• Pleural effusions or peritoneal ascites 
• Thrombocytopenia (platelet count <100 x 109/L) 
• Peripheral blood involvement (>5.0 x 109/L malignant cells) 
Laboratory 
5. Adequate hematologic function defined as: 
• Hemoglobin ≥8.0 g/dL  
• Platelet count ≥50 x 109/L (50,000 cells/mm3) 
• Absolute neutrophil count (ANC) ≥1.0 x 109/L (1,000 cells/mm3) 
6. Adequate renal and hepatic function defined as: 
• Estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault) 
• Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤3 x upper 
limit of normal (ULN) 
• Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome such that 
bilirubin ≤3 x ULN or is of non-hepatic origin) 
7. PT/INR <1.5 x ULN (unless treated with warfarin or other vitamin K antagonists such 
that INR ≤3.0) and PTT (aPTT) <1.5 x ULN  
Demographic 
8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2. 
Ethical/Other 
9. Female subjects of reproductive potential must have a negative urine/serum pregnancy 
test upon study entry. Female subjects who are of non-reproductive potential 
(ie, post menopausal by history - no menses for ≥1 year; OR history of hysterectomy; 
OR history of bilateral tubal ligation; OR history of bilateral oophorectomy) are exempt 
from pregnancy testing. 

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10. Male and female subjects of reproductive potential who agree to use both a highly 
effective method of birth control (eg, implants, injectables, combined oral 
contraceptives, some intrauterine devices [IUDs], complete abstinence2, or sterilized 
partner) and a barrier method (eg, condoms, cervical ring, sponge, etc) during the 
period of therapy. For female subjects, these birth control requirements must be 
adhered to for 90 days after the last dose of ibrutinib/placebo and 12 months after the 
last dose of rituximab, whichever is later. For male subjects, these birth control 
requirements must be adhered to for 90 days after the last dose of ibrutinib/placebo. 
11. Subjects must not be incarcerated and must be freely willing and able to provide 
informed consent (e.g., adults under legal protection measure [e.g., under 
guardianship/curatorship] or unable to express their consent and select adults under 
psychiatric care). Investigator's discretion should be applied. 
 
4.2. 
Exclusion Criteria 
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria: 
Disease-Related 
1. Transformed lymphoma; if clinical evidence of transformed lymphoma is present (high 
lactate dehydrogenase [LDH] and/or high maximum standard uptake value [SUVmax] of 
a lymph node/lesion on positron emission tomography [PET] scanning, LDH and 
SUVmax level cutoff per investigator's clinical judgement), transformation should be 
ruled out by biopsy of the suspicious lymph node/lesion.  
2. Prior treatment for follicular lymphoma (eg, systemic anti-cancer therapy or involved 
site radiotherapy). 
3. Medically apparent central nervous system lymphoma or leptomeningeal disease. 
Concurrent Conditions 
4. History of other malignancies, except:  
• Malignancy treated with curative intent and with no known active disease present for 
≥3 years before the first dose of study treatment and felt to be at low risk for 
recurrence by treating physician. 
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease. 
                                                   
 
2 Complete abstinence is a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 
http://www.hma.eu/fileadmin/dateien/Human Medicines/01 
About HMA/Working Groups/CTFG/2014 09 HMA CTFG Contraception.pdf 

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• Adequately treated carcinoma in situ without evidence of disease.  
5. Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., 
or chronic administration of >20 mg/day of prednisone or equivalent) within 28 days of 
the first dose of study treatment. For indications other than lymphoma or management 
of lymphoma-related symptoms, the following are exceptions to this criterion: 
• Intranasal, inhaled, topical corticosteroids or local corticosteroid injections (eg, intra-
articular injection)  
• Systemic corticosteroids at doses not to exceed 20 mg/day of prednisone or its 
equivalent 
• Corticosteroids as pre-medication for hypersensitivity reactions (eg, CT scan pre-
medication) 
6. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study 
treatment. 
7. Known bleeding disorders (eg, von Willebrand's disease or hemophilia). 
8. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
9. Known history of human immunodeficiency virus (HIV) or active infection with 
hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for 
hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have 
a negative polymerase chain reaction (PCR) result before enrollment. Those who are 
PCR positive will be excluded. In equivocal cases, hepatitis B or C PCR may be 
performed and must be negative for enrollment. 
10. Any uncontrolled active systemic infection or recent infection requiring intravenous 
antibiotic treatment that was completed ≤14 days before the first dose of study 
treatment. 
11. Major surgery within 4 weeks of first dose of study treatment. 
12. Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator's opinion, could compromise the subject's safety or put the study outcomes 
at undue risk. 
13. 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 randomization. 
14. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel 
obstruction. 
15. Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any 
component of rituximab. 

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16. Prior use of an anti-CD20 agent or an inhibitor of Bruton's tyrosine kinase (BTK) (eg, 
rituximab, ibrutinib) (NOTE: use of any prior treatment for follicular lymphoma is not 
permitted per protocol). 
17. Any investigational drug within 4 weeks prior to randomization or concurrent 
enrollment in another therapeutic investigational clinical treatment study. 
18. Subject who received systemic administration of a strong cytochrome P (CYP) 450 3A 
inhibitor within 7 days prior to the first dose of ibrutinib or subject who requires 
continuous treatment with a strong CYP 450 3A inhibitor (see Appendix C). 
19. Currently active, clinically significant hepatic impairment Child-Pugh class B or C 
according to the Child Pugh classification (see Appendix F). 
20. Lactating or pregnant. 
21. Unwilling or unable to participate in all required study evaluations and procedures. 
22. 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. 
Treatment Allocation and Blinding 
5.1.1. 
Randomization, Stratification and Placebo Control 
Central randomization will be implemented in this study. Randomization will be used to 
minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that 
known and unknown subject attributes (e.g., demographic and baseline characteristics) are 
evenly balanced across treatment groups, and to enhance the validity of statistical 
comparisons across treatment groups. Two randomization schemes will be generated: one for 
each geographic region (North America versus Rest of World). Under each scheme, subjects will 
be randomized based on the following stratification factors:  
• Age 60-69 vs. ≥70 years 
• FLIPI-1 score at Screening (low vs. intermediate/high) 
• ECOG performance status score (0/1 vs. 2) 
Subjects will be randomized at a 3:1 ratio to receive either Treatment Arm A 
(ibrutinib/rituximab) or Treatment Arm B (placebo/rituximab) within each randomization 
stratum. A placebo control will be used to establish the frequency and magnitude of changes in 
clinical endpoints that may occur in the absence of active treatment. 
Subjects who discontinue study treatment due to any reason other than withdrawal of consent for 
follow-up will be followed for overall survival. Subsequent anticancer therapies, best response to 
therapy, and information about other malignancies will be collected. 

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The interactive voice or web response system (IXRS) will assign a unique treatment code, which 
will dictate the treatment assignment and matching study treatment kit for the subject. The 
requestor must use his or her own user identification and personal identification number when 
contacting the IXRS, and will then provide the relevant subject details to uniquely identify the 
subject. 
5.1.2. 
Blinding 
Blinded treatment will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints. This is a double-blind study; therefore, subjects, investigators, and the 
Sponsor's study team members will remain blinded to treatment assignment. The investigator 
will not be provided with randomization codes. 
Data that may potentially unblind the treatment assignment (i.e., study drug plasma 
concentrations) will be handled with special care to ensure that the integrity of the blind is 
maintained and the potential for bias is minimized. This may include making special provisions, 
such as segregating the data in question from view by the investigators, clinical team, or others 
as appropriate until the time of database lock and/or unblinding. 
Under normal circumstances, the blind should not be broken. The blind should be broken only if 
specific emergency treatment/course of action would be dictated by knowing the treatment status 
of the subject. In such cases, the investigator may in an emergency determine the identity of the 
treatment by contacting the IXRS. It is recommended that the investigator contact the sponsor or 
its designee, if possible, to discuss the particular situation before breaking the blind. Telephone 
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In 
the event the blind is broken, the sponsor must be informed as soon as possible. The date, time, 
and reason for the unblinding must be documented in the source documents. The documentation 
received from the IXRS indicating the code break must be retained with the subject's source 
documents in a secure manner. A subject whose treatment assignment has been unblinded may 
continue the study treatment if receiving clinical benefit and the subject should continue to return 
for scheduled study evaluations. The single-blind (i.e., subject remains blinded to treatment 
assignment) should be maintained provided the subject's safety is not compromised. 
Subjects, investigators, and the sponsor's study team members will remain blinded to treatment 
assignment until the primary analysis is completed. Examples of personnel who may be 
unblinded during the study are: 
• The independent DMC, and the independent biostatistician and statistical programmers 
from an independent Statistical Support Group who are responsible for preparing interim 
tables, listings, and graphs for DMC review. Unblinding procedures and the control of the 
unblinded data are described in the DMC charter. 
• Sponsor's representative responsible for pharmacokinetics testing and analysis. 
• Sponsor safety representative to fulfill regulatory reporting requirements for suspected 
unexpected serious adverse events. 

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• In case of an urgent safety concern, site personnel and the sponsor may be unblinded, if 
treatment assignment information is needed to determine further actions to address the 
urgent safety concern (e.g., life-threatening event, medication error, such as an accidental 
overdose). 
5.2. 
Study Treatment 
• All eligible subjects for randomization will be treated with rituximab in combination with 
either ibrutinib (Arm A) or matching placebo (Arm B) according to the dose and schedule 
outlined in Table 2. 
• Treatment with ibrutinib or placebo, referred to as study drug, will continue until disease 
progression, unacceptable toxicity, withdrawal of consent for treatment, or study end, 
whichever comes first. All subjects treated in this study will follow guidelines for dosing 
and toxicity management as described in Section 5.3.1 and Section 5.3.2 of the protocol 
for study drug (ibrutinib/placebo) and rituximab, respectively. 
5.2.1. 
Route and Schedule 
Table 2. 
Treatment, Dose, and Schedule of Administration for Study Treatment 
Study Treatment 
Dose and Schedule of Administration 
Study drug (ibrutinib/placebo) 
4 x 140 mg capsules (560 mg ibrutinib or placebo) orally 
administered daily beginning from Cycle 1, Day 1 (at least 
24 cycles). 
Rituximab 
375 mg/m2 IV per regional prescribing information administered 
weekly for four consecutive weeks, beginning from Cycle 1, 
Day 1, followed by maintenance rituximab administered every 
8 weeks up to 12 doses (approximately 2 years) beginning Cycle 3, 
Day l. 
Rituximab administration days: Cycle 1, Days 1, 8, 15, 22 and 
Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23 and 25 on Day 1 (a total 
of 16 doses of rituximab will be given during the study).  
NOTE: No rituximab will be given in Cycle 2. 
 
5.3. 
Study Medications 
5.3.1. 
Ibrutinib/Placebo (Study Drug) 
For the purposes of this study, study drug refers to both ibrutinib and placebo, the blinded label 
study drug. All subjects will follow the guidelines for ibrutinib dosing and toxicity management. 
Ibrutinib/placebo should be administered as described in Table 2 until one or more of the 
discontinuation criteria in Section 9.2 are met. 

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5.3.1.1. 
Ibrutinib/Placebo: Formulation/Packaging/Storage 
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 IB for a list of excipients.  
Matching placebo capsules are provided as a hard gelatin capsule and look identical to ibrutinib 
capsules. 
The ibrutinib and placebo capsules will be packaged in opaque high-density polyethylene plastic 
bottles with labels bearing the appropriate label text as required by governing regulatory 
agencies. Study drug (ibrutinib/placebo) will be dispensed in child-resistant packaging.  
Refer to the Pharmacy Manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling. 
5.3.1.2. 
Ibrutinib/Placebo: Dose and Administration 
Study drug (ibrutinib/placebo) is recommended to be self-administered on an outpatient basis. 
Blinded study medication will be administered for continuous daily dosing. 
Study drug (4 capsules) is administered orally once daily. The capsules are to be taken around 
the same time each day with 8 ounces (approximately 240 mL) of water. The capsules should be 
swallowed intact and subjects 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 6.2.1 and Appendix C). 
If a dose is not taken at the scheduled time, 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. 
The first dose will be delivered in the clinic on Cycle 1, Day 1, after which subsequent dosing 
will be self-administered daily by the subjects typically on an outpatient basis. Please refer to 
Table 3 and Section 8 for oral dose and administration instructions on pharmacokinetic visits; on 
these days, study drug will be administered in clinic as soon as the subject comes into clinic and 
after pre-dosing procedures. Pre-medications and rituximab will then be administered as outlined 
in Section 5.3.2.2. 
Study drug will be dispensed to subjects in bottles. Unused study drug must be returned to the 
site and drug accountability records (Section 12.8) updated. Returned capsules must not be 
redispensed to anyone. 
Study drug is continuous (without interruptions) throughout the Treatment Phase. If rituximab 
infusion is delayed due to scheduling conflicts or toxicity, study drug dosing should continue. 

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Table 3. 
Study Drug (Ibrutinib/Placebo) Administration 
Study Drug 
Ibrutinib/placebo 
Schedule of Administration  Daily  
Route/Regimen 
Oral 
In-clinic dosing days (Cycle 1, Day 1 and 22; Cycle 3, Day 1): 
supervised by site staff; given as soon as the subject comes into clinic 
and after pre-dosing procedures. Pre-medications and rituximab will 
then be administered. 
Home administration days: self-administered by subject. 
Dose 
560 mg (4 x 140 mg capsules) or placebo 
Dosing Instructions 
Take the study drug around the same time each day with approximately 
8 ounces of water. Swallow capsules whole (shouldn't open, break, or 
chew). A missed dose is taken as soon as possible on the same day, 
with a return to the normal schedule the following day. Extra capsules 
to make up for a missed dose should not be taken. For days with 
rituximab scheduled but not in-clinic dosing days as indicated above, 
take the study drug prior to clinic visit. 
 
COVID-19 Pandemic-Related Direct-to-Patient Shipments 
If a subject is unable to come to the study site to pick up their study drug due to COVID-19, 
study drug may be shipped from the study site directly to the study subject's home via a direct-to-
patient (DTP) shipment if the following criteria are met: 
• DTP shipment of study drug is allowed by local regulations and the relevant ethics 
committee 
• Subject agrees to have the study drug shipped directly to their home. 
Of note: 
• Shipments may also include other study supplies (e.g., drug dosing diaries, paper copies 
of PROs).   
• Instructions will be provided by AbbVie as to how a study site can initiate a DTP 
shipment using Marken, a global vendor selected by AbbVie to provide this service when 
necessary.  Shipments of study drugs from the study site to a subject's home will be 
appropriately temperature controlled (qualified shipper or temperature monitoring) within 
the labeled storage conditions.  Signature is required upon delivery; due to COVID-19- 
related social distancing, this may be provided by the courier after delivery.  
Documentation of the shipment is to be retained by the clinical site. 
• AbbVie will not receive subject identifying information related to these shipments, as the 
site will work directly with the courier. 
 

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The study site is responsible for meeting IRB/IEC reporting requirements related to DTP 
shipments of study drug, and for obtaining consent to provide delivery information to the courier 
and documenting this consent in source documents.  
5.3.1.3. 
Ibrutinib/Placebo: Overdose 
There is no specific experience in the management of ibrutinib overdose in subjects. 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 (ibrutinib IB). 
Refer to Section 11.3 for further information regarding special reporting situations as a result of 
overdose.  
5.3.1.4. 
Ibrutinib/Placebo: Dose Modification for Ibrutinib/Placebo-Related Adverse 
Reactions 
For an ibrutinib/placebo-related adverse reaction, the recommendations for dose modification of 
ibrutinib/placebo are provided in Table 4 and Table 5 if any of the following hematologic or non-
hematologic toxicities occur: 
• Grade 3 or greater neutropenia with infection or fever 
• Grade 4 neutropenia (ANC<500/µL) for more than 7 days. See Section 6.1 for 
instructions regarding the use of growth factor support.  
• Grade 3 thrombocytopenia (platelets<50,000/µL) in the presence of clinically significant 
bleeding events. 
• Grade 4 thrombocytopenia (platelets<25,000/µL). 
• Grade 3 or greater non-hematological toxicity (Note: Table 5 recommendations for 
Grade 3 or higher cardiac failure and cardiac arrhythmias) 
• Grade 2 cardiac failure (Table 5) 
• Any other Grade 4 or unmanageable Grade 3 hematological toxicity. 
If clinically indicated, the use of anticoagulants or antiplatelet agents may be considered for the 
thromboprophylaxis of atrial fibrillation (Section 6.2.3). 
For other grade 3 or 4 AEs, and grade 2 AEs that are deemed per the investigator potentially 
manageable by dose reduction, these can be managed with a one dose level dose reduction. 
In the event that the investigator feels deviation from the recommendations above is required, 
please consult the Medical Monitor to discuss. 

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If administration of study drug is delayed or discontinued for toxicity that does not require 
rituximab to be held for toxicity, rituximab dosing should continue at the investigator's 
discretion. 
Study drug should be discontinued in the event of a toxicity considered to be related to study 
drug requiring a dose hold lasting more than 28 days, unless reviewed and approved by the 
Medical Monitor. 
Dose changes must be recorded in the Dose Administration eCRF. 
Table 4. 
Ibrutinib/Placebo: Study Drug Dose Modifications for Events not 
Specified in Table 5 
Occurrence 
Action to be Taken  
First 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at original 
dose level (ie, 4 capsules [560 mg/day])a 
Second 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose level 
lower (ie, 3 capsules [420 mg/day])  
Third 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose level 
lower (ie, 2 capsules [280 mg/day]) 
Fourth 
Discontinue study drug 
a. 
When resuming treatment, restart at the same or lower dose based on benefit risk evaluation. If the toxicity reoccurs, reduce 
daily dose by 140 mg. 
 
For required dose modification for hepatic impairment refer to Section 5.3.1.5 and for 
concomitant treatment with CYP3A inhibitors refer to Section 6.2.1. If a subject is being dosed 
at 280 mg due to hepatic impairment or concurrent CYP3A inhibitor administration, dose level is 
to be reduced by one capsule to 140 mg at the second occurrence of AEs as described above. 

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Table 5. 
Ibrutinib Dose Modifications for Cardiac Failure or Cardiac Arrhythmias 
Events  
Occurrence 
Action  
Grade 2 cardiac failure  
First 
 Hold study drug until recovery to Grade ≤ 1 or 
baseline; restart at 1 dose level lower (3 capsules 
[ie, 420 mg daily])  
Second 
Hold study drug until recovery to Grade ≤ 1 or 
baseline; restart at 1 dose level lower (2 capsules 
[ie, 280 mg daily])  
Third 
Discontinue study drug  
Grade 3 cardiac arrhythmias  
First 
Hold study drug until recovery to Grade ≤ 1 or 
baseline; restart at 1 dose level lower (3 capsules 
[ie, 420 mg daily])a  
Second 
Discontinue study drug  
Grade 3 or 4 cardiac failure  
  
Grade 4 cardiac arrhythmias  
First 
Discontinue study drug  
a. 
Evaluate the benefit risk before resuming treatment.  
 
5.3.1.5. 
Ibrutinib/Placebo: 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 have at enrollment or develop mild liver impairment while on 
study (Child-Pugh class A), the recommended dose reduction for ibrutinib/placebo 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 F). 
5.3.2. 
Rituximab 
Rituximab (Rituxan®) is indicated for the treatment of patients with relapsed or refractory, 
low-grade or follicular, CD20-positive, B-cell NHL as a single agent (MabThera® SmPC 2023, 
Rituxan® USPI 2021). In addition, rituximab, as a single-agent is currently a recommended 
therapy for elderly or infirm patients with previously untreated FL per clinical guidelines 
(NCCN 2020, Dreyling 2014).  
All subjects in Arms A and B will receive rituximab and will follow the regional labeling 
information for rituximab premedication, dosing and toxicity management (MabThera® SmPC 
2023, Rituxan® USPI 2021). 

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5.3.2.1. 
Rituximab: Formulation/Package/Storage 
Rituximab is a highly purified 1328-amino acid antibody with an approximate molecular weight 
of 145 kd. The chimeric mouse/human anti-CD20 antibody is a glycosylated IgG1 
immunoglobulin containing murine light- and heavy-chain variable regions and human γ1 
heavychain and κ light-chain constant regions. Rituximab is a sterile, clear, colorless, 
preservative-free liquid concentrate for IV administration. Rituximab is supplied at a 
concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials. The 
product is formulated for IV administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium 
citrate dihydrate, 0.7 mg/mL polysorbate 80, and Sterile Water for Injection. The pH is adjusted 
to 6.5 (MabThera® SmPC 2023, Rituxan® USPI 2021). 
Rituximab vials should be stored refrigerated between 2°C to 8°C (36°F to 46°F). Vials should 
be protected from light. Do not freeze or shake.  
For more information regarding stability and storage refer to the Pharmacy Manual and regional 
labeling information (MabThera® SmPC 2023, Rituxan® USPI 2021).  
5.3.2.2. 
Rituximab: Dose and Administration 
The first dose of rituximab will be administered IV beginning on Cycle 1, Day 1 in the Induction 
portion (Cycle 1) of the Treatment Phase. Rituximab will continue to be administered at the 
clinical site weekly for a total of four consecutive weekly doses. Rituximab doses during 
induction may be adjusted within a 3-day window due to scheduling conflicts. A minimum of 
5 days between doses of rituximab is required. 
Maintenance administration of rituximab will begin on Cycle 3, Day 1 of the Treatment Phase 
(5 weeks ± 3 days after the last induction treatment on Cycle 1, Day 22) and continue every 
8 weeks for a total of 12 doses (Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, and 25 on Day 1). 
Rituximab doses during Cycle 3 may be adjusted within a 3-day window. For Cycle 5 and 
beyond, rituximab maintenance administration visits may be adjusted within a 7-day window due 
to scheduling conflicts.  
Dosage calculations for rituximab will be based on the subject's body surface area (BSA) based 
on height and weight obtained at the Screening visit. Actual body weight will be used for dose 
calculations. If the height and weight were not recorded at Screening, they may be obtained on 
Cycle 1, Day 1 and used for the dose calculations. Dose modification for changes in a subject's 
weight are not required per protocol but may be performed per institutional standard. 
Rituximab will be administered IV by clinic staff according to the regional prescribing 
information. Premedication consisting of an analgesic/antipyretic (e.g., acetaminophen or 
paracetamol) and an antihistamine (e.g., diphenhydramine) should always be administered 
before each infusion of rituximab as outlined in the regional product information 

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(MabThera® SmPC 2023, Rituxan® USPI 2021). Premedication will be given prior to each 
administration. Rituximab should not be mixed or diluted with other drugs. 
In the event of an infusion reaction, institute medical management (e.g., glucocorticoids, 
epinephrine, bronchodilators, or oxygen), as appropriate. If hypersensitivity (non-IgE-mediated) 
or an infusion reaction develops, the infusion should be temporarily slowed or interrupted.  
Depending on the severity of the infusion reaction and the required interventions, treatment with 
rituximab may be temporarily or permanently discontinued. See Section 5.3.2.5 for further 
instructions. 
Some individual subjects may require close monitoring during the first and all subsequent 
infusions, e.g., subjects who have pre-existing cardiac or pulmonary conditions, prior clinically 
significant cardiopulmonary AEs or high numbers of circulating malignant cells (≥25,000/mm3) 
with or without evidence of high tumor burden. 
Unused rituximab must be disposed of according to the sites drug disposal policy and drug 
accountability records updated. 
5.3.2.3. 
Rituximab: Overdose 
There has been no experience with overdose in human clinical trials. The highest intravenous 
dose of rituximab tested in humans to date is 5000 mg (2250 mg/m2), tested in a dose escalation 
study in subjects with chronic lymphocytic leukemia. No additional safety signals were 
identified (MabThera® SmPC 2023). 
Subjects who experience overdose should have immediate interruption of their infusion and be 
closely monitored (MabThera® SmPC 2023).  
In the postmarketing setting, five cases of rituximab overdose have been reported. Three cases 
had no reported adverse event. The two adverse events that were reported were flu-like 
symptoms, with a dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of 
rituximab (MabThera® SmPC 2023). 
Refer to Section 11.3 for further information regarding special reporting situations as a result of 
overdose. 
5.3.2.4. 
Rituximab: Dose Modification for Rituximab-Related Adverse Reactions 
At the investigator's discretion, the rituximab dose should be held for any unmanageable, 
potentially rituximab-related toxicity that is consistent with the regional prescribing information 
and the rules outlined in this section. Rituximab should be held for any rituximab-related Grade 4 
toxicity or for any, clinically significant, unmanageable potentially rituximab-related non-
hematological Grade 3 adverse events. Rituximab may be held for a maximum of 28 consecutive 
days for a rituximab-related toxicity, unless reviewed and approved by the Medical Monitor. 

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The dose of rituximab should be modified according to the dose modification guidelines in 
Table 6 if any Grade 4 or unmanageable non-hematologic Grade 3 toxicity attributed to 
rituximab occurs. Dose modifications of rituximab must be recorded in the case report form 
(CRF). 
Table 6. 
Rituximab: Dose Modification for Toxicity 
Occurrence 
Action to be Taken 
First, Second, Third 
Withhold rituximab until recovery to Grade ≤1 or baseline; may restart at 
original dose level 
Fourth 
Discontinue rituximaba 
a. 
If rituximab is discontinued for toxicity prior to the completion of induction treatment (Cycle 1), the subject will 
discontinue study drug and be followed for progression. If rituximab is discontinued for toxicity during the maintenance 
phase, the subject may continue on study drug. 
Note: for guidance on management of rituximab in relation to infusion reactions see 
Section 5.3.2.5. 
A missed dose of rituximab during the induction phase in Cycle 1 for any reason will not be 
made up (i.e., the dose will be skipped) during Cycle 1; the visit window for Cycle 1 is ± 3 days.  
• If the subject skips dosing of rituximab during Cycle 1 due to reasons other than not 
being able to tolerate rituximab, subject can make up the induction phase dosing as soon 
as possible during Cycle 2 as long as there is a minimum of 5-day window between doses 
and 5-day window prior to Cycle 3 Day 1. 
• If induction phase cannot be completed prior to 5 days of Cycle 3 Day 1, subject can 
begin maintenance rituximab dosing according to the protocol schedule if only one 
induction phase dose is missed. If more than one induction phase dose is missed, please 
contact PCYC Medical Monitors for further guidance. 
A missed dose of rituximab during the maintenance phase in Cycles 3-25 may be given within 
the defined visit window (i.e., ± 3 days for Cycle 3 and ± 7 days for Cycles 5-25). 
If rituximab dosing is delayed for toxicity that does not require study drug (ibrutinib/placebo) to 
be held for toxicity, administration of study drug should continue at the investigator's discretion. 
If a rituximab infusion is delayed due to scheduling delays, administration of study drug should 
continue. 
Any other clinically important events where dose delays may be considered appropriate by the 
Investigator must be discussed with the Medical Monitor. 
Upon recovery, subjects should resume the protocol-specified treatment schedule as soon as 
possible. 

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5.3.2.5. 
Rituximab: Dose Interruption for Infusion-Related Reactions 
Modify administration of rituximab for infusion-related reactions of any severity as described 
below. 
• 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. 
• 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, then 
complete the infusion at the decreased rate. If symptoms do not improve, or worsen, 
discontinue the infusion. 
• 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. 
5.3.2.6. 
Rituximab: Dose Reduction 
There will be no dose reductions for rituximab. Particular attention should be paid to the 
Warnings and Precautions sections of the product label. 
5.3.2.7. 
Rituximab: Dose Discontinuation  
Rituximab should be discontinued in the event of a rituximab toxicity requiring a dose hold 
lasting more than 28 days, unless reviewed and approved by the Medical Monitor. If rituximab is 
discontinued for toxicity prior to the completion of induction treatment (Cycle 1), the subject 
will discontinue study drug (ibrutinib/placebo) and be followed for progression. If rituximab is 
discontinued for toxicity during the maintenance phase, the subject may continue on study drug. 
5.4. 
Study Treatment Compliance 
5.4.1. 
Study Drug (Ibrutinib/Placebo) Compliance 
The study drug (ibrutinib/placebo) is to be prescribed only by the Principal Investigator or a 
qualified physician or other licensed prescriber listed as a Sub-Investigator on the Form FDA 
1572/Investigator Information and Agreement (IIA). The study site personnel must maintain all 
study drug records in the study file, and record all study drug's dispensing and returning on the 
drug accountability form and in the subject's source documents. The study drug 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 IXRS will be used to assign study drug kits for each 
subject enrolled with each cohort assignment. 

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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 drug to each study visit. The 
site personnel must reconcile and document the returned capsules from the study subjects at each 
study visit to ensure compliance with study drug administration. Instructions for self-
administration and storage conditions of study drug will be provided to the subjects by the site 
personnel. Precautions associated with the use of study drug and prohibited concomitant 
medications must be reviewed with the study subjects by the Investigator or 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.  
5.4.2. 
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. 
5.5. 
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 
outcomes at risk. For a complete list of criteria for permanent discontinuation of study treatment, 
refer to Section 9.2. 
An End of Treatment Safety Follow up visit (Section 8.2.3) is required for all subjects except for 
those subjects who have withdrawn full consent. 
5.6. 
Replacement of Subjects 
If a subject discontinues study treatment at any time, the subject will not be replaced. 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES 
Concomitant therapies must be recorded from the time of ICF signing and recorded continuously 
from the time of signing the ICF to 30 days after the last dose of study treatment. 
6.1. 
Permitted Concomitant Medications  
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
including prophylaxis for infusion-related reactions are permitted. Use of neutrophil growth 
factors (filgrastim and pegfilgrastim) or red blood cell growth factors (erythropoietin) is 

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permitted per institutional policy, in accordance with the ASCO guidelines (Smith 2006) or 
local/regional guidelines. Transfusions may be given in accordance with institutional policy.  
After consultation with the Medical Monitor the following may be considered: hormonal or bone 
sparing treatment for non-B-cell malignancies, or localized radiotherapy for medical conditions 
other than the underlying B-cell malignancies.  
Corticosteroids for non-cancer-related medical reasons at doses equivalent to ≤20 mg per day of 
prednisone or its equivalent are permitted. Corticosteroids as pre-medication for hypersensitivity 
reactions (e.g., CT scan pre-medication or infusion-related reaction) are also permitted. Short 
courses (less than 14 days) of corticosteroid treatment for non-cancer-related medical reasons 
(e.g., joint inflammation, asthma exacerbation, rash, antiemetic use and infusion reactions) at 
doses that do not exceed 100 mg per day of prednisone or equivalent are permitted. 
Corticosteroid treatment courses of 14 days or more may be considered after consultation with 
the Medical Monitor. For purposes of premedication or management of rituximab infusion 
reactions only, 100 mg prednisone (or its equivalent) per day may be exceeded. 
COVID-19 Pandemic-Related Vaccination Guidance 
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., mRNA, non-
replicating viral vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be 
administered during screening, the treatment period, or follow up, as long as components of the 
vaccine are not contraindicated. 
The decision to receive a locally available vaccine is encouraged, but should be based on local 
guidance and an individual discussion between the treating physician and the subject. 
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine details 
eCRF.  Refer to Section 11.4.9 for instructions on reporting any adverse events associated with 
the COVID-19 vaccine. 
6.2. 
Medications to be Used with Caution 
6.2.1. 
CYP3A Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A4. Concomitant use of ibrutinib and drugs that 
strongly or moderately inhibit CYP3A can increase ibrutinib exposure and strong CYP3A 
inhibitors should be avoided.  
• Strong inhibitors of CYP3A (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, 
saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone, and cobicistat) 
should be avoided and an alternative with less CYP3A inhibitory potential should be 
considered. If the benefit outweighs the risk and a strong CYP3A inhibitor must be used, 
see recommended dose modifications in the table below.  

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• If a moderate CYP3A inhibitor (e.g., fluconazole, erythromycin, amprenavir, aprepitant, 
atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, imatinib, verapamil, 
amiodarone, dronedarone) is indicated, reduce ibrutinib dose as per recommended dose 
modifications in the table below. Avoid grapefruit and Seville oranges during 
ibrutinib/placebo treatment, as these contain moderate inhibitors of CYP3A (see 
Section 5.3.1.2). 
• No dose adjustment is required in combination with mild inhibitors.  
 
Recommended dose modifications are described below: 
Patient Population 
Co-administered Drug 
Recommended Ibrutinib Dose for the 
Duration of the Inhibitor Usea 
B-Cell Malignancies • 
Mild CYP3A inhibitors 
560 mg once daily per indication. No 
dose adjustment required. 
• 
Moderate CYP3A inhibitors 
280 mg once daily. 
• 
Voriconazole  
• 
Posaconazole at doses less than 
or equal to suspension 200 mg 
BID  
140 mg once daily. 
• 
Other strong CYP3A inhibitors 
• 
Posaconazole at higher dosesb  
• 
Avoid concomitant use and consider 
alternative with less CYP3A 
inhibitory potential. 
• 
If these inhibitors will be used 
short-term (such as anti-infectives 
for seven days or less), interrupt 
ibrutinib. 
• 
If the benefit outweighs the risk, 
and long-term dosing with a 
CYP3A inhibitor is required (more 
than seven days), reduce ibrutinib 
dose to 140 mg once daily for the 
duration of the inhibitor use. 
a. 
Monitor for adverse reactions to ibrutinib and interrupt or modify dose as recommended (see Dosage and 
Administration). 
b. 
Posaconazole at higher doses (posaconazole suspension 200 mg three times daily or 400 mg twice daily, posaconazole IV 
injection 300 mg once daily, posaconazole delayed release tablets 300 mg once daily). 
 
Avoid concomitant use of strong CYP3A inducers (e.g., 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 C. For further 
information, please refer to the current version of the ibrutinib IB and examples of inhibitors, 
inducers, and substrates can be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
This website is continually revised and should be checked frequently for updates. 

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6.2.2. 
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 study drug. 
6.2.3. 
Antiplatelet Agents and Anticoagulants 
Warfarin or other vitamin K antagonists as well as supplements such as fish oil and vitamin E 
preparations should be avoided if possible. Use ibrutinib with caution in subjects requiring 
anticoagulants or medications that inhibit platelet function. Subjects with congenital bleeding 
diathesis have not been studied. Study drug should be held at least 3 to 7 days pre- and post-
surgery depending upon the type of surgery and the risk of bleeding (see Section 6.4). 
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/placebo should be held and not be restarted until the 
subject is clinically stable and has no signs of bleeding. No dose reduction is required when 
study drug is restarted. Subjects should be observed closely for signs and symptoms of bleeding. 
6.3. 
Prohibited Concomitant Medications 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy is 
prohibited while the subject is receiving study treatment. See Section 6.1 for limited exceptions. 
Corticosteroids for the treatment of the underlying malignancy are prohibited. Corticosteroids for 
non-cancer-related medical reasons at doses >20 mg per day of prednisone or equivalent for 
14 days or longer are prohibited, unless approved by the Medical Monitor. See Section 6.1 for 
limited exceptions following consultation with the Medical Monitor. 
The Medical Monitor must be notified in advance (or as soon as possible thereafter) of any 
instances in which prohibited therapies are administered. 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures 
Ibrutinib may increase the risk of bleeding with invasive procedures or surgery. The following 
guidance should be applied to the use of ibrutinib in the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving study drug. 

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6.4.1. 
Minor Surgical Procedures 
For minor procedures (such as a central line placement, needle biopsy, lumbar puncture [other 
than shunt reservoir access], thoracentesis, or paracentesis) study drug should be held for at least 
3 days prior to the procedure and should not be restarted for at least 3 days after the procedure. 
For bone marrow biopsies that are performed while the subject is on study drug, it is not 
necessary to hold study drug. 
6.4.2. 
Major Surgical Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, study drug 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. 
6.4.3. 
Emergency Procedures 
For emergency procedures, study drug should be held as soon as possible 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. 
Description of Procedures 
7.1.1. 
Assessments  
Screening clinical and laboratory assessments must be performed within 28 days of and prior to 
randomization. 
7.1.1.1. 
Informed Consent 
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved ICF confirming his or her 
willingness to participate in this study before any study-specific screening procedures are 
performed. Subjects must also grant permission to use protected health information per the 
Health Insurance Portability and Accountability Act (HIPAA) or similar local requirement. In 
addition, subjects must sign all approved ICF amendments per the site IRB/REB/IEC guidelines 
during the course of the study.  
7.1.1.2. 
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 and prior to first dose on Day 1 
(Section 4). 

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7.1.1.3. 
Medical History and Demographics 
The subject's relevant medical 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 will be 
recorded. 
7.1.1.4. 
Follicular Lymphoma International Prognostic Index-1 (FLIPI-1) 
The FLIPI-1 is a validated prognostic scoring system based on five adverse factors 
(Solal-Céligny 2004). The parameters include age, Ann Arbor stage, and number of nodal areas 
involved, hemoglobin levels and serum LDH levels (Table 10). Each of these adverse factors is 
assigned one point if positive, the points are totaled to give the final FLIPI-1 score and 
lymphoma prognoses are based on this score. See Appendix D. 
7.1.1.5. 
Diagnostic Tissue Block(s) or Slides 
Sites will be required to submit diagnostic biopsy materials (formalin-fixed, paraffin-embedded 
[FFPE] tissue block(s) or minimum 10 slides, preferably of lymph node origin) to a central 
laboratory for confirmation of diagnosis of FL. If an archived specimen is not available or 
contains insufficient material, a fresh tumor biopsy will be required. A portion of the FFPE tissue 
block or slides collected for confirmation of disease may be used for the assessment of molecular 
and genetic biomarkers. Prior to randomization, a copy of the report confirming the diagnosis of 
FL from the local laboratory may be acceptable to demonstrate a diagnosis of FL. This report, 
confirming the diagnosis of FL, may contain morphology, expression of B-cell lymphoma-2 
(Bcl-2) in association with other relevant markers (e.g., CD10 and CD19) or evidence of t(14;18) 
as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain 
reaction. A copy of the report containing this information must be sent to the central laboratory 
along with the diagnostic biopsy material. For subjects who do not have this diagnostic report 
available, a tumor tissue block or slides must be sent to the central laboratory and confirmation 
of FL diagnosis must be obtained from the central laboratory prior to enrollment. 
7.1.1.6. 
Prior and Concomitant Medications 
All active medications from the signing of ICF through 30 days after the last dose of study 
treatment will be documented. 
7.1.1.7. 
Adverse Events 
The accepted regulatory definition for an adverse event (AE) is provided in Section 11.1. The 
occurrence of AEs at the time the ICF is signed until the first dose of study treatment should be 
entered in the medical history in the eCRF. Any medical occurrence after the first dose with 
study treatment until 30 days after the last dose of study treatment that meet the AE definition 
must be recorded as an AE in the eCRF. Laboratory abnormalities designated clinically 

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significant by the investigator will also be documented as AEs. Additional important 
requirements for AE and SAE reporting are explained in Section 11.4 
7.1.1.8. 
Physical Examination 
The Screening and End of Treatment Safety Follow-up visit physical examination will include, at 
a minimum, the general appearance of the subject, height (Screening only) and weight, and 
examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen and extremities, 
musculoskeletal system, nervous system, and lymphatic system. A limited symptom-directed 
physical examination is required at Day 1 of Cycle 1 and 2, Day 15 of Cycle 1, as well as Day 1 
of each odd cycle starting at Cycle 3, Response Evaluation Visits and Treatment Termination 
and should include assessment of the lymphatic system, liver and spleen. See time points as 
specified in the Schedule of Assessments (Appendix A) 
7.1.1.9. 
Eye-related Symptom Assessment 
The subjects will be asked about eye-related symptoms at Screening and during each physical 
examination. See time points as specified in the Schedule of Assessments (Appendix A). 
If there are any eye-related symptoms of severity Grade ≥2 at Screening or if the subject 
develops any eye-related symptoms of severity Grade ≥2 while on study treatment, an 
ophthalmologic evaluation/consult must be performed and the outcome must be reported on the 
ophthalmologic eCRF. 
7.1.1.10. 
B-Symptoms 
The subject will be asked about the occurrence of B-symptoms at Screening and at every 
Response Evaluation Visit. See time points as specified in the Schedule of Assessments 
(Appendix A). At Screening, collection of B-symptoms will include unexplained weight loss 
>10% within the last 6 months, unexplained fever >38°C for at least 3 consecutive days within 
the last 3 months, and drenching night sweats within the last 3 months. At every Response 
Evaluation Visit, collection of B-symptoms will include unexplained weight loss >10% within 
the last month, unexplained fever >38°C for at least 3 consecutive days within the last month, 
and drenching night sweats within the last month. Any new or worsening of a pre-existing B-
symptom should be recorded as an AE. 
7.1.1.11. 
ECOG 
The ECOG performance status index is provided in Appendix B. The ECOG performance status 
will be assessed at time points specified in the Schedule of Assessments (Appendix A). 

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7.1.1.12. 
Vital Signs 
Vital signs will include blood pressure, heart rate, and body temperature and will be assessed at 
time points specified in the Schedule of Assessments (Appendix A). Blood pressure should be 
obtained after the subject has been resting in the sitting position for at least 3 minutes. 
7.1.1.13. 
Patient Reported Outcomes (PRO) 
The PRO instrument FACT-Lym (Appendix H), will be administered to all randomized subjects 
in this study. These questionnaires are to be completed by the subject prior to any other study 
procedures at time points specified in the Schedule of Assessments (Appendix A). 
The purpose of the FACT-Lym questionnaire is to provide an assessment of the subject's own 
functional status, well-being and lymphoma symptoms over time. The FACT-Lym was 
originally developed to assess functional status and well-being of patients with non-Hodgkin 
lymphoma (Eremenco 2004). Reliability and validity have been assessed in non-Hodgkin 
lymphoma (Webster 2005). The FACT-Lym consists of the Functional Assessment of Cancer 
Therapy - General (FACT-G) and a lymphoma specific additional concerns subscale (Lym). 
Responses to all items are rated on a 5-point scale ranging from 0 "not at all” to 4 "very much”. 
The FACT-G consists of three 7 item subscales scored 0 to 28 (physical well-being, social well-
being, and functional well-being) plus one 6 item subscale (emotional well-being) scored 0 to 24. 
The recall period is the past 7 days. The lymphoma scale includes 15 items and scores range 
from 0 to 60. Two summary scores may also be calculated: the FACT-Lym total score (FACT-G 
plus Lym) and the FACT-Lym trial outcome index (TOI) score (physical wellbeing+functional 
well-being+lymphoma). The subscale of most interest in this study will be the Lym subscale. 
Carter et al (Carter 2008) and Cella et al (Cella 2005) reported a minimal important change score 
for the Lym subscale in a relapsed/refractory MCL population range from approximately 2.9 to 
5.4. Therefore, a 5-point change in the Lym subscale was selected as a conservative estimate of 
clinically meaningful deterioration in lymphoma symptoms. Time to complete the FACT-Lym is 
approximately 7 to 12 minutes. All translations not currently available will be completed 
according to best practices guidelines (Wild 2005). 
7.1.2. 
Laboratory 
7.1.2.1. 
Hematology 
Hematology parameters will include a complete blood count: white blood cells, red blood cells, 
hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils. 
Hematology parameters will be evaluated using a central laboratory at time points specified in 
the Schedule of Assessments (Appendix A). 
7.1.2.2. 
Chemistry (Serum) 
Serum chemistry parameters will include sodium, potassium, chloride, blood urea nitrogen 
(BUN)/ urea, creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline 

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phosphatase, total bilirubin, LDH, phosphate, bicarbonate and uric acid. Serum chemistry 
parameters will be evaluated using a central laboratory at time points specified in the Schedule of 
Assessments (Appendix A). 
7.1.2.3. 
Coagulation Studies 
Measurement of PT/INR and aPTT will be evaluated using a central laboratory at time points 
specified in the Schedule of Assessments (Appendix A). 
7.1.2.4. 
Hepatitis Serologies 
Hepatitis serologies include hepatitis C antibody, hepatitis B surface antigen, and hepatitis B 
core antibody and will be evaluated using a central laboratory. If hepatitis B core antibody, 
hepatitis B surface antigen, or hepatitis C antibody is positive, then PCR to quantitate hepatitis B 
DNA or hepatitis C RNA must be performed and must be negative prior to randomization. In 
equivocal cases, hepatitis B or C PCR will be performed using a central laboratory and must be 
negative for enrollment. 
7.1.2.5. 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose. 
Urinalysis will be performed using a local laboratory at time points specified in the Schedule of 
Assessments (Appendix A). 
7.1.2.6. 
Pregnancy Test 
Serum or urine pregnancy test will be required at Screening by local laboratory only for women 
of reproductive potential. A serum or urine pregnancy test will also be performed on Day 1 prior 
to first dose. If positive, pregnancy must be ruled out by ultrasound to be eligible. A urine 
pregnancy test will be conducted using a local laboratory at time points specified in the Schedule 
of Assessments (Appendix A); if a time point is missed this can be performed at next visit. This 
test may be performed more frequently if required by local regulatory authorities.  
7.1.3. 
Diagnostics/Procedures 
7.1.3.1. 
Electrocardiograms (ECGs) 
Electrocardiograms (ECGs) should be performed at the investigator's discretion, particularly in 
subjects with arrhythmic symptoms (e.g., palpitations, lightheadedness, atrial fibrillation) or new 
onset dyspnea. 
During visits in which both ECGs and blood draws are performed, ECGs should be performed 
first. At Screening and at the End of Treatment Safety Follow-up visit, a 12-lead ECG will be 
done in triplicate (≥1 minute apart). Subjects should be in a supine position and resting for at 

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least 10 minutes before obtaining the ECGs. Abnormalities noted at Screening should be 
included in the medical history.  
7.1.3.2. 
Radiographic Imaging Assessments (CT/MRI) 
Pretreatment tumor assessment will be performed within 60 days before randomization, at the 
latest prior to the first dose of study treatment. A CT scan (with contrast unless contraindicated) 
of the neck, chest, abdomen, and pelvis and any other disease sites and a PET scan are required 
for the pretreatment tumor assessment. Information on extranodal involvement (e.g., gastric or 
ocular disease) will also be recorded in the source documents. Lesions in anatomical locations 
that are not well visualized by CT may be measured by MRI instead. 
In the case where CT with contrast is contraindicated, an alternative would be MRI with 
gadolinium contrast of the abdomen and pelvis and CT of the chest and neck without contrast. In 
this case, neck nodes cannot be used as target lesions. Subjects who have baseline target lesions 
identified by neck CT obtained with contrast and then cannot receive contrast for a post-dose 
neck CT will have the involved target lesions included in the response assessment. 
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 to the imaging vendor, 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 (e.g., central imaging vendor). At the Sponsor's discretion, 
the Sponsor or its designee may conduct an independent review of the scans for disease response 
evaluation. 
7.1.3.3. 
Positron Emission Tomography (PET) Scan 
Whole body FDG-PET scan (skull base to the proximal femur) will be performed for Screening 
purpose up to 60 days before randomization, at the latest prior to the first dose of study treatment 
and should be considered at the time of maximal tumor reduction to confirm CR if the scan was 
positive or indeterminate at Screening. 
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7.1.3.4. 
Tumor Tissue Biopsy (Optional) 
It is strongly recommended that a fresh tumor biopsy (excision, core needle biopsy, or fine 
needle aspiration) should be collected at disease progression for biomarker assessments. 
7.1.3.5. 
Bone Marrow Biopsies and Aspirate for Bone Marrow Involvement  
At Screening or up to 60 days before randomization or prior to first study treatment dose at the 
latest, a unilateral bone marrow core biopsy must be obtained and a sample should be sent to the 
local laboratory for bone marrow involvement assessment and to the central laboratory if 
samples are available. In cases where the bone marrow core biopsy cannot be obtained due to 
access related or patient condition related issues the bone marrow aspirate sample should be 
obtained instead. The Screening bone marrow biopsy/aspirate will be assessed at a local 
pathology laboratory (by the site) to determine bone marrow involvement with lymphoma. 
To confirm CR if bone marrow involvement was positive or indeterminate at Screening, bone 
marrow core biopsy, or aspirate if biopsy not possible, assessments should be performed in a 
local laboratory. A sample of the bone marrow biopsy or aspirate should be sent to the central 
laboratory for central review if available. It is preferable that the bone marrow biopsy or aspirate 
be performed within 30 days of initial documentation of CR. 
The following material will be sent to the central laboratory at Screening for all subjects and to 
confirm CR if bone marrow was positive at Screening: 
• Any remaining bone marrow core biopsy for potential confirmation of bone marrow 
involvement 
• Any remaining bone marrow aspirate for potential confirmation of bone marrow 
involvement  
• Copies of redacted pathology reports for contemporaneous samples reviewed locally 
 
Refer to the laboratory manual for instructions on collecting and processing of these samples. 
7.1.3.6. 
Bone Marrow Aspirate and Blood Samples for Minimal Residual Disease 
(MRD) 
Assessment of MRD in bone marrow aspirate 
In subjects with positive bone marrow involvement by histology at baseline (Screening), samples 
of bone marrow aspirate will be collected for MRD analysis. The bone marrow aspirates (bone 
marrow core biopsies are not suitable for MRD analysis due to calcification) will be sent to a 
central laboratory for MRD analysis. Bone marrow aspirates for MRD will be collected as follows: 
1) At Screening or up to 60 days before randomization or prior to the first study treatment dose at 
the latest; 2) At the time of radiographic complete response (CR), preferably within 30 days of 
initial documented CR. 

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Assessment of MRD in peripheral blood 
Samples of peripheral blood will be collected for MRD analysis for all enrolled subjects. The 
peripheral blood samples will be sent to a central laboratory for MRD analysis. Peripheral blood 
for MRD analysis will be collected as follows: 1) At Screening or Cycle 1 Day 1 Pre-dose; 2) At 
clinical complete response (CR); 3) At every disease assessment visit (every 16 weeks until 
Cycle 37, then every 24 weeks thereafter) after first CR visit. 
Peripheral blood MRD samples should also be collected in patients who meet the criteria for a 
CR based on CT scan (clinical complete response), however, are unable to undergo a bone 
marrow biopsy in order to analyse MRD after potential CR as per Appendix G. 
MRD-negative is defined as undetectable MRD in a bone marrow aspirate and/or peripheral 
blood from each subject who has achieved a clinical complete response. 
MRD-positive relapse is defined as a detectable increase in disease, in a peripheral blood and/or 
bone marrow aspirate sample. 
Refer to the laboratory manual for instructions on collecting and processing of these samples. 
7.1.4. 
Pharmacokinetics/Biomarkers 
7.1.4.1. 
Pharmacokinetics 
Plasma concentrations of ibrutinib and metabolite PCI-45227 and serum concentrations of 
rituximab will be determined using validated analytical methods. Other potential metabolites of 
ibrutinib may be explored. Refer to the Schedule of Assessments (Appendix A) and the 
Pharmacokinetic Sample Schedules (Table 7 and Table 8). Refer to the laboratory manual for 
instructions on collecting and processing these samples.  
On the days of study drug PK sampling, the clinical staff will instruct the subject to not take their 
study drug before arrival at the clinic (i.e., Cycle 1, Day 22 and Cycle 3, Day 1). Study drug 
intake will be observed by clinic staff. The actual time (versus requested time) that each sample 
is drawn must be recorded using a 24-hour format. The same clock should be used for recording 
the time of dosing. 
Table 7. 
Pharmacokinetic Sample Schedule for Study Drug (Ibrutinib/Placebo)  
Arms 
Cycle 
Day 
Pre-
dosea 
Time After Dosingb 
 
1h ± 15 min 
2 h ± 15 min 
4 h ± 30 min 
A and B 
1 
22 
X 
X 
X 
X 
3 
1 
X 
 
 
 
a. 
Pre dose samples should be collected prior to the administration of ibrutinib/placebo and rituximab 
b. 
Time after dosing of ibrutinib/placebo 
 

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Table 8. 
Pharmacokinetic Sample Schedule for Rituximab  
Arms 
Cycle 
Day(s) 
Pre-doseb 
A and B 
1 
1a, 8, 15, 22a 
X 
3 
1a 
X 
5 
1 
X 
7 
1 
X 
9 
1 
X 
11 
1 
X 
a. 
Pre dose samples should be collected prior to the administration of ibrutinib/placebo and rituximab 
b. 
Pre dose samples should be collected prior to the administration of rituximab 
 
7.1.4.2. 
Exploratory Genetic and Molecular Biomarkers 
Peripheral blood samples and a buccal swab will be collected and sent to the central laboratory at 
selected timepoints specified in the Schedule of Assessments (Appendix A). Tumor cells from 
peripheral blood, bone marrow and/or tumor tissue may be studied for gene and/or protein 
expression profiling including but not limited to Bcl-2 gene and protein expression, as well as 
gene sequencing to identify genomic alterations in BTK and other related kinases or critical 
genes. These efforts may identify biomarkers that could support the understanding of the disease 
and that could associate with response/resistance to ibrutinib treatment.  
Biological specimens collected at specified time points during the study may be used for 
pharmacodynamic and biomarker assessments including kinase activity, sequencing expression 
analysis, immunophenotyping (T cell repertoire) and secreted protein analyses.  
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 rituximab, to understand FL, to understand sensitivity or resistance to the 
investigational products tested in this study, and to develop tests/assays related to ibrutinib and 
rituximab and FL. 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. 
7.2. 
Efficacy Evaluations 
Eligible subjects must have at least 1 measurable site of disease by radiological assessment 
(Cheson 2014). Efficacy evaluations will be conducted as specified in the Schedule of 
Assessments (Appendix A) and may include the following: computed tomography (CT) scans, 
magnetic resonance imaging (MRI), positron emission tomography (PET) using [18F]-
fluorodeoxyglucose (FDG), bone marrow aspirate and biopsy, physical examination including 
lymphoma B symptoms, or other procedures as necessary. These assessments should be 

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performed throughout the study at each time point using the same method of assessment used to 
assess disease at baseline. If study drug (ibrutinib/placebo) is held before a scheduled response 
assessment, then the response assessment can be delayed up to 2 weeks to allow re-initiation of 
study drug prior to the scheduled response assessment. Images will be sent to a central imaging 
vendor. Subject self-reported lymphoma related symptoms and concerns will be measured by the 
lymphoma subscale of the FACT-Lym (Appendix H). 
Response assessments will be completed by the investigator using the revised criteria for 
malignant lymphoma described by the International Working Group for NHL (Cheson 2014). At 
Screening, up to six target lesions will be selected and will be followed for the duration of the 
study. All target lesions must be followed and mentioned in the radiology report at all subsequent 
response assessments.  
Lesions in anatomical locations that are not well visualized by CT may be measured by 
MRI instead. 
Caution must be exercised not to confuse a possible tumor flare with progressive disease. 
Delayed responses after a tumor flare have been reported in follicular lymphoma. In order to 
accommodate the potential for immune flare (pseudoprogression), treatment with study drug 
(ibrutinib/placebo) and/or rituximab (if ongoing) may continue between the initial assessment of 
suspected progression and confirmation of progression. Subjects with radiographic PD who, in 
the Investigator's opinion, continue to receive clinical benefit from their treatment may continue 
to receive study treatment as dictated in the protocol after consultation with the Medical Monitor 
and at the Investigator's discretion. In the absence of clinically significant deterioration, a CT 
scan or biopsy may be performed at least 4 weeks later to confirm PD. If PD is confirmed at the 
later time point, PD should be assigned to the prior time point at which PD criteria were also 
met. Study treatment should be discontinued if there is confirmed PD per Revised Criteria for 
Response Assessment of Malignant Lymphoma (Cheson 2014). 
Refer to Appendix G for response criteria. 
7.3. 
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 A) for the timing and frequency of all sample collections. 
Instructions for the collection, handling, and shipment of samples are found in the Laboratory 
Manual. 

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7.4. 
COVID-19 Pandemic and Geo-Political Conflict in Ukraine and Surrounding 
Impacted Countries Provisions 
The COVID-19 pandemic and geo-political conflict in Ukraine and surrounding impacted 
regions have posed significant challenges in performing protocol-specified procedures.  To 
ensure the safety of study participants and minimize risks to the integrity of the study, alternative 
methods for study assessments, activities, data collection, or study drug shipments are being 
implemented for impacted sites and study participants in these regions/countries as needed.   
Alternative methods or protocol modifications that may be employed include the following: 
Study Drug Interruption or Discontinuation: 
Delays in study drug dosing must be discussed with the sponsor medical contact, along with the 
possibility of premature discontinuation from study drug.  The investigator should contact the 
sponsor medical contact before discontinuing a subject from the study for a reason other than 
described in the protocol to ensure all acceptable mitigation steps have been explored. 
Study Drug Dispensation and/or Administration: 
If a subject is unable to come to the study site to pick up their study drug, a DTP study drug 
shipment to the subject may be made if allowed by local regulations. Follow the instructions in 
Section 5.3.1.2 for DTP shipments.  
Study Visits: 
Study visits may be impacted and include changes such as phone or virtual visits, visits at 
alternative locations, or changes in the visit frequency and timing of study procedures, among 
others.  Every effort should be made to ensure the safety of subjects and site staff, while 
maintaining the integrity of the study.  If visits cannot be conducted, discuss the next steps with 
the sponsor medical contact. 
Blood Chemistry and Hematology: 
If subjects cannot have blood drawn for laboratory testing at the study site (i.e., due to travel 
restrictions, changes in local regulations, etc.), if possible, arrange for subjects to have laboratory 
work done at a local laboratory, hospital, or other facility.  Local laboratory results should be 
obtained along with reference ranges and kept within the subjects' source documentation.  The 
investigator should review local laboratory results as soon as possible. 
If laboratory samples cannot be obtained, study drug administration may be continued, provided 
the investigator has reviewed all prior laboratory results and confirms and discusses with the 
subject that there is no safety concern for the subject to continue use of the study drug in the 
absence of current laboratory results.   

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8. 
STUDY PROCEDURES 
The study is divided into a Screening Phase, a Treatment Phase, and a Follow-up Phase. The 
Schedule of Assessments (Appendix A) summarizes the frequency and timing of efficacy, PK, 
and safety measurements applicable to this study. All subjects enrolled will undergo the same 
study procedures throughout the study unless otherwise noted. 
Screening procedures will be performed up to 28 days before randomization, unless otherwise 
specified. All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF 
before any study-specific screening procedures are performed. After signing the ICF, completing 
all screening procedures, and being deemed eligible for entry, subjects will be randomized. 
Procedures that are performed prior to the signing of the ICF and are considered standard of care 
may be used as screening assessments if they fall within the screening window. Central 
laboratory results will be used for confirmation of eligibility. Only in the event of unresulted 
analyses will local laboratory results be acceptable to confirm eligibility. 
8.1. 
Screening/Consenting Visit 
The ICF must be signed before any study-specific screening procedures are performed. The 
following procedures will be performed during the Screening Visit within 28 days prior to 
randomization, unless otherwise noted: 
• Medical history including demographic information 
• Determination of FLIPI-1 score 
• Obtain a bone marrow aspirate and core biopsy if not performed within 60 days prior to 
the randomization for bone marrow involvement and MRD testing as described in 
Section 7.1.3.5 and Section 7.1.3.6. The procedure can be performed prior to first dose of 
study treatment at the latest. 
• Collect blood sample for MRD baseline. The procedure can be performed prior to first 
dose of study treatment at the latest. 
• Complete physical exam including height and weight (may use prior height measurement 
if available in source documents) 
• Eye-related symptom assessment 
• B-symptoms assessment 
• Obtain vital signs (including blood pressure, heart rate, and body temperature) after the 
subject has rested in the sitting position for ≥ 3 minutes 
• Evaluation of ECOG performance status 
• Obtain triplicate 12-lead ECG (≥1 minute apart) after the subject has been in a supine 
position and resting for at least 10 minutes 
• Record prior medication history including over-the-counter drugs, vitamins and herbs  
• Record any adverse events since signing the ICF 

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• Imaging by CT or other modality as described in Section 7.1.3.2 if not performed within 
60 days prior to randomization  
• Imaging by PET as described in Section 7.1.3.3 if not performed within 60 days prior to 
randomization  
• Collect blood and urine samples for the following clinical laboratory tests: 
o Hematology 
o Serum chemistry 
o Coagulation (PT/INR, aPTT) 
o Serum or urine pregnancy test (for women of reproductive potential only) 
o Hepatitis serologies 
o Urinalysis 
• Calculation of creatinine clearance using Cockcroft-Gault or creatinine clearance 
calculated based on 24-hour urine collection. The 24-hour urine collection may be 
evaluated by a local laboratory. 
• Obtain tumor tissue biopsy for confirmation of diagnosis  may be archival. Slides or 
tumor block may be either new or from a previous biopsy and any remaining sample may 
be used for biomarker evaluation. See Section 7.1.3.4 for additional details. 
• Confirm eligibility (per inclusion/exclusion criteria in Section 4) and randomize subject 
via the IXRS. Dosing should occur within 72 hours of randomization. 
8.2. 
Treatment Phase 
Following completion of the Screening Visit and once eligibility has been confirmed, subjects 
will be randomized via an automatic IXRS or alternative system provided by the Sponsor. 
Randomization should occur as close to the time of the expected first dose as possible and not 
more than 72 hours prior to expected first dose of study treatment. 
Study treatment should be continued until disease progression, unacceptable treatment-related 
toxicity, or other reasons outlined in Section 9.2 and Section 9.3. Local laboratory results may be 
used to guide all dosing-related decisions. In the event of clinically suspected disease 
progression, the subject should continue to receive study treatment until disease progression is 
confirmed by Investigator using the revised criteria for malignant lymphoma described by the 
International Working Group for NHL (Cheson 2014). 
Refer to the Schedule of Assessments (Appendix A) for a complete list of procedures to be 
performed at each scheduled study visit. 
8.2.1. 
Treatment Visits 
8.2.1.1. 
Cycle 1, Day 1 
The last measurements taken on Day 1 of Cycle 1 before administration of study treatment or at 
Screening (whichever value is last) will be defined as baseline for safety assessments and 

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treatment decisions. Screening evaluations and laboratory values that were obtained prior to 
Day 1 of Cycle 1 may be used as baseline assessments if they were collected within 7 days of the 
start of study treatment.  
Pre-dose 
• PRO assessment 
• Limited symptom-directed physical exam including weight and eye-related symptom 
assessment and evaluation of lymphatic system, liver and spleen.  
• Evaluation of ECOG performance status 
• Vital signs including blood pressure, heart rate, and body temperature 
• Review of concomitant medications 
• Collect blood and urine samples for the following clinical laboratory tests (This applies to 
clinical laboratory tests in all visits): 
o Hematology 
o Serum chemistry 
o Serum or urine pregnancy test (for women of reproductive potential only) 
• Obtain research laboratory samples for: 
o Buccal swab 
o Blood sample for rituximab PK 
o Blood sample for MRD baseline if not done during Screening 
Dosing and Post-Dose 
• Dispense study drug (ibrutinib/placebo) 
• In-clinic administration of study drug as soon as the subject comes into clinic and after 
pre-dosing procedures. Pre-medications and rituximab will then be administered. 
• In-clinic administration of rituximab 
• Record any AEs and concomitant medications 
8.2.1.2. 
Cycle 1, Day 8 
Pre-dose 
• Review of AEs and concomitant medications 
• Collect blood samples for the following clinical laboratory tests: 
o Hematology 
o Serum chemistry 
• Obtain research laboratory blood samples for: 
o Rituximab PK 

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Dosing and Post-Dose 
• In-clinic administration of rituximab 
• Review of AEs and concomitant medications 
8.2.1.3. 
Cycle 1, Day 15 
Pre-dose 
• Limited symptom-directed physical exam including weight and eye-related symptom 
assessment and evaluation of lymphatic system, liver and spleen.  
• Evaluation of ECOG performance status 
• Vital signs 
• Review of AEs and concomitant medications 
• Collect blood samples for the following clinical laboratory tests: 
o Hematology 
o Serum chemistry 
• Obtain research laboratory blood samples for: 
o Rituximab PK 
Dosing and Post-Dose 
• In-clinic administration of rituximab 
• Review of AEs and concomitant medications 
8.2.1.4. 
Cycle 1, Day 22 
Pre-dose 
• Review of AEs and concomitant medications 
• Collect blood samples for the following clinical laboratory tests: 
o Hematology 
o Serum chemistry 
• Obtain research laboratory blood samples collected for: 
o Study drug (ibrutinib/placebo) PK 
o Rituximab PK 
Dosing and Post-Dose 
• In-clinic administration of study drug as soon as the subject comes into clinic and after 
pre-dosing procedures. Pre-medications and rituximab will then be administered. 
• In-clinic administration of rituximab 

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• Obtain research laboratory blood samples collected for: 
o Study drug pharmacokinetics (1, 2 and 4 hours after administration of study drug). 
See Table 7 in Section 7.1.4.1 for additional details. 
• Review of AEs and concomitant medications 
8.2.1.5. 
Cycle 2, Day 1 
Pre-dose 
• Limited symptom-directed physical exam including weight and eye-related symptom 
assessment and evaluation of lymphatic system, liver and spleen.  
• Evaluation of ECOG performance status 
• Vital signs 
• Collect blood samples for the following clinical laboratory tests: 
o Hematology 
o Serum chemistry 
• Review of AEs and concomitant medications 
• Drug accountability 
• Dispense study drug 
8.2.1.6. 
Cycle 3, Day 1 
Pre-dose 
• PRO assessment 
• Limited symptom-directed physical exam including weight and eye-related symptom 
assessment and evaluation of lymphatic system, liver and spleen.  
• Evaluation of ECOG performance status 
• Vital signs 
• Review of AEs and concomitant medications 
• Collect blood and urine samples for the following clinical laboratory tests: 
o Hematology 
o Serum chemistry 
o Urine pregnancy test (every 8 weeks from Day 1 [or at the closest associated visit] for 
women of reproductive potential only) 
• Obtain research laboratory blood samples collected for: 
o Study drug pharmacokinetics 
o Rituximab pharmacokinetics 

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Dosing and Post-Dose 
• Drug accountability 
• In-clinic administration of study drug as soon as the subject comes into clinic and after 
pre-dosing procedures. Pre-medications and rituximab will then be administered. 
• In-clinic administration of rituximab 
• Review of AEs and concomitant medications 
8.2.1.7. 
Cycle 5, Day 1: First Response Evaluation Visit 
Pre-dose 
• PRO assessment 
• Limited symptom-directed physical exam including weight and eye-related symptom 
assessment and evaluation of lymphatic system, liver and spleen.  
• Evaluation of ECOG performance status 
• Vital signs 
• B-symptom assessment 
• Review of AEs and concomitant medications 
• Collect blood and urine samples for the following clinical laboratory tests: 
o Hematology 
o Serum chemistry 
o Urine pregnancy test (every 8 weeks from Day 1 [or at the closest associated visit] for 
women of reproductive potential only) 
• Obtain research laboratory blood samples collected for: 
o Rituximab pharmacokinetics  
• Imaging by CT/MRI  
• Overall Response Assessment 
• To confirm a suspected CR: 
o Imaging by PET to confirm CR if screening PET was positive 
o Bone marrow core biopsy or aspirate if biopsy not possible, to confirm CR (local 
testing and if samples available, potentially central) as well as aspirate for central 
MRD assessment, if there was evidence of lymphoma involvement in the bone 
marrow at baseline by histology 
• For subjects achieving a CR, research laboratory blood sample collected for: 
o Determination of MRD by peripheral blood assessment is repeated at each response 
evaluation visit  
Dosing and Post-Dose 
• Drug accountability 
• Dispense study drug 

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• In-clinic administration of rituximab 
• Review of AEs and concomitant medications 
8.2.1.8. 
Cycles 7 – 25 (odd cycles only), Day 1 
Pre-dose 
• Limited symptom-directed physical exam including weight and eye-related symptom 
assessment and evaluation of lymphatic liver and spleen.  
• Evaluation of ECOG performance status 
• Vital signs 
• Review of AEs and concomitant medications 
• Collect blood and urine samples for the following clinical laboratory tests: 
o Hematology 
o Serum chemistry 
o Urine pregnancy test (every 8 weeks from Day 1 [or at the closest associated visit] for 
women of reproductive potential only) 
• (Cycle 7, 9, and 11 only) Obtain research laboratory blood samples collected for: 
o Rituximab pharmacokinetics  
Dosing and Post-Dose 
• Drug accountability 
• Dispense study drug 
• In-clinic administration of rituximab 
• Review of AEs and concomitant medications 
NOTE: For cycle visits aligning with response assessment visits, see also Section 8.2.1.10 for the 
full list of assessments to be completed. Assessments are to be performed only one time for a 
given visit (i.e., only one set of vital signs needs to be obtained if a regularly scheduled visit is 
also a response evaluation visit). 
8.2.1.9. 
Cycles 27 until Treatment Termination (odd cycles only), Day 1  
• Limited symptom-directed physical exam including weight and eye-related symptom 
assessment and evaluation of lymphatic system, liver and spleen.  
• Evaluation of ECOG performance status 
• Vital signs 
• Review of AEs and concomitant medications 
• Collect blood and urine samples for the following clinical laboratory tests: 
o Hematology 
o Serum chemistry 

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o Urine pregnancy test (every 8 weeks from Day 1 [or at the closest associated visit] for 
women of reproductive potential only) 
• Drug accountability 
• Dispense study drug 
NOTE: For cycle visits aligning with response assessment visits, see also Section 8.2.1.10 for the 
full list of assessments to be completed. Assessments are to be performed only one time for a 
given visit (i.e., only one set of vital signs needs to be obtained if a regularly scheduled visit is 
also a response evaluation visit). 
8.2.1.10. 
Response Evaluation Visits  
Response assessments will be performed every 4 Cycles or 16 weeks (±7 days) starting at 
Cycle 5 until completion of the Cycle 37 Visit and then every 6 Cycles or 24 weeks (±7 days) 
thereafter until Treatment Termination. All visits will be scheduled in relation to Cycle 1 Day 1. 
Visit windows are relative to the Cycle 1 Day 1 visit date.  
Response assessment visits on an every 16-week schedule will occur as follows: Cycle 5, 9, 13, 
17, 21, 25, 29, 33, and 37. Response assessment visits on an every 24-week schedule will begin 
with Cycle 43 and continue every 6 cycles as follows: Cycle 49, 55, 61, 67, 73, 79, 85, 91, 97, 
103, etc. 
The following procedures will be performed: 
• PRO assessment 
• Limited symptom-directed physical exam including weight and eye-related symptom 
assessment and evaluation of lymphatic system, liver and spleen.  
• Evaluation of ECOG performance status 
• Vital signs 
• B-symptom assessment 
• Review of AEs and concomitant medications 
• Collect blood and urine samples for the following clinical laboratory tests: 
o Hematology 
o Serum chemistry 
o Urine pregnancy test (every 8 weeks from Day 1 [or at the closest associated visit] for 
women of reproductive potential only) 
• Drug accountability 
• Dispense study drug 
• Imaging by CT/MRI  
• Overall response assessment 
• To confirm a suspected CR: 
o Imaging by PET to confirm CR if screening PET was positive 

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o Bone marrow core biopsy, or aspirate if core biopsy not possible, to confirm CR 
(local testing and if samples available, potentially central) as well as aspirate for 
central MRD assessment, if there was evidence of lymphoma involvement in the bone 
marrow at baseline by histology 
• For subjects achieving a CR, research laboratory blood sample collected for: 
o Determination of MRD by peripheral blood assessment is repeated at each response 
evaluation visit after CR is achieved  
8.2.2. 
Suspected PD and/or Treatment Termination Visit  
The suspected PD or treatment termination visit should be performed at any time during the 
study, if based on clinical evaluation, the investigator suspects PD, or if the subject discontinues 
treatment for any other reason. If the subject comes in for a regular study visit and the 
investigator wants to discontinue treatment at that time, the regular visit will become the 
termination visit. Any additional procedures that would not be performed for the regular study 
visit should be performed for the treatment termination visit. The suspected PD visit may be 
repeated during the course of the study if PD is not confirmed. Each subject will have only one 
treatment termination visit.  
The following procedures will be performed: 
• PRO assessment 
• Limited symptom-directed physical exam including weight and eye-related symptom 
assessment and evaluation of lymphatic system, liver and spleen. 
• Evaluation of ECOG performance status 
• Vital signs 
• Review of AEs and concomitant medications 
• Collect blood samples for the following clinical laboratory tests: 
o Hematology 
o Serum chemistry 
o Coagulation  
• Optional tumor tissue biopsy (Section 7.1.3.4): It is strongly recommended that a fresh 
tumor tissue biopsy (excision, core needle biopsy, or fine needle aspiration) should be 
collected at disease progression for biomarker assessments. 
• CT or MRI (if clinically indicated) 
• Overall response assessment 
• Drug accountability 
• For subjects achieving a CR, research laboratory blood sample collected for: 
o Determination of MRD by peripheral blood assessment for subjects terminating 
treatment for reasons other than disease progression. 

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8.2.3. 
End of Treatment Safety Follow-up Visit  
A Safety Follow-up visit should occur 30 days (±7 days) from the last dose of study treatment or 
prior to the start of a new anticancer treatment. If the subject starts a new anticancer treatment 
less than 7 days after the treatment termination visit, only those procedures not conducted at the 
treatment termination visit should be performed at the Safety Follow-up visit.  
Subjects who withdraw consent to treatment may still participate in Safety Follow-up. 
The following procedures will be performed at the Safety Follow-up visit: 
• Complete physical exam including weight and eye-related symptom assessment 
• Evaluation of ECOG performance status 
• Vital signs 
• Review of AEs and concomitant medications 
• 12-lead ECG (in triplicate [≥1 minute apart]) 
• Collect blood samples and urine for the following clinical laboratory tests: 
o Hematology 
o Serum chemistry 
o Coagulation 
o Urine pregnancy test (for women of reproductive potential only) 
o Urinalysis 
8.3. 
Follow-up Phase  
Once a subject has completed the End of Treatment Safety Follow-up visit they will enter the 
Follow-up Phase. Subjects that discontinue treatment for reasons other than progressive disease 
and full withdrawal of consent will participate in ongoing response follow-up. 
8.3.1. 
Response Follow-up 
Subjects who discontinue the study for reasons other than PD through Cycle 37 will be followed 
every 16 weeks until the date that would have corresponded to the planned Cycle 37 and then 
every 24 weeks (±7 days) from the last CT or MRI scan until PD, up to the end of the study. 
Subjects who discontinue the study for reasons other than PD after Cycle 37 will be followed 
every 24 weeks (±7 days) from last CT or MRI scan until PD, up to the end of the study. During 
this period, scans and related response evaluation assessments will be carried out as follows: CT 
scan for target, non-target, and new lesion assessment, radiographic spleen and liver assessment, 
and overall disease assessment. In cases where the subject is being evaluated for CR, the 
following should also be performed: PET scan to confirm CR; bone marrow disease assessment 
to confirm CR; and MRD central lab upon CR.  

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8.3.2. 
Survival Follow-Up, Subsequent Anticancer Therapy Collection, and Long-
term Surveillance of Other Malignancies  
Once a subject progresses (for subjects who have not withdrawn consent for follow-up), he/she 
will be contacted approximately every 24 weeks (±7 days) from the last dose by clinic visit or 
telephone to assess survival for up to the end of the study. Subsequent anticancer therapies, best 
response to therapy, and information about other malignancies will be collected. Subjects will be 
contacted until death, subject withdrawal, lost to follow-up, or study termination by the Sponsor, 
whichever occurs first. 
8.3.3. 
Missed Evaluations 
Missed evaluations should be rescheduled and performed as close to the original scheduled date 
as possible. An exception is made when rescheduling becomes, in the investigator's opinion, 
medically unnecessary or unsafe because it is too close in time to the next scheduled evaluation. 
In that case, the missed evaluation should be abandoned. 
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: 
• Progressive disease  
• Unacceptable toxicity: an intercurrent illness or AE that prevents further administration 
of study treatment or completion of rituximab dosing during induction phase  
• Withdrawal of consent for treatment by subject 
• Investigator decision (such as chronic noncompliance, significant protocol deviation, or 
best interest of the subject) 
• Study termination by Sponsor 
• 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/or survival.  
The investigator should notify the Sponsor within 24 hours if a subject discontinues study 
treatment (ibrutinib/placebo and/or rituximab) due to disease progression and should provide 
documentation of disease progression for review by the Medical Monitor. If a subject shows 
signs of disease progression on physical examination or laboratory assessment, the subject 

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should continue study treatment until disease progression is confirmed by the investigator using 
the revised criteria for malignant lymphoma described by the International Working Group for 
NHL (Cheson 2014). These subjects should stay in the study to be followed for survival.  
9.3. 
Withdrawal from Study 
Withdrawal from study (including all follow-up) will occur under the following circumstances: 
• Withdrawal of consent for follow-up observation by the subject 
• Lost to follow-up 
• Study termination by Sponsor 
• Death 
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: 
• Reason for withdrawal 
• Whether the subject withdraws full consent (i.e., withdraws consent to treatment and all 
further contact) or partial consent (i.e., withdraws consent to treatment but agrees to 
participate in follow-up visits). 
10. 
STATISTICAL METHODS AND ANALYSIS 
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan. 
This study evaluates ibrutinib + rituximab (Arm A) vs. placebo + rituximab (Arm B) with 
2 interim analyses and the primary analysis planned when the study observes 200 PFS events, or 
if pre-specified boundaries are crossed at an interim analysis. The final analysis for OS is 
planned when 165 OS events are observed or five years after enrollment of the last subject, 
whichever is earlier. 
10.1. 
Subject Information 
10.1.1. 
Intent-to-Treat (ITT) Population 
The ITT population consists of all subjects randomized. The ITT population will be the primary 
population for all efficacy analyses. All the subjects will be analyzed according to the treatment 
arms to which they are randomized.  

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10.1.2. 
Safety Population 
The Safety population consists of all subjects who received at least 1 dose of study treatment 
(rituximab, ibrutinib/placebo). 
10.1.3. 
Pharmacokinetic Population  
All subjects who received at least 1 dose of study treatment and had at least one post-treatment 
sample obtained. 
10.2. 
Endpoints  
10.2.1. 
Primary Endpoint 
• Progression-free survival (PFS) 
10.2.2. 
Secondary Endpoints 
• Overall response rate (ORR) (Cheson 2014) 
• Overall survival (OS)  
• Infusion-related reaction rate (Arm A vs. Arm B) 
• Duration of response (DOR) as assessed by investigator 
• Frequency, severity, seriousness, and relatedness of adverse events (AEs) 
10.2.3. 
Exploratory Endpoints  
• Health-related quality of life (QOL) as measured by the FACT-Lym  
• Pharmacokinetic parameters or metrics of systemic exposure of ibrutinib and rituximab 
• Evaluation and/or identification of relevant patient populations defined by biomarker(s)  
• Minimal residual disease (MRD)-negative rate defined as the proportion of FL subjects 
who reach MRD-negative disease status 
• Complete response rate at 30 months (CR30) as defined by the International Working 
Group (IWG) Revised Response Criteria for Malignant Lymphoma (Cheson 2014) 
10.3. 
Sample Size Determination 
Sample Size Consideration for PFS 
A sample size of approximately 440 subjects will be randomized to Arms A and B to evaluate 
whether Arm A will result in prolongation of progression-free survival (PFS) when compared to 
Arm B in treatment naïve subjects with follicular lymphoma. The sample size is determined 
according to the Group Sequential Design. For this calculation, the references used for the 
assumptions were Hainsworth 2002, Ghielmini 2004, Zucca 2019, and Fowler 2020. Assuming 
exponential survival distribution for the PFS events and 66.7% improvement in median PFS of 
Arm A over Arm B (a hazard ratio [HR] of 0.60), the study has ~ 87% power with 200 observed 

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PFS events using an overall 1-sided significance level of 0.025. For the sample size calculation, a 
median PFS of 28 months in the control arm, the actual enrollment rates using the 3-month 
average until November 2020, and a projected enrollment rate of 8 subjects per month afterwards 
were used. Two interim analyses are planned with the first interim analysis (IA1) for futility and 
the second interim analysis (IA2) for efficacy. The first interim analysis (IA1, futility) will be 
conducted when approximately 55% of the 200 PFS events have occurred. The futility boundary 
is based on a Rho parameter of 5. The second interim analysis (IA2) for efficacy is planned after 
approximately 75% of the 200 PFS events (ie, 150 PFS events) are observed and after the last 
subject has been enrolled, with approximately 90% of the subjects reaching at least 1 year of 
study follow-up. The efficacy boundary is based on the unequally weighted Bonferroni method 
allocating 1-sided alpha of 0.001 to IA2 and 0.024 to the primary analysis (PA) (Table 9). 
Table 9. 
Futility and Efficacy Boundaries for Interim Analysis for PFS 
Look # 
Info. 
Fraction 
Events 
Cum. 1-sided α 
Spent 
Boundary (1-sided p-value) 
Efficacy 
Futility 
1 
0.55 
110 
0 
NA 
0.5596 
2 
0.75 
150 
0.001 
0.001 
NA 
3 
1 
200 
0.025 
0.024 
0.024 
 
Power Consideration for ORR 
For ORR if we assume a response rate of 0.57 (Zucca 2019) in Arm B and a response rate of 
0.73 (PCYC-1125-CA;Fowler 2020) in Arm A, then the power will be approximately 85% for a 
1-sided alpha of 0.025 and sample size of 440. 
Power Consideration for OS 
The final analysis for OS is planned when 165 OS events are observed or five years after 
enrollment of the last subject, whichever is earlier. The study has ~80% power for the OS 
analysis at an overall 1-sided alpha of 0.025 when 165 OS events have occurred. An interim 
analysis for OS will be conducted at the time of the primary analysis of PFS when the superiority 
boundaries for PFS and ORR are crossed. It is anticipated that 140 and 165 OS events in total 
will be observed at the interim analysis (at ~77 months, corresponding to the timing of the PFS 
PA) and the final analysis (at ~91 months), respectively. This is based on the assumption that the 
36-month OS landmark estimate is 73% for Arm B (Batlevi 2020) and 82.8% for Arm A 
(PCYC-1125-CA; Fowler 2020), i.e., a HR of 0.6 and control arm median OS of 79.29 months. 
The 1-sided alpha boundaries are 0.015 and 0.0207 at the interim analysis and final analysis, 
respectively, based on Lan-DeMets spending function with O'Brien-Fleming boundary ensuring 
control of overall type-1 error. In addition, a separate futility analysis without spending alpha is 
planned for OS at the second interim analysis, and details will be described in the SAP. The 
Sponsor may consider extending follow-up to attain more OS events to account for the impact of 
COVID-19. 

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The futility and efficacy interim analyses will be performed by the DMC. The Sponsor will 
remain blinded to the data and interim results if the study will continue. Exact alpha boundary 
will be calculated using the actual events observed at the interim analyses. Details will be 
included in the SAP.  
10.4. 
Efficacy Analysis Methods for Primary and Secondary Endpoints 
10.4.1. 
Analysis Study  
10.4.1.1. 
Primary Endpoint PFS 
Progression Free Survival, as assessed by the investigator, will be analyzed in the ITT 
population, comparing the 2 treatment arms (Arm A and Arm B) at an overall 1-sided 0.025 
significance level using the log-rank test stratified by the randomization stratification factors: age 
group, FLIPI-1 score and ECOG performance status score. Distribution of PFS will be 
summarized for each treatment arm using the Kaplan-Meier (KM) method. The estimate of the 
hazard ratio between the two arms and its corresponding 95% CI will be computed using a Cox 
proportional hazards model stratified by the randomization stratification factors. In stratified 
efficacy analysis, small strata are combined to form bigger strata with ≥10 events and 
≥40 patients in each stratum. 
PFS is defined as duration from the date of randomization to the date of first documentation of 
disease progression or date of death due to any cause, whichever is first reported, prior to the use 
of subsequent anti-cancer therapy. Subjects who initiated subsequent anti-cancer therapy before 
disease progression or death will be censored at the last adequate disease assessment before the 
use of subsequent anti-cancer therapy. Subjects who are progression-free and alive, or have 
unknown status will be censored at the last adequate disease assessment. Subjects with no 
postbaseline disease assessment will be censored at randomization date. Adequate disease 
assessment is defined as having sufficient evidence to correctly indicate that progression has or 
has not occurred.  
Supplementary/sensitivity analyses may be conducted using different censoring rules and will be 
described in the SAP.  
10.4.1.2. 
Secondary Endpoints ORR and OS 
If the primary endpoint comparison of PFS between Arms A and Arm B has demonstrated 
statistical significance, then secondary endpoints will be tested sequentially following a 
hierarchical order with ORR ranked first followed by OS.  
ORR of the two treatment arms will be compared using the Cochran-Mantel-Haenszel (CMH) 
chi-square test, stratified by the randomization stratification factors, under the hierarchical 
procedure. 

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Overall survival is defined as the interval between the date of randomization and the date of the 
subject's death from any cause. If a subject is not known to have died (this includes subject with 
unknown death date), OS will be censored at the date the subject was last known to have been 
alive. Subjects who are known to be alive as of their last known status will be censored at their 
date of last contact. Subjects who are lost to follow-up will be censored at the date the subject is 
last known to have been alive. The last known alive date will be determined by selecting the last 
available date of any study procedures.  
OS will be analyzed using the same method as for PFS. 
The details of estimand framework, stratification factors used in the stratified analysis, and other 
statistical details will be specified in the SAP. 
10.5. 
Safety Analysis 
Analysis of safety data will be conducted on the Safety Population, which includes enrolled 
subjects who receive at least 1 dose of ibrutinib/placebo or rituximab. The baseline value is 
defined as the last value collected on or prior to the first dose date of ibrutinib/placebo or 
rituximab, whichever comes first. 
The safety variables to be analyzed include exposure to ibrutinib/placebo or rituximab, AEs, 
deaths, clinical laboratory test results (hematology and chemistry), ECOG performance status 
score, physical examination, and vital sign measurements. 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.  
10.5.1. 
Adverse Events 
Adverse event parameters to be evaluated are the type, incidence, and intensity of AEs; the 
relationship of AEs to study treatment; and the action taken with respect to study treatment due 
to AEs. 
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  
The treatment-emergent period is defined as the period of time from the first dose of study 
treatment, until the earlier of:  
• Thirty days following the last dose of ibrutinib/placebo or 30 days following the last dose 
of rituximab, whichever occurs later 
OR 
• The start date of a new anticancer therapy. 
 

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The Treatment-emergent adverse events (TEAEs) are those events that: 
• Are not present prior to the treatment-emergent period and occur during the treatment-
emergent period, 
• The onset dates are missing, and end dates are during treatment-emergent period, 
• Are considered related to study drug by the investigator regardless of the start dates of the 
events, or 
• Are present prior to the treatment-emergent period but worsen in severity during the 
treatment-emergent period or are subsequently considered related to study drug by the 
investigator.  
All TEAEs will be included in the analysis. For each AE, the number and percentage of subjects 
who experience at least one occurrence of the given event will be summarized. The number and 
percent of subjects with TEAEs will be summarized according to intensity (CTCAE, v4.03) 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 severe AE or a SAE. 
10.5.2. 
Clinical Laboratory Tests 
Laboratory tests will be summarized separately for hematology and serum chemistry. Local 
laboratory results will be standardized using the International System SI unit. Selected 
hematologic and chemistry laboratory parameters are detailed in Section 7. All laboratory values 
will be graded using the NCI CTCAE v4.03. The worst toxicity grade during the study will be 
tabulated. 
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. 
10.6. 
Analysis Methods for Selected Exploratory Endpoints 
10.6.1. 
Pharmacokinetic Analysis 
The plasma concentration data for ibrutinib and PCI-45227 will be summarized using descriptive 
statistics at each time-point. Population PK analysis of plasma concentration-time data of 
ibrutinib will be performed using nonlinear mixed-effects modeling. Data may be combined with 
data from other studies to support a relevant population PK model. Available subject 
characteristics (e.g., demographics, laboratory variables, genotypes, etc.) will be tested as 
potential covariates affecting PK parameters. Details will be given in a population PK analysis 
plan and the results of the population PK analysis will be presented in a separate report.  
Ibrutinib PK data in this study will be compared to observed/reported concentration data for 
ibrutinib and/or population PK models to explore the potential for a pharmacokinetic interaction 

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between ibrutinib in combination use with rituximab. Rituximab concentration data in this study 
will be compared between two arms with and without ibrutinib to explore the potential for a 
pharmacokinetic interaction between rituximab in combination use with ibrutinib. 
For the drug combination of ibrutinib and rituximab, model-derived exposure parameters (PK 
parameters) may be used to explore PK/PD correlation between the exposure of ibrutinib and its 
active metabolites with relevant clinical or biomarker information to assess effectiveness and 
toxicity. 
10.6.2. 
Biomarker Analyses 
As an exploratory objective, subgroups defined by molecular and genetic biomarkers at baseline 
will be tested for interaction of the treatment effects over strata as a potential predictive marker. 
10.6.3. 
Patient-reported Outcomes (PRO) as Measured by FACT-Lym 
Subject compliance on PRO measure by visit, a maximum change from the baseline score, a 
change from the baseline per visit over time, and the portion of subjects who meet the particular 
post-baseline improvement/worsening criteria, if applicable, will be summarized by treatment 
arm. Time to improvement/worsening will be summarized by treatment arm. 
Analysis methods for exploratory endpoints not described above will be detailed in the SAP.  
10.7. 
Data Monitoring Committee (DMC) 
An independent DMC will be established to review unblinded data at pre-defined time points to 
ensure the continuing safety of the subjects enrolled/randomized in this study. The DMC will 
consist of at least two medical experts in relevant therapeutic area and at least one statistician. 
At least three safety review meetings are planned that will occur approximately 1 month after 
88 subjects have been randomized (20% of expected enrollment), 1 month after 220 subjects 
have been randomized (50% of expected enrollment), and 1 month after all subjects have been 
randomized. Additional meetings may be considered as needed by the DMC. The safety review 
will focus on deaths, treatment discontinuations, serious adverse events, Grade ≥3 events, and 
events of special interest. Based on the results from these scheduled safety review meetings, the 
DMC chair may request additional safety interim analyses and more frequent monitoring. 
Two interim analyses are planned, and both will be performed by the DMC. The first interim 
analysis (IA1) is for futility and is to be conducted when approximately 55% of the 200 PFS 
events have occurred. The second interim analysis (IA2) is for efficacy and is planned after 
approximately 75% of the 200 events (150 PFS events) are observed and after the last subject has 
been enrolled.  
Details on the DMC responsibilities, authorities, review process, access to unblinded data will be 
documented in the DMC charter. 

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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. 
Definitions 
11.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a subject 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 treatment, whether or not considered related to the study treatment 
(ICH-E2A 1995). 
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
The term "disease progression” should not be reported as an AE term. As an example, 
"worsening of underlying disease” or the clinical diagnosis that is associated with disease 
progression should be reported. 
Adverse events may include, but are not limited to: 
• Subjective or objective symptoms provided by the subject and/or observed by the 
investigator or study staff including laboratory abnormalities of clinical significance. 
• Any AEs experienced by the subject through the completion of final study procedures. 
• AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
were not present before the AE reporting period  
• Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies). 
The following are NOT considered AEs: 
• 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. 
• Pre-planned or elective hospitalization: A hospitalization planned before signing the 
ICF is not considered an SAE, but rather a therapeutic intervention. However, if during 

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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. 
• Diagnostic Testing and Procedures: Testing and procedures should not be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported. 
11.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) based on International Conference on Harmonisation (ICH) and 
EU Guidelines on Pharmacovigilance for Medicinal Products for Human Use is any untoward 
medical occurrence that at any dose: 
• Results in death (ie, the AE actually causes or leads to death). 
• Is life-threatening. Life-threatening is defined as an AE in which the subject 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 lifethreatening. 
• Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the subject's ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
Is an important medical event that may not result in death, be immediately lifethreatening or 
require hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the subject or subject 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. 
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) of AEs. The CTCAE v4.03 
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Should a subject experience any AE not listed in the CTCAE v4.03, the following grading 
system should be used to assess severity: 
• Grade 1 (Mild AE)  experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject's daily activities 
• 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 
• 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 
• Grade 4 (Life-threatening or disabling AE)  experiences which cause the subject to be in 
imminent danger of death 
• Grade 5 (Death-related to AE)  experiences which result in subject death 
11.1.4. 
Causality (Attribution) 
The investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study treatment 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. 
 
11.1.5. 
Serious Adverse Reactions and Suspected Unexpected Serious Adverse 
Reactions 
The following definitions will be used for Serious Adverse Reactions (SAR) and Suspected 
Unexpected Serious Adverse Reaction (SUSAR):  
SAR is defined as all noxious and unintended responses to an investigational medicinal product 
(IMP) related to any dose administered that result in an SAE as defined in Section 11.1.2. 

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SUSAR refers to individual SAE case reports from clinical trials where a causal relationship 
between the SAE and the IMP was suspected by either the sponsor or the investigator, and is 
unexpected (not listed in the applicable Reference Safety Information). 
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and 
local requirements, including reporting to the Eudravigilance database in accordance with EU 
Clinical Trial Regulation.  
11.2. 
Unexpected Adverse Events 
An "unexpected” AE is an AE that is not listed in the IB/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 IB referred only to elevated hepatic enzymes 
or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be "unexpected” 
(by virtue of greater specificity) if the IB/package insert listed only cerebral vascular accidents. 
"Unexpected” also refers to AEs that are mentioned in the IB 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. 
11.3. 
Special Reporting Situations 
Special reporting situation on a Sponsor study may require expedited reporting and/or safety 
evaluation include, but are not limited to: 
• Overdose of any study treatment 
• Suspected abuse/misuse of a study treatment 
• Inadvertent or accidental exposure to a study treatment 
• Medication error involving a product (with or without subject exposure to the study 
treatment, e.g., name confusion) 
Occurrence of any special reporting situations should be recorded in the eCRF. If any special 
reporting situation meets the criteria of an AE, it should be recorded on the AEs eCRF. If the AE 
is considered serious, it should be recorded on the AEs eCRF as serious and should be reported 
on the Serious Adverse Event Report Form. The Serious Adverse Event Report Form should be 
sent via email or fax to Pharmacyclics Drug Safety or designee within 24 hours of awareness. 
11.4. 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators 
11.4.1. 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time points 
during the study. All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, detected through physical examination, clinically significant 

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laboratory test, or other means, will be recorded in the subject's medical record and on the AEs 
CRF and, when applicable, on the Serious Adverse Event Report Form. 
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), severity, 
regulatory seriousness criteria (if applicable), suspected relationship to the investigational 
product, and any actions taken. 
11.4.2. 
Adverse Event Reporting Period 
All AEs whether serious or non-serious, will be documented from the time signed and dated ICF 
is obtained until 30 days following the last dose of study treatment. SAEs will be reported to the 
Sponsor Drug Safety via an SAE reporting form and will be recorded in the eCRF from the time 
of ICF signing. Non-serious AEs will be recorded in the source documents from the time of ICF 
signing and will be recorded in the eCRF from the first dose of study treatment. 
Serious adverse events reported after 30 days following the last dose of study treatment should 
also be reported if considered related to study treatment. Resolution information after 30 days 
should be provided.  
Progressive disease should NOT be reported as an event term, but instead symptoms/clinical 
signs of disease progression may be reported (See Section 11.1.1). 
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 (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as "upper respiratory infection”). Investigators must record in the CRF their opinion concerning 
the relationship of the AE to study therapy. All measures required for AE management must be 
recorded in the source document and reported according to Sponsor instructions. 
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself. Autopsy and postmortem reports must be 
forwarded to the Sponsor, or designee, as outlined above, if allowed per local regulatory 
guidelines. 
If a death occurs within 30 days after the last dose of study treatment, the death must be reported 
to the Sponsor as a SAE.  
11.4.3. 
Reporting Requirements for Serious Adverse Events 
All SAEs (initial and follow-up information) will be reported on the Serious Adverse Event 
Report Form and sent via email or fax to Pharmacyclics Drug Safety, or designee, within 
24 hours of the discovery of the event or information. Pharmacyclics may request follow-up and 

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other additional information from the investigator (e.g., hospital admission/discharge notes and 
laboratory results). The contact information (phone, email and fax) for Pharmacyclics Drug 
Safety can be found on the Serious Adverse Event Report Form and instructions.  
A single DSUR will be provided for all IMPs used in the clinical trial. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value/status is available 
• The event can be attributed to agents other than the study treatment or to factors unrelated 
to study conduct. 
• It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow up after 
demonstration of due diligence with follow-up efforts) 
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities 
and governing bodies according to the local regulations.  
The investigator (or Sponsor where required) must report these events to the appropriate 
Independent Ethics Committee/ Research Ethics Board/Institutional Review Board 
(IEC/REB/IRB) that approved the protocol unless otherwise required and documented by the 
IEC/REB/IRB. 
11.4.4. 
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 initial dose to 6 months after the last dose of study drug or 12 months after the last dose 
of rituximab, whichever comes later. A male subject must immediately inform the investigator if 
his partner becomes pregnant from the time of initial dose to 6 months after the last dose of study 
drug. Any female subjects receiving study treatment(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.  
Although pregnancy itself is not regarded as an AE, the outcome will need to be documented. 
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period as described above must be reported. Any occurrence of pregnancy must be recorded on 
the Pregnancy Report Form Part I and sent via email or fax 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 SAE. 
11.4.5. 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any 
protocol- specified follow-up periods including post-progression follow-up for overall survival. 
If observed, enter data in the corresponding eCRF.  
11.4.6. 
Eye-Related Adverse Events 
New or worsening eye-related symptoms that are Grade 2 or higher, or a symptom that was 
Grade 2 or higher at baseline worsens, should be evaluated by an ophthalmologist whose 
findings should be reported on the ophthalmologic eCRF. 
11.4.7. 
Adverse Events of Special Interest (AESI) 
Specific AEs, or groups of AEs, will be followed as part of standard safety monitoring activities 
by the Sponsor. These events (regardless of seriousness) should be reported on the Serious 
Adverse Event Report Form and sent via email or fax to Pharmacyclics Drug Safety, or designee, 
within 24 hours of awareness.  
11.4.8. 
Major Hemorrhage 
Major hemorrhage is defined as any of the following:  
• Any treatment-emergent hemorrhagic AEs of Grade 3 or higher* 
• Any treatment-emergent serious adverse events of bleeding of any grade 
• 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 11.4.7 above. 

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11.4.9. 
COVID-19 Pandemic-Related Provisions for Adverse Event Reporting 
Supplemental study case report forms will be completed in the event of COVID-19-related 
missed/virtual visits, study drug interruptions or discontinuations, vaccines, or adverse events 
(including capture of specific signs/symptoms of infection and testing results). 
SARS-CoV-2 infections will be captured as adverse events if a subject is experiencing symptoms 
of COVID-19 (please refer to CRF Completion Guidelines). If the event meets the criteria for a 
serious adverse event (SAE), then follow the SAE reporting directions per the protocol and 
above.  The following COVID-19-related supplemental eCRFs will be completed (for both 
serious and nonserious events) as applicable: 
• COVID-19 Visit Impact 
• COVID-19 Lab Test 
• COVID-19 Vaccine Details 
Reactions known to be associated with the SARS-CoV-2 vaccine should be reported as adverse 
events. If the event meets the criteria for an SAE, then follow the SAE reporting directions.  All 
adverse events associated with the SARS-CoV-2 vaccine will be linked to the vaccine on the 
COVID-19 Vaccine eCRF. 
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 global 
and local regulations (including US Code of Federal Regulations [CFR] Title 21and EU Clinical 
Trial Regulation), and with the ethical principles laid down in the Declaration of Helsinki. 
Investigators should notify AbbVie if any urgent safety measures are taken to protect the subjects 
against any immediate hazard. 
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 (e.g., 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 ICF must also be approved by the IRB/REB/IEC before the implementation of 
changes in this study. 
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. 

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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. 
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 the Food and Drug Administration (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 (ICH E6) and with applicable regulatory requirements, 
including EU Clinical Trial Regulation. 
12.5. 
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 
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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. 
Before subject data are shared with AbbVie, the study investigator and staff will replace the 
subject's name, address, and contact information with a generic code which AbbVie cannot link 
to that subject's identity to protect the confidentiality of the data. 
For the personal data that AbbVie acting as sponsor of the submitted study controls and 
maintains, AbbVie has developed a robust security program focused on due diligence in design, 
managed change, and information security governance. Information Security policies govern the 
Information Security functions including identity and access management, operations, 
infrastructure, application, and third-party security requirements. The risk-based AbbVie Data 
Classification Tool dictates the level of scrutiny and control required for the relevant activities 
per AbbVie Information Security policies taking into account the sensitivity of the data. 
AbbVie has a data protection impact assessment (DPIA) program to ensure and document the 
appropriate controls and safeguards stated above are in place for clinical trial data that it controls 
and maintains, and these processing activities respect privacy of clinical trial subjects. AbbVie 
also maintains robust security incident response policies and procedures, including requirements 
for the containment of any data-related incidents, the mitigation measures where needed, and 
notification to authorities or affected individuals where required. 
AbbVie as the sponsor shall document any personal data breaches for which it is a controller and 
notify where required the competent national supervisory authority without undue delay and at 
the latest within 72 hours after becoming aware of such an incident. AbbVie shall create and 
maintain appropriate records of such an incident.   
12.6. 
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, 

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IRB/REB/IEC approval letters (dated), signed Form FDA 1572/IIA 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 case report forms (CRFs), and documentation of CRF 
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.  
The investigator must notify Pharmacyclics and obtain written approval from Pharmacyclics 
before destroying any clinical study documents or images (e.g., 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. 
12.7. 
Case Report Forms and Record Maintenance 
The case report forms 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 (e.g., physicians' notes, nurses' notes, clinic charts 
and other study-specific source documents). Authorized study site personnel (i.e., listed on the 
Delegation of Authority log) will complete CRFs designed for this study according to the 
completion guidelines that will be provided. The investigator will ensure that the CRFs are 
accurate, complete, legible, and completed within a reasonable period 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 

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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 (e.g., paper, CD, or other appropriate media) 
for archiving at the study site. 
12.8. 
Investigational Study Treatment Accountability 
Ibrutinib and any comparator used must be kept in a locked limited access room. The study 
treatment must not be used outside the context of the protocol. Under no circumstances should 
the investigator or other site personnel supply ibrutinib or comparator to other investigators, 
subjects, or clinics or allow supplies to be used other than as directed by this protocol without 
prior authorization from Pharmacyclics. 
Accountability records for ibrutinib and any comparator 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 Treatment Accountability Log must be used for drug accountability. For 
additional details on investigational product management, please refer to the Pharmacy Manual. 
12.9. 
Study Monitoring/Audit Requirements  
Representatives of Pharmacyclics or its designee will monitor this study until 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 all certified copies of documents are available during 
monitoring visits for all screened and enrolled subjects. During the COVID-19 pandemic and 
geo-political conflict in Ukraine and surrounding impacted regions, remote data 
review/verification may be employed if allowed by the local regulatory authority, IRB/REB/IEC, 
and the study site. 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 designated agents and authorized employees of the 
appropriate Regulatory Authority to inspect the facilities used in this study and, for purposes of 

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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 
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. 
12.10. 
Investigator Responsibilities 
A complete list of investigator responsibilities are outlined in the clinical trial research 
agreement and the Statement of Investigator Form FDA 1572/IIA, 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. 
Clinical research studies sponsored by AbbVie are subject to the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practices (GCP), as well as and applicable laws, regulations, and guidelines. Certain 
laws, regulations, or guidelines may apply to conduct of the study at investigator's site even if 
such laws, regulations or guidelines originate in a foreign jurisdiction. The investigator agrees 
and acknowledges that applicable law or regulation may require AbbVie to submit inspection 
reports, instances of significant non-compliance with the study protocol, or other documents 
regarding conduct of the study at the investigator's site to regulatory authorities, and such 
documents may be publicly disclosed by such authorities. In signing the Investigator Agreement, 
the investigator also agrees to the following. 
Report the following to AbbVie within 1 calendar day of becoming aware: 
• Any departure from relevant clinical trial regulation, GCP, or the trial protocol that has 
affected or is likely to affect to a significant degree the following: 
o Rights, safety, physical or mental integrity of the subjects of the clinical trial 

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o Scientific value of the clinical trial, reliability or robustness of data generated 
• Any unanticipated problems involving risks to human subjects  
Where required by local regulation, inform relevant Ethics Committees / Institutional Review 
Boards and other appropriate individuals (e.g. Co-ordinating Investigator, Institution Director). 
12.11. 
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. 
12.12. 
Financial Disclosure 
A separate financial agreement will be made between each principal investigator and 
Pharmacyclics or its authorized representative before the study treatment is delivered. 
For this study, each investigator and Sub-Investigator (as designated on the Form FDA 1572/IIA) 
will provide a personally signed Financial Disclosure Form in accordance with § 21 CFR 54. 
Each investigator will notify Pharmacyclics or its authorized representative of any relevant 
changes in financial disclosure information during the conduct of the study and for 1 year after 
the study has been completed. 
12.13. 
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. 
12.14. 
Protocol Amendments 
Pharmacyclics will initiate any change to the protocol in a protocol amendment document. 
The amendment will be submitted to the regulatory authorities and IRB/REB/IEC together with, 

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if applicable, a revised model ICF. Written documentation of regulatory authorities, 
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 
any change in risk and/or change in scope must be provided to subjects already actively 
participating in the study, and they must read, understand and sign each revised ICF confirming 
their willingness to remain in the trial. 
No other significant or consistent change in the study procedures, except to eliminate an 
immediate hazard, shall be effected without the mutual agreement of the investigator and 
Pharmacyclics. 
12.15. 
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.  
AbbVie is committed to fostering the highest standard of conduct related to Scientific 
Publications and transparency, while at the same time, protecting its confidential information.  
Authorship related to scientific publications shall be determined in accordance with and 
governed by the criteria defined by the International Committee of Medical Journal Editors 
("ICMJE”) "Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly 
Work in Medical Journals.”  AbbVie's role in support of the Study should be appropriately 
disclosed in any scientific publications. 
12.16. 
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. 
12.17. 
Start-of-Study, End-of-Study, and Study Completion 
The start-of-study is defined as the date of the first site activated.  
The end-of-study is defined as the date of end-of-study participation by the last subject in the last 
country where the study was conducted [e.g., last post treatment safety follow-up or last survival 
follow-up, whichever comes last].  

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The study is expected to be completed after the final analysis for OS, or five years after 
enrollment of the last subject, or the time point all subjects have exited the study for any reason, 
or upon study termination at the Sponsor's discretion, whichever occurs first. 

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13. 
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with indolent non-hodgkins lymphoma. J Clin Oncol 2002;20:4261-7. 
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Hodgkin's lymphoma. Semin Oncol. 2003;30 Supp2:9-15. 
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2003;10:2363-7. 
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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cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome 
for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of 
a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 
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Hurria A, Hurria A, Brogan K, et al. Effect of creatinine clearance on patterns of toxicity in older patients 
receiving adjuvant chemotherapy for breast cancer. Drugs Aging. 2005;22:785-91. 
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Belgium; 2020. 
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Irish JM, Czerwindki DK, Nolan GP and Levy R. Altered B-cell receptor signaling kinetics distinguish 
human follicular lymphoma B cells from tumor-inflatrating nonmalignant B cells. Blood 
2006;108:3135-42. 
MabThera® (rituximab) Summary of Product Characteristics. Roche Registration Limited, United 
Kingdom; 2023. 
Maloney D, Smith B, Appelbaum F. The anti-tumor effect of monoclonal anti-CD20 antibody (MAB) 
therapy includes direct anti-proliferative activity and induction of apopthosis in CD20 positive 
non-Hodgkin's Lymphoma (NHL) cell lines. Blood 1996;88:637a.  
Marcus R, Hagenbeek A. The therapeutic use of rituximab in non-Hodgkin's lymphoma. Eur J Haematol. 
2007;67:5-14. 
Martinez AE, Lin L, Dunphy HC. Grading of follicular lymphoma. Comparison of routine histology with 
immunochemistry. Arch Pathol Lab Med. 2007;131:1084-8. 
Morton L, Wang S, Devesa S, et al. Lymphoma incidence patterns byWHO subtype in the United States, 
1992-2001. Blood. 2006;107:265-76. 
Nabhan C, Byrtek M, Latta S, et al. Age differences in disease characteristics, patterns of care, and 
outcomes of follicular lymphoma (FL) in the United States (US): report from the National Lymphocare 
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Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
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Pugh RN, Murray-Lyon IM, Dawson L, et al. Transection of the oesophagus for bleeding oesophageal 
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Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour 
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containing doxorubicin in patients with advanced follicular lymphoma. 
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Solal-Céligny P, Lepage E, Brousse N, et al. Doxorubicin-containing regimen with or without interferon 
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14. 
APPENDICES 

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e. 
Hepatitis serologies will be evaluated. If hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody is positive, then PCR to quantitate hepatitis B DNA or 
hepatitis C RNA must be performed and must be negative prior to randomization.  
f. 
A serum or urine pregnancy test is required at Screening and Cycle 1, Day 1; a urine pregnancy test may be performed at the other time points indicated. Additional 
pregnancy tests may be performed, as determined necessary by the investigator or required by local regulation to establish the absence of pregnancy at any time during a 
subject's participation in the study. 
g. 
PRO: To be completed prior to any assessments and before being clinically evaluated by the study nurse or physician (after informed consent).  
h. 
CT/MRI and PET scan: Baseline CT/MRI and PET scan can be performed up to 60 days before randomization. 
i. 
Bone marrow aspirate and biopsy: 1) At Screening, a unilateral bone marrow core biopsy must be obtained for assessment of bone morrow involvement by local laboratory. In 
cases if the bone marrow biopsy cannot be obtained due to access related or patient condition related issues the bone marrow aspirate sample should be obtained instead. 
Alternatively results of bone marrow involvement from a bone marrow aspirate and core biopsy performed up to 60 days before randomization will be acceptable. Bone 
marrow core biopsy and aspirate samples should be submitted to the central laboratory for potential confirmation of bone marrow involvement when available. 2) To confirm 
complete response if bone marrow involvement positive at baseline, bone marrow biopsy, or aspirate if core biopsy not possible, assessments should be performed in a local 
laboratory and bone marrow core biopsy / aspirate samples should be sent to central lab for potential confirmation if available. All pathology reports for bone marrow 
involvement should be sent to central lab. 3) For MRD assessments, aliquot of aspirate should be submitted to the central laboratory at Screening as well as at CR, if bone 
marrow positive at Screening. 4) For all subjects, a peripheral blood sample for minimal residual disease evaluation should be collected at Screening or latest at C1D1 Pre
dose. For subjects who achieve a CR, a peripheral blood sample for minimal residual disease evaluation should be collected at every disease assessment visit (every 16 weeks 
starting from Cycle 5 through Cycle 37, then every 24 weeks thereafter) starting with the first CR visit. (see Section 7.1.3.5 and Section 7.1.3.6). 
j. 
Sparse pharmacokinetic (PK) sampling: PK samples for study drug (ibrutinib/placebo) will be collected at pre dose and 1, 2, and 4 hours post dose on Cycle 1, Day 22. PK 
samples will be collected at pre dose only on Cycle 3, Day 1. PK samples for rituximab will be collected at pre dose only on Cycle 1, Days 1, 8, 15, and 22 and pre dose on 
Cycle 3, 5, 7, 9, and 11 on Day 1. 
k. 
Study drug compliance review: Includes subject instruction and routine review of study drug diary and evaluation of contents of study drug containers from home 
administration. 
l. 
Response Evaluation Visits: If study drug (ibrutinib/placebo) is held before a scheduled response assessment, then the response assessment can be delayed up to 2 weeks to 
allow re initiation of study drug prior to the scheduled response assessment. Subjects who discontinue study treatment for reasons other than progressive disease will 
participate in ongoing response evaluation assessments as detailed in Section 8.3.1. 
m. End of Treatment Safety Follow Up: 30 ±7 days after last dose of study treatment or prior to subsequent therapy. May occur sooner if subject is scheduled to start a new 
anticancer treatment. 
n. 
Randomization should occur as close to the time of the expected first dose as possible and not more than 72 hours prior to the expected first dose of study treatment.  
o. 
Subjects will be randomized to a study treatment assignment and will continue on this study treatment assignment until study treatment discontinuation as described in the 
protocol Section 8. 
p. 
Peripheral blood MRD assessment for subjects terminating study treatment who have not experienced progressive disease. 
q. 
Once a subject progresses, he/she will be contacted approximately every 24 weeks from the last dose by clinic visit or telephone to assess survival for up to the end of the 
study. Subsequent anticancer therapies, best response to therapy, and information about other malignancies will be collected. 
 

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Appendix B. 
ECOG Performance Status Scores 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status** 
0 
Fully active, able to carry on all predisease 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 MM, Creech RH, Tormey DC, et al: 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 C. 
Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A enzymes are defined as follows. Refer to Section 6.2.1 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 
 
voriconazole 
 
Moderate inhibitors: 
 
aprepitant 
 
amprenavir 
 
amiodarone 
 
atazanavir 
 
ciprofloxacin 
 
crizotinib 
 
darunavir/ritonavir 
 
dronedarone 
 
erythromycin 
 
diltiazem  
 
fluconazole 
 
fosamprenavir 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
imatinib 
 
Weak inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All other inhibitors: 
 
chloramphenicol 
 
delaviridine 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
star fruit 
 

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Appendix E. 
New York Heart Association (NYHA) Functional Classification 
Class 
Functional Capacity: How a patient with cardiac disease feels during physical 
activity 
I 
Patients with cardiac disease but resulting in no limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or 
anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea or 
anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be present 
even at rest. If any physical activity is undertaken, discomfort increases. 
Source:  
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart 
and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253 256. 
 

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Appendix F. 
Child-Pugh Score for Subjects with Liver Impairment 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT/INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
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. 
 

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Appendix H. 
FACT-Lym (Version 4) 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
                      
             
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
    
  
    
    
 
 
 
 
 
 
 
 
 
 
 
 
                   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
                                      
 
 
 
 
 
 
 
                      
 
 
 
 
 
 
 
 
 
  
    
    
 
 
 
 
 
 
                        
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
                                  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IMBRUVICA® (ibrutinib) 
PCYC-1141-CA-Amendment 5 
10 May 2024 
Pharmacyclics LLC 
Proprietary and Confidential 
Page 121 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
    
   
 
 
 
 
 
 
        
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
   
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
       
   
      
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
      
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IMBRUVICA® (ibrutinib) 
PCYC-1141-CA-Amendment 5 
10 May 2024 
Pharmacyclics LLC 
Proprietary and Confidential 
Page 122