Clinical trial NCT02165397
Conditions: Waldenström's Macroglobulinemia
Keywords: Ibrutinib Pharmacyclics PCYC Lymphoma Btk inhibitor WM Rituximab Rituxan Waldenström's Waldenstrom Macroglobulinemia non-Hodgkin lymphoma NHL
Sponsor: Pharmacyclics LLC.
Start date: 2014-07-07; Completion date: 2019-11-07
Enrollment: 181 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of ibrutinib in combination with rituximab in participants with Waldenström's macroglobulinemia (WM).

Detailed description:

Arms: arm 1: Ibrutinib: 420 mg (3 capsules x 140 mg) orally administered daily beginning from Day 1. Rituximab: 375 mg/m\^2 intravenous (IV) per package insert weekly for four consecutive weeks, followed by a second four-weekly rituximab course after a three-month interval. arm 2: Placebo: 3 capsules of placebo orally administered daily beginning from Day 1. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks, followed by a second four-weekly rituximab course after a three-month interval. arm 3: Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1.
Interventions: intervention 1: Ibrutinib intervention 2: Placebo intervention 3: Rituximab
Intervention descriptions: intervention 1: Participants will receive 420 mg of Ibrutinib orally. intervention 2: Participants will receive placebo capsules orally. intervention 3: Participants will receive rituximab 375 mg/m\^2 IV.

Protocol documents:
Prot_000.pdf: 
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PROTOCOL
TITLE:
iNNOVATE Study: A Randomized, Double-Blind, Placebo-
Controlled, Phase 3 Study of Ibrutinib or Placebo in Combination 
with Rituximab in Subjects with Waldenström’s
Macroglobulinemia
PROTOCOL NUMBER:
PCYC-1127-CA
STUDY DRUG:
Ibrutinib (PCI-32765)
IND NUMBER:
102,688
EudraCT NUMBER:
2013-005478-22
SPONSOR MEDICAL 
MONITOR:
Pharmacyclics LLC
Phone:
Fax:
Email:
SPONSOR:
Pharmacyclics LLC
995 East Arques Avenue 
Sunnyvale, CA 94085-4521
United States of America
DATE FINAL:
Amendment 1: 
Amendment 2:
Amendment 2.1:
Amendment 3:
22 January 2014
07 March 2014
09 February 2015
02 June 2015 (UK only)
09 October 2015
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




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TABLE OF CONTENTS
PROTOCOL APPROVAL PAGE ............................................................................................................ 2 
TABLE OF CONTENTS ........................................................................................................................... 3 
LIST OF APPENDICES ............................................................................................................................ 7 
LIST OF IN-TEXT TABLES .................................................................................................................... 7 
SYNOPSIS................................................................................................................................................... 8 
ABBREVIATIONS................................................................................................................................... 14 
1. BACKGROUND................................................................................................................................. 16 
1.1. 
Description of Waldenström’s Macroglobulinemia .................................................................. 16 
1.1.1. 
Existing Therapies in WM............................................................................................ 17 
1.1.2. 
BTK Inhibition as a Treatment Option for WM........................................................... 18 
1.2. 
Investigational Product Name and Description......................................................................... 19 
1.3. 
Summary of Nonclinical Data ................................................................................................... 20 
1.3.1. 
Pharmacology............................................................................................................... 20 
1.3.2. 
Safety Pharmacology and Toxicology.......................................................................... 20 
1.3.2.1. Carcinogenesis, Mutagenesis, Impairment of Fertility.................................. 21 
1.4. 
Summary of Clinical Data ......................................................................................................... 21 
1.4.1. 
Pharmacokinetics and Product Metabolism ................................................................. 21 
1.5. 
Summary of Clinical Safety of Ibrutinib ................................................................................... 22 
1.5.1. 
Monotherapy Studies.................................................................................................... 22 
1.5.2. 
Combination Therapy Studies ...................................................................................... 22 
1.5.3. 
Risks ............................................................................................................................. 23 
1.5.3.1. Bleeding-Related Events............................................................................... 23 
1.5.3.2. Infections....................................................................................................... 23 
1.5.3.3. Cytopenias..................................................................................................... 23 
1.5.3.4. Atrial Fibrillation........................................................................................... 23 
1.5.3.5. Second Primary Malignancies....................................................................... 24 
1.5.3.6. Tumor Lysis Syndrome................................................................................. 24 
1.5.3.7. Diarrhea......................................................................................................... 24 
1.5.3.8. Rash............................................................................................................... 24 
1.6. 
Summary of Clinical Data with Ibrutinib in WM...................................................................... 24 
1.6.1. 
Study PCYC-04753...................................................................................................... 24 
1.6.2. 
Study NCT01614821.................................................................................................... 25 
1.7. 
Justification of Study Design and Dose Rationale .................................................................... 26 
2. STUDY OBJECTIVE ........................................................................................................................ 27 
2.1. 
Primary Objective...................................................................................................................... 27 
2.2. 
Secondary Objective(s).............................................................................................................. 28 
2.3. 
Exploratory Objectives.............................................................................................................. 28 
3. STUDY DESIGN ................................................................................................................................ 29 
3.1. 
Overview of Study Design ........................................................................................................ 29 
3.1.1. 
Study Schema............................................................................................................... 31 
3.1.2. 
Study Population .......................................................................................................... 32 
3.2. 
Study Rationale ......................................................................................................................... 32 
3.3. 
Statement of Compliance........................................................................................................... 33 
4. SUBJECT SELECTION.................................................................................................................... 33 
4.1. 
Eligibility Criteria for the Randomized Study (Arm A and Arm B) ......................................... 33 
4.1.1. 
Inclusion Criteria.......................................................................................................... 33 
4.1.2. 
Exclusion Criteria......................................................................................................... 36 


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4.2. 
Eligibility Criteria for Open-label Substudy Treatment Arm C ................................................ 37 
4.2.1. 
Inclusion Criteria.......................................................................................................... 37 
4.2.2. 
Exclusion Criteria......................................................................................................... 37 
5. TREATMENT OF SUBJECTS......................................................................................................... 38 
5.1. 
Randomization and Blinding..................................................................................................... 38 
5.2. 
Study Treatment ........................................................................................................................ 39 
5.2.1. 
Treatment Arm A (Ibrutinib/Rituximab)...................................................................... 40 
5.2.2. 
Treatment Arm B (Placebo/Rituximab) ....................................................................... 40 
5.2.3. 
Treatment Arm C (Ibrutinib Open-label Substudy)...................................................... 40 
5.3. 
Study Medication....................................................................................................................... 40 
5.3.1. 
Ibrutinib/Placebo .......................................................................................................... 40 
5.3.1.1. Formulation/Packaging/Storage.................................................................... 40 
5.3.1.2. Dose and Administration............................................................................... 41 
5.3.1.3. Overdose ....................................................................................................... 41 
5.3.1.4. Dose Hold, Reduction or Discontinuation of Study Drug 
(Ibrutinib/Placebo) ........................................................................................ 42 
5.3.1.5. Dose Modification of Study Drug (Ibrutinib/Placebo).................................. 42 
5.3.1.6. Dose Modification for Hepatic Impaired Subjects........................................ 43 
5.3.2. 
Rituximab ..................................................................................................................... 43 
5.3.2.1. Formulation, Packaging, and Storage of Rituximab ..................................... 43 
5.3.2.2. Dosage, Preparation and Administration of Rituximab ................................ 44 
5.3.2.3. Dose Delay of Rituximab.............................................................................. 44 
5.3.2.4. Dose Interruption of Rituximab .................................................................... 45 
5.3.2.5. Dose Modification of Rituximab................................................................... 45 
5.3.2.6. Rituximab Associated “IgM flare”................................................................ 46 
5.4. 
Criteria for Permanent Discontinuation of Study Drug............................................................. 46 
6. CONCOMITANT MEDICATIONS/PROCEDURES .................................................................... 46 
6.1. 
Concomitant Medications.......................................................................................................... 46 
6.1.1. 
Permitted Concomitant Medications ............................................................................ 46 
6.1.2. 
Medications to be Used with Caution........................................................................... 47 
6.1.2.1. CYP3A Inhibitors/Inducers........................................................................... 47 
6.1.2.2. Drugs That May Have Their Plasma Concentrations Altered By 
Ibrutinib......................................................................................................... 47 
6.1.2.3. Concomitant Use of QT Prolonging Agents ................................................. 47 
6.1.2.4. Concomitant Use of Antiplatelet Agents and Anticoagulants....................... 47 
6.1.3. 
Prohibited Concomitant Medications........................................................................... 48 
6.2. 
Procedures ................................................................................................................................. 48 
6.2.1. 
Minor Surgical Procedures........................................................................................... 48 
6.2.2. 
Major Surgical Procedures ........................................................................................... 48 
6.2.3. 
Emergency Procedures ................................................................................................. 48 
6.3. 
Plasmapheresis .......................................................................................................................... 49 
7. STUDY EVALUATIONS .................................................................................................................. 49 
7.1. 
Screening/Administrative.......................................................................................................... 49 
7.1.1. 
Informed Consent......................................................................................................... 50 
7.1.2. 
Confirm Eligibility ....................................................................................................... 50 
7.1.3. 
Medical History and Demographics............................................................................. 50 
7.1.4. 
Prior and Concomitant Medications............................................................................. 50 
7.1.5. 
Adverse Events............................................................................................................. 50 
7.1.6. 
Physical Examination ................................................................................................... 50 
7.1.7. 
Eye-related Symptom Assessment ............................................................................... 51 


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7.1.8. 
ECOG ........................................................................................................................... 51 
7.1.9. 
Vital Signs .................................................................................................................... 51 
7.1.10. Patient-Reported Outcomes.......................................................................................... 51 
7.1.10.1. EQ-5D-5L...................................................................................................... 51 
7.1.10.2. FACT-An ...................................................................................................... 51 
7.2. 
Clinical Laboratory Assessments .............................................................................................. 52 
7.2.1. 
Hematology .................................................................................................................. 52 
7.2.2. 
Chemistry (Serum) ....................................................................................................... 52 
7.2.3. 
Coagulation Studies...................................................................................................... 52 
7.2.4. 
Hepatitis Serologies...................................................................................................... 52 
7.2.5. 
Serum Viscosity............................................................................................................ 52 
7.2.6. 
Serum Free Light Chain Assay..................................................................................... 52 
7.2.7. 
β2 -microglobulin......................................................................................................... 53 
7.2.8. 
Pregnancy Test ............................................................................................................. 53 
7.3. 
Diagnostics/Procedures ............................................................................................................. 53 
7.3.1. 
ECG.............................................................................................................................. 53 
7.3.2. 
Bone Marrow Sampling and Pathological diagnosis.................................................... 53 
7.4. 
Pharmacokinetics/Biomarkers................................................................................................... 54 
7.4.1. 
Pharmacokinetics.......................................................................................................... 54 
7.4.2. 
Predictive Biomarkers and Mechanisms of Resistance................................................ 55 
7.4.3. 
T/B/NK Cell Count....................................................................................................... 55 
7.4.4. 
Genetic and Molecular Prognostic Markers ................................................................. 56 
7.5. 
Efficacy Evaluations.................................................................................................................. 56 
7.5.1. 
Quantitative Serum Immunoglobulin........................................................................... 57 
7.5.2. 
Serum Immunofixation................................................................................................. 57 
7.5.3. 
Serum Protein Electrophoresis (SPEP)......................................................................... 57 
7.5.4. 
Radiographic Imaging .................................................................................................. 57 
7.5.4.1. Radiographic Assessment ............................................................................. 58 
7.6. 
Sample Collection and Handling............................................................................................... 59 
7.7. 
Treatment with Ibrutinib for Subjects on Control Arm (Arm B) Following IRC-
Confirmed Disease Progression................................................................................................. 59 
7.7.1. 
Criteria for Next-line Ibrutinib Therapy....................................................................... 59 
7.7.2. 
Next-line Ibrutinib Therapy Treatment Phase.............................................................. 60 
8. STUDY PROCEDURES.................................................................................................................... 60 
8.1. 
Overview ................................................................................................................................... 60 
8.2. 
Screening Phase......................................................................................................................... 61 
8.2.1. 
Screening Visit ............................................................................................................. 61 
8.3. 
Treatment Phase ........................................................................................................................ 62 
8.3.1. 
Week 1.......................................................................................................................... 62 
8.3.2. 
Weeks 2-4 (Arm A and Arm B ONLY) ....................................................................... 63 
8.3.3. 
Weeks 5-16 (every 4 weeks) ........................................................................................ 63 
8.3.4. 
Week 17........................................................................................................................ 64 
8.3.5. 
Weeks 18-20 (For Arm A and Arm B ONLY)............................................................. 65 
8.3.6. 
Week 21........................................................................................................................ 65 
8.3.7. 
Week 25- until PD or Unacceptable Toxicity (Every 8 Weeks) .................................. 65 
8.3.8. 
Suspected PD Visit....................................................................................................... 66 
8.3.8.1. End-of-Treatment Visit ................................................................................. 67 
8.4. 
Follow-up Phase ........................................................................................................................ 67 
8.4.1. 
Response Follow-Up Visits (Until PD)........................................................................ 67 
8.4.2. 
Survival Follow-up....................................................................................................... 68 


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9. SUBJECT COMPLETION AND WITHDRAWAL ....................................................................... 68 
9.1. 
Completion ................................................................................................................................ 68 
9.2. 
Withdrawal from Study Treatment............................................................................................ 68 
9.3. 
Withdrawal from Study ............................................................................................................. 69 
10. STATISTICAL METHODS AND ANALYSIS............................................................................... 69 
10.1. General Consideration............................................................................................................... 70 
10.2. Randomization........................................................................................................................... 70 
10.3. Analysis Populations ................................................................................................................. 70 
10.4. Subject Information................................................................................................................... 71 
10.5. Sample Size Determination (Treatment Arms A and B)........................................................... 71 
10.6. Efficacy Analysis....................................................................................................................... 72 
10.6.1. Primary Endpoint.......................................................................................................... 72 
10.6.2. Secondary Endpoints.................................................................................................... 72 
10.6.2.1. Overall Response Rate .................................................................................. 73 
10.6.2.2. Hematologic Improvement............................................................................ 73 
10.6.2.3. Time to Next Treatment ................................................................................ 73 
10.6.2.4. Overall Survival (OS).................................................................................... 73 
10.6.3. Exploratory Efficacy Endpoints ................................................................................... 73 
10.6.3.1. FACT-An ...................................................................................................... 73 
10.6.3.2. Euro QoL 5 Dimension Questionnaire (EQ-5D-5L)..................................... 74 
10.6.3.3. Duration of Response.................................................................................... 74 
10.6.3.4. Clinical Response Rate.................................................................................. 74 
10.6.3.5. Efficacy Assessments by Investigator........................................................... 74 
10.6.4. Other Exploratory Endpoints........................................................................................ 74 
10.6.4.1. Pharmacokinetic Analyses ............................................................................ 74 
10.6.4.2. Medical Resource Utilization and Health Economics Analyses ................... 75 
10.6.4.3. Biomarker Analyses ...................................................................................... 75 
10.7. Safety Endpoints and Methods.................................................................................................. 75 
10.8. Interim Analysis ........................................................................................................................ 76 
10.9. Final Analysis............................................................................................................................ 77 
10.10. Independent Review Committee (IRC) ..................................................................................... 77 
10.11. Independent Data Monitoring Committee (DMC) .................................................................... 77 
11. ADVERSE EVENT REPORTING................................................................................................... 78 
11.1. Adverse Event Definitions and Classifications ......................................................................... 78 
11.1.1. Adverse Events............................................................................................................. 78 
11.1.2. Severity Criteria (Grade 1-5)........................................................................................ 79 
11.1.3. Causality (Attribution).................................................................................................. 80 
11.2. Unexpected adverse events........................................................................................................ 80 
11.3. Documenting and Reporting of Adverse Events ....................................................................... 81 
11.3.1. Reporting of “IgM flare” (Tumor flare) ....................................................................... 81 
11.3.2. Special Reporting Situations ........................................................................................ 81 
11.3.3. Adverse Event Reporting Procedures........................................................................... 82 
11.3.3.1. All Adverse Events........................................................................................ 82 
11.3.3.2. Reporting Criteria for Serious Adverse Events............................................. 83 
11.3.4. Adverse Events of Special Interest (AESI) .................................................................. 83 
11.3.4.1. Major Hemorrhage ........................................................................................ 83 
11.3.5. Pregnancy ..................................................................................................................... 84 
11.3.6. Other Malignancies ...................................................................................................... 84 
11.3.7. Eye-related Adverse Events.......................................................................................... 84 
12. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .................................... 85 


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12.1. Regulatory and Ethical Compliance.......................................................................................... 85 
12.2. Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval ............................................................................................ 85 
12.3. Informed Consent ...................................................................................................................... 85 
12.4. Quality Control and Quality Assurance..................................................................................... 86 
12.5. Protected Subject Health Information Authorization ................................................................ 86 
12.6. Study Files and Record Retention ............................................................................................. 86 
12.7. Case Report Forms and Record Maintenance ........................................................................... 87 
12.8. Investigational Study Drug Accountability ............................................................................... 88 
12.9. Study Monitoring/Audit Requirements ..................................................................................... 88 
12.10. Investigator Responsibilities...................................................................................................... 89 
12.11. Sponsor Responsibilities............................................................................................................ 89 
12.12. Financial Disclosure .................................................................................................................. 90 
12.13. Liability and Clinical Trial Insurance........................................................................................ 90 
12.14. Protocol Amendments ............................................................................................................... 90 
12.15. Publication of Study Results...................................................................................................... 91 
12.16. Study Discontinuation ............................................................................................................... 91 
13. REFERENCES ................................................................................................................................... 92 
14. APPENDICES .................................................................................................................................... 96 
LIST OF APPENDICES
Appendix 1. 
Schedule of Assessments.................................................................................................. 97 
Appendix 2. 
ECOG Status Scores ....................................................................................................... 100 
Appendix 3. 
Inhibitors and Inducers of CYP3A ................................................................................. 101 
Appendix 4. 
Modified 6th WM Response Criteria (NCCN 2014) for Investigator Assessment......... 102 
Appendix 5. 
New York Heart Association Functional Classification................................................. 103 
Appendix 6. 
WM IPSS Calculation..................................................................................................... 104 
Appendix 7. 
EQ-5D-5L Health Questionnaire.................................................................................... 105 
Appendix 8. 
FACT-An (Version 4)..................................................................................................... 108 
Appendix 9. 
Schedule of Assessments for Subjects Treated with Placebo in Combination with 
Rituximab and Documented IRC confirmed Progression who Elect to Receive 
Next-line Ibrutinib Therapy............................................................................................ 111 
Appendix 10. 
Child-Pugh Score............................................................................................................ 112 
LIST OF IN-TEXT TABLES 
Table 1: 
WM International Prognostic Scoring System (IPSS)1..................................................... 17 
Table 2: 
Study Drug (Ibrutinib/Placebo) Dose Modifications........................................................ 43 
Table 3: 
Dose Modification for Rituximab Toxicity ...................................................................... 45 
Table 4: 
Pharmacokinetic Sample Schedule................................................................................... 55 
Table 5: 
Grading for Adverse Events of IgM Associated Tumor Flare.......................................... 81 


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SYNOPSIS
Study Title:
iNNOVATE Study: A Randomized, Double-Blind, Placebo-Controlled, 
Phase 3 Study of Ibrutinib or Placebo in Combination with Rituximab in 
Subjects with Waldenström’s Macroglobulinemia
Protocol Number:
PCYC-1127-CA
Study Phase:
Phase 3 
Study Duration:
Estimated to be 4 years
Investigational Product 
and Reference Therapy:
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) 
administration.
Matching placebo will be supplied as hard gelatin capsules and will look 
identical to ibrutinib capsules.
Rituximab will be available as 100 mg/10 mL and 500 mg/50 mL solution 
in a single-use vial for intravenous (IV) administration.
Objectives:
Primary Objective:
To evaluate the effect of the addition of ibrutinib to rituximab on 
progression-free survival (PFS) assessed by an independent review 
committee (IRC) in subjects with Waldenström’s macroglobulinemia
(WM).  Efficacy evaluation will be based on the modified Consensus 
Response Criteria from the VIth International Workshop for WM
(IWWM) (NCCN 2014).
Secondary Objectives:
Efficacy
To compare the treatment arms in terms of the following:
• Overall Response Rate (ORR) assessed by IRC (≥PR; according to 
the modified VIth IWWM [NCCN 2014] criteria).
• Hematological improvement measured by hemoglobin.
• Time to next treatment (TTnT)
• Overall survival (OS).
Safety
• To evaluate the safety and tolerability of ibrutinib when combined 
with rituximab therapy compared to rituximab in combination with 
placebo.
Exploratory Objectives:
• Patient-reported outcomes (PRO) and disease-related symptoms 
according to FACT-An
• Patient-reported outcomes (PRO) and disease-related symptoms 
according to Euro QoL 5 dimension questionnaire (EQ-5D-5L).
• Duration of Response (DOR) according to IRC assessment.
• Clinical response rate (CRR) assessed by IRC (≥MR; according to 
the modified VIth IWWM [NCCN2014] criteria. 


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• Efficacy assessment by Investigator (≥PR and ≥MR; according to 
the modified VIth IWWM [NCCN 2014] criteria).
• To determine the pharmacokinetics (PK) of ibrutinib in 
combination with rituximab in subjects with WM.
• Evaluation of medical resource utilization (MRU) (e.g. 
requirements of plasmapheresis, transfusions and use of growth 
factors).
• Prognostic and predictive biomarkers and genetics relative to 
treatment outcomes.
Open-label Substudy Treatment Arm C
• To evaluate the efficacy and safety of ibrutinib monotherapy in 
WM subjects who are considered refractory to their last prior 
rituximab-containing therapy. Efficacy and safety analysis will be 
conducted separately from the randomized study 
Study Design:
This is a Phase 3, multicenter, randomized, double-blind study of oral 
ibrutinib or placebo in combination with intravenous rituximab therapy in 
subjects with WM. 
Approximately 150 subjects will be randomized between Arm A 
(ibrutinib and rituximab) and Arm B (placebo and rituximab) and
stratified according to: 
• WM International Prognostic Scoring System (IPSS) assessed at
Screening (Low vs. Intermediate vs. High)
• Number of prior systemic treatment regimens (0, 1-2 vs. ≥3)
• ECOG status (0-1 vs. 2)
Access to next-line ibrutinib (cross-over) for subjects treated with placebo 
in combination with rituximab (Arm B) may be provided after confirmed 
disease progression (by IRC) and disease requiring treatment.
Open-label Substudy Treatment Arm C
Up to 30 eligible subjects will be enrolled in the open-label ibrutinib 
monotherapy substudy (Treatment Arm C). For details regarding 
inclusion/exclusion criteria refer to Section 4.2.
Subjects eligible for the randomized trial (Arm A or Arm B) are not 
eligible for participation in the substudy (Arm C). 
Population:
Subjects must have a centrally confirmed clinicopathological diagnosis of 
WM in accordance with the consensus panel of the Second International 
Workshop on WM (Owen 2003). 
Subjects must be in need of treatment in accordance with the “Consensus 
Panel Two” recommendations from the Second International Workshop 
on WM (Kyle 2003).
Centers:
Multicenter-International


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Inclusion Criteria:
Refer to Section 4 for the 
complete and detailed list of 
inclusion/exclusion criteria.
Refer to Section 4.2 for 
eligibility criteria for open-
label substudy treatment 
Arm C.
Disease Related
•
Subjects with untreated or previously treated Waldenström’s
Macroglobulinemia
•
Previously treated Waldenström’s Macroglobulinemia must have 
either documented disease progression or had no response (stable 
disease) to the most recent treatment regimen
•
Centrally confirmed clinicopathological diagnosis of WM in 
accordance with the consensus panel of the Second International 
Workshop on WM (Owen 2003).
•
Measurable disease defined as serum monoclonal IgM >0.5 g/dL.
•
Symptomatic disease meeting at least 1 of the recommendations from 
the Second International Workshop on Waldenström's 
Macroglobulinemia for requiring treatment (Kyle 2003).
Laboratory
•
Adequate hematological function defined as: 
o
Absolute neutrophil count >750 cells/mm3 (0.75 x 109/L)
independent of growth factor support within 7 days of the first 
dose of study drug.  
o
Platelet count >50,000 cells/mm3 (50 x 109/L) without 
transfusion support within 7 days of the first dose of study drug. 
o
Hemoglobin ≥8 g/dL without transfusion or growth factor 
support within 7 days of the first dose of study drug.
•
Adequate hepatic and renal function defined as:
o
Serum aspartate transaminase (AST) or alanine transaminase 
(ALT) <3.0 x upper limit of normal (ULN).
o
Estimated Creatinine Clearance ≥30 mL/min.
o
Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s 
syndrome or of non-hepatic origin).
•
PT/INR ≤1.5 x ULN and PTT (aPTT) ≤1.5 x ULN unless 
abnormalities are unrelated to a coagulopathy or bleeding disorder 
(when treated with warfarin or other vitamin K antagonists, then INR 
≤3.0).
Demographic
•
Men and women ≥18 years of age.
•
Eastern Cooperative Oncology Group (ECOG) performance status 
0 to 2.
Exclusion Criteria:
Refer to Section 4 for the 
complete and detailed list of 
inclusion/exclusion criteria
•
Known involvement of the central nervous system by WM.
•
Refractory to prior rituximab-containing therapy defined as:
o
Relapse after the last rituximab-containing therapy <12 months 
since last dose of rituximab,
OR


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Refer to Section 4.2 for 
eligibility criteria for open-
label substudy treatment 
Arm C.
o
Failure to achieve at least a MR after the last rituximab-
containing therapy.
•
Rituximab treatment within the last 12 months before the first dose of 
study drug  
•
Prior exposure to ibrutinib or other BTK inhibitors.
•
Received any WM-related therapy (e.g. chemotherapy, 
immunotherapy, investigational drug) ≤30 days prior to first 
administration of study treatment.
•
Plasmapheresis <35 days prior to the initiation of study drug, except 
when at least one serum IgM central assessment was performed 
during the screening period and was >35 days from the most recent 
plasmapheresis procedure.
o
Subjects with high IgM values or viscosity symptoms during 
screening may receive plasmapheresis prior to initiating study 
drug (Refer to Section 6.3) if the previous plasmapheresis was 
performed >35 days before the plasmapheresis performed during 
screening (in order to obtain a true baseline IgM value for 
efficacy evaluations).  
•
History of other malignancies, except: 
o
Malignancy treated with curative intent and with no known 
active disease present for ≥3 years before the first dose of study 
drug and felt to be at low risk for recurrence by treating 
physician.
o
Adequately treated non-melanoma skin cancer or lentigo 
maligna without evidence of disease.
o
Adequately treated carcinoma in situ without evidence of 
disease. 
•
History of stroke or intracranial hemorrhage within 12 months prior 
to enrollment.
•
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.
•
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.
•
Requires treatment with a strong cytochrome P450 (CYP) 3A 
inhibitor (see Appendix 3).
•
Lactating or pregnant.
•
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).


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Study Treatment:
1:1 Randomization between Arm A & Arm B
Arm A: Oral ibrutinib 420 mg daily (3 capsules) continuously until 
evidence of progressive disease or no longer tolerated by the subject in 
combination with rituximab 375 mg/m2 IV weekly for 4 consecutive
weeks, followed by a second 4-weekly rituximab course after a 3-month 
interval.
Arm B: Oral matching placebo capsules daily (3 capsules) continuously 
until evidence of progressive disease or no longer tolerated by the subject
in combination with rituximab 375 mg/m2 IV weekly for 4 consecutive 
weeks, followed by a second 4-weekly rituximab course after a 3-month 
interval.
Access to next-line ibrutinib monotherapy (cross-over) for subjects 
treated in Arm B may be provided after confirmed disease progression 
(by IRC) and disease requiring treatment (Refer to Section 7.7).
Open-label Substudy Treatment Arm C 
Arm C: Oral ibrutinib 420 mg daily (3 capsules) continuously until 
evidence of progressive disease or no longer tolerated by the subject. 
Concomitant Therapy:
Refer to Section 6 for information on concomitant therapy.
Safety Plan:
The safety of this study will be monitored by an independent Data 
Monitoring Committee (DMC) in accordance with the Sponsor’s
procedures.
Statistical Methods and 
Data Analysis:
Primary Efficacy Analysis:
The primary efficacy analysis of the randomized study will be performed 
using the intent-to-treat (ITT) population based on IRC assessed PFS. All 
subjects will be followed for PFS until a PFS event occurs (progression or 
death) or until the data cutoff.  PFS will be assessed based on the 
modified VIth IWWM (NCCN 2014) response criteria for WM and will be 
analyzed using the Kaplan-Meier method. The randomized treatment 
arms (Arm A and Arm B) will be compared using log-rank test.
Subgroup analyses will be performed for selected subgroups (eg, prior 
WM treatment history: untreated versus previously treated) to assess the 
consistency of treatment effect across subgroups.
Secondary Efficacy Analysis:
Multiplicity adjustment for the randomized treatment arm comparisons
will be made to control the overall type 1 error based on hierarchical 
testing procedure. The order of the secondary endpoints will be specified 
in the Statistical Analysis Plan (SAP).  Overall response rate (ORR) will 
be compared using the chi-square test.  The percentage of subjects with 
sustained hematological improvement as measured by change in 
hemoglobin level will be presented and compared using the chi-square 
test.  The distribution of the time to improvement will be summarized 
using the Kaplan-Meier method as appropriate.  The distribution of OS 
and TTnT will be estimated using the Kaplan-Meier method similar to 
PFS.  Survival rate for OS at landmark points will be summarized based 
on the Kaplan-Meier method. 


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Exploratory Efficacy Analysis:
Other time-to-event analysis will be analyzed by the same method as PFS
using stratified or unstratified log-rank tests as appropriate.  Categorical 
endpoints will be compared between the two randomized treatment arms 
using chi-square test as appropriate. For FACT-An, change in scores from 
baseline to each assessment will be summarized descriptively and 
compared between the two treatment arms.
Open-label Substudy Treatment Arm C 
PFS, ORR, hematological improvement measured by hemoglobin, TTnT, 
FACT-An, OS and other efficacy parameters will be summarized 
descriptively for the open-label ibrutinib monotherapy (Arm C). No 
comparator analysis will be done with Arms A or B. 
Safety Analysis:
Detailed tabulations of safety data (adverse events, clinical laboratory 
tests and other safety endpoints) will be summarized by treatment arms 
for all subjects receiving the study drug. Summary statistics will include 
means, standard deviations, and medians for continuous variables and 
proportions for categorical variables.
The end of the study will occur approximately 3 years after the last 
subject is randomized, or the Sponsor terminates the study, whichever 
comes first.
Safety analysis for Treatment Arm C will be conducted separately.
Interim Analysis
One interim analysis using the Lan DeMets alpha spending function based 
on O’Brien-Fleming boundary will be conducted at 70% information.
Sample Size Determination
The sample size for the randomized portion of the study is calculated 
based on the assumption that the median PFS is 15 months for the 
rituximab and placebo arm and the enrollment rate will be 12 subjects per 
month. Approximately 150 eligible subjects will be enrolled to observe 
71 PFS events in approximately 27 months from the first subject 
randomized.  Based on the assumed 2-fold improvement in median PFS 
of the rituximab in combination with ibrutinib arm (Arm A) over 
rituximab and placebo arm (Arm B) (hazard ratio of 0.5), the study has at 
least 80% power to achieve a statistical significance level of 5% (2-sided) 
under exponential distribution for PFS.
The sample size for the substudy (Arm C) is not determined according to 
statistical calculation as the intent of this substudy is to provide WM 
subjects who are considered refractory to the last prior rituximab-
containing therapy access to ibrutinib as well as evaluate safety and 
efficacy in the monotherapy setting. Up to 30 subjects will be enrolled in 
this substudy. 


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ABBREVIATIONS
AE
adverse event 
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the curve
ß2M
beta 2-microglobulin
BCR
B-cell receptor
BR
bendamustine and rituximab
BTK
Bruton’s tyrosine kinase
CBC
complete blood count
CFR
Code of Federal Regulations
CI
confidence interval
CLL
chronic lymphocytic leukemia
CR
complete response
CRF
case report form (paper or electronic as appropriate for this study)
CRR
clinical response rate
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Event 
CYP
Cytochrome P
DLBCL
diffuse large B-cell lymphomas
DMC
Data Monitoring Committee
DOR
duration of response
EDC
electronic data capture
eCRF
electronic case report form
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EMA
European Medicines Agency
EMSO
European Society for Medical Oncology
EOT
End-of-Treatment visit
EQ-5D-5L
Euro QoL 5 dimension questionnaire 
FCR
Fludarabine, cyclophosphamide, and rituximab 
FDA
Food and Drug Administration 
GCP
Good Clinical Practice
HBV
hepatitis B virus
HCV
hepatitis C virus 
HIV
human immunodeficiency virus
HIPAA
Health Insurance Portability and Accountability Act 
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgA
immunoglobulin A
IgG
immunoglobulin G
IgM
immunoglobulin M
IPSS
International Prognostic Scoring System
IRB
Institutional Review Board
IRC
independent review committee 
ITT
intent-to-treat
IV
Intravenous


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IWWM
International Workshop on Waldenström’s Macroglobulinemia
IWRS
interactive web response system
LPL
lymphoplasmacytic lymphoma
MAPK
mitogen-activated protein kinase
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MGUS
Monoclonal Gammopathy of Undermined Significance
MR
minor response 
MRI
magnetic resonance imaging 
MRU
medical resource utilization
NCCN
National Comprehensive Cancer Network
ORR
Overall Response Rate
OS
Overall survival 
PD
Progressive disease
PET
positron emission tomography 
PFS
progression-free survival
PK
Pharmacokinetic
PO
oral 
PR
Partial response
PRO
patient-reported outcome(s)
PTT
partial thromboplastin time
REB
Research Ethics Board
R-CHOP
rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone
SAE
serious adverse event 
SI
Standard International units
SPEP
Serum protein electrophoresis
STAT3
signal transducer and activator of transcription 3 signaling
TTnT
Time to next treatment
ULN
Upper limit of normal
VGPR
very good partial response
USP
United States Pharmacopeia
WHO
World Health Organization
WM
Waldenstrӧm's Macroglobulinemia


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1.
BACKGROUND
1.1.
Description of Waldenström’s Macroglobulinemia 
Waldenström’s macroglobulinemia (WM) is a distinct lymphoproliferative B-cell disorder 
characterized by infiltration of lymphoplasmacytic cells into the bone marrow along with 
demonstration of an immunoglobulin (Ig) M monoclonal gammopathy in the serum. It is a 
subtype of lymphoplasmacytic lymphoma (LPL) as defined by the Revised European-American 
Lymphoma and the World Health Organization (WHO) classification systems (Harris 1994; 
Harris 1999). Although most cases of LPL are WM, there are exceptions in which the diagnosis 
of WM does not apply, for example, primary lymph node-based presentations of LPL, or 
lymphoplasmacytic B-cell proliferations in the bone marrow associated with IgA or IgG 
gammopathies (Buske 2013).
The disease begins with a malignant change to the B-cell during its maturation so that it 
continues to reproduce more malignant B-cells, resulting in an overproduction of monoclonal 
IgM antibody.  Clinical manifestations of WM include cytopenias resulting from bone marrow 
infiltration by lymphoplasmacytic cells and IgM paraprotein related symptoms such as 
cryoglobulinemia, the cold agglutinin syndrome, demyelinating neuropathy, and symptomatic 
hyperviscosity.
Waldenström’s macroglobulinemia, which constitutes 1–2% of hematologic malignancies, is an 
orphan indication; the overall incidence of WM is 3 per million persons per year with 
approximately 1500 new cases diagnosed in the US each year.  The most recognized risk factor 
for developing WM is IgM Monoclonal Gammopathy of Undermined Significance (MGUS), 
which confers a 46-fold higher relative risk compared to the general population.  Recently, a 
somatic mutation of the MYD88 gene (L265P) has been identified that appears to drive WM 
growth and proliferation.
WM remains an incurable disease with variability in outcome.  Approximately 75% of patients 
are symptomatic and therefore require treatment to control symptoms related to tumor burden.  
The symptoms and signs of WM may vary but are usually related to signs of bone marrow 
infiltration such as anemia or cytopenias, or symptoms and signs due to hyperviscosity resulting 
from elevated IgM levels in the serum.  Asymptomatic patients should be observed and serum 
IgM levels alone are not a basis for treatment.
Anemia is the most frequent cytopenia requiring medical management, and with progression of 
their illness, WM patients become dependent on repeated blood transfusions for refractory 
anemia.  These supportive measures do not treat the underlying biology of the disease and are 
often associated with iron overload.
Factors associated with a poor prognosis include advanced age, high beta 2-microglobulin (ß2M), 
low albumin, cytopenias, serum IgM monoclonal protein, and organomegaly.  An international 
prognostic scoring system for newly diagnosed WM patients was recently developed 


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(Morel 2009) based on 5 factors:  Age (>65 years) ß2M (>3mg/L), anemia (Hb ≤11.5 g/dL), 
thrombocytopenia (≤100 x 109/L), IgM monoclonal gammopathy (>7.0 g/dL) with 5-year 
survival ranging from 36% to 87% in high and low-risk patients, respectively (Table 1).
Table 1:
WM International Prognostic Scoring System (IPSS)1
Low-risk
Intermediate-risk
High-risk
Number of risk factors
< 1 (except age)
2 or age > 65 years
> 2 Risk factors
Percentage of patients 
27%
38%
35%
5-year survival rate
87%
68%
36%
1 Morel 2009
1.1.1.
Existing Therapies in WM
Ibrutinib was approved by the US Food and Drug Administration (FDA) on 29 January 2015 for 
the treatment of Waldenström’s Macroglobulinemia and represents the first therapy approved for 
the treatment of this disease.  More recently, the European Medicines Agency (EMA) approved 
ibrutinib on 08 July 2015 for the treatment of adult patients with Waldenström’s 
Macroglobulinemia (WM) who have received at least one prior therapy, or in first line treatment 
for patients unsuitable for chemoimmunotherapy.  Treatment options currently used for WM 
were originally developed from other lymphoproliferative diseases including multiple myeloma, 
non-Hodgkin’s lymphoma, and chronic lymphocytic leukemia (CLL).  The primary treatment 
options for WM include alkylating agents (eg, cyclophosphamide or bendamustine), nucleoside 
analogs (cladribine or fludarabine), rituximab alone, or rituximab in combination with alkylator-
based chemotherapy.  Bortezomib-based therapy, nucleoside analogue-based therapy, 
thalidomide, or bendamustine are also other treatment options (NCCN 2014).
Single agent use in relapsed/refractory WM has been assessed primarily in single arm Phase 2 
studies in modest numbers of subjects (Rourke 2010).  However, a number of issues have made 
comparisons across studies difficult.  In several studies, heterogeneous populations have been 
enrolled, some including both previously untreated and treated subjects.  In addition, response 
criteria varied depending on whether the International Workshop on Waldenström’s
Macroglobulinemia (IWWM) consensus guidelines were used, and if so, which version was 
used.  In particular, the category of minor response (MR) was first introduced and defined by the 
Third IWWM (Treon 2006) and subsequently is often included to report overall response rates in 
newer trials.  
Current treatment options do not target disease-specific abnormalities and are each associated 
with treatment-related side effects, particularly in older adults, that may be life-threatening.  In 
particular, a recent analysis of long-term safety of fludarabine and chlorambucil in WM showed 
a marked increase in transformation into an aggressive form of lymphoma or into the 
development of acute myelogenous leukemia/myelodysplasia among patients that received a 


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nucleoside analog versus other therapies for their WM (Buske 2013). Although the overall 
response rates (ORRs) are high with initial therapies, in the salvage setting, the ORR is only in 
the range of 30% to 50%, with a median response duration of one year or less.  Overall, there is a 
paucity of data describing the outcomes of patients with recurrent disease due to a lack of 
prospective and retrospective studies.  As a result, there are limited data available to support 
salvage therapies and few effective agents are available for relapsed or refractory WM. 
There is also an emerging concern in evaluating treatment outcomes with newer biologically 
targeted agents, such as rituximab, alemtuzumab, bortezomib, and everolimus.  Some 
investigators have reported that there are circumstances where the serum IgM level is discordant 
with effects on the bone marrow.  Bortezomib and everolimus can suppress IgM levels 
independent of killing tumor cells in certain patients (Strauss 2006; Treon 2007; Treon 2011) and 
another study showed that in patients treated with selective B-cell–depleting agents, such as 
rituximab and alemtuzumab, residual IgM-producing B cells are spared and continue to persist, 
thus potentially skewing the relative response and assessment to treatment (Varghese 2009).
1.1.2.
BTK Inhibition as a Treatment Option for WM
A widely expressed mutation, MYD88 L265P, was recently identified and provides insight into a 
potential oncogenic driving event in WM (Treon 2012).  The MYD88 L265P mutation was 
present in more than 90% of tumor samples from patients with WM.  Although highly associated 
with WM, the MYD88 L265P mutation is not entirely specific; it has also been reported in a 
subset of diffuse large B-cell lymphomas (DLBCLs) and also occurs in a subset of other 
low-grade B-cell lymphoproliferative disorders (Ngo 2011; Xu 2013). This mutation results in 
tonic MYD88-IRAK signaling that activates the NF-κB and mitogen-activated protein kinase
(MAPK) pathways that are important for the growth and survival of WM cells (Treon 2012).
The role of Bruton’s tyrosine kinase (BTK) signaling, and the impact of inhibition of BTK on 
WM cell signaling and survival has been studied in MYD88 L265P-expressing WM cells 
(Yang 2012).  
Ibrutinib, a potent and selective inhibitor of BTK, reduces the association of BTK to MYD88 
L265P, but not to MYD88 WT and significantly reduced downstream NF-κB, MAPK, and signal
transducer and activator of transcription 3 (STAT3) signaling, and induced apoptosis in the 
MYD88 L265P-expressing cell lines BCWM.1 and MCWL-1 (Yang 2013).  In addition, 
ibrutinib demonstrated robust killing in combination with a MYD88 inhibitor in primary WM 
patients' bone marrow tumor cells.  These preclinical studies provided a strong rationale for 
further investigation of ibrutinib in WM.
In summary, ibrutinib is hypothesized to have potentially important clinical activity in WM by 
virtue of the role of BTK as a critical signaling kinase in the MYD88 signaling pathway.  
Moreover, ibrutinib represents a therapeutic option targeted to a specific signaling pathway 
involved in WM, in contrast to the currently utilized agents. 


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1.2.
Investigational Product Name and Description
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor of Bruton’s 
tyrosine kinase (BTK).  Inhibition of BTK blocks downstream B-cell receptor (BCR) signaling 
pathways and thus prevents B-cell proliferation. In vitro, ibrutinib inhibits purified BTK and 
selected members of the kinase family with 10-fold specificity compared with non-BTK kinases. 
Ibrutinib (Imbruvica®) is approved by the FDA for the treatment of 1) mantle cell lymphoma 
(MCL) in patients who have received at least one prior therapy, 2) chronic lymphocytic leukemia 
(CLL) in patients who have received at least one prior therapy, 3) CLL in patients with 17p 
deletion, and 4) Waldenström’s Macroglobulinemia. Additionally, full marketing approval in the 
EU was granted by the EMA for the treatment of adult subjects in the following indications:  
(1) relapsed or refractory MCL, (2) CLL who have received at least 1 prior therapy, (3) CLL in 
the presence of del17p or the TP53 mutation in subjects unsuitable for chemoimmunotherapy 
(first-line), and (4) WM who have received at least one prior therapy, or in first line treatment for 
patients unsuitable for chemoimmunotherapy.  Ibrutinib is currently under investigation in 
various indications as a single agent and in combinations.
B cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release.  B-cells express cell surface 
immunoglobulins comprising the B-cell receptor (BCR), which is activated by binding to 
antigen.  Antigen binding induces receptor aggregation and the clustering and activation of 
multiple tyrosine kinases, which in turn activate further downstream signaling pathways 
(Bishop 2003). 
The process of B-cell maturation, including immunoglobulin chain rearrangement and somatic 
mutation, is tightly regulated.  It is thought that B-cell lymphomas and CLL result from 
mutations and translocations acquired during normal B-cell development (Shaffer 2002).  
Several lines of evidence suggest that signaling through the BCR is necessary to sustain the 
viability of B-cell malignancies.  
The role of BTK in BCR signal transduction is demonstrated by the human genetic 
immunodeficiency disease X-linked agammaglobulinemia and the mouse genetic disease X-
linked immunodeficiency, both caused by a mutation in the BTK gene.  These genetic diseases 
are characterized by reduced BCR signaling and a failure to generate mature B-cells.  The BTK 
protein is expressed in most hematopoietic cells with the exception of T-cells and natural killer
(NK) cells, but the selective effect of BTK mutations suggests that its primary functional role is 
in antigen receptor signaling in B-cells (Satterthwaite 2000).  
Data from Study PCYC-04753 demonstrate that although ibrutinib is rapidly eliminated from 
the plasma after oral administration, once daily dosing with ibrutinib is adequate to sustain 
maximal pharmacodynamic activity for 24 hours postdose at dose levels ≥2.5 mg/kg.  In Study 
PCYC-04753, the BTK occupancies for the 2.5 mg/kg/day to 12.5 mg/kg/day cohorts and for the 


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560 mg continuous dosing cohort, were all above 90% at either 4 or 24 hours after drug 
administration.
For the most comprehensive nonclinical and clinical information regarding ibrutinib background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to 
the latest version of the ibrutinib Investigator's Brochure.
1.3.
Summary of Nonclinical Data
Ibrutinib is a first-in-class, potent, orally administered covalent inhibitor of Bruton’s tyrosine 
kinase (BTK) currently under investigation in various B-cell malignancies.  
For the most comprehensive nonclinical and clinical information regarding ibrutinib, please refer 
to the current version of the Investigator's Brochure. 
1.3.1.
Pharmacology 
Ibrutinib was designed as a selective and covalent inhibitor of the BTK protein (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 B-cell receptor and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM 
stimulation followed by CD69 expression (Herman 2011).
Ibrutinib arrested cell growth and induced apoptosis in human B-cell lymphoma cell lines in 
vitro and inhibited tumor growth in vivo in xenograft models (Herman 2011). Ibrutinib also 
inhibited adhesion and migration of mantle cell lymphoma (MCL) cells in co-culture and 
reduced tumor burden in lymph node and bone marrow in a murine model of MCL dissemination 
and progression (Chang 2013a; Chang 2013b).
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current Investigator’s Brochure (IB).
1.3.2.
Safety Pharmacology and Toxicology
In safety pharmacology assessments, 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 in the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation).  Additional toxicity findings seen in only one species with no observed human 


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correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog).  
In vitro and in vivo genetic toxicity studies showed that ibrutinib is not genotoxic.  In a rat 
embryo-fetal toxicity study, ibrutinib administration was associated with fetal loss and 
malformations (teratogenicity) at ibrutinib doses that result in approximately ≥8 times and 
20 times the exposure (AUC) in subjects administered the dose of 420 mg daily, respectively.
For the most comprehensive nonclinical and clinical information regarding ibrutinib, please refer 
to the current version of the Investigator’s Brochure.
1.3.2.1.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with ibrutinib.
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo 
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.
Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology 
studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects 
on reproductive organs.
1.4.
Summary of Clinical Data
1.4.1.
Pharmacokinetics and Product Metabolism
Following oral administration of ibrutinib at doses ranging from 1.25 to 12.5 mg/kg/day as well 
as fixed dose levels of 420, 560, and 840 mg/day (Studies PCYC-04753-CA, PCYC-1102-CA, 
PCYC-1104-CA), exposure to ibrutinib increased as doses increased with substantial 
intersubject variability.  The mean half-life (t1/2) of ibrutinib across 3 clinical studies ranged 
from 4 to 9 hours, with a median time to maximum plasma concentration (Tmax) of 2 hours.  
Administration of 420 mg ibrutinib with a high-fat breakfast in subjects with chronic 
lymphocytic leukemia (CLL) approximately doubled the mean systemic exposure compared to 
intake after overnight fasting with median time to Tmax delayed from 2 to 4 hours.  Ibrutinib was 
extensively metabolized to the dihydrodiol metabolite PCI-45227, a reversible inhibitor of BTK,
with approximately 15 times lower inhibitory potency compared to ibrutinib.  The metabolite-to-
parent AUC ratio ranged from 0.7 to 3.4.  Steady-state exposure of ibrutinib and PCI-45227 was 
less than 2-fold of first dose exposure.
The results of human mass balance study of [14C]-ibrutinib conducted in six healthy male 
subjects demonstrated that less than 10% of the total dose of [14C]-ibrutinib is renally excreted, 
whereas approximately 80% is recovered in feces.  Subjects with mild and moderate renal 
insufficiency (creatinine clearance >30 mL/min) were eligible to enroll in Study PCYC-1102-CA 
in which pharmacokinetic (PK) assessments were included.  No dose adjustment is needed for 


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mild or moderate renal impairment (greater than 30 mL/min creatinine clearance).  There is no 
data in patients with severe renal impairment or patients on dialysis.  The study of ibrutinib in 
hepatic impaired subjects is currently in progress.
1.5.
Summary of Clinical Safety of Ibrutinib
A brief summary of safety data from monotherapy and combination therapy studies is provided 
in below. For more comprehensive safety information please refer to the current version of the 
IB. Additional safety information may be available for approved indications in regional 
prescribing labels where the study is conducted (eg, USPI, SmPC). 
1.5.1.
Monotherapy Studies
Pooled safety data for a total of 1071 subjects treated with ibrutinib monotherapy from 9 studies 
in B-cell malignancies, which includes subjects from 2 randomized-control studies who crossed 
over from comparator treatment or placebo to receive ibrutinib monotherapy, are summarized 
below.
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1071):
Most frequently reported 
TEAEs >10%  
Most frequently reported 
Grade 3 or 4 TEAEs >2% 
Most frequently reported 
Serious TEAEs >1% 
Diarrhea
Neutropenia
Pneumonia
Fatigue
Pneumonia
Atrial fibrillation
Nausea
Thrombocytopenia
Febrile neutropenia
Cough
Anemia
Pyrexia
Anemia
Hypertension  
Pyrexia
Atrial fibrillation
Neutropenia 
1.5.2.
Combination Therapy Studies
Pooled safety data for a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in B-cell malignancies, which included 1 randomized-control 
study, are summarized below. Therapies used in combination with ibrutinib in these studies, 
included BR (bendamustine and rituximab), FCR (fludarabine, cyclophosphamide, and 
rituximab), ofatumumab, and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, 
and prednisone).
Most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy (N=423):


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Most frequently reported 
TEAEs >10%  
Most frequently reported 
Grade 3 or 4 TEAEs >2% 
Most frequently reported 
Serious TEAEs >1% 
Neutropenia
Neutropenia
Febrile neutropenia
Diarrhea
Thrombocytopenia
Pneumonia
Nausea
Febrile neutropenia
Atrial fibrillation
Thrombocytopenia
Pneumonia
Pyrexia
Fatigue
Hypertension 
1.5.3.
Risks
1.5.3.1.
Bleeding-Related Events
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, 
epistaxis, and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal 
bleeding, intracranial hemorrhage, and hematuria. Use of ibrutinib in subjects requiring other 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding.
Subjects with congenital bleeding diathesis have not been studied. See Section 6.1.2.4 for 
guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See 
Section 6.2 for guidance on ibrutinib management with surgeries or procedures.
1.5.3.2.
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy. At least 25% of subjects 
with MCL and 35% of subjects with CLL had Grade 3 or greater infections per NCI Common 
Terminology Criteria for Adverse Events (CTCAE). The most commonly reported infections 
include pneumonia, cellulitis, urinary tract infection and sepsis. Although causality has not been
established, cases of progressive multifocal leukoencephalopathy (PML) have occurred in 
patients treated with ibrutinib.
1.5.3.3.
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. 
1.5.3.4.
Atrial Fibrillation
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, acute infections, and a previous history of atrial
fibrillation. For atrial fibrillation which persists, consider the risks and benefits of ibrutinib 
treatment and follow the protocol dose modification guidelines (see Sections 5.3.1.4 and 5.3.1.5).


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1.5.3.5.
Second Primary Malignancies
Second primary malignancies, most frequently skin cancers, have occurred in subjects treated 
with ibrutinib. Second primary malignancies including non-skin carcinomas have occurred in 
patients treated with ibrutinib. The most frequent second primary malignancy was non-
melanoma skin cancer.
1.5.3.6.
Tumor Lysis Syndrome
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with single 
agent ibrutinib or in combination with chemotherapy. Subjects at risk of TLS are those with 
comorbidities and/or risk factors such as high tumor burden prior to treatment, increased uric 
acid (hyperuricemia), elevated LDH, bulky disease at baseline, and pre-existing kidney 
abnormalities.
1.5.3.7.
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 Sections 5.3.1.4 and 5.3.1.5).
1.5.3.8.
Rash
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy.  In a randomized Phase 3 study (PCYC-1112-CA), rash 
occurred at a higher rate in the ibrutinib arm than in the control arm. Most rashes were mild to 
moderate in severity.
1.6.
Summary of Clinical Data with Ibrutinib in WM
1.6.1.
Study PCYC-04753
Pharmacyclics LLC sponsored a Phase 1 dose escalation study (Study PCYC-04753) that 
enrolled subjects with a variety of B-cell malignancies (Advani 2013).  Ibrutinib was well 
tolerated at doses that led to >90% occupancy of the BTK active site.  In this study, the ORR in 
54 evaluable subjects was 57%, including a complete response rate of 16%.  The study enrolled 
4 male subjects with relapsed/refractory WM who received a median of 3 prior systemic 
regimens and were treated at 2 different dose levels (560 mg/day and 12.5 mg/kg/day). IgM 
values at baseline varied between 4.4–5.5 g/dL.  All 4 subjects experienced at least 1 adverse 
event (AE), and serious adverse events (SAEs) were reported in 3 subjects.  The majority of AEs 
were Grade 1 and unrelated to ibrutinib, with the exception of 3 Grade 2 AEs (hypertension, 
atrial fibrillation [also an SAE], and pyrexia; all unrelated to ibrutinib), and 1 Grade 4 AE of 
neutropenia (unrelated to ibrutinib).  The 5 reported SAEs were all unrelated to ibrutinib 
(2 subjects each with Grade 1 febrile neutropenia and 1 subject with Grade 2 atrial fibrillation, 


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Grade 1 pneumonia, and Grade 1 pneumonitis).  No subjects required a dose reduction or 
discontinued due to an AE.  The majority of AEs did not require treatment; the remainder was 
readily managed with concomitant medications.   
One out of the 4 subjects achieved disease stabilization according to the treating physician but 
ultimately discontinued ibrutinib due to progressive disease after 8 months.  Three out of the 
4 subjects achieved a partial response (PR) (IgM reduction of at least 50% from baseline).  The 
induced responses were durable, and all 3 subjects rolled over onto the extension Study 
PCYC-1103-CA and continue to receive treatment with ibrutinib for more than 4 years.  In 
addition to the clinically significant IgM decrease in the 3 responders, all 4 subjects had an 
increase in their hemoglobin and hematocrit over treatment time.  Preliminary safety data from 
the ongoing PCYC-1103-CA study have indicated that all 4 subjects experienced at least 1 AE 
grade 3 or higher, but no SAEs have been reported to date on the long term extension.
1.6.2.
Study NCT01614821
NCT01614821, an ongoing Investigator-sponsored study conducted under IND 113,935 at Dana 
Farber Cancer Institute, Memorial Sloan-Kettering Cancer Center, and Stanford University and 
led by Dr. Steven Treon at the Dana Farber Cancer Institute, was initiated in May 2012 in 
subjects who received at least 1 prior therapy for WM and met the criteria for further treatment 
according to the consensus panel criteria from the Second IWWM (Kyle 2003).  In this Phase 2 
study, ibrutinib is administered orally 420 mg once daily and continued for 2 years or until 
progressive disease or intolerability.  
Enrollment of 63 subjects was completed in June 2013 (43 subjects at Dana Farber Cancer 
Institute, 10 subjects at Stanford University, and 10 subjects at Memorial Sloan-Kettering Cancer 
Center) and represents one of the largest single-arm studies conducted specifically in patients 
with WM.  A study progress update of 63 subjects, including 17 with refractory disease was 
presented at the American Society of Hematology in December 2013 (Treon 2013). Median 
baseline characteristics included an age of 63 years, 2 prior therapies (range 1-6), hematocrit of 
30.8%, hemoglobin of 10.5 g/dL, serum IgM of 3,610 mg/dL, serum M-protein of 2.14 g/dL.  At
the time of best response, median serum IgM levels and M-protein declined to 1,340 mg/dL and 
0.84 g/dL, respectively, and median hematocrit and hemoglobin rose to 38.1% and 12.6 g/dL, 
respectively.  Thirty-four subjects had a 6-month bone marrow assessment showing tumor 
reduction from a median of 70% to 45%.  With a median follow-up of 6 cycles (range 2-15), the 
best overall response rate, with minor response (MR) or better based on the consensus criteria 
adapted from the 3rd International Workshop on WM, is 81% (4 very good partial response 
[VGPR]; 32 PR, 15 MR), with a major response rate (PR or better) of 57.1% and a median time 
to response of 4 weeks. Eleven subjects have stable disease, and 1 subject did not respond to 
ibrutinib treatment. Grade >2 treatment-related toxicities include thrombocytopenia (14.3%); 
neutropenia (19.1%); stomatitis (1.6%); atrial fibrillation (1.6%); diarrhea (1.6%); herpes zoster 
(1.6%); hematoma (1.6%); hypertension (1.6%) and epistaxis (1.6%). Fifty-nine subjects remain 
on study with 7 subjects receiving reduced doses of ibrutinib. 


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Results indicate that ibrutinib has been well tolerated in this ongoing study, and the current 
safety profile is similar to the overall clinical safety profile obtained with the monotherapy 
administration of ibrutinib.  These data were the basis of the most recent approval of 
IMBRUVICA in WM (IMBRUVICA® USPI, January 2015, IMBRUVICA® Prescribing 
Information, 2015).
1.7.
Justification of Study Design and Dose Rationale 
Rituximab is a chimeric human/mouse antibody that targets the CD20 surface antigen
(Cheson 2002) which is almost always present on WM cells (San Miguel 2003; Konoplev 2005;
Dimopoulos 2009).  As a single agent at standard dose (ie, 4 weekly infusions at 375 mg/m2), 
rituximab induced a partial response in 35% of untreated and in 20% of previously treated 
patients and the median duration of response was 27 months in a study conducted by ECOG 
(Gertz 2004). An extended rituximab regimen (rituximab for 4 weeks and for those without 
progression at week 12, 4 additional weekly infusions of rituximab) reported higher response 
rates (44% and 48%) (Dimopoulos 2002a; Treon 2005) and a median PFS in patients with 
relapsed WM of around 15 months and 18 months in patients with no prior therapies
(Treon 2005; Ghobrial 2004; Dimopoulos 2002b). As a single agent rituximab is neither 
myelosuppressive nor stem cell toxic. Thus, based on this positive toxicity profile, rituximab 
single agent therapy  is an appropriate therapy for WM patients who present with cytopenias, 
impaired performance, neuropathy or cold-agglutinin anemia (Kilidireas 2006) and is a 
recommended therapy for previously treated WM by current National Comprehensive Cancer 
Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines.
The rationale for use of ibrutinib in the proposed study is based on the results from Studies 
PCYC-04753 and an ongoing Investigator-initiated study conducted under IND 113,935 that 
demonstrate promising single-agent activity in subjects with previously treated WM 
(Section 1.6.1 and Section 1.6.2, respectively).
A Phase 2 investigator-initiated study of continuously administered ibrutinib (420 mg) in 
combination with rituximab (375 mg/m2) administered weekly for the first four weeks (cycle 1), 
then monthly until cycle 6 indicated that ibrutinib in combination with rituximab was safe and 
well tolerated regimen for subjects with high-risk CLL. At 18 months the approximate PFS was 
78%; with an approximate OS of 84%. This combination induced high rates of durable responses 
with an overall response rate of 95% (8% CR) (Burger 2014). For further details, see 
Section 3.2.
Additional Phase 1 combination studies (PCYC-1108-CA and PCYC-1109-CA) demonstrated 
that ibrutinib could be safely combined with chemoimmunotherapy regimens such as 
bendamustine/rituximab (BR) and monoclonal CD̻20 antibody, ofatumumab, and even more, 
the combinations may enhance its clinical activity in subjects with relapsed and refractory CLL. 
In study PCYC-1108-CA, ibrutinib in combination with the BR regimen resulted in an overall 
response rate of 93% (13% CR). The toxicity profile of the combination is similar to that of BR 
alone (Brown 2013). In study PCYC-1109-CA, ibrutinib in combination with ofatumumab 


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resulted in an overall response rate of up to 100% when combining these 2 agents, without 
additional toxicity (Jaglowski 2012).  
A Phase 1b/2 study (PCYC-1102-CA) demonstrated that continuous ibrutinib monotherapy once 
daily (either at 420 mg or 840 mg) in treatment naïve CLL/SLL patients (n=31) was safe and 
well tolerated with a trend toward improved tolerability with continued time on treatment.  With 
a median follow-up of 22.1 months, 26 out of 31 patients remained on study treatment with only 
two discontinuations due to adverse events (O’Brien 2013).  This single agent therapy induced 
high rates of durable responses with an overall response rate of 87%, with 13% achieving a CR.  
The 30 month PFS rate was 96.3% and corresponding OS was 96.6% with the median PFS and 
OS not yet reached (O’Brien 2014).
In addition, a Phase 1b study (DBL1002) in subjects with treatment naïve NHL demonstrated 
that ibrutinib in combination with R-CHOP had an acceptable safety profile with encouraging 
efficacy leading to a Phase 3 randomized trial design in de novo DLBCL.  Of the 33 patients 
enrolled, 30 completed 6 cycles of therapy, with only one discontinuing for an adverse event.
The overall response rate in DLBCL was 100%, with a CR rate ≥60%.  There were no 
unexpected adverse events noted during the course of the study (Younes 2014).
The proposed dose for ibrutinib is 420 mg per day (3 x 140-mg capsules) administered once 
daily without interruption. In the ongoing Phase 2 study (NCT01614821), the 420 mg dose 
administered once daily appeared safe and favorable responses were seen in subjects with 
previously treated WM as outlined in Section 1.5.2. In addition, ibrutinib at a dose of 420 mg 
per day was safely combined in the above-mentioned combination studies with rituximab, BR 
(PCYC-1108-CA) or ofatumumab (PCYC-1109-CA).
As the PCYC-04753 study and ongoing phase 2 study have shown promising single-agent 
activity, an open-label ibrutinib substudy (Arm C) is included to further investigate the safety 
and efficacy of ibrutinib monotherapy in subjects with WM who would otherwise be excluded 
from the randomized study because they are considered refractory to the last prior rituximab-
containing therapy.
2.
STUDY OBJECTIVE 
2.1.
Primary Objective
To evaluate the effect of the addition of ibrutinib to rituximab on progression-free survival (PFS) 
assessed by an independent review committee (IRC) in subjects with WM. Efficacy evaluations
will be based on the modified Consensus Response Criteria from the VIth International 
Workshop for WM (NCCN 2014).


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2.2.
Secondary Objective(s)
Efficacy
To compare the treatment arms in terms of the following:
•
Overall Response Rate (ORR) assessed by IRC (≥PR; according to the modified VIth
IWWM [NCCN 2014] criteria).
•
Hematological improvement measured by hemoglobin.
•
Time to next treatment (TTnT).
•
Overall survival (OS).
Safety
•
To evaluate the safety and tolerability of ibrutinib when combined with rituximab therapy 
compared to rituximab in combination with placebo.
2.3.
Exploratory Objectives
•
Patient-reported outcomes (PRO) and disease-related symptoms according to FACT-An. 
•
Patient-reported outcomes (PROs) and disease-related symptoms according to Euro QoL 
5 dimension questionnaire (EQ-5D-5L).
•
Duration of response (DOR) according to IRC assessment.
•
Clinical response rate (CRR) assessed by IRC (≥MR; according to the modified VIth
IWWM [NCCN 2014] criteria).
•
Efficacy assessment by Investigator (≥PR and ≥MR; according to the modified VIth
IWWM [NCCN 2014] criteria).
•
To determine the pharmacokinetics (PK) of ibrutinib in combination with rituximab in 
subjects with WM.
•
Evaluation of medical resource utilization (MRU) (eg, requirements of plasmapheresis, 
transfusions and use of growth factors).
•
Prognostic and predictive biomarkers and genetics relative to treatment outcomes.
Open-label Substudy Treatment Arm C 
The objectives are to evaluate the efficacy and safety of open-label ibrutinib monotherapy in 
WM subjects who are considered refractory to the last prior rituximab-containing therapy (refer 
to Section 4.2). PFS, ORR, hematological improvement measured by hemoglobin, TTnT, FACT-
An, OS and other efficacy parameters as well as safety analyses will be summarized 
descriptively for Arm C. No comparator analysis will be done with Arms A or B. 


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3.
STUDY DESIGN 
3.1.
Overview of Study Design
This is a randomized, placebo-controlled, double-blind, Phase 3 study designed to evaluate 
whether treatment with ibrutinib in combination with rituximab will result in an improvement in 
PFS compared to placebo in combination with rituximab in subjects with WM. In addition, an 
open-label ibrutinib substudy is included to further investigate the safety and efficacy of ibrutinib 
monotherapy in subjects with WM who are considered refractory to the last prior rituximab-
containing therapy (refer to Section 4.2).
The study duration is estimated to be 4 years with approximately 1.5 years of enrollment and 
3 years of follow up. The end of study will occur approximately 3 years after the last subject is 
randomized, or the Sponsor terminates the study, whichever comes first. 
Approximately 150 subjects will be randomized in a 1:1 ratio to receive ibrutinib and rituximab 
(Treatment Arm A) or placebo and rituximab (Treatment Arm B).
Up to 30 subjects will be enrolled in the open-label ibrutinib monotherapy substudy (Treatment 
Arm C).
The study will include a Screening Phase, Treatment Phase and a Follow-Up Phase. 
The Screening Phase assessments will be performed within 30 days prior to study treatment and 
will begin on the day the subject signs informed consent. During the Screening Phase, the 
subjects’ eligibility will be determined. Eligible subjects must have clinicopathological
diagnosis of Waldenström’s macroglobulinemia (WM) confirmed by central pathology review 
and in accordance with the consensus panel of the Second International Workshop on WM 
(Owen 2003). Subjects with previously treated WM must have documented relapsed/refractory 
disease from their most recent prior therapy according to the modified WM consensus criteria.
Further, subjects must have symptomatic disease meeting at least 1 of the recommendations from 
the Second International Workshop on Waldenström's Macroglobulinemia for requiring 
treatment. Subjects who meet all the inclusion/exclusion criteria are eligible to enter the study.
The Treatment Phase will extend from randomization (Arm A and Arm B) or first dose of study 
drug (Arm C) until the End-of-Treatment Visit (which should occur 30 days from of last dose of 
study drug or prior to the start of a new anticancer treatment). Initiation of study treatment 
should occur within 72 hours of randomization.  All subjects in Arms A and B will receive 
intravenous rituximab weekly for 4 consecutive weeks, followed by a second course of rituximab 
administered weekly for 4 consecutive weeks after a 3-month interval. In addition, all subjects
in Arms A and B, according to randomization, will receive oral study drug (ibrutinib or matching 
placebo), administered daily and continuously until criteria for permanent discontinuation of 
study drug are met (Section 9.2), such as IRC confirmed disease progression, study drug is no 
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and continuously until criteria for permanent discontinuation of study drug are met. Further 
information on dosing is provided in Section 5. Efficacy evaluations will be performed as 
specified in Section 7.5. Subjects with IRC confirmed progressive disease must discontinue all 
study treatment and may be assessed for potential cross over treatment.
After the End-of-Treatment Visit (30 days ± 3 days from last dose of study drug or prior to the 
start of a new anticancer treatment) has been performed, subjects will continue to be monitored 
through either response follow-up or survival follow-up and will continue until death, lost to 
follow-up, consent withdrawal, or study end, whichever occurs first.
•
The Response Follow-up Phase will occur for subjects who discontinue for reasons other 
than disease progression and will include efficacy assessments every 12 weeks until 
disease progression confirmed by an independent review committee (IRC), regardless of 
initiation of subsequent anticancer treatment. Subjects with IRC confirmed disease 
progression during the Response Follow-up Phase will continue to be followed in the 
Survival Follow-Up Phase.
•
The Survival Follow-up Phase will occur for subjects with IRC confirmed disease 
progression and will be followed for survival, subsequent anti-cancer therapy and other
malignancies every 12 weeks until study end.
Access to next-line ibrutinib (cross-over) for subjects with IRC confirmed disease progression 
and treated with placebo in combination with rituximab (Arm B) may be provided as outlined in 
Section 7.7.
An independent Data Monitoring Committee (DMC) will be formed and constituted according to 
regulatory agency guidelines. Detailed information regarding the composition of the DMC and 
detailed DMC procedures will be provided in a separate charter. The DMC will review the 
safety data periodically and the interim analysis results and provide recommendations according 
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3.1.2.
Study Population
Subjects with untreated or previously treated WM will be evaluated in this study.
Eligible subjects must have a centrally confirmed clinicopathological diagnosis of WM as 
defined by consensus panel of the Second International Workshop on WM (Owen 2003); and 
must be in need of treatment in accordance with the “Consensus Panel Two” recommendations 
from the Second International Workshop on Waldenström’s Macroglobulinemia (Kyle 2003).
Those subjects who have been previously treated must have documented relapsed/refractory 
disease to their most recent prior therapy.
Subjects in Arms A and B who had previously received a rituximab-containing regimen should 
have a documented response (at least MR) on the last prior rituximab-containing regimen and 
any previous rituximab therapy must have ended at least 12 months prior to enrollment in this 
protocol. Subjects who do not meet these rituximab-related criteria may be eligible to enroll in 
the open-label ibrutinib monotherapy substudy (Arm C).
3.2.
Study Rationale 
This is a randomized, double-blind, Phase 3 study designed to assess the safety and efficacy of 
ibrutinib in combination with rituximab compared to placebo in combination with rituximab in 
subjects with WM. 
Rituximab, given either as a single agent or in combination, is currently a recommended therapy 
for previously treated and untreated WM in NCCN 2012 and ESMO 2013 guidelines
(Anderson 2012; Buske 2013). All subjects will receive rituximab therapy; the study will 
include two treatment arms with approximately 75 subjects in both treatment arms to observe 
71 PFS events. Assuming a 2-fold improvement (hazard ratio of 0.5) in median PFS of the 
rituximab in combination with ibrutinib arm over rituximab and placebo arm (median PFS 
assumption for rituximab and placebo arm is 15 months), the study has at least 80% power to 
achieve a statistical significance level of 5% (2-sided) under exponential distribution for PFS.
The proposed dose for rituximab is 375 mg/m2 intravenous (IV) administered once weekly for 
4 weeks followed by a second four-weekly rituximab course after a three-month interval. This 
dose was given in two single-arm published studies and provided the most current treatment 
guidance for rituximab in relapsed/refractory WM (Dimopoulos 2002a; Treon 2005).
The proposed dose for ibrutinib is 420 mg per day (3 x 140-mg capsules) administered once daily 
without interruption. In the ongoing Phase 2 study (NCT01614821), the 420 mg dose 
administered once daily demonstrated a favorable benefit/risk profile in subjects with previously 
treated WM as outlined in Section 1.6.2.


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Ibrutinib at 420 mg in combination with rituximab 375 mg/m2 intravenous (IV) has been shown
to be a safe, well tolerated and an active treatment regimen in high-risk CLL subjects
(Burger 2014). At a median follow up of 16.8 months, 31 of 40 subjects continued on therapy 
(14 out of 20 with del17p or TP53 mutation) without disease progression. 39 subjects were 
evaluable for response assessment per 2008 IWCLL guidelines; 34 (87%) achieved partial 
remission (PR), and three (8%) complete remission (CR), accounting for an ORR of 95%. The 
ORR in the 20 patients with del17p or TP53 mutation was 90% (16 PR, 2 CR). Among the 9
subjects that came off study, four subjects came off study because of possibly treatment-related 
toxicity (two pneumonia, one pulmonary infection and one grade 3 mucositis), three subjects had 
progressive disease (including one Richter’s transformation), and two subjects died while on 
therapy unrelated to study treatment (one due to infectious complications and one due to 
respiratory and cardiovascular failure while in remission). Treatment generally was well 
tolerated, with infectious complications (8 cases of pneumonia and 9 cases of upper respiratory 
infections) being the most common complication.  There were nine Grade 3 or higher, possibly 
related AEs: lung infection (n=2), neutropenia (n=2), upper respiratory infection (n=1), 
transaminase increase (n=1), mucositis (n=1), and peripheral neuropathy (n=1). Milder toxicities 
included Grade 1-2 bruising and rash (n=15), nausea or acid reflux (n=10), Grade 2 subdural 
hematoma (n=1), fatigue (n=7), bone pain, myalgias, and arthralgia (n=13), or diarrhea (n=17).  
Taken together, these data support the utility of the proposed combination of rituximab and 
ibrutinib in subjects with WM.
Ibrutinib monotherapy has indicated favorable responses in subjects who failed prior CD20 
therapy alone or in combination with other agents based on the findings in an ongoing Phase 2 
study in WM (NCT01614821, refer to Section 1.6.2). Therefore, subjects who are considered 
refractory to the last prior rituximab-containing therapy may be eligible to enroll in the open-
label monotherapy substudy (Treatment Arm C).
3.3.
Statement of Compliance
This study will be conducted in compliance with this protocol, principles of International 
Conference on Harmonisation (ICH), Good Clinical Practice (GCP), Declaration of Helsinki, 
and all applicable national and local regulations governing clinical studies.
4.
SUBJECT SELECTION
4.1.
Eligibility Criteria for the Randomized Study (Arm A and Arm B)
4.1.1.
Inclusion Criteria
To be enrolled in the study, each potential subject must satisfy all of the following inclusion 
criteria.


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Disease Related
1. Subjects with untreated or previously treated Waldenström’s Macroglobulinemia
a.
Previously treated subjects must have either documented disease progression or had no 
response (stable disease) to the most recent treatment regimen.
2. Centrally confirmed clinicopathological diagnosis of WM in accordance with the consensus 
panel of the Second International Workshop on WM (Owen 2003).
3. Measurable disease defined as serum monoclonal IgM >0.5 g/dL.
4. Symptomatic disease meeting at least 1 of the recommendations from the Second 
International Workshop on Waldenström Macroglobulinemia for requiring treatment
(Kyle 2003):
a.
Constitutional symptoms documented in the subject’s chart with supportive objective 
measures, as appropriate, defined as one or more of the following disease-related 
symptoms or signs:
i.
Unintentional weight loss ≥10% within the previous 6 months prior to 
Screening
ii.
Fevers higher than 100.5°F or 38.0°C for 2 or more weeks prior to 
Screening without evidence of infection 
iii.
Night sweats for more than 1 month prior to Screening without evidence 
of infection
b.
Clinically relevant fatigue which is not relieved by rest due to WM
c.
Symptomatic hyperviscosity or serum viscosity levels greater than 4.0 centipoises
d.
Lymphadenopathy which is either symptomatic or bulky (≥5 cm in maximum 
diameter)
e.
Symptomatic hepatomegaly and/or splenomegaly and/or organ tissue infiltration
f.
Peripheral neuropathy due to WM
g.
Symptomatic cryoglobulinemia
h.
Cold agglutinin anemia
i.
IgM related immune hemolytic anemia and/or thrombocytopenia
j.
Nephropathy related to WM
k.
Amyloidosis related to WM
l.
Hemoglobin ≤10g/dL
m. Platelet count <100x109/L
n.
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Laboratory
5. Adequate hematologic function defined as: 
a.
Absolute neutrophil count >750 cells/mm3 (0.75 x 109/L) independent of growth 
factor support within 7 days of the first dose with study drug.  
b.
Platelet count >50,000 cells/mm3 (50 x 109/L) without transfusion support within 
7 days of the first dose of study drug.
c.
Hemoglobin ≥ 8 g/dL without transfusion or growth factor support within 7 days of 
the first dose of study drug.
6. Adequate hepatic and renal function defined as:
a.
Serum aspartate transaminase (AST) or alanine transaminase (ALT) <3.0 x upper 
limit of normal (ULN).
b.
Estimated Creatinine Clearance ≥30 mL/min).
c.
Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-
hepatic origin).
7. PT/INR ≤1.5 x ULN and PTT (aPTT) ≤1.5 x ULN unless abnormality is unrelated to a 
coagulopathy or bleeding disorder (when treated with warfarin or other vitamin K 
antagonists, then INR ≤3.0).
Demographic
8. Men and women ≥18 years of age.
9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
Ethical/Other
10. Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no
menses for ≥2 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR 
history of bilateral oophorectomy). Female subjects of reproductive potential must have a 
negative pregnancy test upon study entry.
11. Male and female subjects of reproductive potential who agree to use highly effective 
methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, 
some intrauterine devices [IUDs], complete abstinencea, or sterilized partner) during the 
period of therapy and for 30 days after the last dose of study drug and 90 days (males) after 
the last dose of study drug.
a 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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4.1.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
1. Known involvement of the central nervous system by WM.
2. Disease that is refractory to the last prior rituximab-containing therapy defined as either 
•
Relapse after the last rituximab-containing therapy <12 months since last dose of 
rituximab, 
OR
•
Failure to achieve at least a MR after the last rituximab-containing therapy.
If the subject meets this exclusion criterion and therefore is excluded from the main 
randomized study, participation in the non randomized substudy (Arm C) may be considered 
(Section 4.2)
3. Rituximab treatment within the last 12 months before the first dose of study drug.
4. Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any component 
of rituximab.
5. Prior exposure to ibrutinib or other BTK inhibitors.
6. Received any WM-related therapy (eg, chemotherapy, immunotherapy, investigational drug)
≤30 days prior to first administration of study treatment.
7. Plasmapheresis <35 days prior to the initiation of study drug, except when at least one serum 
IgM central assessment was performed during the screening period and was >35 days from 
the most recent plasmapheresis procedure.
•
Subjects with high IgM values or viscosity symptoms during screening may receive 
plasmapheresis prior to initiating study drug (refer to Section 6.3) if the previous 
plasmapheresis was performed >35 days before the plasmapheresis performed during 
screening (in order to obtain a true baseline IgM value for efficacy evaluations).
8. 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 drug 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.
9. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
10. Recent infection requiring systemic treatment that was completed ≤14 days before the first 
dose of study drug.
11. Known bleeding disorders (eg, von Willebrand’s disease) or hemophilia.


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12. History of stroke or intracranial hemorrhage within 12 months prior to enrollment.
13. Known history of infection with human immunodeficiency virus (HIV).
14. Active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) defined 
by positive polymerase chain reaction (PCR).
15. Any uncontrolled active systemic infection.
16. Major surgery (as defined in Section 6.2.2) within 4 weeks of first dose of study drug.
17. 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.
18. 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.
19. 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.
20. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see Appendix 3).
21. Lactating or pregnant.
22. Unwilling or unable to participate in all required study evaluations and procedures.
23. 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).
4.2.
Eligibility Criteria for Open-label Substudy Treatment Arm C  
4.2.1.
Inclusion Criteria 
To be enrolled in the substudy, each potential subject must meet all of the inclusion criteria 
defined in Section 4.1.1. IN ADDITION, the following criterion must be met:
1. Disease that is refractory to the last prior rituximab-containing therapy defined as either 
•
Relapse after the last rituximab-containing therapy <12 months since last dose of 
rituximab, 
OR
•
Failure to achieve at least a MR after the last rituximab-containing therapy.
4.2.2.
Exclusion Criteria
The exclusion criteria for the substudy are identical to those of the main randomized study as 
described in Section 4.1.2, EXCEPT for criteria 2, 3, and 4, which are related to prior rituximab 
use and do not apply for the substudy Arm C.


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5.
TREATMENT OF SUBJECTS 
5.1.
Randomization and Blinding
After the subject has completed all baseline (screening) procedures and met all requirements of 
the inclusion/exclusion criteria, study site personnel will submit the Eligibility Worksheet to the 
Medical Monitor or Sponsor designee for approval. In order to begin treatment, study personnel 
will register the subject into the Interactive Web Response System (IWRS) to have drug assigned 
to that subject. The first dose of study drug should be administered after randomization, but no 
more than 72 hours after the subject has been randomized by IWRS.
Approximately 150 subjects will be randomized in a 1:1 ratio to each of the 2 treatment arms:
•
Treatment Arm A: Oral Ibrutinib in combination with intravenous Rituximab 
•
Treatment Arm B: Oral Placebo in combination with intravenous Rituximab 
Central randomization will be implemented in this study. Randomization will be stratified using 
the following stratification factors and subjects will be randomized in a 1:1 ratio to receive either 
ibrutinib/rituximab or placebo/rituximab) within each randomization stratum: 
a)
WM IPSS assessed at Screening (Low vs. Intermediate vs. High)
b)
Number of prior systemic treatment regimens (0, 1-2 vs. ≥3)
c)
ECOG status (0-1 vs. 2)
The interactive web response system (IWRS) will assign a unique treatment code, which will 
dictate the treatment assignment and matching study drug kit for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS, and will then give the relevant subject details to uniquely identify the subject.
Subjects eligible for open-label substudy Arm C will be enrolled using the IWRS to obtain a 
unique treatment code.
Blinding
This is a double-blind study; therefore, subjects, investigators, and the Sponsor’s study team 
members will remain blinded to treatment assignment. The investigator may request to unblind 
subjects who meet the criteria for next-line therapy with ibrutinib per Section 7.7. After the 
request is reviewed, by the Sponsor’s designee, the investigator will be informed if the request to 
unblind can be approved.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.


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Data that may potentially unblind the treatment assignment (ie, 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 
for subjects who meet the criteria for next-line therapy with ibrutinib and after approval is
received from the Sponsor’s designee per Section 7.7, or if specific emergency treatment/course 
of action would be dictated by knowing the treatment status of the subject. In such cases, the 
investigator may in an emergency determine the identity of the treatment by contacting the 
IWRS. It is recommended that the investigator contact the sponsor or its designee, if possible, to 
discuss the particular situation before breaking the blind. Telephone contact with the sponsor or 
its designee will be available 24 hours per day, 7 days per week. In the event the blind is broken, 
the sponsor must be informed as soon as possible. The date, time, and reason for the unblinding 
must be documented by the IWRS in the appropriate section of the eCRF and in the source 
document. The documentation received from the IWRS indicating the code break must be 
retained with the subject's source documents in a secure manner. 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 (ie, 
subject remains blinded to treatment assignment) should be maintained provided the subject’s 
safety is not compromised.
At the time of the interim analysis, the randomization codes and, if required, the translation of 
randomization codes into treatment and control groups will be disclosed to those authorized and 
only for those subjects included in the interim analysis.
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).
Oral study medications (ibrutinib/placebo) are recommended to be administered on an outpatient 
basis. Subjects will be randomized to ibrutinib or matching placebo in a 1:1 ratio. Blinded study 
medication will be administered for continuous daily dosing.
Open-label Substudy Treatment Arm C
Up to 30 subjects will be enrolled in an open-label substudy:
•
Treatment Arm C: Oral ibrutinib 
All subjects eligible for the substudy will be treated with ibrutinib monotherapy with continuous 
daily dosing. 


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All subjects treated in this substudy will follow guidelines for ibrutinib/placebo dosing and 
toxicity management as described for the randomized treatment arms (Arm A and Arm B) in the 
protocol. 
5.2.1.
Treatment Arm A (Ibrutinib/Rituximab)
Ibrutinib:
420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1
Rituximab:
375 mg/m2 IV per package insert weekly for four consecutive weeks, followed by 
a second four-weekly rituximab course after a three-month interval.
Day 1 of Weeks 1-4 and Weeks 17-20 (total of 8 infusions of rituximab)
5.2.2.
Treatment Arm B (Placebo/Rituximab)
Placebo:
3 capsules of placebo orally administered daily beginning from Day 1 in Week 1
Rituximab:
375 mg/m2 IV per package insert weekly for four consecutive weeks, followed by 
a second four-weekly rituximab course after a three-month interval.
Day 1 of Weeks 1-4 and Weeks 17-20 (total of 8 infusions of rituximab)
5.2.3.
Treatment Arm C (Ibrutinib Open-label Substudy)
Ibrutinib:
420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1
5.3.
Study Medication
5.3.1.
Ibrutinib/Placebo
For the purposes of this study, ibrutinib and placebo refers to the blinded label study drug used in 
this study in treatment arms A and B.  All subjects will follow the guidelines for ibrutinib dosing 
and toxicity management. Study drug refers to both ibrutinib and placebo. In the substudy
(Arm C), subjects will receive ibrutinib and will also follow the guidelines for ibrutinib dosing 
and toxicity management.
5.3.1.1.
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 Investigator's Brochure 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.  All study drugs will be dispensed in child-resistant packaging.


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Refer to the pharmacy manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling.
Study drug labels will contain information to meet the applicable regulatory requirements.
5.3.1.2.
Dose and Administration
Study drug (3 capsules) is administered orally once daily with approximately 8 ounces (240 mL) 
of water. The capsules should be swallowed whole and should not be opened, broken, or 
chewed. The use of strong CYP3A inhibitors/inducers, and grapefruit and Seville oranges 
should be avoided for the duration of the study (Appendix 3).
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. Missed doses of study drug will not be made up.
The first dose will be administered in the clinic on Day 1 of Week 1, after which study drug will 
be self-administered daily by the subjects on an outpatient basis. Study drug will be dispensed to 
subjects in bottles. Unused study drug dispensed during previous visits must be returned to the 
site and drug accountability records (Section 12.8) updated at each visit.  Returned capsules must 
not be re-dispensed to anyone.
Study drug will be dosed 0-30 minutes before the rituximab infusion at the Week 4 visit.
Study drug dosing is continuous (without interruptions) throughout the Treatment Phase. If 
rituximab infusion is delayed due to scheduling conflicts, study drug dosing should continue. 
Refer to Section 7.4.1 for oral dose and administration instructions on PK sampling visits.
5.3.1.3.
Overdose
Any dose of study drug administered in excess of that specified in this protocol is considered to 
be an overdose.  Signs and symptoms of an overdose that meet any Serious Adverse Event 
criterion must be reported as a Serious Adverse Event in the appropriate time frame and 
documented as clinical sequelae to an overdose.
There is no specific experience in the management of ibrutinib overdose in patients. No 
maximum tolerated dose was reached in the Phase 1 study in which subjects received up to 
12.5 mg/kg/day (1400 mg/day). Healthy subjects were exposed up to single dose of 1680 mg.
One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) 
after a dose of 1680 mg. Subjects who ingested more than the recommended dosage should be 
closely monitored and given appropriate supportive treatment.
Refer to Section 11.3.3.2 for further information regarding AE reporting. 


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5.3.1.4.
Dose Hold, Reduction or Discontinuation of Study Drug (Ibrutinib/Placebo)
Treatment with study drug should be withheld for any unmanageable, potentially study drug-
related non-hematological toxicity that is Grade 3 or higher in severity and any hematologic 
toxicity meeting the criteria in Section 5.3.1.5.  Subjects who require full-dose of anticoagulant 
treatment (eg, heparin) should have study drug held until stable on anticoagulant therapy 
(Section 6.1.2.4).  Subjects that require an invasive procedure or surgery must have study drug 
withheld according to the guidance in Section 6.2.  Any other clinically important events where 
dose delays may be considered appropriate by the Investigator must be discussed with the 
Medical Monitor.
Study drug may be withheld for a maximum of 28 consecutive days for toxicity. Study drug 
should be discontinued in the event of a toxicity lasting more than 28 days, unless reviewed and 
approved by the Medical Monitor.
5.3.1.5.
Dose Modification of Study Drug (Ibrutinib/Placebo)
The dose of study drug should be modified according to the dose modification guidance in 
Table 2 if any of the following toxicities occur:
•
Grade 4 ANC (<500/μL) for more than 7 days. The use of neutrophil growth factors is 
permitted per American Society of Clinical Oncology (ASCO) guidelines and must be 
recorded in the electronic case report form (eCRF).  Refer to Section 6 for instruction 
regarding the use of growth factor support.
•
Grade 3 thrombocytopenia (platelets <50,000/μL) in the presence of Grade ≥2 bleeding 
events.
•
Grade 4 thrombocytopenia (platelets<25,000/μL).
•
Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic 
and/or anti-diarrheal therapy.
•
Any other Grade 4 or unmanageable Grade 3 toxicity attributed to study drug.
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anticoagulants or 
antiplatelet agents may be considered for the thromboprophylaxis of atrial fibrillation 
(Section 6.1.2.4).


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Table 2:
Study Drug (Ibrutinib/Placebo) Dose Modifications
Occurrence
Action to be Taken
First
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at original dose 
level
Second
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose level 
lower (ie, 280 mg/day / 2 capsules)
Third
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose level 
lower (ie, 140 mg/day / 1 capsule)
Fourth
Discontinue study druga
a If the oral study drug (ibrutinib/placebo) is discontinued for toxicity, subject will end the Treatment Phase of the 
study.
Please see Section 6.1.2.1 for guidelines for management of study drug in subjects who require 
treatment with a strong CYP3A inhibitor. 
Subjects enrolled in Arm C will receive ibrutinib monotherapy and will follow the same dose 
modifications as outlined for ibrutinib/placebo above.  All dose modifications/reductions of the 
blinded oral study drug or open-label ibrutinib must be recorded in the eCRF.
5.3.1.6.
Dose Modification for Hepatic Impaired Subjects
Ibrutinib is metabolized in the liver. For subjects with mild liver impairment (Child-Pugh class 
A), the recommended dose for ibrutinib/placebo is 280 mg daily (two capsules). For subjects 
with moderate liver impairment (Child-Pugh class B), the recommended dose is 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 10).
5.3.2.
Rituximab
All subjects in Arms A and B will receive rituximab and will follow the package insert for 
rituximab dosing and toxicity management.
5.3.2.1.
Formulation, Packaging, and Storage of Rituximab
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. 
Rituximab vials should be stored refrigerated between 2° to 8°C (36° 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.


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5.3.2.2.
Dosage, Preparation and Administration of Rituximab
The first dose of rituximab will be administered IV on Day 1 of Week 1 of the Treatment Phase, 
and will continue to be administered at the clinical site weekly for four consecutive weeks, 
followed by a second four-weekly rituximab course after a three-month interval (Week 1, 2, 3, 4
and 17, 18, 19, and 20).  Rituximab doses may be delayed for up to 3 days due to scheduling 
conflicts.
Rituximab will be administered IV by clinic staff according to the prescribing information.
Study drug will be administered 0–30 minutes prior to rituximab infusion at the Week 4 visit.
Rituximab should not be mixed or diluted with other drugs.
Rituximab will be administered as an IV infusion.  Premedication will be given prior to each 
administration.
Premedication: Prior to each infusion administer acetaminophen (or equivalent) and an 
antihistamine.
•
First Infusion: Initiate rituximab infusion at a rate of 50 mg/hr.  In the absence of infusion 
toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum 
of 400 mg/hr.
•
Subsequent Infusions: If no infusion reactions occur during the first infusion, initiate 
rituximab infusion at a rate of 100 mg/hr.  In the absence of infusion toxicity, increase 
rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr.
In the event of an infusion reaction, institute medical management (eg, 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.
The infusion can continue at one-half the previous rate upon improvement of subject symptoms.
Depending on the severity of the infusion reaction and the required interventions, treatment with 
rituximab may be temporarily or permanently discontinued. See Section 5.3.2.3 for further 
instructions.
Unused rituximab must be disposed of according to the sites drug disposal policy and drug 
accountability records updated.  
5.3.2.3.
Dose Delay of Rituximab
In order to initiate a subsequent dose with rituximab, the subject must not have any 
unmanageable, potentially rituximab-related non-hematological toxicity that is Grade 3 or higher 
in severity.  
Any other clinically important events where dose delays may be considered appropriate by the 
Investigator must be discussed with the Medical Monitor.  


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If a dose is missed due to scheduling conflicts, it can be delayed up to 3 days after the scheduled 
time.  If dosing must be delayed for more than 3 days for reasons other than toxicity, contact the 
Medical Monitor. 
Rituximab may be withheld for a maximum of 28 consecutive days for toxicity.  Rituximab 
should be discontinued in the event of a rituximab toxicity lasting more than 28 days, unless 
reviewed and approved by the Medical Monitor.
5.3.2.4.
Dose Interruption of Rituximab
Modify administration of rituximab for infusion-related reactions of any severity.  
•
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 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.
5.3.2.5.
Dose Modification of Rituximab
The dose of rituximab should be modified according to the dose modification guidelines in 
Table 3 if any of the following toxicities occur:
•
Any Grade 4 or unmanageable Grade 3 non-hematologic toxicity attributed to rituximab.
Note: For guidance on management of rituximab in relation to infusion reactions see 
Section 5.3.2.4.
Table 3:
Dose Modification for Rituximab Toxicity 
Occurrence
Action to be Taken
1st-3rd
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, subject may continue on study drug (ibrutinib/placebo).


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5.3.2.6.
Rituximab Associated “IgM flare” 
Plasmapheresis may be indicated before or during the initial rituximab therapy to avoid or to 
mange IgM-flare related complications such as hyperviscosity (Refer to Section 6.3).
Therapy with rituximab is commonly associated with a surge of IgM levels (IgM flare). This 
initial transient increase of IgM levels mostly does not indicate disease progression at treatment 
initiation and subjects may continue therapy with rituximab. The occurrence of rituximab 
associated IgM flare should be recorded as an adverse event (Refer to Section 11.3.1).  If 
necessary additional laboratory tests, physical examinations, and in the case of previous 
lymphadenopathy or splenomegaly, computed tomography (CT) scans might be performed to 
discriminate IgM flare from disease progression and all relevant tests needed to be recorded in 
the eCRF.
5.4.
Criteria for Permanent Discontinuation of Study Drug
Investigators are encouraged to keep a subject who is experiencing clinical benefit in the study 
unless IRC confirmed disease progression, 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 Visit (Section 8.3.8.1) is required for all subjects except for those subjects 
who have withdrawn full consent. 
6.
CONCOMITANT MEDICATIONS/PROCEDURES
6.1.
Concomitant Medications
6.1.1.
Permitted Concomitant Medications
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted.  Use of granulocyte colony-stimulating factors or erythropoietin growth factors is 
permitted per institutional policy and in accordance with the ASCO guidelines (Smith 2006).  
Transfusions may be given in accordance with institutional policy.
Short courses (≤14 days) of steroid treatment for non-WM related medical reasons (eg, 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. In addition, for subjects 
with chronic medical conditions, continuous administration of up to 20 mg per day of prednisone 
or equivalent is permitted for the treatment of this medical condition where no acceptable 
therapeutic alternative is available.
The use of these medications/transfusions must be recorded in the electronic case report form 
(eCRF).


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6.1.2.
Medications to be Used with Caution
6.1.2.1.
CYP3A Inhibitors/Inducers
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong CYP3A4
(eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, 
itraconazole, and nefazadone) or moderate CYP3A inhibitors and consider alternative agents 
with less CYP3A inhibition. If a strong CYP3A inhibitor must be used, reduce the ibrutinib to 
140 mg or withhold treatment temporarily for the duration of the inhibitor use. Subjects should 
be monitored for signs of ibrutinib toxicity. If a moderate CYP3A inhibitor must be used, reduce 
ibrutinib to 140 mg for the duration of the inhibitor use.  No dose adjustment is required in 
combination with mild inhibitors. Avoid grapefruit and Seville oranges during ibrutinib
treatment, as these contain moderate inhibitors of CYP3A (see Section 5.3.1.2).
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and 
St. John’s Wort). Consider alternative agents with less CYP3A induction.
A list of common CYP3A inhibitors and inducers is provided in Appendix 3; a comprehensive 
list of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. This website is continually revised and 
should be checked frequently for updates.
For the most comprehensive effect of CYP3A inhibitors or inducers on ibrutinib exposure, please 
refer to the current version of the IB.
6.1.2.2.
Drugs That May Have Their Plasma Concentrations Altered By Ibrutinib
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor (with an IC50 of 2.15 μg/mL).  Ibrutinib is not expected to have systemic drug-drug 
interactions with P-gp substrates. However, it cannot be excluded that ibrutinib could inhibit 
intestinal P-gp after a therapeutic dose. There is no clinical data available. Therefore, to avoid a 
potential interaction in the GI tract, narrow therapeutic range P-gp substrates such as digoxin, 
should be taken at least 6 hours before or after ibrutinib.
6.1.2.3.
Concomitant Use of QT Prolonging Agents
Any medications known to cause QT prolongation should be used with caution; periodic ECG 
and electrolyte monitoring should be considered. 
6.1.2.4.
Concomitant Use of 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. Use ibrutinib with caution in subjects requiring anticoagulants 
or medications that inhibit platelet function.  Subjects with congenital bleeding diathesis have not 


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been studied. Ibrutinib should be held at least 3 to 7 days pre- and post-surgery depending upon 
the type of surgery and the risk of bleeding (see Section 6.2).
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.
6.1.3.
Prohibited Concomitant Medications
Any other chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy are 
prohibited while the subject is receiving study drug.
Corticosteroids for the treatment of the underlying disease are prohibited. Please refer to 
Section 6.1.1 for corticosteroid use in other medical situations. 
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which use of prohibited therapies are considered.
6.2.
Procedures
The following guidance should be applied during the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving study drug.
6.2.1.
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.
6.2.2.
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.  
6.2.3.
Emergency Procedures
For emergency procedures, study drug should be held after the procedure for at least 7 days after 
the urgent surgical procedure.


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6.3.
Plasmapheresis
Initial transient increases in serum IgM levels (IgM flare) are common (in up to 50% of patients) 
3 to 4 weeks after initiation of rituximab therapy (Treon 2005; Ghobrial 2004; Dimopoulos 
2002a). This flare may persist for up to 4 months and does not indicate treatment failure but may 
necessitate plasmapheresis to reduce hyperviscosity (Dimopoulos 2002a; Ghobrial 2004; 
Dimopoulos 2002b) or other clinical symptoms.
•
Plasmapheresis at the discretion of the treating physician should be considered in subjects 
with IgM values above 5000 mg/dL before start of the treatment regimen to avoid clinical 
symptomatic ‘IgM flare’ on study treatment.
•
Plasmapheresis should be considered in patients with signs of symptomatic 
hyperviscosity before start of the treatment regimen.
•
Plasmapheresis should be considered in subjects who developed a clinically symptomatic 
‘IgM flare’ (eg. hyperviscosity syndrome) on study treatment.
o
This initial transient increase of IgM levels will most likely not indicate disease 
progression and subjects may continue therapy with rituximab.
o
Increase of IgM levels after the first 16 weeks of study treatment should be 
considered progressive disease and further use of plasmapheresis should be discussed 
with the Medical Monitor. 
In the event that a subject requires plasmapheresis prior to study treatment, the IgM level 
obtained prior to plasmapheresis should be considered as the baseline value and study treatment 
should be initiated shortly thereafter (not more than 7 days) after last plasmapheresis. 
IgM level obtained within five half-lives (ie, ≤35 days) after the last plasmapheresis should not 
be considered for response evaluation.  An IgM level obtained more than 35 days after 
plasmapheresis can be used in response determination.
The IgM level prior to and after each plasmapheresis during the screening phase and during the 
study should be collected centrally and will be recorded in the electronic case report form 
(eCRF).
7.
STUDY EVALUATIONS 
All subjects enrolled in the study, whether they are in the randomized treatment arms (Arm A 
and B) or in the ibrutinib monotherapy substudy (Arm C), will undergo the same study 
evaluations throughout the study.
7.1.
Screening/Administrative
All screening clinical and laboratory assessments must be performed within 30 days of first dose 
of study drug and prior to randomization.


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7.1.1.
Informed Consent
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved informed consent form (ICF) 
confirming his or her willingness to participate in this study before any study-specific screening 
procedures are performed. In addition, subjects must sign all approved ICF amendments per the 
site IRB/REB/IEC guidelines during the course of the study. 
7.1.2.
Confirm Eligibility
All necessary procedures and evaluations must be performed to document that the subject meets 
all of the inclusion criteria and none of the exclusion criteria (Section 4). Study site personnel 
will submit the Eligibility Worksheet to the Medical Monitor or Sponsor designee for approval to 
proceed with randomization. 
7.1.3.
Medical History and Demographics
The subject’s complete history through review of medical records and by interview will be 
collected and recorded. Concurrent medical signs and symptoms must be documented to 
establish baseline severities. A disease history, including the date of initial diagnosis and list of 
all prior anticancer treatments, dates administered, and responses and duration of response to 
these treatments, also will be recorded. 
7.1.4.
Prior and Concomitant Medications
All medications from the time of signed consent through 30 days after the last dose of study drug 
will be documented.  After a subject discontinues study treatment, receipt of all subsequent 
anticancer therapies will be collected until death, subject withdrawal of full consent, loss to 
follow-up, or study termination by Sponsor, whichever comes first.
7.1.5.
Adverse Events
The accepted regulatory definition for an adverse event is provided in Section 11.1.  All medical 
occurrences that meet the adverse event definition must be recorded from the time the ICF is 
signed until 30 days after the last dose of ibrutinib.  Laboratory abnormalities designated 
clinically significant by the Investigator will also be recorded as adverse events.  Additional 
important requirements for adverse event and serious adverse event reporting are explained in 
Section 11.2.
7.1.6.
Physical Examination
The Screening, Week 1, Suspected PD, End-of-Treatment and Follow-Up 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, extremities, 
musculoskeletal system, nervous system, and lymphatic system.


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A limited symptom-directed physical examination will be required after Week 1 at time points 
specified in the Schedule of Assessments (Appendix 1).
7.1.7.
Eye-related Symptom Assessment
The subjects will be asked about eye-related symptoms at Screening and after Week 1 at time 
points specified in the Schedule of Assessments (Appendix 1).
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. 
7.1.8.
ECOG
The ECOG performance index is provided in Appendix 2. The ECOG performance status will 
be assessed at time points specified in the Schedule of Assessments (Appendix 1). 
7.1.9.
Vital Signs
Vital signs will include weight, blood pressure, heart rate, and body temperature and will be 
assessed at time points specified in the Schedule of Assessments (Appendix 1).
7.1.10.
Patient-Reported Outcomes
The PRO instruments, EQ-5D-5L (Appendix 7), FACT-An (Appendix 8), 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 weeks specified in the Schedule of Assessments.
7.1.10.1.
EQ-5D-5L
The EQ-5D-5L is a standardized instrument used to measure of health outcome (EuroQol 
Group 1990). The EQ-5D-5L is a revised version of the traditional EQ-5D-3L and consists of a 
5-item questionnaire and a “thermometer” visual analogue scale ranging from 0 (worst 
imaginable health state) to 100 (best imaginable health state).  The scores for the 5 dimensions 
are used to compute a single utility score ranging from 0 to 1, representing the general health 
status of the individual. The 5 dimensions evaluated are mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression.
7.1.10.2.
FACT-An
The Functional Assessment of Cancer Therapy–Anemia(FACT-An) for anemia and fatigue is a 
47-item cancer specific questionnaire consisting of a core 27-item general questionnaire (FACT-
G Total) measuring physical well-being, social/family well-being, emotional well-being, and 
functional well-being, as well as a 20-item anemia/fatigue questionnaire (FACT-An Anemia 


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subscale) (Cella 1997; Yellen 1997; Cella 2003).  Responses to all items are rated on a 5-point 
scale ranging from 0 “not at all” to 4 “very much”. The recall period is the past 7 days.
7.2.
Clinical Laboratory Assessments 
7.2.1.
Hematology
Hematology will be evaluated by a central laboratory and will include a complete blood count 
(CBC) with white blood cell differential. In the event that the submitted central laboratory 
sample is unable to be resulted (ie, specimen clotted, hemolysis, etc.), local laboratory results 
may be used to support eligibility.
7.2.2.
Chemistry (Serum)
Serum chemistry will be evaluated by a central laboratory and include sodium, potassium, 
chloride, blood urea nitrogen (BUN), creatinine, glucose, calcium, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, lactate dehydrogenase (LDH), phosphate, uric acid, 
magnesium and bicarbonate.  In the event that the submitted central laboratory sample is unable 
to be resulted (ie, specimen clotted, hemolysis, etc.), local laboratory results may be used to 
support eligibility.
7.2.3.
Coagulation Studies
Measurement of prothrombin time (PT)/INR, and activated partial thromboplastin time (aPTT) 
will be performed at Screening, Week 17 and at the End-Of-Treatment visit using a central 
laboratory. In the event that the submitted central laboratory sample is unable to be resulted (ie, 
specimen clotted, hemolysis, etc.), local laboratory results may be used to support eligibility.
7.2.4.
Hepatitis Serologies
Hepatitis serologies include hepatitis C antibody, hepatitis B surface antigen, and hepatitis B 
core antibody and will be evaluated by local laboratory.  PCR must be confirmed negative prior 
to randomization for subjects who are hepatitis B core antibody positive, hepatitis B surface 
antigen positive or hepatitis C antibody positive.
7.2.5.
Serum Viscosity
Measurement of resistance of blood to flow for evaluation of hyperviscosity syndrome will be 
performed at Screening by central laboratory.
7.2.6.
Serum Free Light Chain Assay
Sample(s) will be sent to a central laboratory for measurement of immunoglobulin-free light 
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7.2.7.
β2 -microglobulin
Samples will be collected at Screening and sent to a central laboratory. 
7.2.8.
Pregnancy Test
Serum pregnancy test will be required at Screening by local laboratory only for women of 
reproductive potential. A 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. This test may be 
performed more frequently if required by local regulatory authorities.
7.3.
Diagnostics/Procedures
7.3.1.
ECG
12-lead ECG will be taken in triplicate (≥1 minute apart) at Screening.
The ECGs should be performed prior to any blood samples being collected. Any clinically 
significant abnormalities noted at Screening should be included in the medical history.  
In addition, ECGs can be performed at the investigator’s discretion, particularly in subjects with 
arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset dyspnea.
7.3.2.
Bone Marrow Sampling and Pathological diagnosis 
Inclusion of the subject in the trial will be based on central pathological assessment and 
histopathological confirmation of lymphoplasmacytic lymphoma (LPL), which is the underlying 
histology of WM. Details regarding the central pathological review will be outlined in a separate 
pathology charter.
A central pathological review will be performed for all subjects. 
The following material will be sent to the central pathology laboratory:
•
Bone marrow trephine (>=1 cm) in a container of neutral buffered formalin (no other 
fixative allowed); Note that the trephine is obligatory for subject enrollment
•
4 bone marrow smears (air dried, unstained)
•
4 blood smears (air dried, unstained)
•
Up to 10 mL of bone marrow aspirate (to be sent to central laboratory)
It is important to have marrow and blood smears sent to central pathology, regardless of whether 
the smears are also reviewed elsewhere, to allow the central hemato-pathologist to generate a 
report based on all morphological features including cytology on smears.


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For cases in which the current marrow trephine is not definitive for LPL/WM, the central 
pathology laboratory may request prior bone marrow and lymph node/soft tissue biopsy 
specimens, to help confirm this diagnosis.  If requested, such material, particularly the paraffin 
blocks, should be sent to central pathology if at all possible.
The following clinical information should be sent to central pathology in all cases:
•
Age, gender
•
Splenomegaly (yes/no)
•
Hepatomegaly (yes/no)
•
Lymphadenopathy (yes/no, at which sites)
•
Monoclonal IgM gammopathy (yes/no, and size of M-spike if present, in g/dL)
•
Leucocyte count, hemoglobin level, thrombocyte count
•
Previous hematological diseases
•
Immunophenotypic profile data if available
•
Autoimmune disease, hemolysis
Additional Bone Marrow assessment should be obtained:
•
to confirm CR at any time
•
pre-dose at Weeks 49 and 97 to assess bone marrow/tissue response
•
at time of progression or at suspected PD due to progressive cytopenia without any other 
evidence of PD
Standard clinical Bone Marrow assessment will be performed at the study center’s local 
laboratory.
7.4.
Pharmacokinetics/Biomarkers 
7.4.1.
Pharmacokinetics
Plasma concentrations of ibrutinib and PCI-45227 will be determined using a validated analytical 
method.  Other potential metabolites of ibrutinib may be explored.  Refer to the Schedule of 
Assessments (Appendix 1) and the Pharmacokinetic Sample Schedule (Table 4).


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Table 4:
Pharmacokinetic Sample Schedule
Study Arm
Week
Study Day
Predose
Time Point Postdosea
1h ± 
15 min
2 h ± 
30 min
4 h ± 
30 min
6 h ± 
1 h
A and B
4
22
X
X
X
X
X
C
5
29
X
X
X
X
X
a Time after ibrutinib/placebo dosing
Refer to the laboratory manual for instructions on collecting and processing these samples.  On 
the day of the sampling visit, the clinical staff will instruct the subject to not take a dose before 
arrival at the clinic.  Study drug intake will be observed by clinic staff.  The actual time (versus 
requested time) that each sample is drawn must be recorded using a 24 hour format.  The same 
clock should be used for recording the time of dosing. In the event that medical management
(use of steroids) is needed, use of steroids for infusion should be recorded.
7.4.2.
Predictive Biomarkers and Mechanisms of Resistance
Identification of signaling pathways or biomarkers that predict sensitivity or resistance to 
ibrutinib will be explored in this study. 
A predose blood sample will be collected at the following visits: Week 1, Week 17, Week 33, 
Week 49; Suspected CR and PD; and End-of-Treatment (EOT).  If a subject progresses and 
returns to clinic within 24 hours after his or her last dose of ibrutinib/placebo, then an additional 
post-progression blood sample will be collected.  If this post-progression blood sample is 
collected, then the biomarker blood sample collection at the EOT Visit is not required.
Samples collected may be used for pharmacodynamic and biomarker assessments including BTK 
and other kinase activity and signaling, expression analysis, sequencing, flow cytometry and 
secreted protein analyses.  Fluids including blood collected during the course of the study may be 
used for, but not limited to, pharmacodynamics, biomarker and pharmacogenomic assessments.
A portion of pre-treatment bone marrow samples collected may be used by Sponsor for further 
biomarker analysis. 
7.4.3.
T/B/NK Cell Count
The blood sample(s) for T/B/NK cell count (CD3+, CD4+, CD8+, CD19+, CD16/56+) must be 
taken predose.  Percentages and absolute counts of CD3+, CD4+, CD8+, CD19+, CD56+ and 
CD16/56+ cells will be collected.  Reference the Laboratory Events Schedule for other sample 
timepoints for this assay.
Testing will be performed at a central laboratory.


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7.4.4.
Genetic and Molecular Prognostic Markers
A blood sample will be collected at pre-dose Week 1 to study pretreatment prognostic factors.
The myeloid differentiation primary response gene 88 (MYD88), C-X-C chemokine receptor 
type 4 (CXCR-4) and other genetic and genomic alterations thought to be prognostic of disease 
and/or treatment outcome may be tested.  
7.5.
Efficacy Evaluations
Efficacy evaluations will be conducted as outlined in the Schedule of Assessments Table 
(Appendix 1). Response assessments will be performed using the modified consensus criteria 
adapted from the VIth International Workshop on WM (NCCN 2014) (Appendix 4).
Progression of nodal and extranodal disease should be evaluated based on the revised criteria for 
malignant lymphoma described in the revised International Working Group for NHL
(Cheson 2007). The spleen is considered nodal disease.
Efficacy evaluation will include the following components:
•
Hematologic parameters by complete blood count (CBC)
•
Quantitative IgM serum immunoglobulins 
•
Quantitative serum-M protein (SPEP)
•
Qualitative serum immunofixation, if applicable 
•
Radiographic evaluation, if applicable  
•
Bone marrow aspirate and biopsy, if applicable
In the event a subject required plasmapheresis prior study treatment, the IgM level obtained prior 
plasmapheresis will be considered as the baseline value and study treatment should be initiated 
shortly thereafter (not more than 7 days) after last plasmapheresis.  IgM level obtained within 
five half-lives (ie, ≤35 days) after plasmapheresis should not be considered as nadir on therapy or 
for response evaluation.  IgM levels obtained more than 35 days after plasmapheresis can be 
used in response determination.
Any suspected case of disease progression should be reported to the Sponsor within 24 hours of 
awareness. If disease progression is suspected solely based on the results of a single examination 
or a single laboratory parameter (eg, IgM), this finding should be confirmed by a subsequent 
evaluation at least within 4 weeks from the first finding. Additional hematologic parameters, 
radiographic evaluation and bone marrow biopsy should be performed at the discretion of the 
treating physician to confirm progressive disease if indicated. 
In general, subjects should continue study treatment until progression is confirmed by a serial 
examination within 4 weeks from the first finding and confirmation by the IRC. When disease 
progression has been confirmed by the IRC, study treatment should be withheld. Once the IRC


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has confirmed disease progression, subjects should continue to adhere to all other study-related 
procedures.  Whenever possible, subsequent anticancer therapy should be withheld until disease 
progression is confirmed by the IRC.
If at any time CR is suspected (serum IgM values in normal range and disappearance of the 
SPEP), all assessments including serum immunofixation, bone marrow assessment and 
radiographic evaluation (if nodal/extranodal disease is present at baseline) must be performed 
according to the IWWM response assessment guidelines.
Determination of progression for the purpose of the primary efficacy endpoint will be performed 
by an IRC independent of Investigators and personnel who are involved in the conduct of the 
study.
Access to next-line ibrutinib (cross-over) for subjects treated with placebo in combination with 
rituximab (Arm B) with IRC confirmed disease progression and symptomatic disease requiring 
treatment may be provided following Sponsor’s designee approval as outlined in Section 7.7.
7.5.1.
Quantitative Serum Immunoglobulin
Testing for IgA, IgG and IgM levels will be performed by central laboratory. 
7.5.2.
Serum Immunofixation 
Samples will be collected and sent to a central laboratory. Repetitive immunofixation on study is 
only required to confirm CR (conducted on the first observation that the subject has no 
detectable monoclonal protein) and then repeated every study visit until disease progression. 
7.5.3.
Serum Protein Electrophoresis (SPEP) 
Sample(s) will be sent to a central laboratory to quantify the serum-M protein.
7.5.4.
Radiographic Imaging
Pretreatment tumor assessment will be performed up to 42 days before the first dose of study 
drug.  Lesions that have been irradiated cannot be included in the tumor assessment unless 
unequivocal tumor progression has been documented in these lesions after radiation therapy.  
A CT scan (with contrast unless contraindicated) of the neck, chest, abdomen, and pelvis must be 
performed.  Information on extranodal involvement will also be recorded.  
In the case where CT with contrast is contraindicated, an alternative would be MRI of the 
abdomen and pelvis and CT of the chest without contrast.
NOTE: Positron emission tomography (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.  


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Additionally, the CT images must be separated from the PET data prior to submitting the data, 
and cannot be transmitted as fused PET/CT 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.
The same imaging method should be used for a given subject throughout the study.  The same 
equipment should be utilized for all scans whenever possible.  The same radiologist should be 
assigned to read all the scans for a given patient throughout the study as much as possible.
All subjects with presence of nodal and/or extranodal disease at Screening per central radiology 
review will require follow up CT scans of the neck, chest, abdomen, and pelvis every 16 weeks 
for the first 2 years and thereafter every 24 weeks, until disease progression is confirmed by the 
IRC (regardless of whether or not the patient remains on treatment). Follow up neck CT scans 
are only required for subjects with evidence of disease involvement in the neck region identified 
during Screening. In the event disease progression is suspected due to physical examination or 
laboratory test, a CT scan should be performed to evaluate nodal or extranodal progression 
regardless if the subject had nodal/extranodal disease at Screening.
7.5.4.1.
Radiographic Assessment
Progression of nodal and extranodal disease should be evaluated based on the revised criteria for 
malignant lymphoma described in the revised International Working Group for NHL
(Cheson 2007). The spleen is considered nodal disease.
Up to 6 measurable lymph nodes (target lesions) should be considered if the long axis is more 
than 1.5 cm regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it 
should only be considered abnormal if its short axis is more than 1.0 cm. Lymph nodes 
≤1.0 cm x ≤1.0 cm will not be considered as abnormal for relapse or progressive disease. In 
addition, target lesions should be clearly measurable in at least 2 perpendicular dimensions and,
if possible, they should be from disparate regions of the body when these areas are significantly 
involved. If additional lesions are present but are not included in the target lesion assessment, 
they can be added as non-target lesions followed throughout the study.
The longest cranial-caudal measurement of the spleen will be assessed at Screening and all 
subsequent timepoints (if applicable).
Nodal progression by imaging is defined as one of the following:
•
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size. 


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•
At least a 50%increase from nadir in the sum of product (SPD) of any previously 
involved nodes, or in a single involved node. To be considered progressive disease, a 
lymph node with a diameter of the short axis of less than 1.0cm must increase by ≥50% 
and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis.
•
At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease.
A central imaging service will be utilized to provide independent radiological assessments for 
independent response evaluation (Refer to Section 10.10). Central radiology review will be 
conducted throughout the study and the details of the central radiology review activities will be 
specified in a separate charter and the SAP.
To ensure the required subsequent CT scans are performed per protocol, the presence of 
nodal/extranodal disease per central radiology review will be communicated to the site.  
However, no further details (eg, measurements or identified target/non-target lesions) will 
be reported back to the site.
7.6.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in source documents for 
transcription to the eCRF or laboratory requisition form.  Refer to the Schedule of Assessments 
(Appendix 1) for the timing and frequency of all sample collections.
Instructions for the collection, handling, and shipment of samples are found in the Laboratory 
Manual.
7.7.
Treatment with Ibrutinib for Subjects on Control Arm (Arm B) Following IRC-
Confirmed Disease Progression
Subjects on the trial who have documented IRC confirmed disease progression and symptomatic 
disease meeting criteria for requiring treatment may be eligible to receive next-line therapy with 
ibrutinib. A request for next-line therapy with ibrutinib must be submitted to the Sponsor’s 
designee who will evaluate the request based on the criteria listed in Section 7.7.1. Local labs 
can be used to determine appropriateness for start of next-line ibrutinib.
Next-line treatment with ibrutinib can be continued until disease progression as determined by 
the Investigator, or until they meet the following criteria for withdrawal in Section 9.
7.7.1.
Criteria for Next-line Ibrutinib Therapy
1. IRC confirmed disease progression and Sponsor approval.


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2. Symptomatic disease meeting at least 1 of the recommendations from the Second 
International Workshop on Waldenström’s Macroglobulinemia for requiring treatment 
(Section 4.1. Inclusion criteria #4).
3. Compliant with the main study protocol procedures and no subsequent WM/anti-cancer 
therapy prior to IRC confirmed disease progression since discontinuing treatment on Arm B.
4. ECOG Performance Status of ≤2 (Appendix 2).
5. Platelet count >50,000 cells/mm3 and absolute neutrophil count >750 cells/mm3.
6. No uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as 
exhibiting ongoing signs/symptoms related to the infection and without improvement, despite 
appropriate antibiotics or other treatment).
7. No currently active clinically significant cardiovascular disease such as uncontrolled 
arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the New 
York Heart Association Functional Classification (Appendix 5), or history of myocardial 
infarction within 6 months prior to first dose with study drug.
8. Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no
menses for ≥2 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR 
history of bilateral oophorectomy). Female subjects of reproductive potential must have a 
negative pregnancy test upon study entry.
9. Male and female subjects of reproductive potential who agree to use highly effective 
methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, 
some intrauterine devices [IUDs], complete abstinenceb, or sterilized partner) during the 
period of therapy and for 30 days after the last dose of study drug and 90 days (males) after 
the last dose of study drug.
7.7.2.
Next-line Ibrutinib Therapy Treatment Phase
Refer to the next-line ibrutinib therapy Schedule of Assessments (Appendix 9) for a complete list 
of procedures to be performed at each scheduled study visit.
8.
STUDY PROCEDURES
8.1.
Overview
The study is divided into a Screening Phase, a Treatment Phase, and a Follow-up Phase.  The 
Schedule of Assessments (Appendix 1) summarizes the frequency and timing of efficacy, PK, 
biomarker, and safety measurements applicable to this study.  All subjects enrolled will undergo 
the same study procedures throughout the study unless otherwise noted.
b 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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8.2.
Screening Phase
Screening procedures will be performed up to 30 days prior to Day 1 of Week 1, 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. All study tests and 
procedures should be performed at the study center at which the subject was enrolled and will be 
receiving treatment. After signing the ICF, screening, and being deemed eligible for entry, 
subjects will be enrolled in the study.
8.2.1.
Screening Visit
The following procedures will be performed at the Screening Visit within 30 days prior to first 
dose of study drug and randomization unless otherwise noted:
•
Medical history including demographic information
•
Perform a complete physical examination, including height and weight (may use prior 
height measurement if available in source documents)
•
Eye-related symptom assessment
•
Evaluation of ECOG performance status
•
Obtain vital signs (including blood pressure, heart rate, and body temperature)
•
Obtain triplicate 12-lead ECG (≥1 minute apart) 
•
Record adverse events since signing the ICF
•
Record concomitant medication history including over-the-counter drugs, vitamins and 
herbs since signing the ICF
•
Imaging by CT or other modality as described in Section 7.5.4 (if not performed within 
42 days prior to first dose of study drug)
•
Obtain a bone marrow aspirate and biopsy (if not performed within 30 days prior to first 
dose of study drug)
•
Obtain blood specimens for the following laboratory tests:
o
Hematology
o
Serum chemistry
o
Coagulation studies (PT/INR, aPTT)
o
Hepatitis serologies 
o
Serum viscosity
o
Serum protein electrophoresis (SPEP)
o
Quantitative serum immunoglobulins (IgA, IgG, and IgM)
o
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o
Serum immunofixation
o
β2-microglobulin
o
Blood smear slides
o
Bone marrow smear slides
•
Obtain serum pregnancy test for women of reproductive potential only
•
Confirm eligibility (per inclusion/exclusion criteria) and randomize/enroll via IWRS.
Dosing should occur within 72 hours of randomization/enrollment.
8.3.
Treatment Phase
Following completion of the Screening Visit and once eligibility has been confirmed for 
treatment Arm A or Arm B, subjects will be randomized via an automatic IWRS or alternative 
system provided by the Sponsor. Randomization should occur as close to the time of the 
expected first dose as possible, i.e. not more than 3 business days prior to expected first dose 
with study drug. Subjects considered refractory to the last prior rituximab-containing therapy 
(refer to Section 4.2) may be enrolled in Arm C via IWRS and receive ibrutinib monotherapy if 
the eligibility criteria as specified in Section 4.2 are met.
Study drug treatment with ibrutinib/placebo should be continued until disease progression, 
unacceptable treatment-related toxicity, or other reasons outlined in Section 9.2. Local labs may 
be used to guide all dosing-related decisions and should be followed up with central labs. In the 
event of clinically suspected disease progression, the subject may continue to receive study 
medication until disease progression is confirmed by the IRC, at the discretion of the 
Investigator. 
Refer to the Schedule of Assessments (Appendix 1) for a complete list of procedures to be 
performed at each scheduled study visit.
8.3.1.
Week 1
Pre-dose
•
PRO assessments 
•
Complete physical exam including weight and height (may use prior height measurement 
if available in source documents)
•
Eye-related symptom assessment
•
ECOG performance status
•
Vitals signs including blood pressure, heart rate, and body temperature
•
Collect blood samples for the following laboratory tests:
o
Hematology
o
Serum chemistry 


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o
Serum protein electrophoresis (SPEP)
o
Quantitative serum immunoglobulins (IgA, IgG, and IgM)
o
Genetic and molecular prognostic markers
o
T/B/NK cell counts
o
Predictive biomarkers and mechanisms of resistance
•
Obtain urine pregnancy dipstick test for women of reproductive potential only
•
Review of AEs and concomitant medications
•
Review inclusion and exclusion criteria to confirm subject eligibility prior to dosing
Dosing and Post-Dose
•
Dispense study drug (ibrutinib/placebo for Arm A and B; open-label ibrutinib for Arm C)
•
Administration of study drug
•
Administration of rituximab (Arm A and Arm B ONLY)  
•
Review of AEs and concomitant medications 
8.3.2.
Weeks 2-4 (Arm A and Arm B ONLY)
Pre dose
•
Collect blood samples for the following laboratory tests:
o
Quantitative serum immunoglobulins (IgA, IgG, and IgM)
•
Review of AEs and concomitant medications
Dosing and Post-Dose
•
Administration of rituximab (Arm A and Arm B only) and study drug
•
Review of AEs and concomitant medications
•
Week 4 Only 
•
PK (predose and post-dose)
8.3.3.
Weeks 5-16 (every 4 weeks)
•
PK (predose and post-dose) for Arm C ONLY (Week 5 Only)
•
Continuous daily dosing of study drug (ibrutinib/placebo or open-label ibrutinib)
•
PRO assessments (Weeks 5, 9 and 13 Only)
•
Symptom-directed Physical Exam
•
Eye-related symptom assessment


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•
Collect blood samples for the following laboratory tests:
o
Hematology
o
Serum chemistry 
o
Serum protein electrophoresis (SPEP)
o
Quantitative serum immunoglobulins (IgA, IgG, and IgM)
•
Overall Disease Assessment
•
Review of AEs and concomitant medications
8.3.4.
Week 17
Pre-Dose
•
PRO Assessments
•
Symptom-directed Physical exam
•
Eye-related symptom assessment
•
ECOG performance status
•
Vitals signs including blood pressure, heart rate, and body temperature
•
Collect blood samples for the following laboratory tests:
o
Hematology
o
Serum chemistry 
o
Coagulation studies (PT/INR, aPTT)
o
Serum protein electrophoresis (SPEP)
o
Quantitative serum immunoglobulins (IgA, IgG, and IgM)
o
T/B/NK cell counts 
o
Predictive biomarkers and mechanisms of resistance
o
CT scan 
o
Overall Disease Assessment
•
Review of AEs and concomitant medications
Dosing and Post-Dose
•
Dispense study drug (ibrutinib/placebo for Arm A and Arm B and open-label ibrutinib 
for Arm C)
•
Administration of study drug
•
Administration of rituximab (Arm A and Arm B ONLY) 
•
Review of AEs and concomitant medications 


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8.3.5.
Weeks 18-20 (For Arm A and Arm B ONLY) 
•
Administration of study drug and rituximab 
•
Review of AEs and concomitant medications
8.3.6.
Week 21
•
PRO assessments
•
Continuous daily dosing of study drug (ibrutinib/placebo or open-label ibrutinib)
•
ECOG performance status
•
Vitals signs including blood pressure, heart rate, and body temperature
•
Symptom-directed Physical Exam
•
Eye-related symptom assessment
•
Collect blood samples for the following laboratory tests:
o
Hematology
o
Serum chemistry 
o
Serum protein electrophoresis (SPEP)
o
Quantitative serum immunoglobulins (IgA, IgG, and IgM)
•
Overall Disease Assessment
•
Review of AEs and concomitant medications
8.3.7.
Week 25- until PD or Unacceptable Toxicity (Every 8 Weeks)
•
PRO assessments (after Week 49, PRO assessments to occur every 16 weeks)
•
Continuous daily dosing of study drug (ibrutinib/placebo or open-label ibrutinib)
•
ECOG performance status
•
Vitals signs including blood pressure, heart rate, and body temperature
•
Symptom-directed Physical Exam
•
Eye-related symptom assessment
•
Collect blood samples for the following laboratory tests:
o
Hematology
o
Serum chemistry 
o
Serum protein electrophoresis (SPEP)
o
Quantitative serum immunoglobulins (IgA, IgG, and IgM)
o
T/B/NK cell counts (Weeks 33 and 49 only) 


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o
Predictive biomarkers and mechanisms of resistance (Weeks 33 and 49 only)
o
Serum free light chain assay (Weeks 49 and 97 only)
•
CT scan (Weeks 33, 49, 65, 81, and 97 and every 24 weeks thereafter)
•
Bone marrow aspirate/biopsy (Weeks 49 and 97) 
•
Overall Disease Assessment
•
Review of AEs and concomitant medications
8.3.8.
Suspected PD Visit
The Suspected PD visit should be performed at any time during the study, if based on clinical 
and/or laboratory evaluation, the Investigator suspects progressive disease (PD), or if the subject 
discontinues treatment for any other reason.  If possible, the visit should be performed within 
24 hours after the subject’s previous dose.  The following procedures will be performed:
•
PRO assessments
•
Complete physical exam including weight
•
Eye-related symptom assessment
•
ECOG performance status
•
Vitals signs (including blood pressure, heart rate, and body temperature)
•
Collect blood samples for the following laboratory tests:
o
Hematology
o
Serum chemistry
o
Serum protein electrophoresis (SPEP)
o
Quantitative serum immunoglobulins (IgA, IgG, and IgM)
o
Serum free light chain assay
o
T/B/NK cell counts 
o
Predictive biomarkers and mechanisms of resistance
•
Imaging by CT, if applicable 
•
Bone marrow aspirate or biopsy, if applicable
•
Overall disease assessment
•
Review of AEs and concomitant medications


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8.3.8.1.
End-of-Treatment Visit
An End-of-Treatment (EOT) visit should occur 30 days (± 7 days) from the last dose of study 
drug or prior to the start of a new anticancer treatment.  If the subject starts a new anticancer 
treatment less than 7 days after the Suspected PD visit, only those procedures not conducted at 
the Suspected PD visit should be performed at the End-of-Treatment visit. 
The following procedures will be performed at the End-of-Treatment visit:
•
PRO assessments
•
Complete physical exam including weight
•
Eye-related symptom assessment
•
ECOG performance status
•
Vitals signs (including blood pressure, heart rate, and body temperature)
•
Collect blood samples for the following laboratory tests:
o
Hematology
o
Coagulation studies (PT/INR, aPTT)
o
Serum protein electrophoresis (SPEP)
o
Quantitative serum immunoglobulins (IgA, IgG, and IgM)
o
T/B/NK cell counts
o
Predictive biomarkers and mechanisms of resistance
•
Review of AEs and concomitant medications
•
Bone marrow aspirate or biopsy, if applicable
•
Overall disease assessment
•
Drug accountability
8.4.
Follow-up Phase
Once a subject has completed the End-of-Treatment Visit they will enter the Follow-Up Phase.  
Subjects who withdraw from treatment for reasons other than PD and withdraw of consent will 
participate in ongoing follow-up visits. 
8.4.1.
Response Follow-Up Visits (Until PD)
Subjects who discontinue the study for reasons other than PD will be followed every 12 weeks 
(±7 days) by clinic visit until disease progression is confirmed by the independent review 
committee (IRC), regardless of initiation of subsequent anticancer treatment. During this period, 
the following procedures will be performed:


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•
Complete physical exam including weight
•
Eye-related symptom Assessment
•
ECOG performance status
•
Vitals signs (including blood pressure, heart rate, and body temperature)
•
Collect blood samples for the following laboratory tests:
o
Hematology
o
Serum protein electrophoresis (SPEP)
o
Quantitative serum immunoglobulins (IgA, IgG, and IgM)
•
PRO assessments
•
Overall Disease Assessment
•
Survival status and new anticancer therapy use
8.4.2.
Survival Follow-up
After IRC confirmed disease progression, subjects will be contacted to assess survival status 
approximately every 12 weeks (±7 days) by clinic visit or telephone to assess survival, the use of 
alternative antineoplastic therapy and occurrence of any other malignancy until death, withdrawal 
by subject, lost to follow-up, or study terminated by Sponsor, whichever comes first. Every effort 
should be made to administer the questionnaire for subjects who are followed by clinic visit. At 
the time of the interim analysis and at study closure, a survival sweep will be conducted. All subjects 
who are on study and not known to have died prior to the survival sweep will be contacted at that 
time.
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:
•
Confirmed progressive disease by IRC
•
Unacceptable toxicity: an intercurrent illness or adverse event that prevents further 
ibrutinib administration 
•
Withdrawal of consent for treatment by subject
•
Investigator decision (such as chronic noncompliance, significant protocol deviation, or 
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•
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 survival. 
The Investigator should notify the Sponsor within 24 hours if a subject discontinues ibrutinib 
treatment due to disease progression and should provide documentation of disease progression 
for review by the Sponsor’s Medical Monitor.  If a subject shows signs of disease progression on 
physical examination or laboratory assessment, the subject may continue study treatment until 
disease progression is confirmed by IRC.  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 
•
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 (ie, withdraws consent to treatment and all 
further contact) or partial consent (ie, withdraws consent to treatment but agrees to 
participate in follow-up visits)
10. STATISTICAL METHODS AND ANALYSIS
Statistical analysis will be performed by the Sponsor or under the authority of the Sponsor.  A 
general description of the statistical methods for the analysis of the efficacy and safety data is 
outlined below.  Specific details will be provided in the Statistical Analysis Plan (SAP).


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10.1.
General Consideration
All analyses will be performed based on data up to the timepoint of clinical cutoff.  Long-term
follow-up data will be summarized separately when the entire study has completed. Statistical
inferences will be based on a 2-sided Type I rate of 0.05 unless otherwise specified.
For the open-label substudy (Arm C), the efficacy and safety outcome of the substudy will be 
descriptively summarized and analyzed separately from the randomized treatment arms (Arm A 
and Arm B).
10.2.
Randomization
For Treatment Arms A and B, central randomization will be implemented in this study.
Subjects who qualify for the substudy will not follow these procedures. Randomization will 
be stratified using the following stratification factors and subjects will be randomized in a 1:1 
ratio to receive either ibrutinib and rituximab or placebo and rituximab) within each 
randomization stratum: 
a) WM IPSS assessed at Screening (Low vs. Intermediate vs. High)
b) Number of prior systemic treatment regimens (0, 1-2 vs. ≥3)
c) ECOG (0-1 vs. 2)
10.3.
Analysis Populations
The analysis populations are defined as:
•
Intent-to-Treat (ITT) population: defined as all randomized (Treatment Arms A and B) 
subjects. Subjects in this population will be analyzed according to the treatment to which 
they are randomized.
•
Safety population: All subjects who received at least 1 dose of study drug. Subjects in 
this population will be analyzed according to the actual treatment received (ie, as treated).
Arm C safety analysis will be conducted separately.
•
Pharmacokinetic-evaluable population: defined as all subjects who received at least 1 
dose of study drug and had at least 1 pharmacokinetic sample obtained post-treatment.
•
Biomarker population: All subjects with sufficient malignant cells collected from at least 
1 timepoint during the study. 
The ITT population will be used to summarize the study population and characteristics, efficacy, 
and PRO data; and the safety population will be used to summarize the safety data, unless 
otherwise specified.


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For the open-label substudy (Arm C), the study population, characteristics, efficacy PRO and 
safety outcome of the substudy will be descriptively summarized based on all subjects who 
received one dose of ibrutinib in Arm C. No comparator analysis will be done with Arms A or 
B.
Additional analysis populations may be included in the SAP to perform sensitivity and other 
exploratory analyses as appropriate.
10.4.
Subject Information
Analyses of disposition, demographic, baseline disease characteristics, and prior and
concomitant therapy will be summarized by study arm based on the ITT population. Analyses 
on treatment compliance and extent of exposure will be similarly summarized based on the 
Safety population. No statistical testing is planned.
Unless otherwise specified, all continuous endpoints will be summarized using descriptive
statistics, which will include the number of subjects with a valid measurement (n), mean,
standard deviation, median, minimum, and maximum. All categorical endpoints will be 
summarized using frequencies and percentages.
10.5.
Sample Size Determination (Treatment Arms A and B)
This study is designed to evaluate the effect of treatment on PFS and is powered for this 
endpoint. The desired operating characteristics for the PFS endpoint are used to determine the 
study’s total sample size and overall duration. The sample size and power calculations are based 
on a 2-sided log-rank test for PFS and the following considerations:
•
1:1 randomization ratio between 2 treatment arms
•
Target hazard ratio of 0.5 with exponential distribution for PFS. Assuming the median 
PFS for the control arm (rituximab+placebo) is 15 months from randomization, a target 
hazard ratio of 0.5 corresponds to 2-fold increase in median PFS for the treatment arm 
(rituximab+ibrutinib) relative to the control (ie, 30 months vs. 15 months, respectively).
•
Minimum 80% power 
•
2-sided overall significance level of 0.05
•
One interim analysis at 70% information (50 PFS events)
The interim analysis will be based on a group sequential design with Lan-DeMets spending 
function with O’Brien-Fleming boundary. Using the above assumptions, and based on an
accrual rate of approximately 12 subjects per month, the study will enroll approximately 
150 subjects (about 75 subjects to each arm) to observe 71 events in approximately 27 months 
from the first subject randomized. Sample size is calculated using the software package, East 6 
(Cytel Software Corp, Cambridge, MA).


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Open-label Substudy Treatment Arm C
The sample size for the substudy (Arm C) is not determined according to statistical calculation as 
the intent of this substudy is to provide WM subjects who are considered refractory to the last 
prior rituximab-containing therapy access to ibrutinib as well as to evaluate safety and efficacy in 
the monotherapy setting. Up to 30 subjects will be enrolled in this substudy.
10.6.
Efficacy Analysis 
Descriptive statistics will be provided by treatment arms. For continuous variables, number of 
observations, means, standard deviations, medians, and ranges will be included.  For categorical
variables, frequency and percentage will be summarized. For time-to-event variables, Kaplan-
Meier estimates will be provided. 
All tests will be conducted at a 2-sided alpha level of 0.05, and 95% confidence intervals (CI) 
will be provided, unless stated otherwise. 
For the open-label substudy (Arm C), all relevant efficacy outcomes will be descriptively 
summarized and analyzed separately from the randomized treatment arms (Arm A and Arm B).
10.6.1.
Primary Endpoint
The primary endpoint is PFS, as assessed by IRC, which is defined as duration from the date of 
randomization to the date of disease progression or death, whichever is first reported, assessed 
according to the modified VIth IWWM (NCCN 2014) criteria.
The log-rank test will be used to compare survival curves between the two treatment arms for the 
primary endpoint, PFS. Additionally, the Kaplan-Meier method will be used to estimate the 
distribution of PFS for each treatment arm and the median PFS will be provided for each 
treatment arm.  The hazard ratio for ibrutinib relative to placebo and its associated 95% CI will 
be calculated based on the Cox proportional hazards model. Sensitivity analyses will be 
described in the SAP as appropriate. Subgroup analyses will be performed for selected
subgroups (eg, prior WM treatment history: untreated versus previously treated) to assess the 
consistency of treatment effect across subgroups.
10.6.2.
Secondary Endpoints
Multiplicity adjustment will be made in a sequential hierarchical manner based on a closed 
testing procedure as outlined in Section 10.8 to control the overall type 1 error. Details will be 
specified in the statistical analysis plan.


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10.6.2.1.
Overall Response Rate
Overall response rate (ORR) is defined as the proportion of subjects who achieve PR or better 
according to the modified VIth IWWM (NCCN 2014) criteria as assessed by IRC.  Overall 
response rate (ORR) will be compared using the chi-square test.
10.6.2.2.
Hematologic Improvement
Hematological improvement as measured by change from baseline hemoglobin level will be 
summarized by treatment arms. The percentage of subjects with sustained hematological 
improvement as measured by change from baseline in hemoglobin level will be presented and 
compared using a chi-square test. The distribution of the time to improvement in hemoglobin 
will be summarized using Kaplan-Meier estimates and time to improvement will be compared
using stratified or unstratified log-rank test as appropriate.
10.6.2.3.
Time to Next Treatment
Time-to-next treatment (TTnT) is measured from the date of randomization to the start date of 
any subsequent WM treatment. Subjects without subsequent treatment will be censored at the 
date of the last study visit. Detailed censoring rules will be included in the SAP.  The analysis of 
TTnT will be analyzed using stratified or unstratified log-rank test as appropriate.
10.6.2.4.
Overall Survival (OS) 
Overall survival (OS) is measured from the date of randomization to the date of the subject’s 
death from any cause. Overall survival will be analyzed using the stratified log-rank test for 
treatment comparison. If the subject is alive or the vital status is unknown, the subject will be 
censored at the date the subject was last known to be alive.  The overall survival distribution and 
median overall survival with its 95% CI will be estimated using the Kaplan-Meier product-limit 
method. The same subgroup analysis of PFS may be performed for overall survival if the 
number of events within each subgroup is sufficient.  The exploratory analysis on the effect of 
cross-over on overall survival may be described in the SAP (eg, detailed censoring rules) and 
performed as appropriate.
10.6.3.
Exploratory Efficacy Endpoints
10.6.3.1.
FACT-An 
PRO and disease-related symptoms according to FACT-An for Anemia/Fatigue is measured by 
change from baseline scores where responses to all items are rated on a 5-point scale ranging 
from 0 “not at all” to 4 “very much”. The recall period is the past 7 days.  Two summary scores 
will be calculated: the FACT-An total score (FACT-G plus An) and the FACT-An subscale 
score. Larger change from baseline scores represents improvement of functional status and well-
being for all subscales and summary scale.


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Detailed instrument description and scoring system as well as additional analyses will be 
described in the SAP.
10.6.3.2.
Euro QoL 5 Dimension Questionnaire (EQ-5D-5L)
For EQ-5D-5L, change in weighted utility score from baseline to each assessment will be 
summarized. The scores for the five categorical dimensions will be used to compute a single 
utility score ranging from zero (0.0) to one (1.0) representing the general health status of the 
patient.  The United Kingdom weights will be used to generate patient utilities from the 
5 dimensions.  Analysis details will be further specified in the SAP.
10.6.3.3.
Duration of Response
Duration of response (DOR) is defined as duration in days from the date of initial documentation 
of a response (PR or better) to the date of first documented evidence of progressive disease or 
death for responders (PR or better) as assessed by the IRC.  DOR will be analyzed descriptively 
using Kaplan-Meier estimate.
10.6.3.4.
Clinical Response Rate
Clinical Response Rate (CRR) is defined as the proportion of subjects who achieve MR or better 
according to the modified IVth IWWM (NCCN 2014) criteria as assessed by the IRC. CRR will 
be analyzed in a similar fashion as ORR.
10.6.3.5.
Efficacy Assessments by Investigator
Investigator-assessed PFS, ORR, CRR and DOR will be analyzed in a similar fashion as 
corresponding endpoints assessed by the IRC. 
10.6.4.
Other Exploratory Endpoints
10.6.4.1.
Pharmacokinetic Analyses 
Plasma concentrations of ibrutinib and metabolite PCI-45227 will be determined using a 
validated analytical method. Other potential metabolites of ibrutinib may be explored.
Bioanalytical data from this study will be used in noncompartmental PK analysis and also may 
be combined with data from other studies performed with ibrutinib in subjects with hematologic 
malignancies as part of a population PK analysis using nonlinear mixed effects models. For the 
population PK analysis, covariates that could potentially correlate with plasma PK parameters 
will be evaluated. The results of the population PK analyses will be presented in a separate 
report.


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10.6.4.2.
Medical Resource Utilization and Health Economics Analyses
Parameters collected for MRU associated with the therapy may include number of 
plasmapheresis, number of blood product transfusions, and number of use of hematopoietic 
growth factors. Those parameters will be summarized with descriptive statistics by treatment 
arm. The SAP will provide additional analysis details.
10.6.4.3.
Biomarker Analyses
Prognostic and predictive biomarkers and genetics relative to treatment outcomes will be 
evaluated, eg, change in peripheral T/B/NK counts and profiling of immunophenotypes; Change 
in secreted protein levels (ie, chemokines, cytokines, growth factors); Identification of 
biomarkers that predict sensitivity or resistance to ibrutinib (ie, GEP, WES, etc.).
A Fisher Exact test or other methods may be used to estimate the association between the clinical 
response rates and each biomarker. The SAP will provide additional analysis details.
10.7.
Safety Endpoints and Methods
Safety parameters of ibrutinib when used in combination with rituximab in subjects with WM
will be evaluated. 
Analysis of safety data will be conducted on the safety population, which includes enrolled 
subjects who receive at least 1 dose of any study drugs. The baseline value for safety 
assessments will be defined as the last value on or before the day of the first dose of study 
drug(s) unless otherwise specified. The safety variables to be analyzed between the two 
treatment arms include adverse events, clinical laboratory test results (hematology and 
chemistry), physical examination findings, and vital signs measurements. Exposure to study 
drug and reasons for discontinuation from study treatment will be tabulated by treatment arms.
In general, continuous variables will be summarized by treatment arms using descriptive 
statistics (n, mean, median, standard deviation, standard error and range).  Categorical variables 
will be summarized by treatment arms using frequencies and percentages.  No formal statistical 
testing is planned between treatment arms.
For the open-label substudy (Arm C), all relevant safety outcomes will be descriptively 
summarized.
In addition to the study monitors and investigators, the DMC will assess toxicity and safety at the 
time point of the pre-scheduled safety analyses.
Adverse Events
The verbatim terms used in the eCRF by Investigators to identify non-hematological adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).
Adverse events (AEs) will be graded by the Investigator according the NCI CTCAE v4.03 or 


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higher. Treatment-emergent adverse events are those adverse events occurring after the first dose 
of study drugs and within 30 days following the last dose of study drug; any adverse event that is 
considered study drug-related regardless of the start date of the event; or any adverse event that 
is present at baseline but worsens after the first administration of study drug in severity or is 
subsequently considered drug-related by the Investigator. All treatment-emergent adverse events 
will be included in the analysis. Adverse event parameters to be evaluated by treatment arms are 
the type, incidence, and intensity of adverse events; the relationship of adverse events to 
ibrutinib; and the action taken with respect to ibrutinib treatment due to adverse events.
Summaries, listings, or subject narratives may be provided, as appropriate, for those subjects 
who die, who discontinue treatment due to an adverse event, or who experience a severe or a 
serious adverse event.
Clinical Laboratory Tests
All central laboratory values will be converted to Standard International units (SI) and classified 
as normal, low, or high based on the SI reference ranges supplied by the central laboratory.
Where local labs are used, values will be converted to PCYC Standard units and flagged against 
PCYC Standard Ranges. Gradable laboratory parameters will be graded using the NCI CTCAE 
Version 4.03 or higher.  Treatment emergent lab abnormalities will be summarized.  
Laboratory tests will be summarized by treatment arms separately for hematology and serum 
chemistry.  Selected hematologic and chemistry laboratory parameters are detailed in 
Section 7.2.  Descriptive statistics will be provided for the values of selected clinical laboratory 
tests at each scheduled on-treatment evaluation including the final value.  Change or percent 
change from baseline to each scheduled on-treatment evaluation and to the final value will also 
be summarized. For selected variables, the mean value and mean percent change over time will 
be presented graphically.
10.8.
Interim Analysis
An interim analysis for the randomized treatment arms (Arm A and Arm B) will be conducted at
approximately 70% information, ~50 PFS events based on IRC assessment.  The interim analysis 
will be performed by an independent statistical supporting group. PCYC will remain blinded to 
the results that are provided to the independent DMC at the interim analysis. In order to preserve 
the study wise two-sided type I error rate of 0.05, the two-sided significance level for PFS will 
be 0.015 at 50 PFS events, based on O’Brien Fleming boundary. However, the alpha spending 
for PFS will be determined based on the actual information fraction using O’Brien-Fleming 
boundary at the time of the interim analysis.
If the primary endpoint achieves statistical significance, tests of secondary endpoints will be 
performed at the two-sided significance level of 0.05 in a sequential hierarchical manner based 
on a closed testing procedure. All key secondary endpoints will be ranked in sequence according 
to a hierarchical order to be specified in the SAP.  Further details regarding interim efficacy 
analysis will be described in the DMC charter and the SAP.


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The ibrutinib monotherapy substudy (Arm C) will not be included in the interim analysis. 
10.9.
Final Analysis
The final analysis will be conducted at approximately 71 PFS events, which are confirmed by the 
IRC for the randomized treatment arms (Arm A and Arm B). The two-sided significance level 
for the primary and all secondary endpoints will be adjusted to account for interim alpha 
spending so the overall two-sided significance level for the study will be preserved at 0.05. Tests 
of secondary endpoints will be performed using the same approach for the interim analysis. The 
ibrutinib monotherapy substudy (Arm C) will be analyzed separately at the final analysis. 
10.10.
Independent Review Committee (IRC)
The IRC will be chaired by a physician with expertise in WM and the IRC will conduct 
progression and response evaluations. The IRC assessment will incorporate nodal and 
extranodal assessments from the central radiology review in addition to the laboratory efficacy 
evaluations outlined in Section 7.5. Details regarding IRC and central radiology review 
activities will be outlined in a separate charter. IRC is established to conduct response 
assessment centrally according to the IRC charter.
10.11.
Independent Data Monitoring Committee (DMC)
The safety and the interim analysis of this study will be monitored by an independent DMC.  The 
independent DMC includes two medical experts in the relevant therapeutic area and one 
statistician to monitor data on an ongoing basis throughout the conduct of the study.
The independent DMC may recommend stopping the study for efficacy if the pre-specified 
stopping boundary is crossed at the interim analysis. In addition to the ongoing safety 
monitoring and planned interim analyses for efficacy, periodic safety review meetings are 
planned. The first DMC meeting will occur approximately 1 month after 30-40 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 independent DMC chair may request additional safety 
analyses and more frequent monitoring. Until the first safety analysis, all deaths, treatment 
discontinuations and serious adverse events will be reviewed in a blinded fashion by the 
sponsor’s responsible physician on an ongoing basis to identify safety concerns, and the 
independent DMC will be informed of any new potential signals. The plan for monitoring 
subject safety and evaluating efficacy, and the roles and responsibilities of the independent 
DMC, will be detailed in the independent 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.
Adverse Event Definitions and Classifications
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 drug, whether or not considered related to the study drug (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.
Disease progression is not an adverse event; rather it may be the cause of an adverse event.  
The clinical diagnosis that is associated with disease progression must be reported as all other 
adverse events.  “Disease progression” should never be used as an adverse event term.
Adverse events may include, but are not limited to:
•
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 (eg, 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 
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However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE.  
Surgeries or interventions that were under consideration, but not performed before 
enrollment in the study, will not be considered serious if they are performed after 
enrollment in the study for a condition that has not changed from its baseline level.  
Elective hospitalizations for social reasons, solely for the administration of 
chemotherapy, or due to long travel distances are also not SAEs.
•
Diagnostic Testing and Procedures: Testing and procedures should not to be reported 
as AEs or SAEs, but rather the cause for the test or procedure should be reported.
Serious Adverse Events
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:
•
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 
life-threatening.
•
Requires in-subject 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 
life-threatening 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.
11.1.2.
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
displays Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE.  
Should a subject experience any AE not listed in the CTCAE v4.03, the following grading 
system should be used to assess severity:


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•
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
11.1.3.
Causality (Attribution)
The Investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study drug caused the event) using the following definitions:
Not Related:
Another cause of the AE is more plausible; a temporal sequence cannot be 
established with the onset of the AE and administration of the 
investigational product; or, a causal relationship is considered biologically 
implausible.
Unlikely:
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely.
Possibly Related:
There is a clinically plausible time sequence between onset of the AE and 
administration of the investigational product, but the AE could also be 
attributed to concurrent or underlying disease, or the use of other drugs or 
procedures.  Possibly related should be used when the investigational 
product is one of several biologically plausible AE causes.
Related:
The AE is clearly related to use of the investigational product.
11.2.
Unexpected adverse events
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is 
not listed at the specificity or severity that has been observed.  For example, hepatic necrosis 
would be “unexpected” (by virtue of greater severity) if the Investigator's Brochure referred only 
to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator's 
Brochure/package insert listed only cerebral vascular accidents.  "Unexpected" also refers to AEs 
that are mentioned in the Investigator's Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the study drug under investigation.


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11.3.
Documenting and Reporting of Adverse Events
11.3.1.
Reporting of “IgM flare” (Tumor flare)
Therapy with rituximab in WM is commonly associated with a surge of IgM levels (IgM flare).
This transient increase of IgM levels will most likely not indicate disease progression and 
subjects may continue therapy with rituximab.
The Medical Dictionary for Regulatory Activities (MedDRA) does not support the reporting of 
“IgM flare” and therefore these events should be reported as an adverse event of 'tumor flare'.
Table 5 provides guidance on grading this particular event.
Table 5:
Grading for Adverse Events of IgM Associated Tumor Flare
“IgM flare” (Tumor flare)
Grade 1
<25% IgM increase during rituximab therapy  
Grade 2
≥25% IgM increase during rituximab therapy  
Grade 3
IgM increase during rituximab therapy associated with clinical intervention (e.g. 
plasmapheresis)\
Grade 4
IgM increase during rituximab therapy associated with life-threatening consequences;
urgent intervention indicated
Grade 5
Death 
11.3.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:
•
Overdose of a study drug
•
Suspected abuse/misuse of a study drug
•
Inadvertent or accidental exposure to a study drug
•
Medication error involving a product (with or without subject/patient exposure to the 
study drug, eg, name confusion, incorrect doses)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF and should be reported on the Serious Adverse Event Worksheet and sent via email 
or fax to Pharmacyclics Drug Safety, or designee, within 24 hours of awareness.


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11.3.3.
Adverse Event Reporting Procedures
11.3.3.1.
All Adverse Events
All subjects who receive at least one dose of study drug(s) will be considered evaluable for 
safety assessments. All adverse events, whether serious or non-serious, will be documented in 
the source documents from the time signed and dated ICF is obtained until 30 days following the 
last dose of study drug. Starting from the time of first dose of study drug, all AEs and SAEs will 
be entered in the eCRF until 30 days after the date of last dose of study drug.  Serious Adverse 
Events that occur during study conduct including the screening period must be reported to the 
Sponsor.  Serious adverse events occurring more than 30 days following the last dose of study 
drug should also be reported if considered related to any of the study drugs. Resolution 
information after 30 days should be provided.  
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. The primary cause of death on the 
autopsy report should be the term reported. Autopsy and postmortem reports must be forwarded 
to the Sponsor, or designee, as outlined above.
If a death occurs within 30 days after the last dose of study drug, the death must be reported to 
the Sponsor as a serious adverse event. 
Progressive disease should NOT be reported as an adverse event term, but instead symptoms/
clinical signs of disease progression may be reported. Otherwise, all events that meet the 
definition of a serious adverse event will be reported as serious adverse events, regardless of 
whether they are protocol-specific assessments.
If study drug is discontinued because of a serious adverse event, this information must be 
included in the serious adverse event report.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document. All records will need to 
capture the details of the duration and the severity of each episode, the action taken with respect 
to the study drug, investigator’s evaluation of its relationship to the study drug, and the event 
outcome. Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be 
reported as "upper respiratory infection"). Investigators must record in the eCRF their opinion 
concerning the relationship of the adverse event to study therapy. All measures required for 
adverse event management must be recorded in the source document and reported according to 
sponsor instructions.


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11.3.3.2.
Reporting Criteria for Serious Adverse Events
All serious adverse events (initial and follow-up information) will be reported on the Serious 
Adverse Event Worksheet 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 other additional information from the Investigator (eg, hospital admission/discharge notes 
and laboratory results). The contact information (phone, email and fax) for Pharmacyclics Drug 
Safety or designee can be found on the Serious Adverse Event Worksheet form and instructions.
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:
•
The event resolves
•
The event stabilizes
•
The event returns to baseline, if a baseline value/status is available
•
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct
•
It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts)
11.3.4.
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 will be reported to Pharmacyclics within 24 hours of awareness 
irrespective of seriousness (ie, serious and non-serious adverse events) following the procedure 
described above for SAEs and will require enhanced data collection.
11.3.4.1.
Major Hemorrhage
Major hemorrhage is defined as any of the following: 
1. Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*
2. Any treatment-emergent serious adverse events of bleeding of any grade
3. Any treatment-emergent central nervous system hemorrhage/hematoma of any grade
*All hemorrhagic events requiring transfusion of red blood cells should be reported as grade 3 or higher 
AE per CTCAE.
Events meeting the definition of major hemorrhage will be captured as an AESI according to 
Section 11.3.4 above.


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11.3.5.
Pregnancy
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy
including the use of contraception or complete abstinence in accordance with the local approved 
rituximab label and ibrutinib guidance.  However, should a pregnancy occur in a female study 
subject, consent to provide follow-up information regarding the outcome of the pregnancy and 
the health of the infant until 30 days old will be requested.
A female subject must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 30 days after the last dose of ibrutinib/placebo or 18 months after the last dose 
of rituximab, whichever occurs later.  A male subject must immediately inform the Investigator
if his partner becomes pregnant from the time of consent to 90 days after the last dose of 
ibrutinib/placebo or 18 months after the last dose of rituximab, whichever occurs later. Any 
female subjects receiving study drug(s) who become pregnant must immediately discontinue 
study drug. 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 adverse event, the outcome will need to be 
documented. Any pregnancy occurring in a subject from the time of consent to 30 days after the 
last dose of ibrutinib/placebo or 18 months after the last dose of rituximab, whichever occurs 
later, must be reported. Any pregnancy occurring in a subject’s partner from the time of consent 
to 90 days after the last dose of ibrutinib/placebo or 18 months after the last dose of rituximab, 
whichever occurs later, 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 serious adverse event.
11.3.6.
Other Malignancies
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies are to be reported for the duration of study treatment and during any protocol-
specified follow-up periods including post-progression follow-up for overall survival.
11.3.7.
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.


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12. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS
12.1.
Regulatory and Ethical Compliance
This clinical study was designed and will be implemented in accordance with the protocol, 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local 
regulations (including US Code of Federal Regulations [CFR] Title 21 and European Directive 
2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki. 
12.2.
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval
The Investigator will submit this protocol, the ICF, IB, and any other relevant supporting 
information (eg,IMPD, 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.  
Following the respective rules and regulations in different countries, amendments to the protocol 
and informed consent form must also be submitted and if necessary 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.
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 
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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 FDA regulations (21 CFR Parts 11, 50, 54, 56, and 312, 
Subpart D – Responsibilities of Sponsors and Investigators), ICH guidelines on GCP (ICH E6),
and/or applicable local country requirements.
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 7.1.1), either as part of the ICF or as a separate signed document (for 
example, in the US, a site-specific HIPAA consent may be used).  The Investigator or designee 
must explain to each subject that for the evaluation of study results, the subject’s protected 
health information obtained during the study may be shared with Pharmacyclics and its 
designees, regulatory agencies, and IRBs/REBs/IECs.  As the study Sponsor, Pharmacyclics will 
not use the subject’s protected health information or disclose it to a third party without applicable 
subject authorization.  It is the Investigator’s or designee’s responsibility to obtain written 
permission to use protected health information from each subject.  If a subject withdraws 
permission to use protected health information, it is the Investigator’s responsibility to obtain the 
withdrawal request in writing from the subject and to ensure that no further data will be 
collected from the subject.  Any data collected on the subject before withdrawal will be used in 
the analysis of study results.
During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations.
12.6.
Study Files and Record Retention
The Investigator must keep a record that lists all subjects who signed informed consent for the
study.  For those subjects subsequently excluded from enrollment, the reason(s) for exclusion is 
to be recorded.
The Investigator/study staff must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified.  Essential 
documentation includes, but is not limited to, the IB, signed protocols and amendments, 
IRB/REB/IEC approval letters (dated), signed Form FDA 1572 and Financial Disclosures, 
signed ICFs (including subject confidentiality information), drug dispensing and accountability 
records, shipping records of investigational product and study-related materials, signed 
(electronically), dated and completed eCRFs, and documentation of eCRF corrections, SAE 
forms transmitted to Pharmacyclics and notification of SAEs and related reports, source 


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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 (eg, scan, radiograph, ECG tracing) at 
any time.  Should an Investigator wish to assign the study records to another party or move them 
to another location, advance written notice must 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
CRFs will be used to collect the clinical study data and must be completed for each enrolled 
subject with all required study data accurately recorded such that the information matches the 
data contained in medical records (eg, physicians’ notes, nurses’ notes, clinic charts and other 
study-specific source documents).  Authorized study site personnel (ie, listed on the Delegation 
of Authority log) will complete CRFs designed for this study according to the completion 
guidelines that will be provided.  The Investigator will ensure that the CRFs are accurate, 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 CRFs 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 CRFs and application of electronic signatures before the start of the study 
and before being given access to the EDC system.  Original data and any changes of data will be 
recorded using the EDC system, with all changes tracked by the system and recorded in an 
electronic audit trail.  The Investigator attests that the information contained in the CRFs is true 
by providing electronic signature within the EDC system.  After database lock, the Investigator 


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will receive a copy of the subject data (eg, paper, CD, or other appropriate media) for archiving 
at the study site.
12.8.
Investigational Study Drug Accountability
Ibrutinib and any comparator used must be kept in a locked limited access room.  The study drug 
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 Drug Accountability Log must be used for drug accountability.  For accurate 
accountability, the following information must be noted when drug supplies are used during the 
study:
1. Study identification number (PCYC-1127-CA)
2. Subject identification number
3. Lot number(s) of ibrutinib or comparator dispensed for that subject
4. Date and quantity of drug dispensed
5. Any unused drug returned by the subject
At study initiation, the monitor will evaluate and approve the site’s procedure for investigational 
product disposal/destruction to ensure that it complies with Pharmacyclics’ requirements.  If the 
site cannot meet Pharmacyclics’ requirements for disposal/destruction, arrangements will be 
made between the site and Pharmacyclics or its representative, for return of unused 
investigational product.  Before disposal/destruction, final drug accountability and reconciliation 
must be performed by the monitor.
All study supplies and associated documentation will be regularly reviewed and verified by the 
monitor.
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.


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To assure the accuracy of data collected in the CRFs, 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.  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 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, both of which are signed by the 
Investigator before commencement of the study.  In summary, the Investigator will conduct the 
study according to the current protocol; will read and understand the IB; will obtain 
IRB/REB/IEC approval to conduct the study; will obtain informed consent from each study 
participant; will maintain and supply to the Sponsor or designee, auditors and regulatory 
agencies adequate and accurate records of study activity and drug accountability for study-
related monitoring, audits, IRB/REB/IEC reviews and regulatory inspections; will report SAEs 
to the Sponsor or designee and IRB/ REB/IEC according to the specifics outlined in this 
protocol; will personally conduct or supervise the study; and will ensure that colleagues 
participating in the study are informed about their obligations in meeting the above 
commitments.
12.11.
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.


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12.12.
Financial Disclosure
A separate financial agreement will be made between each Investigator and Pharmacyclics or its 
authorized representative before the study drug is delivered.
For this study, each Investigator and Sub-investigator (as designated on the Form FDA1572) will 
provide a 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.
If a bodily injury is sustained, resulting directly from the use of the study drug, Pharmacyclics 
will reimburse for reasonable physician fees and medical expenses necessary for treatment of 
only the bodily injury which is not covered by the subject’s medical or hospital insurance, 
provided that the injury is not due to a negligent or wrongful act or omission by the Investigator/ 
study staff.  The ICF will include a description of this reimbursement policy, 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, as appropriate,
together with, if applicable, a revised model ICF.  Written documentation of health authority 
and/or IRB/REB/IEC and required site approval, as applicable, 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 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.


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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. Pharmacyclics adheres to the 
guidelines on authorship established by the International Committee of Medical Journal Editors 
statement on Authorship and Contribution (http://www.icmje.org/ethical_1author.html).
In most cases, the Investigators at the sites with the highest accruals of eligible subjects shall be 
listed as lead authors on manuscripts and reports of study results.  The Medical Monitor, study 
director and/or lead statistician may also be included in the list of authors.  This custom can be 
adjusted upon mutual agreement of the authors and Pharmacyclics and in accordance with 
current standards for authorship as recorded in professional conference and journal submission 
instructions.
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.


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13. REFERENCES
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18. Ghobrial IM, Uslan DZ, Call TG, et al. Initial increase in the cryoglobulin level after rituximab 
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Management: Definitions and Standards for Expedited Reporting (ICH-E2A).  March 1995.
25. Jaglowski SM, Jones JA, Flynn JM, et al. A phase Ib/II study evaluating activity and tolerability of 
BTK inhibitor PCI-32765 and ofatumumab in patients with chronic lymphocytic leukemia/small 
lymphocytic lymphoma (CLL/SLL) and related diseases [abstract]. ASCO. 2012. Abstract 6508.
26. Kilidireas C, Anagnostopoulos A, Karandreas N, et al. Rituximab therapy in monoclonal IgM-related 
neuropathies. Leuk Lymphoma. 2006;47:859-64.
27. Konoplev S, Medeiros LJ, Bueso-Ramos CE, Jorgensen JL, Lin P. Immunophenotypic profile of 
lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia. Am J Clin Pathol 2005;124:414-
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28. Kyle RA, Treon SP, Alexanian R, et al. Prognostic markers and criteria to initiate therapy in 
Waldenström’s macroglobulinemia: consensus panel recommendations from the Second International 
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29. Morel P, Duhamel A, Gobbi P, et al. International prognostic scoring system for Waldenström’s
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31. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. 
Nature. 2011;470:115-9.  
32. O’Brien S, Furman RR, Coutre SE, et al.  Independent evaluation of ibrutinib efficacy 3 years post-
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including deletion 17p disease.  J Clin Oncol. 2014:32(5s):abstract 7014
33. O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic 
lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial.  
Lancet Oncol. 2014;15:48-58.


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35. Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological definition of Waldenström’s
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36. Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine 
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38. Rourke M, Anderson KC, Ghobrial IM. Review of clinical trials conducted in Waldenström’s
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43. Strauss SJ, Maharaj L, Hoare S, et al. Bortezomib therapy in patients with relapsed or refractory 
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52. Yang G, Zhou Y, Liu X, et al. A mutation in MYD88 (L265P) supports the survival of 
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14. APPENDICES


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Appendix 1.
Schedule of Assessments 
Screening 
Phase
Treatment Phase
Post-Treatment/
Follow-Up Phase
Study Weeks
1
2
3
4
5-16
q4 weeks
17
18
19
20
21
25+
q8 weeks
Suspected 
PD Visit
End-of-
Treatment 
Visits
Response 
Follow-Up
Visits
(Until PD)
q12 weeks
Survival 
Follow-Up
q12 weeks
Study Day
1
1
1
1
1
1
Study Windows
-30 days
+ 3 days
± 3 days
+ 3 days
± 3 days ± 3 days
anytime
± 7 days
± 7 days
± 7 days
Study Drug Administration
ARM A and ARM B 
Rituximab  375 mg/m2 IVa
x
x
x
x
x
x
x
x
Ibrutinib/Placebo 420mg PO
Continuous dosing until PD or unacceptable toxicity
ARM C (Substudy)
Open-label ibrutinib 420mg PO
Continuous dosing until PD or unacceptable toxicity
Dispense Study Drug 
(ibrutinib/placebo)
x
x
x
x
x
Administrative Procedures
Informed consentr
Xr
Confirm eligibility & randomize
X
x
Medical history and Demographics
X
PRO assessmentsb
x
x
x
x
x
x
x
x
xc
Safety Assessments
Physical exam (height at Screening 
only)
xd
xd
xe
xe
xe
xe
xd
xd
xd
Eye-related symptom assessment
X
x
x
x
x
x
x
x
x
ECOG status
X
x
x
x
x
x
x
x
Vital signs
X
x
x
x
x
x
x
x
ECG
X
Additional assessments may be performed if clinically indicated during the course of the study
Clinical Laboratory Assessments
Hematology
X
x
x
x
x
x
x
x
x
Serum chemistry
X
x
x
x
x
x
x
Coagulation (PT, INR, and aPTT)
X
x
x
Pregnancy testf
X
x
Hepatitis serologies
X
Serum viscosityg
X
Serum immunofixationh
X
β2-microglobulin
X
PKi
x
Week 5 
Only


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Screening 
Phase
Treatment Phase
Post-Treatment/
Follow-Up Phase
Study Weeks
1
2
3
4
5-16
q4 weeks
17
18
19
20
21
25+
q8 weeks
Suspected 
PD Visit
End-of-
Treatment 
Visits
Response 
Follow-Up
Visits
(Until PD)
q12 weeks
Survival 
Follow-Up
q12 weeks
Study Day
1
1
1
1
1
1
Study Windows
-30 days
+ 3 days
± 3 days
+ 3 days
± 3 days ± 3 days
anytime
± 7 days
± 7 days
± 7 days
Efficacy Assessments
Serum protein electrophoresis 
(SPEP)
x
x
x
x
x
x
x
x
x
Quantitative serum immunoglobulins 
(IgA, IgG and IgM)
x
x
xj
xj
xj
x
x
x
x
x
x
x
Serum free light chain assay
x
Weeks 
49 and 97
x
CT Scans 
xk
xl
xl
xm
Bone Marrow Aspirateo and 
Biopsyn
x
Weeks 
49 and 97 
(± 2 weeks)
x
x
Overall Disease Assessment
x
x
x
x
x
x
x
Survival Status and new anticancer 
therapy
x
x
Ongoing Subject Assessments
Concomitant medications
x
Continuous from Informed Consent to 30 days after last dose of study drug
Adverse events
x
Continuous from Informed Consent to 30 days after last dose of study drug
Biomarkers
T/B/NK cell counts
x
x
Weeks 
33 and 
49 Only
x
x
Predictive biomarkers & 
mechanisms of resistancep
xq
x
Weeks 
33 and 
49 Only
x
x
Abbreviations: aPTT=activated partial thromboplastin time; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end-of-treatment; INR=international normalized 
ration; PD=progressive disease; PO=orally; PRO=patient-reported outcome; PT=prothrombin time; q4 weeks=every 4 weeks; q 8 weeks = every 8 weeks; q12 weeks=every 12 weeks
Footnote:
a
Rituximab doses may be delayed for up to 3 days due to scheduling conflicts.
b PRO questionnaires should be completed prior to any assessments, and before being clinically evaluated by the study nurse or physician.  The questionnaires 
will be administered at Week 1 and, thereafter PROs will be performed every 4 weeks for the first 6 months, every 8 weeks beginning at Week 25, and 
thereafter every 16 weeks beginning at Week 49 until disease progression, death, or study end, whichever comes first.  


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c Following disease progression, every effort should be made to administer the questionnaire every 12 weeks for the first 6 months during the survival follow-up 
period, unless death or study closure, whichever occurs first.
d Physical Examination includes: general appearance of subject, examination of skin, eyes and fundi, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal system, lymphatic system, and nervous system.
e Only a limited symptom-directed physical examination is required.  Review of symptoms should include inquiry of ocular symptoms; subjects should be 
referred to an ophthalmologist for a formal examination if any Grade ≥2 symptoms are reported.
f
Women of reproductive potential only. Serum pregnancy test required at Screening and urine pregnancy test required at Day 1 prior to first dose. If the test 
result is positive, the pregnancy must be ruled out by ultrasound to be eligible.
g Subsequent Serum viscosity (after Screening) should be performed at the discretion of the treating physician in any subject with signs and symptoms 
suggesting a hyperviscosity syndrome.
h Repetitive serum immunofixation on study is only required to confirm CR (conducted on the first observation that the subject has no detectable monoclonal 
protein) and then repeated every time until disease progression.
i Pharmacokinetic samples will be drawn for all subjects according to the schedule in Section 7.4.1. Week 4 PK will only be required for Arm A and Arm B. 
Week 5 PK will only be required for Arm C. 
j These parameters will be used to assess possible IgM flare after initiating treatment for safety observations for Treatment Arm A and Arm B only.
k CT scans of the neck, chest, abdomen, and pelvis should be obtained during Screening (up to 42 days before first dose) for each subject.
l
Follow-Up CT scans will be required at Weeks 17, 33, 49 65, 81, 97 and thereafter every 24 weeks for all subjects with measureable nodal/extranodal disease 
per central radiology review during Screening.  Additional assessments may be performed if clinically indicated during the course of the study at any time. 
m CT scan at Suspected PD visit may be performed if clinically indicated as reason for progression. 
n Bone marrow aspirate and biopsy required at Screening, Weeks 49 and 97 (± 2 weeks) to confirm paraprotein changes, and at any time as determined 
necessary or to confirm a complete response if the subject has no detectable monoclonal protein, and if clinically indicated at disease progression or end-of-
treatment visit. A portion of these samples may be used for biomarker assessments.
o With Bone Marrow Aspirate prepare 4 smears, perform required assays at site and submit up to 10 mL aspirate to central lab
p Biomarker sample: One 8.5 mL blood sample in Acid Citrate Dextrose (ACD) and one 10mL blood sample in Sodium Heparin will be collected for biomarker 
evaluations at the beginning of Week 1, Week 17, Week 33 and Week 49.  Additional samples will also be obtained at the time of complete response 
assessment and at disease progression (or at End-of Treatment Visit for subjects who discontinue treatment without disease progression). 
q Portion of sample collected at Week 1 will be used for evaluation of genetic and molecular prognostic markers. 
r
All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF before any study-specific screening procedures are performed.  
s
30 days from last dose of study drug or prior to the start of a new anticancer treatment. 


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Appendix 2.
ECOG Status Scores
Status
Eastern Cooperative Oncology Group (ECOG) Performance Status**
0
Fully active, able to carry on all 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, M.M., Creech, R.H., Tormey, D.C., 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 3.
Inhibitors and Inducers of CYP3A
Inhibitors and inducers of CYP3A are defined as follows.  A comprehensive list of inhibitors can be 
found at the following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. The general 
categorization into strong, moderate, and weak inhibitors according to the website is displayed below.  
Refer to Section 6.1.2.1 on instructions for concomitant use of CYP3A inhibitors or inducers with 
ibrutinib.
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
Moderate inhibitors:
Rifampin
Aprepitant
St. John’s Wort
Erythromycin
Troglitazone
diltiazem 
Fluconazole
grapefruit juice
Seville orange juice
Verapamil
Weak inhibitors:
Cimetidine
All other inhibitors:
Amiodarone
NOT azithromycin
Chloramphenicol
Boceprevir
Ciprofloxacin
Delaviridine
diethyl-dithiocarbamate
Fluvoxamine
Gestodene
Imatinib
Mibefradil
Mifepristone
Norfloxacin
Norfluoxetine
star fruit
Telaprevir
Troleandomycin
Voriconazole
Source:http://medicine.iupui.edu/clinpharm/ddis/table.aspx.


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Appendix 4.
Modified 6th WM Response Criteria (NCCN 2014) for Investigator Assessment
Modified WM Response Criteria for Investigator Assessment of Response and Progression*
Category
Response Criteria
Complete Response 
(CR)
•
Serum IgM values in normal range
•
Disappearance of monoclonal protein by immunofixation
Note: Reconfirmation of CR status is required with a second immunofixation at 
any time point
•
No histological evidence of bone marrow involvement
•
Complete resolution of  lymphadenopathy4/splenomegaly if present at baseline
Very Good Partial 
Response (VGPR)
•
At least 90% reduction of serum IgM from baseline or serum IgM values in 
normal range 
•
Reduction in lymphadenopathy4/splenomegaly if present at baseline
Partial Response (PR)
•
At least 50% reduction of serum IgM from baseline 
•
Reduction in lymphadenopathy4/splenomegaly if present at baseline
Minor Response (MR)
•
At least 25% but <50% reduction of serum IgM from baseline
Stable Disease (SD)
•
Not meeting criteria for CR, VGPR, PR, MR, or progressive disease (PD)
Progressive Disease 
(PD) 
At least one of the following 
•
A ≥25% increase in serum IgM with a total increase of at least 500 mg/dL from 
nadir1
o
Confirmation of the initial IgM increase is required when IgM is sole 
criterion for progressive disease.
•
Appearance of a new lymph nodes > 1.5 cm in any axis, ≥50% increase from 
nadir in sum of product of diameters (SPD) of more than one node, or ≥ 50% 
increase in longest diameter of a previously identified node > 1 cm in short axis2
•
Appearance of  new splenomegaly or  ≥50% increase from nadir in enlargement 
of the spleen2
•
Appearance of  new extranodal disease 2/3
•
New or recurrent involvement in the bone marrow
•
New symptomatic disease on the basis of malignant pleural effusion, Bing Neel 
(WM CNS disease) syndrome, amyloidosis or light chain deposition disease, or 
other paraprotein mediated disorder.
1.
Nadir for serum IgM is defined as the lowest serum IgM value obtained at any time from baseline onwards 
with the exception that serum IgM levels post-plasmapheresis will not be considered for up to 35 days.
2.
For additional clarification to assess the appearance or progression of existing nodal and extranodal disease 
(Refer to Section 7.5.4.) 
3.
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. 
4.
Sum of the products of multiple lymph nodes (as evaluated by CT scans) or the longest diameter of one 
target lymph node
*   The primary efficacy evaluations are based on IRC evaluation. In addition, eligibility for potential next-line 
therapy with ibrutinib will be based on IRC confirmed progression.  The IRC assessment will incorporate 
assessments from the central radiology review and the details regarding the IRC evaluation for response and 
progression will be outlined in a separate charter.


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Appendix 5.
New York Heart Association Functional Classification
NYHA Class 
Symptoms
NYHA Class Symptoms
I
No symptoms and no limitation in ordinary physical activity, eg, shortness of breath 
when walking, climbing stairs etc.
II
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, 
eg, walking short distances (20–100 m).
Comfortable only at rest.
IV
Severe limitations.  Experiences symptoms even while at rest.  Mostly bedbound patients.


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Appendix 6.
WM IPSS Calculation
Factors associated with Prognosis
Value
Age 
> 65 years
Hemoglobin 
≤ 11.5 g/dL
Platelet count
≤ 100 x 109/L
β2-microglobulin 
> 3 mg/L
Serum monoclonal IgM 
> 7.0 g/dL
Risk Category
Score
I   (low risk)
0 or 1 factors (≤ 65 years)
II  (intermediate risk)
2 factors OR age > 65 years
III (high risk)
> 2 factors
An international prognostic scoring system for newly diagnosed WM patients was recently developed 
(Morel et al, 2009) based on 5 factors associated with a poor prognosis include advanced age, high beta 
2-microglobulin (ß2M), low albumin, cytopenias, serum IgM monoclonal protein, and organomegaly


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Appendix 7.
EQ-5D-5L Health Questionnaire


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Appendix 8.
FACT-An (Version 4)
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 
7 days.
PHYSICAL WELL-BEING
Not at 
all
A little 
bit
Some
what
Quite
a bit
Very 
much
GP1
I have a lack of energy............................................
0
1
2
3
4
GP2
I have nausea...........................................................
0
1
2
3
4
GP3
Because of my physical condition, I have trouble 
meeting the needs of my family..............................
0
1
2
3
4
GP4
I have pain...............................................................
0
1
2
3
4
GP5
I am bothered by side effects of treatment..............
0
1
2
3
4
GP6
I feel ill....................................................................
0
1
2
3
4
GP7
I am forced to spend time in bed.............................
0
1
2
3
4
SOCIAL/FAMILY WELL-BEING
Not at 
all
A little 
bit
Some
what
Quite
a bit
Very 
much
GS1
I feel close to my friends.........................................
0
1
2
3
4
GS2
I get emotional support from my family.................
0
1
2
3
4
GS3
I get support from my friends .................................
0
1
2
3
4
GS4
My family has accepted my illness.........................
0
1
2
3
4
GS5
I am satisfied with family communication about 
my illness ................................................................
0
1
2
3
4
GS6
I feel close to my partner (or the person who is 
my main support)....................................................
0
1
2
3
4
Q1
Regardless of your current level of sexual activity, 
please answer the following question. If you prefer 
not to answer it, please mark this box 
and go to the next section.
GS7
I am satisfied with my sex life................................
0
1
2
3
4


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Please circle or mark one number per line to indicate your response as it applies to the past 
7 days.
EMOTIONAL WELL-BEING
Not at 
all
A little 
bit
Some
what
Quite
a bit
Very 
much
GE1
I feel sad.................................................................
0
1
2
3
4
GE2
I am satisfied with how I am coping with my 
illness .....................................................................
0
1
2
3
4
GE3
I am losing hope in the fight against my illness.....
0
1
2
3
4
GE4
I feel nervous..........................................................
0
1
2
3
4
GE5
I worry about dying................................................
0
1
2
3
4
GE6
I worry that my condition will get worse...............
0
1
2
3
4
FUNCTIONAL WELL-BEING
Not at 
all
A little 
bit
Some
what
Quite
a bit
Very 
much
GF1
I am able to work (include work at home)..............
0
1
2
3
4
GF2
My work (include work at home) is fulfilling ........
0
1
2
3
4
GF3
I am able to enjoy life .............................................
0
1
2
3
4
GF4
I have accepted my illness ......................................
0
1
2
3
4
GF5
I am sleeping well ...................................................
0
1
2
3
4
GF6
I am enjoying the things I usually do for fun..........
0
1
2
3
4
GF7
I am content with the quality of my life right now .
0
1
2
3
4


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Please circle or mark one number per line to indicate your response as it applies to the past
7 days.
ADDITIONAL CONCERNS
Not 
at all
A little 
bit
Some
what
Quite
a bit
Very 
much
HI7
I feel fatigued..........................................................
0
1
2
3
4
HI12
I feel weak all over..................................................
0
1
2
3
4
An1
I feel listless (“washed out”)...................................
0
1
2
3
4
An2
I feel tired................................................................
0
1
2
3
4
An3
I have trouble starting things because I am tired ....
0
1
2
3
4
An4
I have trouble finishing things because I am tired..
0
1
2
3
4
An5
I have energy...........................................................
0
1
2
3
4
An6
I have trouble walking ............................................
0
1
2
3
4
An7
I am able to do my usual activities .........................
0
1
2
3
4
An8
I need to sleep during the day .................................
0
1
2
3
4
An9
I feel lightheaded (dizzy) ........................................
0
1
2
3
4
An10
I get headaches........................................................
0
1
2
3
4
B1
I have been short of breath......................................
0
1
2
3
4
An11
I have pain in my chest ...........................................
0
1
2
3
4
An12
I am too tired to eat.................................................
0
1
2
3
4
BL4
I am interested in sex ..............................................
0
1
2
3
4
An13
I am motivated to do my usual activities ................
0
1
2
3
4
An14
I need help doing my usual activities......................
0
1
2
3
4
An15
I am frustrated by being too tired to do the things 
I want to do .............................................................
0
1
2
3
4
An16
I have to limit my social activity because I am 
tired .........................................................................
0
1
2
3
4


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Appendix 9.
Schedule of Assessments for Subjects Treated with Placebo in Combination 
with Rituximab and Documented IRC confirmed Progression who Elect to 
Receive Next-line Ibrutinib Therapy
Study Weeks
Assessment for 
Eligibility for 
Next-line 
Ibrutinib 
Therapy
Treatment Phase
Follow-up 
Phase
Every 4 weeks 
for 16 weeks
Every 8 weeks 
thereafter
until PD 
End-of-
Treatment
Visit
Follow-up 
(Every 
12 weeks)
Study Windows
±3 d
±3 d
30 (±3 d)
±7 d
Study Drug 
Administration
Ibrutinib 420 mg per day 
PO
Continuous Daily Dosing
Procedures
IRC-confirmed PD a
x
Sponsor’s Designee
approval
x
Concomitant medications
x
x
x
x
Adverse events 
x
x
x
Physical examination, 
vital signs, ECOG 
xb
x
x
x
Hematology c
xb
x
x
x
Serum chemistryc
xb
x
x
x
Serum immunoglobulinsc
(IgM)
xb
x
x
x
Investigator assessment 
of response and for 
progression
x
x
Survival status
x
Subsequent anticancer 
therapies
x
d=day; ECOG=Eastern Cooperative Oncology Group; IRC=Independent Review Committee; PD=progressive disease; PO=oral; 
qd=once daily
a
Documentation from IRC required for Sponsor’s designee approval to receive next-line ibrutinib therapy
b
Assessments for next-line ibrutinib should be performed ±10 days from unblinding 
c
Assessments performed by local laboratory 


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Appendix 10. Child-Pugh Score
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 (1964) “Surgery and portal hypertension”. In Child CG. The liver and portal
hypertension. Philadelphia:Saunders. pp. 50-64.  
2.
Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R (1973). “Transection of the oesophagus 
for bleeding oesophageal varices”. The British journal of surgery, 60 (8): 646-9

SAP_001.pdf: 
PCYC-1127-CA 
Statistical Analysis Plan 
Page 1 of 8 
 
 
Proprietary and Confidential 
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Statistical Analysis Plan Addendum for Final CSR 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ibrutinib 
or Placebo in Combination with Rituximab in Subjects with Waldenström’s 
Macroglobulinemia 
PCYC-1127-CA 
21 October 2019 
Confidentiality Statement 
The information in this document is considered privileged and confidential by Pharmacyclics LLC., and may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board approval and informed consent, 
or as required by Federal and State Laws.  Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed. 
 
 
NCT02165397




PCYC-1127-CA 
Statistical Analysis Plan 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
CSR 
clinical study report 
ITT 
intent-to treat 
PD 
progressive disease 
PFS 
progression-free survival 
TEAE 
treatment-emergent adverse events 
 
 


PCYC-1127-CA 
Statistical Analysis Plan 
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Table of Contents 
LIST OF ABBREVIATIONS ............................................................................................................................... 3 
1. 
INTRODUCTION ..................................................................................................................................... 5 
2. 
ADDITIONAL ANALYSES ......................................................................................................................... 5 
2.1. 
Progression-Free Survival after Subsequent Anti-neoplastic Therapy (PFS2) .............................. 5 
2.2. 
Prevalence of Treatment-Emergent Adverse Events (TEAEs) ....................................................... 5 
2.3. 
Overall Survival (OS) after crossover to Next-line Ibrutinib for Crossover Subjects ..................... 6 
Appendix ....................................................................................................................................................... 7 
Table 1 Summaries of Data and Statistical Methods ................................................................................ 7 
 
 


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1. INTRODUCTION 
This SAP is to describe the final analyses of data in evaluation of efficacy and safety of Study PCYC-
1127-CA to support the Final CSR. The final analyses will be based on the final data extract. This SAP 
describes the additional analyses to the primary CSR SAP, dated 13 October 2017. All analyses that were 
performed previously for the primary CSR will follow the primary CSR SAP and will not be described 
again in this document. The additional analyses to support the Final CSR will be described in Section 2 
(see summary in appendix Table 1). 
2. ADDITIONAL ANALYSES 
2.1.
Progression-Free Survival after Subsequent Anti-neoplastic Therapy (PFS2)  
Progression-free survival after subsequent anti-neoplastic therapy will be defined for all subjects in the 
ITT population as the duration of time from date of randomization to the date of the earliest of the 
following 3 types of events:  

PD per investigator response assessment after administration of the first subsequent anti-
neoplastic therapy 

Death at any time on study due to any cause 

Initiation of a second subsequent anti-neoplastic therapy 
For subjects randomized to placebo + rituximab arm, ibrutinib as next-line therapy will be considered as a 
subsequent anti-neoplastic therapy in the analysis of PFS2. Subjects who did not experience a PFS2 event 
will be censored at the later date of last available survival status and last adequate assessment. Subjects 
with no available survival status information and no adequate assessment after initiation of first 
subsequent anti-neoplastic therapy, will be censored at date of first subsequent anti-neoplastic therapy + 
1.
Subjects without a baseline assessment, or with no adequate post baseline assessment and did not start 
first subsequent anti-neoplastic therapy, will be censored at the date of randomization.  
The same methods used to analyze PFS will be used to analyze PFS2.  
2.2.
Prevalence of Treatment-Emergent Adverse Events (TEAEs) 
The prevalence of TEAE will be analyzed for all combined arms with planned treatment of ibrutinib 
(Arms A+C). The summaries of disposition, demographic and baseline characteristics for Arms A+C will 
be presented. 
The summaries of exposure, TEAEs, and laboratory data will be presented by ibrutinib exposure intervals 
of 0-1 year, 1-2 years, 2-3 years, 3-4 years, 4-5 years, and >5 years (may be adjusted based on the actual 
data to ensure there are relatively enough subjects in the highest yearly interval) and overall.   


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Statistical Analysis Plan 
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
The exposure summary table will be presented by the actual time on ibrutinib treatment during 
each yearly interval.  

The TEAEs summaries (excluding TEAEs leading to deaths and other malignancies) will be 
presented by ibrutinib treatment duration yearly intervals and included an additional period of up 
to 30 days after the last dose following discontinuation of ibrutinib to cover the treatment-
emergent period. 

All TEAEs leading to deaths will be presented by yearly intervals of study duration.  

Other malignancies will be presented by yearly intervals of study duration, which includes time 
on study to capture events that occurred after discontinuation of ibrutinib (i.e. beyond the 30-day 
window). 
Note that the lower limit of the yearly interval will be included in the previous interval and the upper limit 
will be included in the current interval (e.g., a TEAE, laboratory finding, or exposure duration ending at 
exactly 4 years will be included in the yearly interval 3- 4 years but not the interval 4-5 years).  For the 
determination of period prevalence, TEAEs still ongoing from the previous exposure period year will be 
included in addition to newly occurring TEAEs in the respective time period.  Multiple events of the same 
preferred term (PT) within the same yearly interval for a subject will be counted only once. Prevalence of 
a specific TEAE during an interval will be computed from the ratio of all subjects with reported events 
(continuing from previous yearly interval or new onset in the interval) and the number of subjects whose 
TEAE period is covering the yearly interval (the end of the TEAE period is later than the beginning of the 
interval).   
Prevalence rates of TEAEs in the overall column will be computed from all subjects who reported at least 
one occurrence of the specific event during the study. 
The plots of diastolic blood pressure and systolic blood pressure over the time for subjects with serious 
hypertension will be provided.       
 
2.3.
Overall Survival (OS) after crossover to Next-line Ibrutinib for Crossover Subjects  
OS after crossover to ibrutinib is defined from date of crossover to ibrutinib to the date of death due to 
any cause. Subjects who are alive or exited the study with unknown death status will be censored at the 
last date known to be alive. OS distribution is estimated by Kaplan-Meier method. Median OS and 
landmark estimates will be provided. 


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APPENDIX 
Table 1 Summaries of Data and Statistical Methods 
Parameters 
Definitions and Statistical Methods
Demographics and 
baseline 
Characteristics
Information obtained at study start. Characteristics included age, gender, 
race, ethnicity, geographic region, weight, height, BSA, number of prior treatment lines, 
estimated creatinine clearance rate and other baseline characteristics.   
Subject disposition
The number of subjects continuing ibrutinib treatment (rollover) and primary reasons for 
discontinuation of treatment for subjects who discontinued ibrutinib will be provided. Time on study 
will be summarized based on follow-up time of overall survival, and the median time on study will be 
estimated using Kaplan-Meier methodology. Information on ibrutinib treatment duration will be 
presented; the number and percentage of subjects with ibrutinib treatment over time will be 
summarized in 1-year intervals. Additionally, subject disposition will be summarized for subjects 
who will be included in each yearly interval. 
Exposure to ibrutinib
Exposure will be summarized by treatment duration, cumulative dose received, and average daily 
dose during each yearly interval. The number of subjects continuing ibrutinib treatment in 
each yearly interval will be also summarized. 
PFS2 assessed by 
investigator 
Duration from date of randomization to the date of the earliest of the following 3 types of events:  
• PD per investigator response assessment after administration of the first subsequent anti-neoplastic 
therapy 
• Death at any time on study from any cause 
• Initiation of a second subsequent anti-neoplastic therapy 
The same methods used to analyze PFS will be used to analyze PFS2. 
OS for crossover 
OS after crossover to ibrutinib is defined from date of crossover to ibrutinib to the date of death due 
to any cause. Subjects who are alive or exited the study with unknown death status will be censored 
at the last date known to be alive. OS distribution is estimated by Kaplan-Meier method. Median OS 
and landmark estimates will be provided. 
Treatment-emergent 
adverse events
All reported AEs satisfying either of the following criteria: 
Ь Those events that occurred or worsened after the first dose of ibrutinib, through the 
treatment phase, and within 30 days following the last dose of ibrutinib or initiation of 
subsequent antineoplastic therapy, whichever occurred first. 
Ь Events with a missing onset date with a resolution date during the ibrutinib treatment 
phase; or 
Ь Events that were considered study drug-related regardless of the start date of the event. 
All available TEAEs will be summarized in this report. Related TEAEs reported after the TEAE 
period will not be included in the ibrutinib exposure yearly intervals because subjects were no longer 
on ibrutinib treatment, but they will be included in the overall column in the TEAE tables. The 
prevalence of safety data will be summarized by exposure period and included TEAEs, Grade 3 or 
higher TEAEs, related TEAEs, SAEs, TEAEs leading to deaths, TEAEs leading to treatment 
discontinuation for subjects who discontinued treatment due to TEAEs. Summary of TEAEs leading 
to discontinuation of ibrutinib will be counted at the yearly interval when subjects discontinued 
ibrutinib. Treatment-emergent AEs leading to death will be counted at the yearly interval when the 
subject died and will be presented by study-duration yearly intervals to capture events that occurred 
after discontinuation of ibrutinib.  
Hemorrhage 
Hemorrhagic events will be identified and summarized by hemorrhage SMQ excluding laboratory 
terms. 
Major hemorrhage is a subset of hemorrhagic events including the following: Grade 3 or higher 
nonserious TEAEs, SAEs, and TEAEs (without regard to grade or seriousness criteria) representing 
CNS hemorrhage. The prevalence of hemorrhage and major hemorrhage TEAEs will be provided. 


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Hypertension 
The prevalence of TEAEs, Grade 3 or higher, and serious hypertension reported after the first dose of 
ibrutinib by yearly intervals will be provided. Hypertension events will be summarized by 
hypertension SMQ narrow. A summary of incidence of new onset for hypertension events within 
each yearly interval will also be provided. Multiple occurrences of the same events within the same 
yearly interval for a subject will be counted only once at the first onset of the event. The number of 
subjects at risk for each interval will include all subjects whose TEAE period was covering the yearly 
interval (the end of the TEAE period was later than the beginning of the interval). The number of 
subjects with and without TEAE hypertension will be summarized by history of hypertensive 
GLVRUGHUVFRQGLWLRQVRURWKHUUHOHYDQWULVNIDFWRUVDQGE\DJHDQG\HDUVROG Summaries of 
time to onset of hypertension Grade 3 and higher and serious events will be provided. Spaghetti plots 
of over time will be provided for subjects who had serious events of hypertension. 
Second Primary 
Malignancies 
(Referred to as 
“Other 
Malignancies” 
for the 
remainder of 
this analysis) 
The prevalence of other malignancies by PT will be provided for both the TEAE period by yearly 
intervals of ibrutinib exposure and for other malignancies reported beyond 30 days of last ibrutinib 
dose. For other malignancies, new malignancies will be obtained from the PTs under the categories 
non-melanoma skin cancer, melanoma skin cancer, and non-skin cancer. Non-skin cancer excludes 
underlying disease or progressive disease malignancies. Due to their long duration and infrequent 
resolution, other malignancies will also be reported by incidence of new onset of events within each 
yearly interval. Multiple occurrences of the same events within the same yearly interval for a subject 
will be counted only once at the first onset of the event. The number of subjects at risk for each 
interval include all subjects whose TEAE period is covering the yearly interval (the end of the TEAE 
period is later than the beginning of the interval).  
Cardiac 
arrhythmias 
For cardiac arrhythmias, the following grouped terms for prevalence will be used: PTs for atrial 
fibrillation and atrial flutter combined as well as the narrow SMQ for ventricular tachyarrhythmias. A 
summary of the prevalence of TEAEs and Grade 3 or higher TEAE by yearly interval will be 
provided.  
Interstitial lung 
disease 
Interstitial lung disease events will be identified by ILD SMQ-narrow. A summary of the prevalence 
of TEAEs and Grade 3 or higher TEAEs by yearly interval will be provided. 
Clinical laboratory 
test 
The summaries of laboratory data will be presented by ibrutinib exposure intervals of 0-1 year, 1-2 
years, 2-3 years, 3-4 years, 4-5 years, and >5 years (may be adjusted based on the actual data to 
ensure there are relatively enough subjects in the highest yearly interval) and overall.   


 
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Statistical Analysis Plan 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ibrutinib 
or Placebo in Combination with Rituximab in Subjects with Waldenström’s 
Macroglobulinemia 
 
 
PCYC-1127-CA 
 
 
13 October 2017 
Version 2.0 
 
 
 
Confidentiality Statement 
The information in this document is considered privileged and confidential by Pharmacyclics LLC., and may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board approval and informed 
consent, or as required by Federal and State Laws.  Persons to whom this information is disclosed must be informed 
that this information is privileged and confidential and that it should not be further disclosed. 
 
 


 
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Revision History 
 
Version 
Number 
Date 
Description 
1.0 
20Apr2016 
Original version 
2.0 
13Oct2017 
Amendment summary: 
This version applies the latest SAP template; structure and contents are 
updated to align with other studies. Below are the major changes made: 
1. Remove the section for objectives of study and add a section for 
endpoints; remove the section for study dosage and administration 
and include the dosing information under the section for study 
design; remove the detailed information in the section for blinding 
and randomization method and refer to the protocol. 
2. Add one secondary endpoint for patient reported outcomes (PRO). 
Update the ordering of secondary endpoints. Add texts indicating 
that overall survival will not be tested at interim analysis and will 
be tested at study closure.  
3. Update the subgroup definition table for subgroup analyses. 
4. Add one sensitivity analysis for progression-free survival and 
subgroup analysis for overall response rate.  
5. Add hemoglobin, tumor involvement of bone marrow, and lymph 
nodes and spleen assessment as exploratory endpoints. 
6. Add handling of missing data for PRO analysis and exploratory 
analyses for PRO data. 
7. Add the following adverse events: hypertension, interstitial lung 
disease, severe cutaneous adverse reactions, rash, cardiac 
arrhythmia excluding atrial fibrillation, infusion related reaction. 
8. Remove exposure-adjusted incidence rates. 


 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .......................................................................................................4 
1. 
INTRODUCTION ..................................................................................................................5 
1.1. 
Study Design ..................................................................................................................5 
1.2. 
Endpoints .......................................................................................................................6 
1.3. 
Statistical Hypotheses ....................................................................................................6 
1.4. 
Sample Size Determination............................................................................................7 
1.5. 
Planned Analyses ...........................................................................................................8 
1.6. 
Testing Procedure and Level of Significance ................................................................8 
1.7. 
Blinding and Randomization Methods ..........................................................................8 
1.7.1. Blinding Method ...............................................................................................8 
1.7.2. Randomization Method ....................................................................................9 
1.8. 
Independent Data Monitoring Committee .....................................................................9 
2. 
GENERAL ANALYSIS CONSIDERATION ......................................................................9 
2.1. 
Analysis Sets ................................................................................................................10 
2.2. 
Definition of Subgroups ...............................................................................................10 
2.3. 
Handling of Missing Data for PRO Analysis ..............................................................11 
3. 
SUBJECT INFORMATION................................................................................................11 
3.1. 
Subject Disposition ......................................................................................................11 
3.2. 
Demographics and Baseline Characteristics ................................................................12 
3.3. 
Prior and Concomitant Medications ............................................................................12 
3.4. 
Extent of Exposure to Study Treatment .......................................................................12 
3.5. 
Previous Treatment History and Subsequent Antineoplastic Therapies ......................12 
4. 
EFFICACY AND SAFETY ANALYSES ...........................................................................12 
4.1. 
Efficacy Analyses ........................................................................................................12 
4.2. 
Safety Analyses ............................................................................................................16 
5. 
MODIFICATION OF ANALYSIS TO THE PROTOCOL .............................................18 
6. 
REFERENCES .....................................................................................................................18 
 
 
LIST OF TABLES 
Table 1 Subgroup Definition .........................................................................................................10 
Table 2 Summary of Efficacy Analyses to be Performed for Arms A and B ................................14 
Table 3 Summary of Safety Analyses to be Performed for all Treatment Arms ...........................17 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
CMH 
Cochran-Mantel-Haenszel 
CR 
complete response 
CRF 
case reported form 
CRR 
clinical response rate 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
data monitoring committee 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
IPSS 
International Prognostic Scoring System 
IRC 
independent review committee 
ITT 
intent-to treat 
IWWM 
International Workshop on Waldenström’s macroglobulinemia 
IWRS 
Interactive Web Response System 
MMRM 
Mixed-Effects Model Repeated Measure 
MR 
minor response 
MRU 
medical resource utilization  
NCCN 
National Comprehensive Cancer Network 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PR 
partial response  
PRO 
patient reported outcome. 
TEAE 
treatment-emergent adverse events 
TTnT 
time to next treatment 
VGPR 
very good partial response 
WM 
Waldenström’s macroglobulinemia 


 
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1. INTRODUCTION 
This statistical analysis plan (SAP) lays out key elements including definitions and statistical 
methods for analysis of data in evaluation of efficacy and safety for the PCYC-1127-CA study. 
Analyses of pharmacokinetics data and biomarkers, and additional analyses of patient-reported 
outcomes (PROs) will be addressed in separate documents.  
1.1. 
Study Design 
This is a randomized, placebo-controlled, double-blind, Phase 3 study designed to evaluate 
whether treatment with ibrutinib in combination with rituximab will result in an improvement in 
progression-free survival (PFS) compared to placebo in combination with rituximab in subjects 
with WM (untreated and previously treated). In addition, an open-label ibrutinib substudy is 
included to further investigate the safety and efficacy of ibrutinib monotherapy in subjects with 
WM who are considered refractory to the last prior rituximab-containing therapy. 
A total of 150 subjects were randomized in a 1:1 ratio to receive ibrutinib and rituximab 
(Treatment Arm A) or placebo and rituximab (Treatment Arm B). 31 subjects were enrolled in 
the open-label ibrutinib monotherapy substudy (Treatment Arm C). All subjects in Arm A and 
Arm B are to receive intravenous rituximab 375 mg/m2 once weekly for 4 consecutive weeks, 
followed by a second 4-weekly rituximab course after a 3-month interval. In addition, all 
subjects in Arm A and Arm B, per randomization, are to receive oral study drug (420 mg 
ibrutinib or matching placebo), administered once daily and continuously until criteria for 
permanent discontinuation of study drug are met. All subjects in Arm C are to receive oral 
ibrutinib 420 mg, administered once daily and continuously until criteria for permanent 
discontinuation of study drug are met. 
The study includes a Screening Phase, Treatment Phase and a Follow-Up Phase. All subjects are 
to be followed for disease progression until a PFS event occurs or until the data cutoff for final 
analysis. 
Access to ibrutinib (cross-over) as next-line therapy for subjects with Independent Review 
Committee (IRC) confirmed disease progression and treated with placebo in combination with 
rituximab (Arm B) are provided as outlined in the protocol. Subjects who have symptomatic 
disease meeting criteria for requiring treatment may be eligible to receive ibrutinib as next-line 
therapy. 
An IRC has been established to conduct response assessment and evaluate disease progression 
status centrally per the IRC charter.  
 
 


 
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1.2. 
Endpoints 
Primary Endpoints 
The primary endpoint is progression-free survival (PFS), as assessed by the IRC based on the 
modified Consensus Response Criteria from the VIth International Workshop for WM (NCCN 
2014). 
Secondary Endpoints 
Secondary endpoints which will be tested include the following: 
x  Overall response rate (ORR) assessed by IRC (≥ partial response [PR]; according to the 
modified VIth IWWM [NCCN 2014] criteria) 
x  Time to next treatment (TTnT) 
x  Rate of sustained hemoglobin improvement  
x  Proportion of subjects with ≥ 3 points increase from baseline by Week 25 in fatigue 
experience score from the FACT-An 5 items assessing fatigue symptoms 
x  Overall survival (OS) 
Safety Endpoints 
Safety endpoints include adverse events, clinical laboratory tests, vital signs and eye-related 
symptoms. 
Exploratory Endpoints 
Exploratory endpoints include PFS by investigator, ORR by investigator, time to sustained 
hemoglobin improvement, duration of response (DOR), clinical response rate (CRR), medical 
resource utilization (MRU), IgM, hemoglobin (Hgb), lymph nodes and spleen measures, tumor 
involvement of bone marrow, EQ-5D-5L visual analog scale and utility score, FACT-An total 
score and subscale scores. 
1.3. 
Statistical Hypotheses 
The primary hypothesis of this study is that the experimental treatment ibrutinib + rituximab 
compared with placebo + rituximab will significantly improve PFS in subjects with WM.  
The statistical hypotheses are as follows:  
H0: The PFS distributions of experimental treatment group, SI(t), and the control group, SC(t), are 
equal at all time points t:  


 
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SI(t) = SC(t), for all t > 0  
versus  
H1: The PFS distributions of experimental treatment group, SI(t), are greater than the control 
group, SC(t), at at least one time point t:  
SI(t) > SC(t), for some t > 0  
These hypotheses will be tested using log-rank test. 
1.4. 
Sample Size Determination 
Treatment Arms A and B 
This study was designed to evaluate the effect of treatment on PFS and was powered for this 
endpoint.  The desired operating characteristics for the PFS endpoint were used to determine the 
study’s total sample size and overall duration.  The sample size and power calculations were 
based on a 2-sided log-rank test for PFS and the following considerations: 
x 1:1 randomization ratio between 2 treatment arms 
x Target hazard ratio of 0.5 with exponential distribution for PFS.  Assuming the median PFS 
for the control arm (rituximab+placebo) was 15 months from randomization (this was based 
on available published data), a target hazard ratio of 0.5 corresponds to 2-fold increase in 
median PFS for the treatment arm (rituximab+ibrutinib) relative to the control (i.e., 30 
months vs. 15 months, respectively) 
x Minimum 80% power  
x 2-sided overall significance level of 0.05 
x One interim analysis at 70% information  
The interim analysis was based on a group sequential design with Lan-DeMets spending function 
with O’Brien-Fleming boundary.  Using the above assumptions and based on an estimated 
accrual rate of approximately 12 subjects per month, the study was to enroll approximately 150 
subjects (about 75 subjects to each arm) to observe 71 events in approximately 27 months from 
the first subject randomized.  Sample size was calculated using the software package, East 6 
(Cytel Software Corp, Cambridge, MA). 
Open-Label Substudy Treatment Arm C 
The sample size for the substudy was not determined according to statistical calculation. 31 
subjects were enrolled in this substudy.  


 
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1.5. 
Planned Analyses 
A pre-specified interim analysis for the randomized treatment arms (Arms A and B) will be 
conducted after observing approximately 70% (~50) PFS events (progressive disease or death) 
based on IRC assessment. The final analysis of PFS will be conducted after approximately 71 
PFS events are confirmed by the IRC for the randomized treatment arms (Arms A and B). The 
ibrutinib open-label monotherapy substudy (Arm C) will be summarized separately at the final 
analysis.  
1.6. 
Testing Procedure and Level of Significance 
Interim Analysis 
In order to preserve the study wise 2-sided type I error rate of 0.05, the 2-sided significance level 
for PFS will be 0.015 at 50 PFS events for the interim analysis, based on O’Brien Fleming 
boundary.  However, the alpha spending for PFS will be determined based on the actual 
information fraction using O’Brien-Fleming boundary at the time of the interim analysis.   
If the primary endpoint achieves statistical significance, tests of secondary endpoints will be 
performed at the 2-sided significance level of 0.05 in a sequential hierarchical manner based on a 
closed testing procedure.  The secondary endpoints will be ranked in sequence according to the 
hierarchical order specified below. OS will not be tested at interim analysis and will be tested at 
study closure.   
1.) ORR 
2.) TTnT 
3.) Rate of sustained hemoglobin improvement 
     4.) Proportion of subjects with ≥ 3 points increase from baseline by Week 25 in fatigue 
experience score  
5.) OS 
Final Analysis 
The 2-sided significance level for the final analysis of primary endpoint (PFS) will be adjusted to 
account for interim alpha spending so the overall 2-sided significance level for the study will be 
preserved at 0.05.  Tests of secondary endpoints will be performed using the same approach for 
the interim analysis.  
1.7. 
Blinding and Randomization Methods 
1.7.1. 
Blinding Method 
Treatment Arms A and B 


 
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This is a double-blind study. The blinding method is described in protocol section 5.1 
Randomization and Blinding.  
Open-Label Substudy Treatment Arm C 
The substudy is open-label. 
1.7.2. 
Randomization Method 
For Treatment Arms A and B, central randomization was implemented in this study. The 
randomization scheme was implemented within the Interactive Web Response System (IWRS).  
Randomization was stratified using the following stratification factors and subjects were 
randomized in a 1:1 ratio to receive either ibrutinib + rituximab or placebo + rituximab within 
each randomization stratum:  
a) WM International Prognostic Scoring System (IPSS) assessed at screening (low vs. 
intermediate vs. high) 
b) Number of prior systemic treatment regimens (0 vs. 1-2 vs. ≥3) 
c) Eastern Cooperative Oncology Group [ECOG] (0-1 vs. 2) 
1.8. 
Independent Data Monitoring Committee 
The safety and the interim analysis of this study are monitored by an independent data 
monitoring committee (DMC). The independent DMC may recommend stopping the study for 
efficacy if the pre-specified stopping boundary is crossed at the interim analysis. In addition to 
the ongoing safety monitoring and planned interim analyses for efficacy, periodic safety review 
meetings are planned. The plan for monitoring subject safety and evaluating efficacy, and the 
roles and responsibilities of the independent DMC, are detailed in the independent DMC Charter. 
2. GENERAL ANALYSIS CONSIDERATION 
Time to event or duration of event endpoints will be based on the actual event date (or censoring 
date) rather than visit number or visit label. Missing efficacy or safety data will not be imputed 
unless otherwise specified. 
In general, the baseline value is defined as the last valid measurement on or prior to the first dose 
of study treatment (ibrutinib/placebo, rituximab). For by-visit analysis, visit windows will be 
used to associate assessment with a scheduled visit and will be created in reference to the date of 
first dose of study treatment to assign visit number based on assessment date. 


 
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2.1. 
Analysis Sets 
Intent-to-Treat Population 
The intent-to-treat (ITT) population includes all randomized subjects (Arms A and B), regardless 
of the actual treatment received. This population will be the primary population for the 
summary/analyses of efficacy endpoints, disposition, demographics and baseline characteristics 
and PRO data. 
Safety Population 
Safety population includes all subjects who received at least 1 dose of study treatment 
(rituximab, ibrutinib/placebo). Subjects in this population will be analyzed as randomized for the 
randomized subjects. The safety population will be used to summarize the safety (including 
dosing) data.   
For the open-label substudy (Arm C), disposition, demographics and baseline characteristics, 
efficacy, PRO and safety outcome will be summarized descriptively based on the safety 
population.   
2.2. 
Definition of Subgroups 
Subgroup analyses will be performed for the selected variables to assess the internal consistency 
of the treatment benefit and/or safety. The subgroup variables and the cutoff values are subject to 
change if warranted to better represent the data. 
Table 1: Subgroup Definition 
 
Subgroup 
Definition of Subgroup 
Analysis Type 
Age 
<65, ≥65 
D, E, S 
Sex 
Male, Female 
D, E, S 
Prior treatment history as recorded on CRFs 
Previously untreated, Previously 
treated 
D, E, S  
Race 
White, Non-White 
E 
Geographic region 
US, Non-US 
E 
Baseline ECOG as recorded on CRFs 
0-1, 2 
E 
Baseline IgM 
<40, ≥ 40 g/L 
E 
Baseline hemoglobin (Hgb) 
≤ 11, >11 g/dL 
E 
Baseline β2-microglobulin 
≤3, >3 mg/L 
E 
WM IPSS as recorded on CRFs 
Low, Intermediate, High 
E 
MYD88 L265P mutational status 
Mutated, No mutation 
E 


 
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Subgroup 
Definition of Subgroup 
Analysis Type 
Concomitant use of moderate and/or strong CYP3A 
inhibitor  
Yes, No 
S 
Baseline creatinine clearance  
<60, ≥60 mL/min 
S 
Baseline liver function based on NCI criteria 
Normal, Abnormal (Mild, 
Moderate, Severe)  
S 
analysis type D= demographic and baseline disease characteristics 
analysis type E= efficacy (Treatment Arms A and B); Considering small sample size in one or more strata, results 
for race, geographic region, ECOG, MYD88 L265P mutational status may be presented separately. 
analysis type S= safety (adverse events) 
IWRS= Interactive Web Response System; ECOG= Eastern Cooperative Oncology Group 
 
2.3. 
Handling of Missing Data for PRO Analysis 
Missing Items within Domains 
FACT-An scores are derived per FACT-An Scoring Guidelines (Version 4). Fatigue subscale 
score is derived per FACIT-Fatigue Subscale Scoring Guidelines (Version 4) from the 13 fatigue 
related items of FACT-An. Similarly, fatigue experience score is calculated from the 5 items 
(HI7, HI12, An1, An2, An5) assessing fatigue symptoms and fatigue impact score is calculated 
from the 8 items (An3-An4, An7-An8, An12, An14-An16) assessing the impact of fatigue.    
If there are missing items, subscale scores are prorated. This is done by multiplying the sum of 
the item scores by the number of items in the subscale, then dividing by the number of items 
answered. A subscale score is calculated only if >50% of the items were answered. The total 
score is calculated as the sum of the prorated subscale scores. Total scores are calculated only if 
the overall item response rate is >80% (i.e. at least 22 of 27 items answered for FACT-G total 
score, and at least 38 of 47 items answered for FACT-An total score).   
3. SUBJECT INFORMATION 
3.1. 
Subject Disposition 
Subject disposition will be summarized by treatment arm. Subject enrollment will be 
summarized by region, country, and investigator.  
Time on study is defined in the same way as overall survival with reversed censoring, i.e., 
subjects who died will be censored at death date. The Kaplan-Meier method will be used to 
estimate the median time on study. 


 
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3.2. 
Demographics and Baseline Characteristics 
Baseline characteristics and demographic information at baseline will be summarized with 
descriptive statistics by treatment arm.  
3.3. 
Prior and Concomitant Medications 
Medications will be coded to a generic name and an Anatomical Therapeutic Chemical (ATC) 
class per the World Health Organization (WHO) drug dictionary. Concomitant medications will 
be summarized by therapeutic class and preferred term and by treatment arm. Concomitant 
medications are defined as medications that were taken at any time on treatment (i.e. from the 
date of the first dose of study treatment through the date of the last dose of study treatment). The 
following concomitant medications will be summarized separately: growth factors, blood 
supportive products and immunoglobulin, CYP3A inhibitors/inducers, anticoagulants and/or 
antiplatelets.  
3.4. 
Extent of Exposure to Study Treatment 
Exposure to study treatment will be summarized by treatment arm. Descriptive statistics will be 
provided for treatment duration and dosing information (e.g. total cumulative dose administered, 
relative dose intensity, dose reduction due to adverse events) for all study treatments.  
3.5. 
Previous Treatment History and Subsequent Antineoplastic Therapies 
Previous treatment history and subsequent WM antineoplastic agents will be summarized 
separately. 
4. EFFICACY AND SAFETY ANALYSES 
4.1. 
Efficacy Analyses 
Treatment Arms A and B 
Efficacy endpoints and analysis methods for the randomized treatment arms (Arms A and B) are 
summarized in Table 2.  
The following two randomization stratification factors will be used for the stratified analysis/test: 
WM IPSS assessed at screening (low, intermediate, high) and number of prior systemic 
treatment regimens (0, ≥1). Due to limited number of subjects with ≥3 prior systemic treatment 
regimens, subjects with 1-2 or ≥3 prior systemic treatment regimens will be categorized into one 
subgroup (i.e. ≥1). All the stratified tests will be based on the randomization stratification factors 
as recorded in IWRS.  
Open-Label Substudy Treatment Arm C 


 
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For the open-label Arm C, the efficacy outcome will be analyzed separately from the randomized 
treatment arms. Time to event variables (e.g. PFS, TTnT, OS, DOR) will be analyzed using 
Kaplan-Meier estimate. For categorical variables (e.g. ORR, rate of sustained hemoglobin 
improvement, CRR), 95% confidence intervals (CIs) will be calculated based on the exact 
binomial distribution. For continuous variables (e.g. IgM, lymph node and spleen measures, 
tumor involvement of bone marrow), descriptive statistics will be calculated. No comparator 
analysis will be done with Arms A or B.  
Note that date of randomization is not applicable for Arm C subjects, therefore date of the first 
dose of ibrutinib will be used in calculating efficacy variables. 
 
 


 
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Table 2: Summary of Efficacy Analyses to be Performed for Arms A and B 
 
Endpoint 
Definition 
Analysis Methods 
Primary Endpoint 
PFS assessed 
by IRC 
Time from the date of randomization to the 
date of first IRC-confirmed disease 
progression (PD) or date of death due to any 
cause, whichever occurs first, regardless of 
the use of subsequent antineoplastic therapy 
prior to documented PD or death. For 
subjects who do not have IRC-confirmed 
PD and not known death as of clinical data 
cutoff, PFS is censored at the date of the 
last evidence of no progression by IRC. 
The treatment effect of ibrutinib + rituximab (Arm A) 
compared to placebo + rituximab (Arm B) will be tested 
with a stratified log rank test adjusted for 2 randomization 
stratification factors. The hazard ratio and its 95% 
confidence interval (CI) based on a Cox regression model 
stratified by the 2 randomization stratification factors will 
be calculated.  Kaplan-Meier analysis for PFS distribution; 
median PFS estimated with 2-sided 95% CI.   
Sensitivity Analyses: 
x 
Subjects who received subsequent antineoplastic 
therapy are censored at the last disease assessment 
showing no evidence of PD before the use of 
subsequent therapy: same analyses as above. 
x 
Subjects who missed ≥2 consecutively planned disease 
assessments immediately before IRC-confirmed PD or 
death are censored at the last disease assessment prior 
to documented PD or death: same analyses as above. 
x 
Investigator assessed PFS: same analyses as above. 
x 
IRC-assessed PFS by unstratified log-rank test and 
unstratified Cox regression model. 
Subgroup Analyses: 
Hazard ratio and its 95% CI based on unstratified Cox 
regression model for each subgroup. 
Secondary Endpoints 
ORR 
assessed by 
IRC  
Proportion of subjects achieving a best 
overall response of confirmed complete 
response (CR), very good partial response 
(VGPR), or PR per the IRC assessment at or 
prior to initiation of subsequent 
antineoplastic therapy.  
ORR will be compared between the two randomized 
treatment arms (ibrutinib + rituximab vs. placebo + 
rituximab) using Cochran-Mantel-Haenszel (CMH) chi-
square test, adjusted for the 2 randomization stratification 
factors. 95% CI for the rate ratio will be calculated. 
Sensitivity Analyses:  
Investigator assessed ORR: same analyses as above.    
Subgroup Analyses:  
Rate ratio and its 95% CI for each subgroup of selected 
variables (e.g. prior treatment history, MYD88 L265P 
mutational status).  
Time to next 
treatment 
Time from the date of randomization to the 
start date of any subsequent WM treatment. 
Same as PFS: stratified log-rank test, stratified Cox 
regression model, and Kaplan-Meier analysis. 


 
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Endpoint 
Definition 
Analysis Methods 
(TTnT) 
Subjects without subsequent treatment are 
censored at the date of the last study visit. 
 
Rate of 
sustained 
hemoglobin 
improvement  
Proportion of subjects achieving a sustained 
improvement in hemoglobin (Hgb) at or 
prior to initiation of subsequent 
antineoplastic therapy. Hgb improvement is 
defined as an increase of ≥ 2 g/dL over 
baseline regardless of baseline value, or an 
increase to >11 g/dL with a ≥0.5 g/dL 
improvement if baseline is ≤ 11 g/dL. 
Sustained Hgb improvement is defined as 
improvement that is sustained continuously 
for ≥ 56 days (8 weeks) without blood 
transfusion or growth factors. 
The two randomized treatment arms will be compared 
(ibrutinib + rituximab vs. placebo + rituximab) using chi-
square test. 95% CI for the rate ratio will be calculated. 
Subgroup Analysis:  
Chi-square test for subjects with Hgb ≤ 11 g/dL at baseline. 
Proportion of 
subjects with 
≥ 3 points 
increase from 
baseline by 
Week 25 in 
fatigue 
experience 
score  
Proportion of subjects with a ≥ 3 points 
increase from baseline in fatigue experience 
score at any time point at or prior to 
initiation of subsequent antineoplastic 
therapy by Week 25. Fatigue experience 
score is calculated from the FACT-An 5 
items (HI7, HI12, An1, An2, An5) 
assessing fatigue symptoms.     
The two randomized treatment arms will be compared 
(ibrutinib + rituximab vs. placebo + rituximab) using chi-
square test. 95% CI for the rate ratio will be calculated. 
 
Overall 
survival (OS) 
Time from the date of randomization to the 
date of death from any cause. For subjects 
who were not known to have died at or prior 
to the clinical cutoff date, OS is censored on 
the date last known alive. 
Unstratified log-rank test, unstratified Cox regression 
model, and Kaplan-Meier analysis. Exploratory analysis 
adjusting the crossover effect may be performed, if needed. 
Exploratory Endpoints 
Time to 
sustained 
hemoglobin 
improvement 
Time from the date of randomization to the 
initial date of sustained hemoglobin 
improvement. 
Descriptive summary statistics for subjects who achieved 
sustained hemoglobin improvement. 
DOR by IRC, 
DOR by 
investigator 
Time from the date of initial documentation 
of a response (PR or better) to the date of 
first documented evidence of PD or death 
for responders (PR or better). The same 
censoring rules for PFS are used for DOR. 
Kaplan-Meier analysis 
CRR by IRC, 
CRR by 
investigator 
Proportion of subjects achieving a best 
overall response of confirmed CR, VGPR, 
PR or MR at or prior to initiation of 
subsequent antineoplastic therapy. 
Same analyses as for ORR 


 
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Endpoint 
Definition 
Analysis Methods 
IgM, Hgb 
Value and change from baseline 
Descriptive summary statistics 
Lymph nodes 
and spleen 
Sum of product of diameters for target 
nodal lesions, spleen depth and spleen 
volume 
Descriptive summary statistics 
Tumor 
involvement 
of bone 
marrow 
Cellularity and intertrabecular space 
Descriptive summary statistics 
Medical 
resource 
utilization 
Number of plasmapheresis, number of 
emergency room visits, number and days of 
hospitalizations 
Descriptive summary statistics  
EQ-5D-5L 
visual analog 
scale and 
utility score, 
FACT-An 
total score 
and subscale 
scores 
Value and change from baseline, proportion 
of subjects achieving clinically meaningful 
improvement, time to improvement. 
Clinically meaningful improvement is 
defined as an increase of ≥7 points for 
visual analog scale (or ≥ 0.08 points for 
utility score, ≥7 points for FACT-An total 
score, ≥6 points for anemia subscale score, 
≥3 points for fatigue subscale score) prior to 
initiation of subsequent antineoplastic 
therapy.   
Descriptive summary statistics. The proportion of subjects 
achieving clinically meaningful improvement will be 
compared between the two randomized treatment arms 
using chi-square test. 95% CI for the rate ratio will be 
calculated. For each parameter, change from baseline up to 
Week 49 will be analyzed using the Mixed-Effects Model 
Repeated Measure (MMRM). The model includes the 
baseline scores, baseline ECOG (0, 1-2), prior treatment 
history on CRF (previously untreated, previously treated), 
WM IPSS on CRF (low, intermediate, high) as covariates; 
treatment, time point and treatment-by-time point 
interaction as fixed effects; and subjects as random effect. 
An unstructured (co)variance structure will be used to 
model the within-subject error. Kenward-Roger's 
approximation will be used to estimate denominator 
degrees of freedom. The 2-sided 95% CIs will be calculated 
for the least square means.   
4.2. 
Safety Analyses 
Safety data will be summarized by treatment arm. Table 3 summarizes the safety analyses to be 
performed for all treatment arms. 
Adverse events (AEs) will be coded in accordance with the Medical Dictionary for Regulatory 
Activities (MedDRA). Severity of AEs will be graded by the investigator according the NCI-
CTCAE v4.03.   
All laboratory values will be converted to and reported as international standard (SI) units. In 
general, only data from the central laboratory will be summarized and analyzed. Laboratory 
parameters will be graded using the NCI CTCAE v4.03. 


 
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Unless otherwise specified, only baseline and post-baseline values collected during the 
treatment-emergent period will be included in the safety analysis. In general, the treatment-
emergent period is defined as the period from the date of the first dose of study treatment 
(rituximab, ibrutinib/placebo) up to 30 days after the date of the last dose of study treatment or 
the day before initiation of subsequent antineoplastic therapy (including crossover ibrutinib), 
whichever comes first. The treatment-emergent period for crossover ibrutinib is defined as the 
period from the date of the first dose of ibrutinib after crossover up to 30 days after the date of 
the last dose of ibrutinib or the day before initiation of subsequent antineoplastic therapy, 
whichever comes first. 
The treatment-emergent adverse events (TEAEs) are those events that occur or worsen during 
the treatment-emergent period or that are related to the study treatment. 
Table 3: Summary of Safety Analyses to be Performed for all Treatment Arms 
 
Endpoint 
Definition 
Analysis Methods 
Adverse 
events 
Treatment-emergent adverse events (TEAEs), serious adverse 
events (SAEs), grade 3 or worse TEAEs, related TEAEs, TEAEs 
leading to treatment discontinuation, TEAEs leading to dose 
reduction, TEAEs leading to death, other AEs (e.g. bleeding 
events, major hemorrhage, hypertension, interstitial lung disease 
(ILD), severe cutaneous adverse reactions (SCAR), rash, cardiac 
arrhythmia excluding atrial fibrillation, infusion-related 
reactions), other malignancies, TEAEs in the crossover period, 
TEAEs in a fixed period (e.g. during the first 9 months) if needed 
Descriptive summary statistics and/or 
listings 
Clinical 
laboratory 
tests 
Worst post-baseline toxicity grade, creatinine clearance, 
abnormal uric acid, liver function abnormalities 
Descriptive summary statistics and/or 
listings; shift from baseline in 
creatinine clearance, shifts from 
baseline in aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT) and bilirubin 
toxicity grade 
Vital signs, 
eye-related 
symptoms 
Blood pressure, heart rate, temperature, respiratory rate, weight, 
proportion of subjects with new or worsening eye-related 
symptoms 
Descriptive summary statistics by 
treatment arm and visit. A data 
listing will be provided for abnormal 
ophthalmologic exam findings. 
 


 
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5. MODIFICATION OF ANALYSIS TO THE PROTOCOL 
Below is the major change made to the analyses in the protocol: 
x Proportion of subjects with ≥ 3 points increase from baseline by Week 25 in fatigue 
experience score is added as one of the secondary endpoints to evaluate the treatment effect 
on fatigue symptoms.  
In addition, Hgb, lymph nodes and spleen measures, and tumor involvement of bone marrow are 
included for exploratory analyses. For the exploratory endpoint time to sustained hemoglobin 
improvement, descriptive statistics will be calculated for subjects who achieved sustained 
hemoglobin improvement. Kaplan-Meier analysis and log-rank test will not be performed. For 
PRO data, exploratory analyses will be conducted for rate of clinically meaningful improvement 
and time to improvement.    
6. REFERENCES 
FACT-An Scoring Guidelines (Version 4). www.facit.org 
FACIT-Fatigue Subscale Scoring Guidelines (Version 4). www.facit.org