Clinical trial NCT01578707
Conditions: Relapsed or Refractory Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Keywords: Chronic SLL CLL Ofatumumab ibrutinib RESONATE Phase III Leukemia Lymphoma
Sponsor: Pharmacyclics LLC.
Start date: 2012-06-01; Completion date: 2018-10-25
Enrollment: 391 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate whether treatment with ibrutinib as a monotherapy results in a clinically significant improvement in progression free survival (PFS) as compared to treatment with ofatumumab in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Detailed description:
Study PCYC-1112-CA is a randomized, multicenter, open-label, phase 3 study of the Bruton's Tyrosine Kinase (BTK) inhibitor Ibrutinib (PCI-32765) versus Ofatumumab in patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Patients randomized to the ofatumumab arm may be considered to receive next subsequent therapy with ibrutinib.

Arms: arm 1: An anti-CD20 monoclonal antibody arm 2: A Bruton Tyrosine Kinase Inhibitor
Interventions: intervention 1: ofatumumab intervention 2: ibrutinib
Intervention descriptions: intervention 1: The ofatumumab (IV) dosage and schedule is 12 doses administered over 24 weeks or until disease progression, unacceptable toxicity.

Week 1: 300 mg initial dose Week 2 through 8: 2,000 mg (once weekly) Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks) intervention 2: ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once daily until disease progression or unacceptable toxicity

Protocol documents:
Prot_000.pdf: 
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PROTOCOL 
TITLE: 
A Randomized, Multicenter, Open-label, Phase 3 Study of the 
Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib versus 
Ofatumumab in Patients with Relapsed or Refractory Chronic 
Lymphocytic Leukemia/Small Lymphocytic Lymphoma 
PROTOCOL NUMBER: 
PCYC-1112-CA 
STUDY DRUG: 
Ibrutinib (PCI-32765) 
IND NUMBER: 
102,688 
EUDRACT NUMBER: 
2012-000694-23 
SPONSOR MEDICAL 
MONITOR: 
George Cole, M.D. 
Pharmacyclics LLC 
Phone: +1 (408) 990-7340 
Fax: 
+1 (408) 215-3684 
Email: gecole@pcyc.com 
SPONSOR: 
Pharmacyclics LLC  
995 East Arques Avenue  
Sunnyvale, CA 94085-4521 
United States of America 
DATE FINAL: 
01 March 2012 
Amendment 1 
28 September 2012 
Amendment 2 
13 December 2012 
Amendment 3 
08 August 2013 
Amendment 4 
24 September 2013 
Amendment 5 
16 January 2014 
Amendment 6 
27 October 2014 
Amendment 7 
28 September 2016 
Confidentiality Statement 
This document contains confidential information of Pharmacyclics LLC that must not be disclosed to 
anyone other than the recipient study staff and members of the institutional review board/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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SYNOPSIS 
Study Title: 
A Randomized, Multicenter, Open-Label, Phase 3 Study of the Bruton’s 
Tyrosine Kinase (BTK) Inhibitor Ibrutinib versus Ofatumumab in Patients 
with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small 
Lymphocytic Lymphoma 
Protocol Number: 
PCYC-1112-CA 
Study Phase: 
3 
Study Duration: 
Estimated to be approximately 6 years 
Investigational Product 
and Reference Therapy: 
Ibrutinib will be supplied as hard gelatin capsules for oral (PO) 
administration. 
Note: “PCI-32765” and “ibrutinib” refer to the same molecule; hereafter, 
“ibrutinib” will be used. 
Ofatumumab will be supplied as a liquid concentrate (20 mg/mL) to be 
diluted for intravenous (IV) administration. 
Objectives: 
Primary Objective: 
To evaluate the efficacy of ibrutinib compared to ofatumumab based on 
independent review committee (IRC) assessment of progression-free 
survival (PFS) per International Workshop on Chronic Lymphocytic 
Leukemia Criteria (IWCLL, Hallek 2008) with incorporation of the 
clarification for treatment related lymphocytosis (Hallek 2012) 
(hereafter referred to as IWCLL 2008 criteria) in patients with relapsed or 
refractory CLL/SLL. 
Secondary Objectives: 
Efficacy 
To compare efficacy between the two treatment groups in terms of: 
• 
To evaluate overall survival (OS)  
• 
To evaluate IRC-assessed overall response rate (ORR) per IWCLL 
2008 criteria 
• 
To evaluate patient-reported outcome (PRO) by FACiT-Fatigue 
• 
To evaluate hematological improvement 
Safety 
• 
To evaluate the safety and tolerability of ibrutinib compared to 
ofatumumab 
Exploratory Objectives: 
• 
To evaluate Investigator-assessed PFS and ORR per IWCLL 2008 
criteria 
• 
To evaluate improvement and/or resolution of disease-related 
symptoms 
• 
To evaluate PRO by EORTC QLQ-C30 and EQ-5D-5L 
• 
To evaluate medical resources utilization (MRU) 


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• 
To determine the pharmacokinetic (PK) characteristics of ibrutinib 
in patients with CLL/SLL 
• 
To investigate predictive biomarkers and mechanism of resistance 
Study Design: 
This is a randomized, multicenter, open-label, Phase 3 study designed to 
compare the efficacy and safety of ibrutinib versus ofatumumab in 
patients with relapsed/refractory CLL or SLL with active disease 
requiring treatment (as defined by IWCLL 2008 criteria for initiation of 
therapy) who have failed at least 1 prior line of therapy and are not 
appropriate candidates for treatment or retreatment with purine analog 
based therapy. 
Eligible patients will be randomized in a 1:1 ratio into 2 arms to receive 
either IV ofatumumab (Treatment Arm A) per package insert or ibrutinib 
(Treatment Arm B) 420 mg daily until disease progression, unacceptable 
toxicity, or criteria specified in Section 10.1, whichever occurs first.  
Two randomization schemes will be generated: one for each geographic 
region (North America versus Rest of World).  Under each scheme, 
patients will be randomized based on the following two stratification 
factors: disease refractory to purine analog and anti-CD20 containing 
chemoimmunotherapy regimen, and the deletion 17p13.1 (17p del).  The 
stratified analysis will be performed based on these two randomization 
stratification factors. 
Assessment for tumor response and progression will be conducted in 
accordance with the IWCLL 2008 criteria for patients with CLL and SLL 
until progressive disease with the modification that isolated treatment-
related lymphocytosis will not be considered as disease progression as 
recommended by the IWCLL 2008 guideline clarification (Hallek 2012) 
and the National Comprehensive Cancer Network (NCCN), 2012 
guidelines and further defined in Section 6.2.5. 
Access to next-line ibrutinib for patients treated with ofatumumab may be 
provided with Medical Monitor approval as outlined in Section 7.3.4. 
Patients will be followed for survival and use of anticancer agents until 
study closure.   
The study will end approximately 5 years after the last patient is enrolled, 
at which time a long-term extension study will be made available for 
patients who choose to continue ibrutinib on a clinical protocol when 
access to commercial ibrutinib is not feasible. 
An independent data monitoring committee (DMC) will monitor the 
safety of the study. 
Population: 
Patients with CLL or SLL who have failed at least 1 prior line of therapy 
and are not considered appropriate for treatment or retreatment with 
purine analog based therapy. 
Centers: 
Multicenter – International 
Key Inclusion Criteria: 
Refer to Section 5 for the 
complete and detailed list of 
inclusion/exclusion criteria. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 
of 0-1. 
• 
Diagnosis of CLL or SLL that meets IWCLL 2008 criteria. 
• 
Active disease meeting at least 1 of the IWCLL 2008 criteria for 
requiring treatment. 


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• 
Must have received at least one prior therapy for CLL/SLL. 
• 
Must not be appropriate for treatment or retreatment with purine 
analog based therapy. 
• 
Measurable nodal disease by CT. 
• 
Must have the following laboratory parameters met for inclusion: 
 
Absolute neutrophil count (ANC) ≥ 750 cells/μL 
(0.75 x 109/L), independent of growth factor support. 
 
Platelet count ≥ 30,000 cells/μL (30 x 109/L) without 
transfusion support. 
 
Serum aspartate transaminase (AST/SGOT) or alanine 
transaminase (ALT/SGPT) < 2.5 x upper limit of normal 
(ULN). 
 
Total bilirubin ≤ 1.5 x ULN. 
 
Estimated creatinine clearance (ie, estimated Glomerular 
Filtration Rate, eGFR) using Cockcroft-Gault ≥ 30 mL/min. 
• 
Patient must be able to receive outpatient treatment and laboratory 
monitoring at the institution that administers study drug for the 
entire study. 
Key Exclusion Criteria: 
• 
Known central nervous system (CNS) lymphoma or leukemia. 
• 
Known prolymphocytic leukemia or history of or currently 
suspected Richter’s transformation. 
• 
Missing or incomplete documentation of cytogenetic and/or FISH 
results reflecting presence or absence of 17p del and the percentage 
of cells with the deletion in patient records prior to randomization. 
• 
Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic 
thrombocytopenic purpura (ITP). 
• 
Prior exposure to ofatumumab or to ibrutinib (PCI-32765) or 
randomization into an ibrutinib study. 
• 
Received any chemotherapy, external beam radiation therapy, 
anticancer antibodies, or investigational drug within 30 days prior 
to first dose of study drug. 
• 
Corticosteroid use > 20 mg within 1 week prior to first dose of 
study drug. 
• 
Radio- or toxin-conjugated antibody therapy within 10 weeks prior 
to first dose of study drug. 
• 
Prior autologous transplant within 6 months prior to first dose of 
study drug. 
• 
Prior allogeneic stem cell transplant within 6 months or with any 
evidence of active graft versus host disease or requirement for 
immunosuppressants within 28 days prior to first dose of study 
drug. 
• 
History of major surgery within 4 weeks prior to first dose of 
study drug. 
• 
History of prior malignancy, with specific exceptions 


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• 
Currently active clinically significant cardiovascular disease or 
history of myocardial infarction within 6 months prior to first dose 
of study drug. 
• 
Known history of infection with human immunodeficiency virus 
(HIV). 
• 
Serologic status reflecting active hepatitis B or C infection. 
• 
Unable to swallow capsules or disease significantly affecting 
gastrointestinal function. 
• 
Uncontrolled active systemic fungal, bacterial, viral, or other 
infection. 
• 
History of stroke or intracranial hemorrhage within 6 months prior 
to randomization. 
• 
Requires or receiving anticoagulation with warfarin or equivalent 
vitamin K antagonists (eg, phenprocoumon) within 28 days of first 
dose of study drug. 
• 
Requires treatment with a strong CYP3A4/5 inhibitor. 
Primary Endpoints: 
The primary endpoint of this study is PFS, as assessed by IRC review per 
IWCLL 2008 criteria. 
Secondary and 
Exploratory Endpoints: 
Secondary Endpoints: 
Efficacy 
To compare efficacy between the two treatment groups in terms of: 
• 
OS.  
• 
ORR defined as the proportion of patients who achieve a response 
(assessed by the IRC per IWCLL 2008 criteria). 
• 
PRO as measured by FACiT-Fatigue. 
• 
Hematological improvement in the subset of patients with 
cytopenia(s) at baseline assessed by time to and percentage of 
patients with improvement in blood counts. 
Safety 
• 
To compare the safety and tolerability between the two treatment 
groups. 
Exploratory Endpoints: 
• 
Investigator-assessed PFS per IWCLL 2008 criteria. 
• 
Investigator-assessed ORR per IWCLL 2008 criteria. 
• 
Improvement and/or resolution of disease-related symptoms 
(weight loss, fatigue, fever, night sweats, abdominal pain due to 
splenomegaly, or anorexia). 
• 
PRO as measured by EORTC QLQ-C30 and EQ-5D-5L. 
• 
MRU associated with the therapy including the number of 
hospitalizations, emergency department visits, blood product 
transfusions, and use of hematopoietic growth factors. 
• 
PK characteristics of ibrutinib in patients with relapsed or refractory 
CLL/SLL. 


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• 
Exploratory analyses based on predictive biomarkers and/or 
mechanisms of resistance. 
Study Treatment: 
Treatment Arm A: Ofatumumab 
Refer to ofatumumab package insert for more details. 
Premedication 
Premedication should be administered per the ofatumumab package 
insert. 
Dosing/Administration 
The ofatumumab dosage and schedule is 12 doses administered over 
24 weeks or until disease progression, unacceptable toxicity, or criteria 
specified in Section 10.1: 
Week 1: 300 mg initial dose 
Week 2 through 8: 2,000 mg (once weekly) 
Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks) 
Ofatumumab should be administered as an intravenous (IV) infusion 
without bolus.  Please see infusions guidelines in Section 6.1.1. 
Following Medical Monitor approval ibrutinib can be administered as 
salvage therapy as outlined in Section 7.3.4. 
Treatment Arm B: Ibrutinib 
Ibrutinib 420 mg (3 x 140-mg capsules) will be administered orally once 
daily until disease progression, unacceptable toxicity, or criteria specified 
in Section 10.1. 
Concomitant Therapy: 
Refer to Section 6.6 for information on concomitant therapy. 
Safety Plan: 
Refer to Section 9.1 and 
DMC charter for details. 
The safety of this study will be monitored by an independent DMC in 
accordance with the Sponsor’s Pharmacovigilance Committee procedures. 
Statistical Methods and 
Data Analysis: 
All efficacy analyses will be performed using the intent-to-treat (ITT) 
population.  All the stratified analyses will be based on the 
two randomization stratification factors: 1) refractory disease 
(presence versus absence) to purine analog and anti-CD20 containing 
chemoimmunotherapy regimen, and 2) status of 17p del (presence versus 
absence). 
Primary Efficacy Analysis: 
PFS as determined by the IRC will be summarized for each treatment arm 
using Kaplan-Meier estimates and compared using stratified log rank test. 
Secondary Efficacy Analysis: 
Overall response rate (ORR) as determined by the IRC will be compared 
using the Cochran-Mantel-Haenszel chi-square test, stratified by the two 
stratification factors (refractory disease and 17p del).  Overall survival 
will be compared using stratified log rank test.  Survival rate at landmark 
points will be summarized based on Kaplan-Meier point estimates and 
compared using the standard normal Z test.   


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Descriptive statistics for change in scores from baseline to each 
assessment will be summarized for the PROs assessed by the 
FACiT-Fatigue.  Time to hematological improvement will be compared 
using unstratified log rank test.  Percentage of patients achieving 
hematological improvement will be compared using the chi-square test. 
Exploratory Efficacy Analysis: 
PFS and ORR as determined by the Investigator will be summarized 
and analyzed similarly to PFS and ORR as determined by the IRC.  
Percentage of patients achieving improvement/or resolution in 
disease-related symptoms will be compared using chi-square test. 
Descriptive statistics for change in scores from baseline to each 
assessment will be summarized for the PROs assessed by 
EORTC QLQ-C30 and EQ-5D-5L. 
Descriptive statistics will be provided for parameters collected for 
medical resource utilization associated with the therapy. 
Safety Analysis: 
Detailed tabulations of safety data (adverse events [AEs] and clinical 
laboratory tests) will be provided for all patients receiving the study drug.  
The number and percent of patients with treatment-emergent AEs will be 
summarized.  Summary of other safety parameters by treatment group 
will be provided where appropriate. 
Interim Analysis 
One interim analysis using the Lan-DeMets alpha spending function 
based on O'Brien-Fleming boundary for both superiority and futility 
(non-binding) will be conducted after observing approximately 117 PFS 
events.  Futility will be evaluated by a one-sided test. The DMC will 
review and evaluate efficacy and safety results.  
Sample Size Determination 
With the agreement from the European (Rapporteur and Co-Rapporteurs) 
and US Health Authorities, the overall two-sided significance level for 
this study is revised from 0.01 to 0.05. Given this revision in overall 
significance level, 176 PFS events provides approximately 90% power to 
detect the target hazard ratio of 0.6 based on a log-rank test and a two-
sided overall significance level of 0.05 adjusted for one planned interim 
analysis.  
 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE .............................................................................................. 2 
SYNOPSIS ..................................................................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................. 9 
LIST OF TABLES ...................................................................................................................... 14 
LIST OF FIGURES .................................................................................................................... 15 
LIST OF APPENDICES ............................................................................................................ 15 
LIST OF ABBREVIATIONS AND DEFINITIONS ............................................................... 16 
1. 
INTRODUCTION ............................................................................................................... 20 
1.1. 
Ibrutinib....................................................................................................................... 20 
1.1.1. 
Mechanism of Action of Ibrutinib ............................................................... 21 
1.1.2. 
Cellular Selectivity of Ibrutinib ................................................................... 21 
1.2. 
Summary of Nonclinical Data .................................................................................... 22 
1.2.1. 
Nonclinical Pharmacology Studies ............................................................. 22 
1.2.2. 
Safety Pharmacology and Toxicology ........................................................ 22 
1.3. 
Summary of Clinical Data .......................................................................................... 23 
1.3.1. 
Pharmacokinetics and Product Metabolism ................................................ 23 
1.3.2. 
Clinical Studies ........................................................................................... 23 
1.3.2.1. Summary of Efficacy of Ibrutinib in CLL/SLL ............................24 
1.3.2.2. Summary of Clinical Safety of Ibrutinib .......................................26 
1.3.3. 
Risks  ........................................................................................................ 27 
1.3.3.1. Bleeding-related Events ................................................................27 
1.3.3.2. Leukostasis ....................................................................................27 
1.3.3.3. Atrial Fibrillation ..........................................................................28 
1.3.3.4. Cytopenias .....................................................................................28 
1.3.3.5. Interstitial Lung Disease (ILD) .....................................................28 
1.3.3.6. Tumor Lysis Syndrome .................................................................28 
1.3.3.7. Lymphocytosis ..............................................................................28 
1.3.3.8. Diarrhea .........................................................................................29 
1.3.3.9. Infections .......................................................................................29 
1.3.3.10. Rash ...............................................................................................29 
1.3.3.11. Non-melanoma Skin Cancer .........................................................29 
1.3.3.12. Hypertension .................................................................................29 
2. 
STUDY RATIONALE ........................................................................................................ 29 
2.1. 
Dose Selection Rationale for Ibrutinib ....................................................................... 30 
2.2. 
Selection of Ofatumumab as Comparator ................................................................... 30 
3. 
STUDY OBJECTIVES ....................................................................................................... 31 
3.1. 
Primary Objective ....................................................................................................... 31 
3.2. 
Secondary Objectives .................................................................................................. 31 
3.3. 
Exploratory Objectives ............................................................................................... 31 
4. 
STUDY DESIGN ................................................................................................................. 32 


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5. 
SELECTION OF PATIENTS ............................................................................................ 34 
5.1. 
Inclusion Criteria ........................................................................................................ 34 
5.2. 
Exclusion Criteria ....................................................................................................... 36 
6. 
TREATMENTS ................................................................................................................... 38 
6.1. 
Ofatumumab ............................................................................................................... 38 
6.1.1. 
Dosage and Administration ......................................................................... 38 
6.1.1.1. Premedication ................................................................................38 
6.1.1.2. Dosage Regimen and Administration ...........................................39 
6.1.2. 
Dose Delay .................................................................................................. 39 
6.1.3. 
Dose Interruption ......................................................................................... 39 
6.1.4. 
Dose Discontinuation .................................................................................. 39 
6.1.5. 
Dose Reduction ........................................................................................... 40 
6.1.6. 
Precautions and Adverse Effects ................................................................. 40 
6.1.6.1. Warnings and Precautions .............................................................40 
6.1.6.2. Adverse Events ..............................................................................40 
6.2. 
Ibrutinib....................................................................................................................... 41 
6.2.1. 
Dosage and Administration ......................................................................... 41 
6.2.2. 
Dose Delay .................................................................................................. 41 
6.2.3. 
Overdose ...................................................................................................... 41 
6.2.4. 
Dose Reduction and Discontinuation .......................................................... 42 
6.2.5. 
Treatment-related Lymphocytosis ............................................................... 42 
6.2.6. 
Dose Modification for Hepatic Impaired Subjects ...................................... 43 
6.2.7. 
Precautions and Adverse Events ................................................................. 43 
6.3. 
Identification of Investigational Product(s) ................................................................ 44 
6.3.1. 
Ibrutinib ....................................................................................................... 44 
6.3.2. 
Ofatumumab ................................................................................................ 44 
6.4. 
Treatment Compliance ................................................................................................ 44 
6.5. 
Randomization and Blinding ...................................................................................... 44 
6.6. 
Concomitant Therapy.................................................................................................. 45 
6.6.1. 
Concomitant Medications to be Used With Caution ................................... 45 
6.6.1.1. Guideline for Use of CYP Inhibiting/Inducing Drugs ..................45 
6.6.1.2. Drugs That May Have Their Plasma Concentrations Altered by 
Ibrutinib .........................................................................................46 
6.6.1.3. Concomitant Use of QT Prolonging Agents .................................46 
6.6.1.4. Concomitant Use of Antiplatelet Agents and Anticoagulants ......46 
6.6.2. 
Prohibited Concomitant Medications .......................................................... 47 
6.6.3. 
Guidelines for Ibrutinib Management with Surgeries or Procedures .......... 47 
7. 
EFFICACY AND SAFETY PROCEDURES ................................................................... 47 
7.1. 
Description of Procedures ........................................................................................... 48 
7.1.1. 
Informed Consent ........................................................................................ 48 
7.1.2. 
Confirmation of Eligibility .......................................................................... 48 
7.1.3. 
Medical History ........................................................................................... 48 
7.1.4. 
Adverse Events ............................................................................................ 48 


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7.1.5. 
Physical Examination, Height and Weight ................................................. 49 
7.1.6. 
Eye-related Symptoms Assessment ............................................................ 49 
7.1.7. 
Disease-related Symptoms .......................................................................... 49 
7.1.8. 
Vital Signs ................................................................................................... 49 
7.1.9. 
Electrocardiogram (ECG) ........................................................................... 49 
7.1.10. ECOG Performance Status .......................................................................... 50 
7.1.11. Cumulative Illness Rating Scale (CIRS) ..................................................... 50 
7.1.12. Prior and Concomitant Medications ............................................................ 50 
7.1.13. Patient-reported Outcomes (PRO) .............................................................. 50 
7.1.13.1. EORTC QLQ-C30 ........................................................................50 
7.1.13.2. EQ-5D-5L .....................................................................................50 
7.1.13.3. FACiT-Fatigue ..............................................................................51 
7.1.14. Pregnancy Test ............................................................................................ 51 
7.1.15. Hepatitis Serologies ..................................................................................... 51 
7.1.16. Hematology ................................................................................................. 51 
7.1.17. Coagulation Studies ..................................................................................... 51 
7.1.18. Serum Chemistry ......................................................................................... 52 
7.1.19. Serum Immunoglobulin and β2-microglobulin ........................................... 52 
7.1.20. Sparse Pharmacokinetics (PK) Sample Collection ..................................... 52 
7.1.21. Pharmacokinetics Sample Collection for Patients Treated with 
Concomitant CYP3A4/5 Inhibitors on Ibrutinib Treatment ....................... 52 
7.1.22. Bone Marrow Aspirate and Biopsy ............................................................. 53 
7.1.23. Cytogenetic CLL FISH Panel ..................................................................... 53 
7.1.24. Determination of T/B/NK Counts ............................................................... 53 
7.1.25. Flow Cytometry-based Immunophenotype Assays ..................................... 54 
7.1.26. Genetic and Molecular Prognostic Markers ................................................ 54 
7.1.27. Exploratory Investigations of Predictive Biomarkers and Mechanism of 
Treatment Resistance .................................................................................. 54 
7.1.28. Computed Tomography (CT) Scans ........................................................... 55 
7.1.29. Medical Resources Utilization (MRU) ....................................................... 55 
7.1.30. Routine Clinical Assessments ..................................................................... 55 
7.1.31. Overall Response Evaluations ..................................................................... 56 
7.1.32. Survival ....................................................................................................... 56 
7.1.33. Subsequent Anticancer Therapies ............................................................... 56 
7.2. 
Drug Concentration Measurements ............................................................................ 57 
7.2.1. 
Sample Collection and Analysis ................................................................. 57 
7.2.2. 
Pharmacokinetic Assessment ...................................................................... 57 
7.3. 
Assessments by Visit .................................................................................................. 58 
7.3.1. 
Screening Phase ........................................................................................... 58 
7.3.2. 
Treatment Phase .......................................................................................... 58 
7.3.2.1. Pre-Dose Week 1 Visit ..................................................................59 
7.3.2.2. Dose Week 1 Visit ........................................................................59 
7.3.2.3. Post-Dose Week 1 Visit ................................................................59 


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7.3.2.4. Week 2, 3, 5, 6, and 7 Visits .........................................................60 
7.3.2.5. Week 4-24 Visits, every 4 weeks ..................................................60 
7.3.2.6. Weeks 36 until Discontinuation of Treatment, every 12 weeks ...61 
7.3.2.7. Response Evaluations, every 12 weeks from first dose until 
progression ....................................................................................61 
7.3.2.8. End-of-Treatment Visit .................................................................61 
7.3.3. 
Follow-up Phase .......................................................................................... 62 
7.3.3.1. Post-treatment Phase .....................................................................62 
7.3.3.2. Post-disease Progression Phase .....................................................62 
7.3.4. 
Treatment with Ibrutinib for Patients on Control Arm ............................... 63 
7.3.4.1. Criteria for Next-line Ibrutinib Therapy .......................................63 
7.3.4.2. Next-line Ibrutinib Therapy Treatment Phase ...............................64 
8. 
MAIN EFFICACY EVALUATIONS ............................................................................... 64 
8.1. 
Definitions................................................................................................................... 64 
8.1.1. 
Refractory .................................................................................................... 64 
8.1.2. 
Relapsed ...................................................................................................... 64 
8.1.3. 
Treatment Failure ........................................................................................ 64 
8.1.4. 
Measurable Disease ..................................................................................... 64 
8.1.5. 
Treatment-related Lymphocytosis ............................................................... 65 
8.1.6. 
Richter’s Transformation ............................................................................ 65 
8.1.7. 
Minimal Residual Disease (MRD) .............................................................. 65 
8.2. 
Radiographic Images Assessment............................................................................... 66 
8.3. 
Guidelines for Evaluation ........................................................................................... 66 
8.4. 
Response Categories ................................................................................................... 66 
8.4.1. 
Complete Response (CR) ............................................................................ 66 
8.4.2. 
Complete Response with an Incomplete Marrow Recovery (CRi) ............. 69 
8.4.3. 
Nodular Partial Response (nPR) ................................................................. 69 
8.4.4. 
Partial Response (PR) .................................................................................. 69 
8.4.5. 
PR with Lymphocytosis .............................................................................. 69 
8.4.6. 
Stable Disease (SD) ..................................................................................... 70 
8.4.7. 
Progressive Disease ..................................................................................... 70 
8.5. 
Sustained Hematological Improvement ...................................................................... 70 
8.6. 
Resolution of Pretreatment Disease-related Symptoms .............................................. 70 
9. 
ASSESSMENT OF SAFETY ............................................................................................. 71 
9.1. 
Safety Monitoring Plan ............................................................................................... 71 
9.2. 
Definitions................................................................................................................... 71 
9.2.1. 
Adverse Events ............................................................................................ 71 
9.2.2. 
Serious Adverse Event ................................................................................ 72 
9.2.3. 
Severity ........................................................................................................ 73 
9.2.4. 
Causality ...................................................................................................... 73 
9.2.5. 
Unexpected Adverse Events ........................................................................ 74 
9.3. 
Documenting and Reporting of Adverse and Serious Adverse Events by 
Investigators ................................................................................................................ 74 


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9.3.1. 
Adverse Event Reporting Period ................................................................. 74 
9.3.2. 
Assessment of Adverse Events ................................................................... 74 
9.3.3. 
Expedited Reporting Requirements for Serious Adverse Events ................ 75 
9.3.4. 
Events of Special Interest ............................................................................ 75 
9.3.4.1. Major Hemorrhage ........................................................................75 
9.3.4.2. Intracranial Hemorrhage ...............................................................75 
9.3.5. 
Other Malignancies ..................................................................................... 76 
9.3.6. 
Pregnancy .................................................................................................... 76 
9.3.7. 
Eye-Related Adverse Events ....................................................................... 76 
9.4. 
Reporting of Serious Adverse Events by Sponsor ...................................................... 76 
10. WITHDRAWAL OF PATIENT FROM TREATMENT OR STUDY .......................... 77 
10.1. Discontinuation of Treatment ..................................................................................... 77 
10.2. Withdrawal from the Study ......................................................................................... 77 
10.3. Extension Study .......................................................................................................... 78 
11. ENDPOINTS ....................................................................................................................... 78 
11.1. Primary ........................................................................................................................ 78 
11.2. Secondary .................................................................................................................... 78 
11.3. Exploratory ................................................................................................................. 78 
12. STATISTICAL CONSIDERATIONS .............................................................................. 79 
12.1. General Considerations ............................................................................................... 79 
12.1.1. Independent Review Committee (IRC) ....................................................... 79 
12.1.2. Data Monitoring Committee (DMC) ........................................................... 79 
12.2. Randomization ............................................................................................................ 80 
12.3. Sample Size considerations ......................................................................................... 80 
12.4. Interim Analysis .......................................................................................................... 80 
12.5. Final Analysis ............................................................................................................. 81 
12.6. Analysis Populations ................................................................................................... 81 
12.6.1. Intent-to-Treat (ITT) Population ................................................................. 81 
12.6.2. Safety Population ........................................................................................ 81 
12.6.3. Pharmacokinetic (PK) Evaluable Population .............................................. 81 
12.6.4. Biomarker Population ................................................................................. 81 
12.7. Control for Bias........................................................................................................... 81 
12.8. Efficacy Analyses ....................................................................................................... 82 
12.8.1. Primary Endpoint and Methods ................................................................... 82 
12.8.2. Secondary Endpoints and Methods ............................................................. 82 
12.8.2.1. Overall Survival (OS) and Survival Rate at Landmark Points .....82 
12.8.2.2. Overall Response Rate ..................................................................82 
12.8.2.3. Patient-Reported Outcome (PRO) Measures ................................83 
12.8.2.4. Hematological Improvements .......................................................83 
12.8.3. Exploratory Endpoints and Methods ........................................................... 83 
12.8.3.1. Investigator-Assessed PFS ............................................................83 
12.8.3.2. Investigator-Assessed ORR ..........................................................83 
12.8.3.3. Improvement of Disease-related Symptoms .................................83 


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12.8.3.4. Patient-Reported Outcome (PRO) Measures ................................83 
12.8.3.5. Biomarker Analysis .......................................................................84 
12.8.3.6. Medical Resource Utilization (MRU) Associated with the 
Therapy .........................................................................................84 
12.8.3.7. Pharmacokinetic (PK) Analysis ....................................................84 
12.9. Safety Analyses ........................................................................................................... 84 
12.9.1. Adverse Events (AEs) ................................................................................. 85 
12.9.2. Laboratory Evaluations ............................................................................... 85 
12.9.3. Vital Signs ................................................................................................... 85 
12.9.4. Other Safety Assessments ........................................................................... 85 
13. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .................... 86 
13.1. Regulatory and Ethical Compliance ........................................................................... 86 
13.2. Institutional Review Board (IRB), Research Ethics Board (REB) and 
Independent Ethics Committee (IEC) Approval ......................................................... 86 
13.3. Informed Consent........................................................................................................ 86 
13.4. Quality Control and Quality Assurance ...................................................................... 87 
13.5. Protected Patient Health Information Authorization .................................................. 87 
13.6. Study Files and Record Retention............................................................................... 87 
13.7. Case Report Forms and Record Maintenance ............................................................. 88 
13.8. Investigational Study Drug Accountability ................................................................ 89 
13.9. Study Monitoring/Audit Requirements ....................................................................... 89 
13.10. Investigator Responsibilities ....................................................................................... 90 
13.11. Sponsor Responsibilities ............................................................................................. 90 
13.12. Financial Disclosure .................................................................................................... 91 
13.13. Liability and Clinical Trial Insurance ......................................................................... 91 
13.14. Protocol Amendments ................................................................................................. 91 
13.15. Publication of Study Results ....................................................................................... 92 
13.16. Study Discontinuation ................................................................................................. 92 
14. REFERENCE LIST ............................................................................................................ 93 
15. APPENDICES ..................................................................................................................... 96 
 
LIST OF TABLES 
Table 1: 
Dose Discontinuation Actions for Ofatumumab .....................................................40 
Table 2: 
Drug Discontinuation Actions for Ibrutinib ............................................................42 
Table 3: 
Evaluable Parameter Requirements.........................................................................66 
Table 4: 
Criteria for Response Categories .............................................................................68 
 
 
 


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LIST OF FIGURES 
Figure 1: 
Progression-Free Survival Kaplan-Meier Curves, Study PCYC-1102-CA ............25 
Figure 2: 
Changes in Peripheral Blood Lymphocyte Counts and Burden of 
Lymphadenopathy in Patients with CLL/SLL, Study PCYC-1102-CA .................26 
LIST OF APPENDICES 
Appendix A: Schedule of Assessments.........................................................................................97 
Appendix B: ECOG Status Scores ................................................................................................98 
Appendix C: Inhibitors and Inducers of CYP3A ..........................................................................99 
Appendix D: Hematologic Adverse Event Grading Scheme (Hallek 2008) ...............................100 
Appendix E: EORTC QLQ-C30 .................................................................................................101 
Appendix F: EQ-5D-5L ..............................................................................................................103 
Appendix G: FACiT-Fatigue ......................................................................................................106 
Appendix H: Cumulative Illness Rating Scale (CIRS) ...............................................................107 
Appendix I: Rai & Binet Staging ..............................................................................................110 
Appendix J: New York Heart Association Functional Classification .......................................111 
Appendix K: Definitions for PCYC-1112-CA Eligibility Criteria .............................................112 
Appendix L: Child-Pugh Score for Subjects with Liver Impairment .........................................113 
Appendix M: Schedule of Assessments for Patients Treated with Ofatumumab who are to 
Receive Next-line Ibrutinib Therapy .....................................................................114 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviations 
17p del 
chromosome deletion 17p13.1 
AE(s) 
adverse event(s) 
AIHA 
autoimmune hemolytic anemia 
ALC 
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BCR 
B-cell receptor 
BFR 
bulky fludarabine-refractory 
BR 
bendamustine/rituximab 
BTK 
Bruton’s tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CD20 
cluster of differentiation 20 
CDC 
complement dependent cytotoxicity 
CFR 
Code of Federal Regulations 
CIRS 
Cumulative Illness Rating Score 
CLL 
chronic lymphocytic leukemia 
CNS 
central nervous system 
CR 
complete remission (response) 
CrCl 
creatinine clearance 
CRF 
case report form 
CRi 
CR with incomplete bone marrow recovery 
CSSR 
Clinical Supplies Shipping Receipt Form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 


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Abbreviations 
Cys 
Cysteine residue 
DLBCL 
diffused large B-cell lymphoma 
DMC 
Data Monitoring Committee 
DR 
double refractory 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EFS 
event-free survival 
EMA 
European Medicines Agency 
EMR 
electronic medical records 
EORTC 
European Organisation for Research and Treatment of Cancer 
EQ-5D-5L 
Euro-QoL five dimension 
ESMO 
European Society for Medical Oncology 
FACiT-Fatigue 
The Functional Assessment of Chronic Illness Therapy-Fatigue 
FCR 
fludarabine/cyclophosphamide/rituximab 
FcγR 
Fc-gamma receptors 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
GCSF 
granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HDPE 
high-density polyethylene 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator's Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IgVH 
immunoglobulin heavy-chain variable 
ILD 
interstitial lung disease 


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Abbreviations 
INR 
international normalized ratio 
IRB 
institutional review board 
IRC 
independent review committee 
ITP 
idiopathic thrombocytopenic purpura 
ITT 
Intent-to-treat 
IV 
Intravenous 
IVIG 
intravenous immune globulin 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IWRS 
Interactive Web Response System 
LDH 
lactate dehydrogenase 
LDT 
lymphocyte doubling time 
LN 
lymph node 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MRU 
medical resources utilization 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
nPR 
nodular partial remission (response) 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy 
PO 
per os (oral) 
PR 
partial remission (response) 
PRO 
patient reported outcome 


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Abbreviations 
PT 
prothrombin time 
QLQ-C30 
Quality of Life Questionaire Core 30 
QTc 
corrected QT interval 
REB 
Research Ethics Board 
RS 
Richter's syndrome 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SCARs 
severe cutaneous adverse reactions 
SD 
stable disease 
SI 
standard international units 
SJS 
Stevens-Johnson Syndrome 
SLL 
small lymphocytic lymphoma 
SOC 
system organ class 
SOP 
standard operating procedures 
SPD 
sum of the product of the diameters 
Tmax 
time to maximum drug concentration 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
USP 
United States pharmacopeial convention 
ZAP-70 
Zeta-chain-associated protein kinase 70 
 


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1. INTRODUCTION 
Chronic Lymphocytic Leukemia (CLL)/ Small Lymphocytic Lymphoma (SLL) are a malignancy 
of B-cells that predominantly affects the older population.  Chemoimmunotherapy, in particular 
the combination of purine analogs (eg, fludarabine) with cyclophosphamide and rituximab, has 
become a standard for the treatment of young and/or fit individuals with CLL who require 
treatment.  However, elderly patients and those with comorbidities are often unable to tolerate 
combination chemoimmunotherapy regimens, or experience inferior clinical outcomes when 
treated with these regimens.  In addition, those patients who have a deletion in the short arm of 
chromosome 17p13.1 (17p del) and/or those who fail to achieve a response or experience short 
remissions to purine analog based therapies have inferior outcomes and may prove to be 
refractory to therapy and/or experience short remission durations and rapid progression of 
disease when treated with standard and currently available treatment regimens. 
The generation and maintenance of normal and malignant B-cells is controlled by biochemical 
signals transmitted by the B-cell receptor (BCR).  Bruton’s Tyrosine Kinase (BTK) is an enzyme 
required for BCR signaling.  Selective BTK inhibition is a novel approach to target diseases 
driven by BCR activation, such as B-cell lymphoma and leukemia. 
Ibrutinib (IMBRUVICA®) is a first-in-class, potent, orally administered, covalently binding 
inhibitor of BTK co-developed by Pharmacyclics LLC and Janssen Research & Development 
LLC for the treatment of B-cell malignancies.   
Ibrutinib has been approved in many regions, including the US and EU, for indications covering 
up to the following: treatment of patients with mantle cell lymphoma (MCL) who have received 
at least 1 prior therapy, patients with CLL/SLL, including CLL/SLL with a deletion of the short 
arm of chromosome 17 (del17p), and patients with Waldenström’s macroglobulinemia.  Ibrutinib 
is currently under investigation in various indications as a single agent and in combinations. 
For the most comprehensive nonclinical and clinical information regarding ibrutinib background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to 
the latest version of the ibrutinib Investigator's Brochure (IB). 
1.1. 
Ibrutinib 
“Ibrutinib” and "PCI-32765” refer to the same molecule; hereafter, “ibrutinib” will be used.  
Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4 d] pyrimidin-1-yl]-1-
piperidinyl]-2-propen-1-one and has a molecular weight of 440.50 g/mole (anhydrous basis).  
Ibrutinib is a white to off-white crystalline solid.  It has a single chiral center and is the 
R-enantiomer.  The investigational drug product, ibrutinib, is an oral formulation containing 
micronized ibrutinib. 


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1.1.1. 
Mechanism of Action of Ibrutinib 
Ibrutinib binds covalently to a cysteine residue (Cys-481) near the BTK active site and inhibits 
the enzymatic activity of purified BTK with a half maximal inhibitory concentration (IC50) of 
0.5 nM (Honigberg 2010; Pan 2007).  Covalent binding to Cys-481 results in irreversible 
inhibition of BTK.  Other kinases that are potentially inhibited by ibrutinib have been identified 
using an Ambit kinome screen.  The inhibitory effect of ibrutinib against the activity of these 
kinases has been characterized in biochemical assays.  Only a small subset of kinases is predicted 
to contain a modifiable cysteine residue homologous to Cys-481 in BTK, and thus have the 
potential to be irreversibly modified by ibrutinib.  The other Cys-481 containing kinases include 
EGFR (IC50 = 12 nM), HER2 (IC50 = 22 nM), HER4 (IC50 = 0.6 nM), ITK (IC50 = 12 nM), 
BMX (IC50 = 1 nM), JAK3 (IC50 = 22 nM), and BLK (IC50 = 1 nM). 
A fluorescently-tagged derivative of ibrutinib was shown to bind predominantly to BTK in 
B-cell lysates suggesting a high degree of specificity within B-cells (Honigberg 2010).  
Ibrutinib also has reversible inhibitory activity against other kinases that do not contain Cys-481 
(Honigberg 2010).  However, assuming a rapid off-rate, any reversible kinase inhibition in vivo 
is likely to be short-lived, since, in humans, the effective half-life of ibrutinib following oral 
dosing is only 1.5 to 3.3 hours (as measured from time of maximum drug concentration [Tmax] 
to 6 hours postdose). 
Thus, by combining fast irreversible binding to BTK with rapid in vivo elimination, ibrutinib 
provides a unique approach to improve selectivity for BTK in vivo relative to reversibly inhibited 
off-target kinases. 
1.1.2. 
Cellular Selectivity of Ibrutinib 
BTK expression is limited to cells of hematopoietic origin.  The cellular selectivity of ibrutinib 
was demonstrated by the observation that ibrutinib inhibits antigen-receptor signaling in B-cells, 
but not in T-cells.  In ex vivo stimulation assays, ibrutinib inhibits human BCR activation 
(IC50 <10 nM) in B-cells, but does not affect T-cell receptor activation (Honigberg 2010).  
It has also been confirmed that ibrutinib inhibits key phosphorylation events downstream of the 
BCR at similar concentrations.  Ibrutinib has been studied in other cell types where the function 
of BTK is understood, including mast cells, basophils, monocytes, macrophages, and platelets.  
Consistent with the functional role of BTK in mast cells and basophils, Pharmacyclics 
determined that ibrutinib fully inhibits degranulation following stimulation at the high-affinity 
Immunoglobulin E (IgE) receptor (MacGlashan 2011; Chang 2011a).  In monocytes and 
macrophages, ibrutinib inhibits the secretion of pro-inflammatory cytokines following 
stimulation at the Fc-gamma receptors (FcγR) by immune complex (Chang 2011a).  Consistent 
with the proposed function of BTK in platelets, unpublished data from Pharmacyclics also shows 
that ibrutinib inhibits shear-force and collagen-induced platelet aggregation in vitro 
(IC50 = 10-100nM). 


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1.2. 
Summary of Nonclinical Data 
For more detailed and comprehensive information of ibrutinib, please refer to the Investigator's 
Brochure (IB). 
1.2.1. 
Nonclinical Pharmacology Studies 
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 Cys-481 in the active site of BTK results in sustained inhibition of BTK 
catalytic activity and enhanced selectivity over other kinases that do not contain a cysteine at this 
position.  When added directly to human whole blood, ibrutinib inhibits signal transduction from 
the BCR and blocks activation of B-cells (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 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). 
1.2.2. 
Safety Pharmacology and Toxicology 
No treatment-related effects were observed in the central nervous system or respiratory system in 
rats at any dose tested. Further, no treatment-related corrected QT interval (QTc) prolongation 
effect was observed at any tested dose in a cardiovascular study using telemetry-monitored dogs. 
Based on data from rat and dog including general toxicity studies up to 13 weeks duration, the 
greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation). Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog). In studies in pregnant 
rats and rabbits, ibrutinib administration was associated with malformations (teratogenicity) at 
ibrutinib doses that result in approximately 14 and 2 times the exposure (area under the 
concentration-time curve [AUC]) in patients administered the dose of 560 mg daily, respectively. 
Fetal loss and reduced fetal body weights were also seen in treated pregnant animals. 
Carcinogenicity studies have not been conducted with ibrutinib. In vitro and in vivo genetic 
toxicity studies showed that ibrutinib is not genotoxic. No effects on fertility or reproductive 
capacities were observed in a study in male and female rats. 


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1.3. 
Summary of Clinical Data 
1.3.1. 
Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased proportionally with substantial intersubject variability.  The mean terminal 
plasma elimination half life (t1/2) of ibrutinib ranged from 4 to 13 hours, with a median time to 
maximum plasma concentration (Tmax) of 2 hours.  Despite the doubling in mean systemic 
exposure when dosed with food, the favorable safety profile of ibrutinib allows dosing with or 
without food.  Ibrutinib is extensively metabolized primarily by cytochrome P450 (CYP) 3A4.  
The on-target effects of the main metabolite PCI-45227 are not considered clinically relevant.  
Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose exposure 
implying non-clinically relevant accumulation.  Less than 1% of ibrutinib is excreted in the 
urine. Ibrutinib exposure is not altered in patients with creatinine clearance (CrCl) >30 mL/min.  
Patients with severe renal impairment or patients on dialysis have not been studied.  Following 
single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with 
mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) 
hepatic impairment compared to subjects with normal liver function.  A higher proportion of 
Grade 3 or higher adverse reactions were reported in patients with B-cell malignancies (CLL, 
MCL and WM) with mild hepatic impairment based on NCI organ dysfunction working group 
(NCI-ODWG) criteria for hepatic dysfunction compared to patients with normal hepatic 
function.   
For the most comprehensive information regarding pharmacokinetics (PK) and product 
metabolism, please refer to the current version of the IB. 
1.3.2. 
Clinical Studies 
As of 4 October 2011, over 300 patients with various B-cell malignancies have received ibrutinib 
in six clinical studies sponsored by Pharmacyclics.  A total of 133 patients with CLL or SLL 
have received single-agent ibrutinib across two clinical studies:  PCYC-04753 in patients with 
recurrent B-cell lymphoma (including 16 CLL/SLL patients) and a Phase 1b/2 study 
(PCYC-1102-CA) in patients with CLL/SLL (n=117).  Two Phase 1b/2 studies are ongoing to 
evaluate the safety and efficacy of ibrutinib in combination with chemoimmunotherapy or CD20 
monoclonal antibody therapy in relapsed or refractory CLL/SLL patients, specifically with 
bendamustine/rituximab (BR) and fludarabine, cyclophosphamide, and rituximab (FCR) in 
Study PCYC-1108-CA, and with ofatumumab in Study PCYC-1109-CA. 
Additional clinical studies of ibrutinib in other B-cell malignancies, specifically mantle cell 
lymphoma (MCL), diffused large B-cell lymphoma (DLBCL and multiple myeloma) have been 
opened and are enrolling patients. 


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1.3.2.1. 
Summary of Efficacy of Ibrutinib in CLL/SLL 
In the Study PCYC-04753, 14/16 (87.5%) patients with CLL or SLL treated with ibrutinib met 
the protocol definition of evaluable for assessment of response.  Twelve (12) of the 14 (86%) 
evaluable patients with CLL or SLL achieved a response by the International Workshop Chronic 
Lymphocytic Leukemia (IWCLL, Hallek 2008) criteria (hereafter referred to as IWCLL 2008 
criteria) or National Cancer Institute (NCI) Working Group Criteria (for SLL).  In patients with 
CLL (n = 11), the time to response was dependent on the time to resolution (< 50% of baseline 
circulating lymphocyte counts) of a treatment-related lymphocytosis that frequently occurs with 
the initiation of ibrutinib therapy.  All responding patients with SLL (n = 5) met the standard 
Non-Hodgkin's lymphoma (NHL) response criteria by the Cycle 2 response assessment. 
As of 25 October 2011, the PCYC-1102-CA study had enrolled 61 relapsed or refractory 
CLL/SLL patients who had previously received purine analog based therapy.  These patients 
were given single-agent ibrutinib, which showed high activity as manifested by a high overall 
response rate (ORR) and an estimated 12-month progression-free survival (PFS) rate of 86%.  
Responses per IWCLL 2008 criteria improved with continued treatment; the ORR was 67% in 
patients treated with ibrutinib 420 mg/day at 12.6 months median follow-up.  Responses were 
independent of high risk factors including disease resistant to purine analog based therapy, 
17p del, age >70 years, and/or pretreatment cytopenias.  The activity of ibrutinib was durable 
with an estimated 12-month PFS rate of 88% (Figure 1) in the 420 mg cohort.  There were no 
differences in clinical activity (ORR or PFS) noted between the two dose levels (420 mg and 
840 mg) (O’Brien 2011). 


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Figure 1: 
Progression-Free Survival Kaplan-Meier Curves, Study PCYC-1102-CA 
 
Pharmacodynamic effect leading to characteristic pattern of response:  Preclinical studies 
have revealed a vital and multifaceted role for BTK and the BCR signaling pathway in B-cell 
leukemogenesis and lymphomagenesis.  These data suggest that the blockade of the BCR 
signaling pathway by ibrutinib in CLL results in three major effects: 1) direct induction of 
apoptosis and 2) inhibition of cell homing and migration to chemokines and with subsequent 
adhesion to cellular substrates, and 3) inhibition of proliferation (Herman 2011; Ponander 2012).  
Owing to the described mechanism of action of BTK inhibition, administration of ibrutinib to 
patients with lymphoproliferative diseases has been associated with mobilization of tumor cells 
from tissue to peripheral blood (Chang 2011b; Burger 2010; Pollyea 2009). 
This effect begins in some cases within hours of the first administration and typically reaches 
peak magnitude within the first 3 months of treatment.  Coincident with the ibrutinib 
treatment-related lymphocytosis is a rapid and substantial decrease in lymph node and/or spleen 
size often observed with or without an improvement in hematologic parameters and/or 
symptomatic improvement of disease-related symptoms.  This effect was noted in CLL/SLL 
patients treated on both PCYC-04753 and PCYC-1102-CA (Figure 2). 


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Figure 2: 
Changes in Peripheral Blood Lymphocyte Counts and Burden of 
Lymphadenopathy in Patients with CLL/SLL, Study PCYC-1102-CA 
 
ALC:  Absolute lymphocyte count; SPD: Sum of products of lymph node dimension 
 
This phenomenon is a pharmacodynamic effect of ibrutinib, in which the inhibition of 
BTK-mediated cellular homing and adhesion results in a mobilization of CLL cells from the 
lymph node to the peripheral blood compartment.  This pattern of response had previously been 
noted with other agents known to inhibit BCR signaling (Friedberg 2008; Furman 2010).  This 
treatment-related lymphocytosis resolves over a variable period of time (median 6 months) with 
the majority of patients meeting IWCLL 2008 criteria for response with continued ibrutinib 
treatment (O’Brien 2011).  As such, an increase in the number of circulating lymphocytes in the 
peripheral blood in the absence of symptoms or other indicators of progressive disease has not 
been considered an indicator of progressive disease by the Investigators in clinical studies with 
ibrutinib.  This is consistent with the recommendation of current National Comprehensive 
Cancer Network (NCCN) NHL 2012 guideline (Cheson 2012, Hallek 2012). 
1.3.2.2. 
Summary of Clinical Safety of Ibrutinib 
A brief summary of safety data from monotherapy 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). 


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Pooled safety data from a total of 1318 subjects treated with ibrutinib monotherapy from 13 
studies that have completed primary analysis or final analysis included in the CSR as of the 
31 May 2016 cutoff date for the current ibrutinib IB update in B-cell malignancies are 
summarized below.  Data for subjects in Study 1112 and in Study MCL3001 who crossed over 
from the comparator arm to ibrutinib treatment after progression are not included.  
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1318): 
Most frequently reported TEAEs 
≥15% a 
Most frequently reported Grade 3 
or 4 TEAEs ≥3% b  
Most frequently reported Serious 
TEAEs ≥2% c  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Pyrexia 
Hypertension   
 
Anemia  
Diarrhea  
 
Neutropenia  
Atrial fibrillation 
 
Upper respiratory tract infection 
 
 
Thrombocytopenia    
 
 
Oedema peripheral    
 
 
a Source is table 6 of ibrutinib IB; b Source is table 8 of ibrutinib IB; c Source is table 9 of ibrutinib IB. 
1.3.3. 
Risks 
1.3.3.1. 
Bleeding-related Events 
There have been reports of hemorrhagic events in patients treated with ibrutinib, both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, epistaxis 
and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria.  Use of ibrutinib in 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 6.6.1.4 for 
guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements.  See 
Section 6.6.3 for guidance on ibrutinib management with surgeries or procedures. 
1.3.3.2. 
Leukostasis 
There were isolated cases of leukostasis reported in subjects treated with ibrutinib.  A high 
number of circulating lymphocytes (> 400,000/µL) may confer increased risk.  For subject and 
ibrutinib management guidance, refer to Section 6.2.5. 


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1.3.3.3. 
Atrial Fibrillation 
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, hypertension, acute infections, and a previous 
history of atrial fibrillation.  Subjects who develop arrhythmic symptoms (eg, palpitations, 
lightheadedness) or new onset of dyspnea should be evaluated clinically, and if indicated, have 
an ECG performed.  For atrial fibrillation which persists, consider the risks and benefits of 
ibrutinib treatment and follow the protocol dose modification guidelines (see Section 6.2.4).   
1.3.3.4. 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib.  Subjects should be monitored for fever, weakness, or 
easy bruising and/or bleeding. 
1.3.3.5. 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in patients treated with ibrutinib.  
Monitor patients for pulmonary symptoms indicative of ILD.  Should symptoms develop follow 
the protocol dose modification guidelines (see Section 6.2.4). 
1.3.3.6. 
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 lactate dehydrogenase (LDH), bulky disease at baseline, and 
pre‐existing kidney abnormalities. 
1.3.3.7. 
Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥ 50% increase from 
baseline and an absolute count > 5000/µL), often associated with reduction of lymphadenopathy, 
has been observed in most subjects with CLL/SLL treated with ibrutinib.  This effect has also 
been observed in some subjects with MCL treated with ibrutinib.  This observed lymphocytosis 
(increase in the number of circulating lymphocytes eg, > 400,000/µL) is a pharmacodynamic 
effect and should not be considered progressive disease in the absence of other clinical findings.  
In both disease types, lymphocytosis typically occurs during the first few weeks of ibrutinib 
therapy and typically resolves within a median of 8 weeks in subjects with MCL and 14 weeks in 
subjects with CLL/SLL.  Lymphocytosis was not observed in subjects with Waldenström’s 
macroglobulinemia treated with ibrutinib.  For subject and ibrutinib management guidance, refer 
to Section 6.2.5. 


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1.3.3.8. 
Diarrhea 
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy.  Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation.  These events are rarely severe.  Should symptoms be severe or prolonged, 
follow the protocol dose modification guidelines (see Section 6.2.4).  
1.3.3.9. 
Infections 
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects 
treated with ibrutinib therapy.  Some of these reported infections have been associated with 
hospitalization and death.  Although causality has not been established, cases of progressive 
multifocal leukoencephalopathy (PML) have occurred in subjects treated with ibrutinib.  
Subjects should be monitored for symptoms (fever, chills, weakness, confusion) and appropriate 
therapy should be instituted as indicated. 
1.3.3.10. Rash 
Rashes have been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with other 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.  Isolated cases of severe cutaneous adverse reactions (SCARs) including 
Stevens-Johnson syndrome (SJS) have been reported in subjects treated with ibrutinib.  Subjects 
should be closely monitored for signs and symptoms suggestive of SCAR including SJS.  
Subjects receiving ibrutinib should be observed closely for rashes and treated symptomatically, 
including interruption of the suspected agent as appropriate.  In addition, hypersensitivity-related 
events including erythema, urticaria, and angioedema have been reported. 
1.3.3.11. Non-melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in patients treated with ibrutinib.  Monitor patients 
for the appearance of non-melanoma skin cancer. 
1.3.3.12. Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib.  Monitor subjects 
for new onset of hypertension or hypertension that is not adequately controlled after starting 
ibrutinib.  Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive 
treatment as appropriate. 
2. STUDY RATIONALE 
This randomized, multicenter, open-label, Phase 3 study is designed to evaluate whether 
treatment with ibrutinib as a monotherapy results in a clinically significant improvement in PFS 


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as compared to treatment with ofatumumab in patients with relapsed or refractory CLL or SLL 
who have failed at least one prior line of therapy and are not considered appropriate for treatment 
with purine analog based therapy. 
The study design aims to confirm the efficacy findings of the ongoing Phase 1b/2 Study 
PCYC-1102-CA for treatment with ibrutinib administered orally once daily in the cohorts of 
patients with CLL/SLL who had failed previous treatment(s).  This study will assess the efficacy 
outcomes between the two arms in relapsed/refractory patients, including those with a 17p del or 
who are refractory to purine analog based therapy.  In addition, this study aims to confirm the 
safety and tolerability of ibrutinib in these patients as compared to an acceptable comparator, 
ofatumumab, in terms of hematologic and infectious toxicities. 
2.1. 
Dose Selection Rationale for Ibrutinib 
A once daily 420 mg dose of ibrutinib has been selected for this Phase 3 study.  This dose and 
regimen were selected in consideration of PK, pharmacodynamics, efficacy, and safety data 
obtained from Studies PCYC-04753 and PCYC-1102-CA as detailed in Section 1.3.  Ibrutinib 
has been administered safely at higher doses in CLL; however 420 mg once daily is considered 
an acceptable dose to achieve the desired biological effect, with no evidence of improved 
responses or improvement in PFS at doses above 420 mg/day (see Figure 1). 
2.2. 
Selection of Ofatumumab as Comparator 
Ofatumumab is a fully humanized type I anti-CD20 monoclonal antibody.  In vitro, it mediates 
complement dependent cytotoxicity (CDC) against rituximab-resistant Raji cells and CLL cells 
with low expression of CD20.  It appears to have greater potency in CDC than rituximab, as well 
as a slower off-rate and more stable CD20 binding (Teeling 2004).  Additionally, it appears to 
bind a different epitope of CD20 than rituximab (Teeling 2006) and has demonstrated clinical 
activity that is independent of prior treatment with rituximab (Wierda 2011).  A Phase 1/2 study 
of ofatumumab in relapsed/refractory CLL patients demonstrated that it is generally 
well-tolerated, even at high doses, and is active, with an ORR of approximately 50%.  
Infusion-related AEs are similar to those reported with rituximab and decrease following the first 
infusion (Coiffier 2008) of ofatumumab.  Ofatumumab was evaluated in patients with 
fludarabine- and alemtuzumab-refractory (double refractory [DR]) and bulky fludarabine- 
refractory (BFR) CLL in a seminal study of 138 patients who have received treatment for 
CLL/SLL.  Patients received 8 weekly infusions of ofatumumab followed by 4 monthly infusions 
over a 24-week period, receiving 300 mg as the first dose and 2000 mg for all doses thereafter 
(Wierda 2010).  The ORR was 58% in the DR CLL group and 47% in the BFR CLL group with 
median PFS of 5.7 months and 5.9 months, and overall survival (OS) of 13.7 months and 15.4 
months, for the two groups respectively.  This data led to FDA (Food and Drug Administration) 
and EMA (European Medicines Agency) approval of ofatumumab in CLL in patients refractory 
to fludarabine and alemtuzumab.  Currently NCCN NHL 2012 guidelines and European Society 


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for Medical Oncology (ESMO) guidelines support the use of ofatumumab in patients who have 
received treatment for CLL/SLL (NCCN 2012; Eichhorst 2011).  The most common AEs for 
ofatumumab are infusion reactions, neutropenia, pneumonia, fevers, cough, and diarrhea.  For 
more information on ofatumumab, please refer to the package insert. 
3. STUDY OBJECTIVES 
3.1. 
Primary Objective 
To evaluate the efficacy of ibrutinib compared to ofatumumab based on independent review 
committee (IRC) assessment of progression-free survival (PFS) per International Workshop on 
Chronic Lymphocytic Leukemia Criteria (IWCLL, Hallek 2008) with incorporation of the 
clarification for treatment related lymphocytosis (Hallek 2012), hereafter referred to as IWCLL 
2008 criteria in patients with relapsed or refractory CLL/SLL. 
3.2. 
Secondary Objectives  
To compare between the two treatment groups in terms of: 
Efficacy 
• To evaluate overall survival (OS) 
• To evaluate IRC-assessed overall response rate (ORR) per IWCLL 2008 criteria 
• To evaluate patient-reported outcome (PRO) by the Functional Assessment of Chronic 
Illness Therapy-Fatigue (FACiT-Fatigue)  
• To evaluate hematological improvement 
Safety 
To evaluate the safety and tolerability of ibrutinib compared to ofatumumab 
3.3. 
Exploratory Objectives 
To evaluate and compare between the two treatment arms in terms of: 
• To evaluate Investigator-assessed PFS and ORR per IWCLL 2008 criteria 
• To evaluate improvement and/or resolution of disease-related symptoms 
• To evaluate PRO by European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaires Core 30 (EORTC QLQ-C30) and EuroQoL 
Five-Dimension (EQ-5D-5L) 
• To evaluate medical resource utilization (MRU) 
• To determine the PK characteristics of ibrutinib in patients with CLL/SLL and to 
determine which, if any, covariates (eg, age, gender, body size, race) influence exposure 
to ibrutinib 


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• To investigate potential predictive biomarkers and mechanisms of resistance for the 
disease 
4. STUDY DESIGN 
This is a randomized, multicenter, open-label, Phase 3 study designed to evaluate the safety and 
efficacy of ibrutinib as compared to ofatumumab in patients with relapsed or refractory 
CLL/SLL who have failed at least one prior line of therapy and are not considered appropriate 
candidates for treatment or retreatment with purine analog based therapy. 
Eligible patients will have been diagnosed with CLL/SLL and have relapsed or refractory disease 
following at least 1 line of prior systemic therapy for CLL/SLL. 
A minimum of 350 patients will be randomized in a 1:1 ratio to receive either ofatumumab 
(Treatment Arm A) or ibrutinib (Treatment Arm B). 
The site will enter eligibility data into an Interactive Web Response System (IWRS) prior to 
randomization. 
Randomization will be used to minimize bias in the assignment of patients to treatment groups, 
to increase the likelihood that known and unknown patient attributes (eg, demographic and 
baseline characteristics) are evenly balanced, and to enhance the validity of statistical 
comparisons across treatment groups.  Two randomization schemes will be generated: one for 
each geographic region (North America versus Rest of World).  Under each scheme, patients will 
be randomized based on the following two stratification factors: 
• Presence versus absence of disease refractory to purine analog and anti-CD20 containing 
chemoimmunotherapy regimen 
• Presence versus absence of 17p del, as defined by the assay specification on pretreatment 
fluorescence in situ hybridization (FISH) or cytogenetics evaluation 
Patient participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. 
The Screening Phase will be up to 28 days prior to first dose of study drug, during which the 
patient’s eligibility and baseline characteristics will be determined. 
The Treatment Phase will extend from randomization until study drug discontinuation.  Patients 
randomized to ofatumumab will receive treatment for up to 6 months per the package insert.  
Patients randomized to ibrutinib will receive study drug daily until disease progression or 
unacceptable toxicity.  Further information on dosing is provided in Section 6.  Regularly 
scheduled disease assessments are required throughout the Treatment Phase. 
The Follow-up Phase will be comprised of 2 phases; the Post-treatment Phase and a Post-disease 
Progression Phase.  The Post-treatment Phase will extend from the discontinuation of treatment 
up until the patient has progressive disease or other criteria listed in Section 10.1.  Response 


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evaluations will be continued every 12 weeks from the initial dose with study drug until 
18 months and then every 24 weeks until disease progression. 
The Post-disease Progression Phase will begin once a patient has progressive disease.  In this 
phase, subsequent anticancer therapy with start date of therapy, IWCLL indication for treatment 
initiation, additional malignancy occurrence, and patient survival status will be recorded.  The 
Post-disease Progression Phase will continue until death, lost to follow up, consent withdrawal, 
or study closure, whichever occurs first.  It is important that survival status be assessed and that 
the date of death is documented for each patient randomized to treatment, regardless of whether 
or not the patient received treatment. 
Assessment of response and progression will be conducted in accordance with the IWCLL 2008 
criteria with the modification that treatment-related lymphocytosis in the absence of other signs 
or symptoms of disease progression will not be considered progressive disease (Section 8.1.5).  
The Investigator will evaluate sites of disease by radiological imaging (primary), physical 
examination or other procedures as necessary, review of hematology and serum chemistry 
results, and disease-related symptoms.  The same methods of assessment used to assess disease 
at baseline should be used throughout the study.  A central laboratory will perform all 
hematology and serum chemistry testing for the primary endpoint analysis.  The primary efficacy 
analysis will be based on assessment from an IRC.  As part of the IRC review, radiographic 
evaluations assessed by independent central radiologists and hematology results from a central 
laboratory will be provided.  Detailed procedures will be described in a separate charter. 
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 
to the charter. 
One interim analysis using Lan-DeMets alpha spending function based on O'Brien-Fleming 
boundary for both superiority and futility (non-binding) is planned for the study.  The interim 
analysis will be conducted after approximately 117 PFS events (progressive disease confirmed 
by the IRC or death, whichever occurs first) have occurred.  The DMC will make 
recommendations based on efficacy boundary guidelines.  If pre-specified boundaries are not 
met at the interim analysis, the final analysis of the study will occur after 176 PFS events have 
been observed.   
Access to next-line ibrutinib for patients treated with ofatumumab may be provided following 
Medical Monitor approval as outlined in Section 7.3.4.  
Pharmacyclics will continue to follow up the patients for at least 5 years after the last patient is 
enrolled, at which time a long-term extension study will be made available for active patients 
who choose to continue ibrutinib on a clinical protocol when access to commercial ibrutinib is 
not feasible.     


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5. SELECTION OF PATIENTS 
5.1. 
Inclusion Criteria 
Patients will be considered for inclusion in this study if they meet all of the following criteria: 
1. Men and women ≥ 18 years of age 
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 
3. Diagnosis of CLL/SLL that meets published diagnostic criteria (Hallek 2008): 
a) monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally 
co-expressing at least one B-cell marker (CD19, CD20, or CD23) and CD5 
b) Prolymphocytes may comprise no more than 55% of blood lymphocytes 
c) There is no evidence of cyclin D1 rearrangement or BCL-1 over expression 
4. Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring 
treatment: 
a) Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia (Hgb < 10 g/dL) and/or thrombocytopenia (platelets 
< 100,000/μL) 
b) Massive (ie, at least 6 cm below the left costal margin), progressive, or symptomatic 
splenomegaly 
c) Massive nodes (ie, at least 10 cm in the longest diameter), progressive, or 
symptomatic lymphadenopathy 
d) Progressive lymphocytosis with an increase of more than 50% over a 2-month period 
or a lymphocyte doubling time (LDT) of less than 6 months.  LDT may be obtained 
by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at 
intervals of 2 weeks over an observation period of 2 to 3 months.  In patients with 
initial blood lymphocyte counts of less than 30 X 109/L (30,000/μL), LDT should 
not be used as a single parameter to define indication for treatment.  In addition, 
factors contributing to lymphocytosis or lymphadenopathy other than CLL 
(eg, infections) should be excluded 
e) Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard 
therapy (see Appendix K) 
f) Constitutional symptoms documented in the patient’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 


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5. Must have received at least one prior therapy for CLL/SLL and not be appropriate for 
treatment or retreatment with purine analog based therapy, defined by at least one of the 
following criteria: 
a) Failure to respond (stable disease [SD] or disease progression on treatment), or a 
progression-free interval of less than 3 years from first dose of treatment with a 
purine analog based therapy and anti-CD20 containing chemoimmunotherapy 
regimen after at least two cycles 
b) Age ≥70 years, who had received >1 prior treatment including at least two cycles of 
an alkylating-agent based (or purine analog based) anti-CD20 antibody containing 
chemoimmunotherapy regimen or ≥2 prior lines of systemic therapy including 
chemotherapy, anti-CD20 or anti-CD52 monoclonal antibodies, or 
immunomodulatory therapy with lenalidomide or thalidomide 
c) Age ≥65 years with co-morbidities, who had received ≥1 prior treatment including at 
least two cycles of an alkylating-agent based (or purine analog based) anti-CD20 
antibody containing chemoimmunotherapy regimen.  Co-morbidities are defined by 
at least one of the following: 
i) Estimated creatinine clearance (ie, estimated Glomerular Filtration Rate, eGFR 
using) Cockcroft-Gault <70 mL/min 
ii) Platelet count <100,000/µL or hemoglobin <10 g/dL 
iii) History of clinically significant autoimmune cytopenia (controlled autoimmune 
hemolytic anemia or immune thrombocytopenia as defined in Appendix K) 
iv) Eastern Cooperative Oncology Group (ECOG) performance score = 1 
d) History of purine analog-associated autoimmune anemia or autoimmune 
thrombocytopenia temporally associated (within 4 weeks) of treatment with a purine 
analog 
e) The presence of 17p deletion by FISH  
6. Measurable nodal disease by computed tomography (CT).  Measurable nodal disease is 
defined as at least one lymph node > 1.5 cm in the longest diameter in a site that has not 
been previously irradiated.  An irradiated lesion may be assessed for measurable disease 
only if there has been documented progression in that lesion since radiotherapy has ended 
7. Meet the following laboratory parameters: 
a) Absolute neutrophil count (ANC) ≥ 750 cells/μL (0.75 x 109/L) and independent of 
growth factor support 7 days prior to assessment 
b) Platelet count ≥ 30,000 cells/μL (30 x 109/L) without transfusion support 7 days 
prior to assessment.  Patients with transfusion-dependent thrombocytopenia are 
excluded 
c) Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) 
< 2.5 x upper limit of normal (ULN) 
d) Total bilirubin ≤ 1.5 x ULN (unless due to Gilbert’s syndrome or patients with 
autoimmune hemolytic anemia that is otherwise controlled) 


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e) Estimated creatinine clearance (ie, estimated Glomerular Filtration Rate, eGFR) 
using Cockcroft-Gault ≥ 30 mL/min 
8. Able to provide written informed consent and can understand and comply with the 
requirements of the study 
9. Able to receive all outpatient treatment, all laboratory monitoring, and all radiological 
evaluations at the institution that administers study drug for the entire study 
10. Female patient of childbearing potential must have a negative serum or urine pregnancy 
test within 3 days of the first dose of study drug and agree to use dual methods of 
contraception during the study and for 1 month following the last dose with ibrutinib or 
12 months following the last dose with ofatumumab.  Post menopausal females 
(>45 years old and without menses for >1 year) and surgically sterilized females are 
exempt from this criterion 
11. Male patient must use an effective barrier method of contraception during the study and 
for 3 months following the last dose if sexually active with a female of childbearing 
potential 
5.2. 
Exclusion Criteria 
Patients will be ineligible for this study if they meet any of the following criteria: 
1. Known central nervous system (CNS) lymphoma or leukemia 
2. Known prolymphocytic leukemia or history of or currently suspected Richter’s 
transformation 
3. Missing or incomplete documentation of cytogenetic and/or FISH results reflecting the 
presence or absence of 17p del and the percentage of cells with the deletion in patient 
records prior to randomization 
4. Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic 
purpura (ITP) defined as declining hemoglobin or platelet count secondary to 
autoimmune destruction within the screening period or requirement for high doses of 
steroids (>20 mg daily of prednisone daily or equivalent).  See Appendix K. 
5. Prior exposure to ofatumumab or to ibrutinib (PCI-32765) or randomization into an 
ibrutinib study 
6. Received any chemotherapy, external beam radiation therapy, anticancer antibodies, 
or investigational drug within 30 days prior to first dose of study drug 
7. Corticosteroid use > 20 mg within 1 week prior to first dose of study drug, except as 
indicated for other medical conditions such as inhaled steroid for asthma, topical steroid 
use, or as premedication for administration of study drug or contrast.  Patients requiring 
steroids at daily doses > 20 mg prednisone equivalent systemic exposure daily, or those 
who are administered steroids for leukemia control or white blood cell count lowering 
are excluded 
8. Radio- or toxin-conjugated antibody therapy within 10 weeks prior to first dose of 
study drug 


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9. Prior autologous transplant within 6 months prior to first dose of study drug 
10. Prior allogeneic stem cell transplant within 6 months prior to randomization or with any 
evidence of active graft versus host disease or requirement for immunosuppressants 
within 28 days prior to first dose of study drug.  
11. Major surgery within 4 weeks prior to first dose of study drug 
12. History of prior malignancy, with the exception of the following: 
a) Malignancy treated with curative intent and with no evidence of active disease 
present for more than 3 years prior to Screening and felt to be at low risk for 
recurrence by treating physician 
b) Adequately treated lentigo maligna melanoma without current evidence of disease or 
adequately controlled non-melanomatous skin cancer 
c) Adequately treated cervical carcinoma in situ without current evidence of disease 
13. 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 J), or history of 
myocardial infarction within 6 months prior to first dose with study drug 
14. Unable to swallow capsules or disease significantly affecting gastrointestinal function 
and/or inhibiting small intestine absorption such as; malabsorption syndrome, resection 
of the small bowel, or poorly controlled inflammatory bowel disease affecting the small 
intestine 
15. 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) or ongoing intravenous anti-infective 
treatment 
16. Known history of infection with human immunodeficiency virus (HIV) 
17. Serologic status reflecting active hepatitis B or C infection.  Patients with hepatitis B core 
antibody positive who are surface antigen negative or who are hepatitis C antibody 
positive will need to have a negative polymerase chain reaction (PCR) result prior to 
enrollment.  Those who are hepatitis B surface antigen positive or hepatitis B PCR 
positive and those who are hepatitis C PCR positive will be excluded. 
18. History of stroke or intracranial hemorrhage within 6 months prior to randomization. 
19. Pregnant or lactating women 
20. Current life-threatening illness, medical condition, or organ system dysfunction which, in 
the Investigator’s opinion, could compromise the patient’s safety or put the study at risk 
21. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists 
(eg, phenprocoumon) within 28 days of first dose of study drug 
22. Requires treatment with a strong CYP3A4/5 inhibitor 


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6. TREATMENTS 
Patients will be randomized 1:1 to either Treatment Arm A or B. 
Treatment Arm A: Ofatumumab IV 
Treatment is 12 IV doses over 24 weeks or until disease progression, unacceptable toxicity, or 
the patient meets any criteria specified in Section 10, whichever occurs first.  Administration of 
ofatumumab will be in accordance with the manufacturer's package insert. 
Treatment Arm B: Ibrutinib PO 
Treatment is 420 mg (3 x 140-mg capsules) administered orally daily to continue until disease 
progression, unacceptable toxicity, or the patient meets any criteria specified in Section 10, 
whichever occurs first. 
6.1. 
Ofatumumab 
6.1.1. 
Dosage and Administration 
6.1.1.1. 
Premedication 
Patients should be premedicated 30 minutes to 2 hours prior to each dose of ofatumumab with 
975-1000 mg acetaminophen/paracetamol; 10 mg Cetirizine orally or equivalent antihistamine, 
either IV or oral; and 100 mg IV prednisolone or equivalent corticosteroid. 
Corticosteroid dose reduction: 
• Do not reduce corticosteroid dose for ofatumumab infusions 1, 2, or 9. 
• Corticosteroid doses may be reduced as follows: 
 
For Doses 3 through 8: 
• If infusion-related reaction ≥ Grade 3 experienced, do not reduce corticosteroid dose for 
subsequent doses. 
• If infusion-related reaction < Grade 3 experienced, may consider gradually reducing 
corticosteroid dose with subsequent doses. 
 
For Doses 10 through 12: 
• If infusion-related reaction ≥ Grade 3 experienced with Dose 9, do not reduce 
corticosteroid dose for subsequent doses. 
• If infusion-related reaction < Grade 3 experienced with Dose 9, may consider 
administering prednisolone 50 – 100 mg (or its equivalent) for subsequent doses. 
Ofatumumab infusion premedication should be administered as outlined above and consistent 
with the package insert.  It is recognized that some institutional variation to these procedures 
may exist, however for the purposes of this study; the package insert instructions must be 
followed.  Routine infusion premedication with corticosteroid doses of > 100 mg IV 
prednisolone (or equivalent) is not permitted. 


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6.1.1.2. 
Dosage Regimen and Administration 
Ofatumumab should be diluted in 0.9% Sodium Chloride Injection, USP and administered as an 
IV infusion.  Do not administer the drug as an IV push or bolus. 
The ofatumumab dosage and schedule is 12 doses administered as follows 
Week 1: 300 mg initial dose 
Weeks 2 through 8: 2,000 mg given weekly 
Weeks 12, 16, 20 and 24: 2,000 mg every 4 weeks 
An observation period following the end of infusion should occur as per the institution’s standard 
practice.  Refer to the Arzerra® package insert for additional administration instructions. 
6.1.2. 
Dose Delay 
Treatment with ofatumumab should be held for any unmanageable, potentially study drug-related 
toxicity that is Grade 3 or greater in severity.  Additional information concerning dose delays can 
be found in Section 6.1.4. 
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 held for a maximum of 28 days from expected dose due to toxicity.  Study 
treatment should be discontinued in the event of a toxicity lasting > 28 days, unless reviewed and 
approved by the Medical Monitor. 
6.1.3. 
Dose Interruption 
Interrupt infusion for infusion-related reactions of any severity.  For Grade 4 infusion-related 
reactions, do not resume the infusion.  For Grade 1, 2, or 3 infusion-related reactions, if reaction 
resolves or remains ≤ Grade 2, resume infusion including increasing infusion rate consistent with 
the package insert according to the initial Grade of the infusion reaction: 
• Grade 1 or 2: Infuse at one-half of the previous infusion rate 
• Grade 3: Infuse at a rate of 12 mL/hour 
6.1.4. 
Dose Discontinuation 
The actions in Table 1 should be taken for the following toxicities: 
• Grade 4 ANC (< 500/µL) for > 7 days (Neutrophil growth factors are permitted per 
ASCO guidelines [Smith 2006] and use must be recorded in the case report form [CRF]). 
• Grade 3 or 4 platelets (< 50,000/µL); or, in patients with baseline thrombocytopenia, a 
platelet decrease of 50-74% from baseline in presence of significant bleeding 
• Grade 4 Platelets (< 25,000/µL); or, in patients with baseline thrombocytopenia, decrease 
of ≥ 75% from baseline or < 20,000/µL, whichever is higher 


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• Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal antiemetic and/or 
anti-diarrheal therapy 
• Any other Grade 4 toxicity or unmanageable Grade 3 toxicity. 
Table 1: 
Dose Discontinuation Actions for Ofatumumab 
Occurrence 
Action 
1st–3rd 
Hold ofatumumab until recovery to Grade ≤ 1 or baseline; may restart at original dose level 
4th 
Discontinue ofatumumab 
In addition, discontinue ofatumumab if progressive multifocal leukoencephalopathy (PML) is 
suspected. 
All patients will be screened for hepatitis B and those with evidence of chronic or active 
infection will be excluded from the protocol.  However, if a patient develops viral hepatitis, they 
should be discontinued from ofatumumab treatment. 
6.1.5. 
Dose Reduction 
As dose reductions are not outlined in the package insert, dose reductions are not allowed for 
ofatumumab during this study. 
6.1.6. 
Precautions and Adverse Effects 
6.1.6.1. 
Warnings and Precautions 
Infusion-Related Reactions:  Premedication and infusion parameters, as outlined in the package 
insert should be used.  Monitor patients closely during infusions and interrupt infusion if any 
reaction occurs. 
Cytopenias:  Monitor blood counts as outlined in the Schedule of Assessments (Appendix A). 
6.1.6.2. 
Adverse Events 
The most common serious adverse events (SAEs) with ofatumumab were infections (including 
pneumonia and sepsis), neutropenia, and pyrexia.  Infections were the most common AEs 
leading to drug discontinuation.  Additional common AEs (≥10%) with ofatumumab were cough, 
diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract 
infections. 


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6.2. 
Ibrutinib 
6.2.1. 
Dosage and Administration 
Ibrutinib 420 mg (3 x 140-mg capsules) is to be administered orally once daily with 8 ounces 
(approximately 240 mL) of water.  The capsules should be swallowed intact and patients should 
not attempt to open capsules or dissolve them in water. 
Each dose of ibrutinib should be taken at approximately the same time each day.  Patients should 
avoid consuming food and beverages containing grapefruit juice or Seville oranges for the 
duration of the study due to CYP3A4/5 inhibition.  If a dose is missed, it can be taken as soon as 
possible on the same day with a return to the normal schedule the following day.   
Ibrutinib will be dispensed to patients in bottles.  Unused ibrutinib dispensed during previous 
visits must be returned to the site and drug accountability records (Section 13.8) updated at each 
visit.  Returned capsules must not be redispensed to anyone.  Ibrutinib should not be dispensed to 
anyone other than a patient enrolled in the study and can only be dispensed in its original bottle. 
6.2.2. 
Dose Delay 
Treatment with ibrutinib should be held for any unmanageable, potentially study drug-related 
toxicity that is Grade 3 or higher in severity.  Please see Section 6.6.1.4 for guidelines for 
management of ibrutinib in patients who require anticoagulant treatment. 
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 held for a maximum of 28 consecutive days for toxicity.  Study treatment 
should be discontinued in the event of a toxicity lasting >28 days, unless reviewed and approved 
by the Medical Monitor. 
6.2.3. 
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 SAE criterion must be 
reported as a SAE 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 (MTD) was reached in the Phase 1 study in which subjects received up 
to 12.5 mg/kg/day (1400 mg/day).  Healthy subjects were exposed up to single dose of 1680 mg. 
One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) 
after a dose of 1680 mg.  Subjects who ingested more than the recommended dosage should be 
closely monitored and given appropriate supportive treatment. 
Refer to Section 9.3 for further information regarding AE reporting. 


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6.2.4. 
Dose Reduction and Discontinuation 
The actions in Table 2 should be taken for the following toxicities: 
• Grade 4 ANC (< 500/µL) for > 7 days (Neutrophil growth factors are permitted per 
ASCO guidelines [Smith 2006] and use must be recorded in CRF). 
• Grade 3 or 4 platelets (< 50,000/µL); or, in patients with baseline thrombocytopenia, a 
platelet decrease of 50-74% from baseline in presence of significant bleeding 
• Grade 4 Platelets (< 25,000/µL); or, in patients with baseline thrombocytopenia, decrease 
of ≥ 75% from baseline or < 20,000/µL, whichever is higher 
• Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal antiemetic and/or 
anti-diarrheal therapy 
• Any other Grade 4 toxicity or unmanageable Grade 3 toxicity. 
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 6.6.1.4).  
Table 2: 
Drug Discontinuation Actions for Ibrutinib 
Occurrence 
Action 
1st 
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; may restart at original dose level 
2nd 
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; restart at one dose level lower (280 mg 
daily) 
3rd 
Hold ibrutinib until recovery to Grade ≤ 1 or baseline; restart at one dose level lower (140 mg 
daily) 
4th 
Discontinue ibrutinib 
Dose changes must be recorded in the Dose Administration CRF. 
6.2.5. 
Treatment-related Lymphocytosis 
Treatment-related lymphocytosis, for the purposes of this protocol, is defined as an elevation in 
blood lymphocyte count of ≥50% compared to baseline that occurs in the setting of improvement 
in at least one other disease-related parameter and is associated with agents known to inhibit 
BCR (see Section 8.1.5 for additional details) (Hallek 2012, NCCN 2012, Cheson 2012).  Given 
the known mechanism of action of BCR-inhibiting agents including ibrutinib, treatment-related 
lymphocytosis is an expected and frequent pharmacodynamic phenomenon observed with 
initiation (or re-initiation) of ibrutinib.  Ibrutinib associated treatment-related lymphocytosis 
generally occurs within the first weeks of therapy, peaks within the first few months, and 
resolves slowly.  Asymptomatic treatment-related lymphocytosis should not be considered an AE 
and patients should remain on study treatment. 


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Specifically, upon initiation of treatment, a transient phase of increase in lymphocyte counts 
(ie, ≥50% increase from baseline and above absolute count of 5,000/µL), often associated with 
reduction of lymphadenopathy, has been observed in most patients (75%) with relapsed/ 
refractory CLL/SLL and some patients (33%) with relapsed/refractory MCL treated with 
ibrutinib monotherapy.  This observed transient lymphocytosis is usually not associated with an 
adverse event and should not be considered progressive disease in the absence of other clinical 
findings. In both disease types, lymphocytosis typically occurs during the first few weeks of 
ibrutinib therapy (median time 1.1 weeks) and resolves within a median of 7.1 weeks in the MCL 
and 18.7 weeks in the CLL patients.  
A substantial increase in the number of circulating lymphocytes has been observed in a subset of 
patients.  There have been isolated cases of leukostasis reported in patients treated with ibrutinib.  
A high number of circulating malignant cells (≥400,000/µL) may confer increased risk; these 
patients should be closely monitored.  Administer supportive care such as hydration and/or 
leukophoresis as indicated.  Ibrutinib may be temporarily held, and Medical Monitor should be 
contacted. 
6.2.6. 
Dose Modification for Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant hepatic 
impairment at the time of screening (Child- Pugh class B or C) are excluded from study 
participation.  For subjects who develop mild liver impairment while on study (Child-Pugh class 
A), the recommended dose reduction for ibrutinib/placebo is to a level of 280 mg daily (two 
capsules).  For subjects who develop moderate liver impairment while on study (Child-Pugh 
class B), the recommended dose reduction is to a level of 140 mg daily (one capsule).  Subjects 
who develop severe hepatic impairment (Child-Pugh class C) must hold study drug until 
resolved to moderate impairment (Child-Pugh class B) or better.  Monitor subjects for signs of 
toxicity and follow dose modification guidance as needed (Refer to  Appendix L). 
6.2.7. 
Precautions and Adverse Events 
The most common treatment-emergent adverse events were diarrhea, fatigue, nausea, cough and 
anemia. Additional common AEs such as peripheral edema, pyrexia, vomiting, constipation, 
upper respiratory tract infection, arthralgia, dyspnea, thrombocytopenia, decreased appetite, 
headache, muscle spasm, neutropenia, contusion, abdominal pain, dizziness, pneumonia, 
myalgia, and dyspepsia have been reported.  In addition, Events of Special Interest are outlined 
in Section 9.3.4.  For complete information on precautions refer to the IB. 


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6.3. 
Identification of Investigational Product(s) 
6.3.1. 
Ibrutinib 
Ibrutinib is provided as hard gelatin capsules containing 140 mg of ibrutinib.  The capsules are 
packaged in opaque high-density polyethylene (HDPE) plastic bottles with labels bearing the 
appropriate label text as required by governing regulatory agencies.  The drug product is 
manufactured for Pharmacyclics LLC by a contract manufacturer.  All formulation excipients are 
compendial and are commonly used in oral formulations. 
The recommended storage condition for ibrutinib capsules is controlled room temperature.  
Formal International Conference on Harmonization (ICH) stability studies are ongoing to 
determine the shelf-life of the product.  Please refer to the Pharmacy Binder and study drug label 
for more detailed information. 
Refer to the IB for additional information regarding the drug product to be used in this study. 
6.3.2. 
Ofatumumab 
Ofatumumab, manufactured by GlaxoSmithKline, is provided in solution in single-use vials.  
Refer to the local ofatumumab package insert for details. 
6.4. 
Treatment Compliance 
Patient compliance with ibrutinib will be assessed by the site pharmacist or designee at each visit 
using direct questioning, examination of patient diaries, and capsule counts.  Ofatumumab 
compliance will be performed by the site pharmacist or designee as patients will not be taking 
the study drug home. 
Compliance will be verified by the Sponsor or designee and will be recorded in the study 
Pharmacy Binder.  The pharmacist or designee will: 
• Maintain records of product delivery, inventory, return, and destruction 
• Maintain temperature monitoring 
• Maintain up-to-date accountability of the study drug in the study drug accountability log 
(or equivalent) 
• Document the use of study product by each patient 
• Return or destroy unused study product as per Sponsor’s instructions 
6.5. 
Randomization and Blinding 
A minimum of 350 patients will be randomized in a 1:1 ratio to each of the 2 treatment arms in 
this study.  Randomization will be used to minimize bias in the assignment of patients to the 
2 treatment arms.  Two randomization schemes will be generated: one for each geographic 
region (North America versus Rest of World).  Under each scheme, randomization will be 


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stratified using the following two factors: 1) presence versus absence of refractory disease to 
purine analog and anti-CD20 containing chemoimmunotherapy regimen, and 2) presence versus 
absence of 17p del. 
This is an open-label study; neither patients nor Investigators will be blinded to treatment. 
The primary efficacy evaluation will be performed by an IRC, which will be blinded to study 
treatment information and lymphocyte count. 
6.6. 
Concomitant Therapy 
6.6.1. 
Concomitant Medications to be Used With Caution 
Antiemetics are permitted if clinically indicated.  Standard supportive care medications are 
permitted; this includes pre-medication for ofatumumab infusion as per the ofatumumab package 
insert.  Use of neutrophil growth factors (filgrastim and pegfilgrastim) is permitted per the 
American Society of Clinical Oncology (ASCO) guidelines (Smith 2006). 
For patients considered at risk for tumor lysis syndrome (TLS): 
Patients with more than one of the following factors are considered to be at increased risk of TLS 
and should be considered for hydration and treatment with an uric acid lowering agent (xanthine 
oxidase inhibitor allopurinol or Uloric [febuxostat] +/- rasburicase per the drug products package 
insert) prior to treatment with study drug, as well as for frequent monitoring of tumor lysis 
associated signs and symptoms. 
• Serum creatinine ≥ 1.5x ULN 
• WBC ≥ 50,000/mm3 
• Uric acid > ULN 
6.6.1.1. 
Guideline for Use of CYP Inhibiting/Inducing Drugs 
Ibrutinib is metabolized primarily by CYP3A4. Avoid co-administration with strong or moderate 
CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. Co-administration 
of ketoconazole, a strong CYP3A inhibitor, in 18 healthy subjects increased dose normalized 
exposure, Cmax and AUC0-last, of ibrutinib by 29- and 24-fold, respectively.  The maximal 
observed ibrutinib exposure (AUC) was ≤2-fold in 37 patients treated with mild and/or moderate 
CYP3A inhibitors when compared with the ibrutinib exposure in 76 patients not treated 
concomitantly with CYP3A inhibitors.  Clinical safety data in 66 patients treated with moderate 
(n=47) or strong CYP3A inhibitors (n=19) did not reveal meaningful increases in toxicities. 
Strong inhibitors of CYP3A (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, and nefazadone) should be avoided. If a strong 
CYP3A inhibitor must be used, consider reducing the ibrutinib to 140 mg or withhold treatment 
temporarily.  Subjects should be monitored for signs of ibrutinib toxicity. If the benefit 
outweighs the risk and a moderate CYP3A inhibitor must be used, reduce ibrutinib to 140 mg for 


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the duration of the inhibitor use.  Monitor subject for toxicity and follow dose modification 
guidance as needed.  For subjects who are already on a moderate CYP3A inhibitor 
concomitantly with ibrutinib without significant toxicity the investigator may consider the 
overall risk-benefit to determine if a dose reduction of ibrutinib is appropriate.  Avoid grapefruit 
and Seville oranges during ibrutinib treatment, as these contain moderate inhibitors of CYP3A 
(see Section 6.2.1).  No dose adjustment is required in combination with weak CYP3A 
inhibitors. 
Co-administration of ibrutinib with strong CYP3A inducer, rifampin, in healthy subjects 
decrease ibrutinib plasma concentration by approximately 10-fold.  Avoid concomitant use of 
strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and St. John’s Wort).  
Consider alternative agents with less CYP3A induction. 
A list of common CYP3A inhibitors and inducers is provided in Appendix C; a comprehensive 
list of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/.  This website is continually revised and 
should be checked frequently for updates. 
6.6.1.2. 
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.  Currently, no clinical data is available; therefore, co-
administration of narrow therapeutic index P-gp substrates (eg, digoxin) with ibrutinib may 
increase the substrate’s blood concentration and should be used with caution and subjects should 
be monitored closely for toxicity. 
6.6.1.3. 
Concomitant Use of QT Prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; periodic 
monitoring with electrocardiograms and electrolytes should be considered. 
6.6.1.4. 
Concomitant Use of Antiplatelet Agents and Anticoagulants 
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib.  
Ibrutinib should be used with caution in patients requiring other anticoagulants or medications 
that inhibit platelet function.  Supplements such as fish oil and vitamin E preparations should be 
avoided.  Subjects with congenital bleeding diathesis have not been studied.  For guidance on 
ibrutinib and the use of anticoagulants during procedures/surgeries see Section 6.6.3.  
Patients requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), 
consider the risks and benefits of continuing ibrutinib treatment.  If therapeutic anticoagulation is 
clinically indicated, treatment with ibrutinib should be held and not be restarted until the patient 


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is clinically stable and has no signs of bleeding.  Patients should be observed closely for signs 
and symptoms of bleeding.  No dose reduction is required when study drug is restarted. 
6.6.2. 
Prohibited Concomitant Medications 
Any chemotherapy, anticancer immunotherapy, corticosteroids (at dosages equivalent to 
prednisone >20 mg/day), experimental therapy, or radiotherapy are prohibited.  Localized, 
hormonal, or bone sparing treatment for non-B cell malignancies may be considered with 
approval of the medical monitor.  Steroids used to premedicate or manage ofatumumab infusion-
related reactions or contrast allergies are permitted.  In addition, short courses (<14 days) of 
treatment for non-cancer related medical reasons (treatment for autoimmune cytopenias are 
permitted) at doses not to exceed 100 mg/day of prednisone or equivalent are permitted.  Routine 
infusion premedication with corticosteroid doses of >100 mg IV prednisolone (or equivalent) is 
not permitted.  Red blood cell growth factors (eg, erythropoietin), platelet growth factors (eg, 
thrombopoietin) and sargramostim are also prohibited for the first six months of study treatment.  
However, initiation of red blood cell growth factors (eg, erythropoietin), platelet growth factors 
(eg, thrombopoietin) and/or sargramostim can be considered after 6 months on study based on 
the indication outlined in the respective package inserts. 
6.6.3. 
Guidelines for Ibrutinib Management with Surgeries or Procedures 
Ibrutinib may increase risk of bleeding with invasive procedures or surgery.  The following 
guidance should be applied during the perioperative period for subjects who require surgical 
intervention or an invasive procedure while receiving ibrutinib:   
• For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 
should be held at least 7 days prior to the intervention and should be held at least 7 days 
after the procedure and restarted at the discretion of the investigator when the surgical 
site is reasonably healed without serosanguineous drainage or the need for drainage 
tubes. 
• For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis) ibrutinib should be held for at least 3 days prior to the procedure and should 
not be restarted for at least 3 days after the procedure.  For bone marrow biopsies that are 
performed while the subject is on ibrutinib, it is not necessary to hold ibrutinib for these 
procedures.   
• For emergency procedures, ibrutinib should be held after the procedure until the surgical 
site is reasonably healed, for at least 7 days after the urgent surgical procedure. 
7. EFFICACY AND SAFETY PROCEDURES 
The Schedule of Assessments is provided in Appendix A.  Descriptions of the scheduled 
evaluations are outlined below. 


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Before study entry, throughout the study, and at the follow-up evaluations, various clinical and 
diagnostic laboratory evaluations are outlined.  The purpose of obtaining these detailed 
measurements is to ensure adequate safety and efficacy assessments.  Clinical evaluations and 
laboratory assessments may be repeated more frequently if clinically indicated. 
7.1. 
Description of Procedures 
7.1.1. 
Informed Consent 
The patient 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.  Patients must also grant permission to use protected health 
information per Health Insurance Portability and Accountability Act (HIPAA).  In addition, 
patients must sign all approved ICF amendments per the site IRB/REC/IEC’s guidelines during 
the course of the study. 
7.1.2. 
Confirmation of Eligibility 
Perform all necessary procedures and evaluations to document that the patient meets each 
eligibility criterion (Section 5).  Please refer to the study manual for a more detailed description 
of the enrollment procedures.  Blood samples for hematology, coagulation, and serum chemistry 
collected at Screening will be evaluated by a central laboratory to confirm eligibility.  If central 
labs submitted during the screening period are unable to be resulted (eg, specimen clotted or 
hemolysis) to support eligibility, the Medical Monitor may review local labs and approve the 
patient for randomization based on these lab values on a case by case basis provided another 
sample is redrawn and submitted prior to treatment. 
7.1.3. 
Medical History 
Collect and record the patient’s complete history including concurrent medical signs and 
symptoms.  Disease history, including the date of initial diagnosis, Rai and Binet staging 
(Appendix I) within 28 days of first dose with study drug, documentation of refractory disease, 
prior anticancer treatments with best responses and progression free interval to these treatments, 
and history of autoimmune CLL complications and their treatment will also be recorded based 
upon available documents and patient history. 
7.1.4. 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 9.2.  All medical occurrences 
that meet the AE definition must be recorded from the time the ICF is signed until 30 days after 
the last dose of study drug.  Laboratory abnormalities designated clinically significant by the 


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Investigator will also be recorded as AEs.  Additional important requirements for AE and SAE 
reporting are explained in Section 9.3. 
7.1.5. 
Physical Examination, Height and Weight 
Physical examinations should include height (Screening only) and weight, examination of the 
skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, and lymphatic system.  The 
lymphatic system examination will include bidimensional measurements of palpable lymph 
nodes and measurement of spleen and liver sizes by centimeters below the costal margin on the 
respective side.  Only physicians, physician assistant, or oncology nurse practitioners should 
perform the lymphatic system examination.  As much as possible, the same person should 
perform all the lymphatic exams for a given patient. 
7.1.6. 
Eye-related Symptoms Assessment 
The patients will be asked about the following eye-related symptoms at Screening and 
throughout the study:  dry eye, watering eye/abnormal discharge, eye pain, blurred vision/double 
vision, decreased visual acuity, photophobia/sensitivity to light, floaters, flashing lights, and eye 
irritation. 
If there are any symptoms of severity ≥ Grade 2 at Screening, an ophthalmologic exam must be 
completed prior to dosing with study drug.  If, during the study, any symptom worsens to 
severity ≥ Grade 2 or a symptom that was Grade 2 or higher at baseline worsens, an 
ophthalmologic exam must be performed. 
7.1.7. 
Disease-related Symptoms 
Disease-related symptoms including fatigue, night sweats, fever, weight loss, anorexia, and 
symptoms of splenomegaly (abdominal pain/discomfort) will be assessed and recorded in the 
patient records. 
7.1.8. 
Vital Signs 
Vital signs will include blood pressure, heart rate, respiratory rate, and body temperature. 
7.1.9. 
Electrocardiogram (ECG) 
Patients should have a 12-lead ECG done at Screening.  Abnormalities should be included in the 
medical history, as appropriate. 
ECGs should be performed at the investigator’s discretion, particularly in patients with 
arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset dyspnea. 


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7.1.10. 
ECOG Performance Status 
The ECOG performance index is provided in Appendix B. 
7.1.11. 
Cumulative Illness Rating Scale (CIRS) 
CIRS is an indicator of illness severity and comorbidity in older patients (Extermann 1998). 
CIRS scoring is to be performed by a licensed provider (eg, physician, physician assistant, or 
nurse) for all patients 65 years and older in the setting of a pretreatment history and physical 
(refer to Appendix H for details). 
7.1.12. 
Prior and Concomitant Medications 
Document all medications from 14 days before the start of study drug administration through 
30 days after the last dose of study drug. 
After a patient discontinues study treatment, receipt of all subsequent anticancer therapies will be 
collected until patient death. 
7.1.13. 
Patient-reported Outcomes (PRO) 
Three PRO instruments, including the EORTC QLQ-C30 (Appendix E), EQ-5D-5L 
(Appendix F), and FACiT-fatigue (Appendix G), will be administered in this study.  These 
questionnaires are to be completed by the patient prior to any other study procedures at required 
visits. 
7.1.13.1. EORTC QLQ-C30 
The EORTC QLQ-C30 includes 30 separate questions (items) resulting in 5 functional scales 
(Physical Functioning, Role Functioning, Emotional Functioning, Cognitive Functioning, and 
Social Functioning), 1 Global Health Status scale, 3 symptom scales (Fatigue, Nausea and 
Vomiting, and Pain), and 6 single items (Dyspnea, Insomnia, Appetite Loss, Constipation, 
Diarrhea, and Financial Difficulties) (Fayers 2001).  The recall period is 1 week (the past week). 
The EORTC QLQ-C30 has been widely used among cancer patients in general, and specifically 
in NHL patients.  It is a reliable and valid measure of PRO in cancer patients and takes about 
11 minutes to administer. 
7.1.13.2. EQ-5D-5L 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome 
(The Euro Qol Group 1990).  The EQ-5D-5L is 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 separate questionnaires are categorical and should not be 
analyzed as cardinal numbers.  However, the scores for the 5 dimensions are used to compute a 


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single utility score ranging from zero (0.0) to 1 (1.0) representing the general health status of the 
individual.  The United Kingdom weights will be used to generate patient utilities from the 
5 dimensions of the EQ-5D-5L in this study. 
7.1.13.3. FACiT-Fatigue 
The FACiT-Fatigue questionnaire is an instrument for use as a measure of fatigue-related quality 
of life in patients with cancer and other chronic diseases (http://www.facit.org).  The 13-item 
FACiT-Fatigue Scale measures each item on a 5‐point Likert scale.  The FACiT-Fatigue Scale 
has been validated in the general population (Cella 2002) as well as in patients with cancer or 
rheumatoid arthritis. 
7.1.14. 
Pregnancy Test 
Pregnancy tests (urine or serum) are required at Screening only for women of childbearing 
potential.  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. 
7.1.15. 
Hepatitis Serologies 
Hepatitis serologies include Hepatitis C antibody, Hepatitis B surface antigen, Hepatitis B 
surface antibody, and Hepatitis B core antibody and will be evaluated by central laboratory.  
Hepatitis B surface antigen must be confirmed negative prior to enrollment.  If Hepatitis B core 
antibody is positive, then Hepatitis B PCR to quantitate Hepatitis B DNA must be performed.  
DNA PCR needs to be confirmed negative (<29 U) prior to randomization in patients who are 
Hepatitis B core antibody positive.  Patients who are hepatitis C PCR positive will be excluded. 
7.1.16. 
Hematology 
Hematology will be evaluated by a central laboratory and will include a complete blood count 
(CBC) with white blood cell differential.  Any missing central lab blood samples should be 
redrawn as soon as possible.  In the event that the missing central lab sample is unrecoverable, 
local lab results will be collected, if available, and entered in the clinical database for response or 
progression confirmation. 
7.1.17. 
Coagulation Studies 
Measurement of prothrombin time (PT)/INR, and activated partial thromboplastin time (aPTT) 
will be performed at Screening using a central laboratory.  Any missing central lab blood 
samples should be redrawn as soon as possible. 


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7.1.18. 
Serum Chemistry 
Serum chemistry will be evaluated by a central laboratory and will include albumin, alkaline 
phosphatase, ALT, AST, blood urea nitrogen (BUN), calcium, creatinine, glucose, lactate 
dehydrogenase (LDH), phosphate, potassium, sodium, total bilirubin, and uric acid.  Any missing 
central lab blood samples should be redrawn as soon as possible. 
7.1.19. 
Serum Immunoglobulin and β2-microglobulin 
Sample(s) will be sent to a central laboratory for quantitative immunoglobulin (IgG, IgM, IgA) 
levels, and serum β2-microglobulin. 
7.1.20. 
Sparse Pharmacokinetics (PK) Sample Collection 
Sparse PK samples will be collected in patients randomized to ibrutinib.  Samples will be 
collected from at least 100 patients.  Five (5) blood samples will be collected per patient on the 
Week 1 Visit. 
1.  Pre-dose  
2.  1 hour (window: 45–75 minutes)  
3. 2 hours (window: 1.5–2.5 hours)  
4.  4 hours (window: 3.5–4.5 hours)  
5.  6 hours (window: 5–8 hours) 
Patients will also undergo sampling at the Week 4* visit.  These patients will be sampled at: 
1.  Pre-dose  
2.  1 hour (window: 45–75 minutes)  
3. 2 hours (window: 1.5–2.5 hours)  
4.  4 hours (window: 3.5–4.5 hours) 
On the day of the sampling visit, the patient will not take a dose before arrival at the clinic.  
Study drug intake will be observed by clinic staff.  The time of the PK sample and the time of the 
study drug dose will be recorded in the CRF. 
*Note:  If patient is unable to complete PK assessments at the Week 4 visit, it is acceptable to 
complete these assessments at the Week 8 visit. 
7.1.21. 
Pharmacokinetics Sample Collection for Patients Treated with Concomitant 
CYP3A4/5 Inhibitors on Ibrutinib Treatment 
For patients who must take strong or moderate CYP3A4/5 inhibitors while on treatment with 
ibrutinib, additional PK collections for evaluation of ibrutinib exposure may be requested at the 
following scheduled visit after concomitant CYP3A4/5 inhibitor has started and still in use.  
PK samples will be collected at: 


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1.  Pre-dose  
2.  1 hour (window: 45–75 minutes)  
3. 2 hours (window: 1.5–2.5 hours)  
On the day of the sampling visit, the patient will not take the dose of ibrutinib before arrival at 
the clinic.  Study drug intake will be observed by clinic staff.  The time of the PK sample and the 
time of the study drug dose will be recorded. 
7.1.22. 
Bone Marrow Aspirate and Biopsy 
For Eligibility 
A unilateral bone marrow aspirate or biopsy must be obtained at Screening or up to 90 days prior 
to randomization.  Patients who have a bone marrow aspirate or biopsy result since completion 
of their last therapy for CLL may use those bone marrow results provided the biopsy or aspirate 
was done <90 days prior to randomization. 
For Response Evaluation 
If the patient’s physical examination findings, laboratory evaluations, and radiographic 
evaluations suggest that CR has been achieved in all response parameters, a bone marrow 
aspirate and biopsy must be obtained to confirm the CR and to evaluate minimal residual disease 
(MRD) by flow cytometry.  In the event a marrow aspirate was not successfully submitted for 
MRD, a peripheral blood sample should be submitted.  In cases where cytopenic progression is 
suspected, a bone marrow aspirate or biopsy should be performed to distinguish autoimmune and 
drug-related cytopenias. 
7.1.23. 
Cytogenetic CLL FISH Panel 
Cytogenetic profiles will use the standard CLL FISH probes to detect abnormalities in 
chromosomes 13q, 12, 11q, and 17p.  Within 90 days prior to randomization, a peripheral blood 
sample or bone marrow sample (aspirate or biopsy) must be tested for FISH analysis for 
stratification purpose.  For patients without lymphocytosis FISH should be performed on the 
bone marrow sample.  A previous FISH and/or cytogenetic result demonstrating the presence of 
17p del as per the assay specification will be considered adequate for stratification provided 
appropriate documentation is available.  Results must be documented in the patient chart prior to 
randomization for the purposes of stratification.  At Screening, peripheral blood will be collected 
for confirmation of FISH result.  Screening peripheral blood (required) and marrow samples 
(where available) will be sent to a central vendor to be tested for 17p del, 13q-, +12, 11q-, to 
assist with the validation of the Abbott probe kit for use as prognostic marker. 
7.1.24. 
Determination of T/B/NK Counts 
In order to monitor the effects of ibrutinib on the immune cells in patients, specifically on the 
normal B cells, T cells and NK cells, whole blood samples will be analyzed for absolute T/B/NK 


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counts (CD3, CD19, CD4, CD8, CD16/56) using a standard cell marker panel.  This assay will 
be performed at the central lab on the same blood sample collected for standard hematology. 
7.1.25. 
Flow Cytometry-based Immunophenotype Assays 
To determine the temporal effect of study drugs on the phenotype of malignant cells in patients, 
blood samples will be collected and analyzed centrally.  Samples taken in the first 6 months will 
be more frequent in order to capture the treatment-effect of lymphocytosis.  Samples will also be 
collected at a suspected CR and at disease progression or discontinuation of treatment.  From 
these samples, peripheral blood mononuclear cells (PBMC) will be separated, collected and 
frozen as viable cells.  The cell pellets will be analyzed at a future date by flow cytometry, for 
expression of cell surface markers including CD3, CD19, CD45, CD5, Igλ/κ+, CXCR4 and 
CD38.  These samples will also be stained intracellularly for Ki67, pBtk, pSyk, pPLCγ, pErk and 
pAkt to monitor changes taking place within the tumor cells. 
7.1.26. 
Genetic and Molecular Prognostic Markers 
A blood sample will be collected and analyzed centrally to study the pretreatment prognostic 
factors.  These prognostic factors have previously been associated with disease outcome in CLL 
patients. 
IgVH and p53 Mutational Status 
One sample will be collected to study leukemia cell immunoglobulin heavy-chain variable 
(IgVH) and p53 mutational status. 
CD38 and ZAP-70 Leukemia Cell Expression 
One sample will be collected to study the leukemia cell expression of CD38 and ZAP-70. 
7.1.27. 
Exploratory Investigations of Predictive Biomarkers and Mechanism of 
Treatment Resistance 
Additional blood samples will be collected and assessed or maintained centrally to evaluate 
potential biomarkers related to response to therapy and/or to investigate potential mechanisms of 
treatment resistance.  These samples may be later characterized by technologies such as gene 
expression profiling, mutational analysis by sequencing, secreted protein analysis, and 
intracellular signaling pathway analysis.  Inhibition of BTK and other related kinases may also 
be explored in these cells.  It is expected that these efforts may identify genes and pathways 
associated with primary or later development of resistance to ibrutinib by comparison of patients 
with variable outcomes which could potentially generate biomarkers that could assist with future 
development of this compound. 


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7.1.28. 
Computed Tomography (CT) Scans 
Radiological imaging by CT with contrast is required and must include the pelvis, abdomen, 
chest, and neck.  Patients who are intolerant to IV CT contrast agents will have CT scans 
performed with oral contrast.  When possible, all patients should have radiographic tumor 
measurements performed at the participating study center or an acceptable alternate imaging 
facility using an identical imaging protocol and similar equipment.  The same imaging 
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. 
Magnetic resonance imaging (MRI) may be used to evaluate nontarget lesions that cannot be 
adequately imaged using CT (in cases where MRI is desirable, the MRI must be obtained at 
baseline and at all subsequent response evaluations).  If MRI is required for any other reason, 
this must be discussed with the study Medical Monitor first. 
CT scans will be performed until disease progression regardless of whether or not the patient 
remains on treatment.  In the event disease progression is suspected due to physical examination 
or laboratory test, a CT scan must be performed to confirm disease progression. 
There must be radiographically measurable disease at Screening (at least one lymph node 
> 1.5 cm in the longest diameter) as outlined in Section 8.1.4.  If the sole lesion lies within the 
field of prior radiotherapy, there must be evidence of disease progression in that lesion. 
Up to 6 measurable lymph nodes (target lesions > 1.5 cm in the longest diameter), clearly 
measurable in 2 perpendicular dimensions, will be followed as target lesions for each patient.  
Measurable sites of disease should be chosen such that they are representative of the patient’s 
disease.  In addition, selection of target lesions should be from as disparate regions of the body 
as possible 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 cranial-caudal measurement of the spleen and longest diameter of the liver will be assessed 
at Screening and all subsequent response evaluations. 
A central imaging service will be utilized to provide independent radiological assessments for 
the purposes of the primary endpoint.  These measurements will not be reported back to the site. 
7.1.29. 
Medical Resources Utilization (MRU) 
Hospitalizations, emergency department visits, blood product transfusions, and hematopoietic 
growth factor use will be collected for each treatment arm. 
7.1.30. 
Routine Clinical Assessments 
Routine clinical assessments include physical exams, recording of symptoms, and hematological 
evaluations to evaluate for both AEs and for disease progression at times when the CT scan is 


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not obtained.  If a patient shows signs of progression, the patient may continue treatment until 
progression is confirmed.  The Investigator should report any suspected disease progression to 
the Sponsor or designee via the electronic data capturing (EDC) system within 24 hours of 
discovery.  Patients should continue to be followed and adhere to study-related procedures until 
progression has been confirmed regardless of the administration of subsequent anticancer 
therapy.  New anticancer therapy may be withheld if clinically appropriate in the absence of 
confirmed progressive disease.  In addition, lab assessments for disease progression will need to 
be confirmed by the central lab. 
7.1.31. 
Overall Response Evaluations 
Overall response assessments will include evaluation of physical exams, recording of symptoms, 
hematological evaluations, and radiographic evaluations per the schedule of assessments (see 
Appendix A and Appendix M).  Patients who have signs and symptoms of progression outside of 
the scheduled assessment, should be evaluated by the investigator with a physical exam and a 
CBC with differential to determine if disease progression is present.  Patients may continue study 
treatment until progression is confirmed by a serial exam at least 2 weeks later.  In addition, 
when clinically appropriate, based on investigator perceived risk benefit assessment, a patient 
may continue treatment until progression is confirmed, unless considered medically 
contraindicated.  New anticancer therapy may be withheld if clinically appropriate in the absence 
of confirmed progressive disease.  The blood samples for response or disease progression 
determination will need to be confirmed by a central laboratory. 
For response assessments occurring without a CT scan, the investigator should evaluate response 
on available clinical data, including physical examinations and laboratory results. For patients 
who appear to be CR by all other parameters, a CT scan and evaluation of MRD status are 
required to confirm CR. 
Following the DMC review of interim efficacy analysis data, procedures surrounding expedited 
reporting of progressive disease are not required and IRC review may no longer occur. 
7.1.32. 
Survival 
After progression, patients will be contacted to assess survival status approximately every 
12 weeks until death, withdrawal by patient, lost to follow-up, or study terminated by Sponsor, 
whichever comes first.  At the time of the interim analysis and at study closure, a survival sweep 
will be conducted.  All patients who are on study and not known to have died prior to the 
survival sweep will be contacted at that time. 
7.1.33. 
Subsequent Anticancer Therapies 
After study drug treatment is complete, the following information on subsequent anticancer 
therapies will be collected approximately every 12 weeks until death, withdrawal by patient, lost 
to follow-up, or study terminated by Sponsor, whichever comes first: 


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• Receipt of all subsequent anticancer therapies 
• IWCLL indication for initiation of subsequent anticancer therapy 
• Response to all subsequent anticancer therapies 
7.2. 
Drug Concentration Measurements 
7.2.1. 
Sample Collection and Analysis 
Sparse PK samples will be collected from at least 100 patients on the ibrutinib arm.  Refer to the 
laboratory binder for instructions on collecting and processing these samples. 
Plasma samples will be analyzed by a validated and specific LC-MS/MS method for the 
determination of ibrutinib and PCI-45227, a metabolite of ibrutinib, in human plasma. 
Exploratory analyses may be performed for other potential metabolites of ibrutinib in plasma. 
7.2.2. 
Pharmacokinetic Assessment 
Plasma concentrations, dosing history, demographic data, and other covariates will be assembled 
into a dataset suitable for a population PK analysis.  The analysis will be performed using 
mixed-effects methods. 
Based on previous PK studies for ibrutinib, it is likely that the structural model will include two 
systemic compartments and first-order absorption and will be linear with respect to dose and 
stationary with respect to time.  Parameters of the PK model will be apparent clearance, apparent 
distribution clearance, apparent distribution volumes (central and peripheral), absorption rate, 
and absorption lag.  Absorption, distribution, and elimination half-lives and steady-state AUC 
will be calculated from these parameters. 
If the assumptions of linearity and stationarity are flawed, other models will be evaluated.  After 
determination of the structural model, covariates will be evaluated for inclusion into the model 
using forward addition.  The final model will be evaluated using one or more of the following 
methods: visual predictive check, likelihood profiles, or bootstrap analysis. 
Similar analyses will be performed for PCI-45227. 
For patients who received CYP3A4/5 inhibitors, as data permitted, a descriptive comparison of 
ibrutinib and PCI-45227 plasma concentrations after ibrutinib administration alone and in 
combination with CYP3A4/5 inhibitors will be explored. 
Pharmacokinetic relationships to pharmacodynamic measures of efficacy or toxicity will also 
be explored. 


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7.3. 
Assessments by Visit 
7.3.1. 
Screening Phase 
The procedures below will be performed for potential patients within 28 days of Week 1 Visit: 
• Informed consent 
• Review of eligibility criteria 
• PRO assessments 
• Adverse events 
• Medical history 
• Physical examination 
• Eye-related symptoms 
• Vital signs 
• 12-lead ECG 
• ECOG performance status 
• Prior medications (including chemotherapy, radiation, over-the-counter drugs, vitamins 
and herbs) 
• Pregnancy test (for women of childbearing potential only) 
• Hepatitis serologies 
• Hematology 
• Coagulation parameters 
• Serum chemistry 
• Genetic and molecular prognostic factors 
• Radiologic exam by CT (within 6 weeks of randomization) 
• Bone marrow biopsy and aspirate (within 90 days of randomization) 
• Cytogenetic, CLL FISH panel (within 90 days of randomization, see Section 7.1.23) 
7.3.2. 
Treatment Phase 
Following completion of the Screening Visit and once eligibility has been confirmed, patients 
will be randomized to either ofatumumab or ibrutinib 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 but no later than 3 business days prior to expected first dose with 
study drug. 
Study drug treatment should be continued until disease progression, unacceptable treatment-
related toxicity, or other reasons outlined in Section 10.1.  Local labs may be used to guide all 
dosing-related decisions and should be followed up with central labs.  In the event of clinically 


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suspected disease progression, the patient may continue to receive study medication until disease 
progression is confirmed at the discretion of the Investigator. 
Refer to the Schedule of Assessments (Appendix A) for a complete list of procedures to be 
performed at each scheduled study visit. 
7.3.2.1. 
Pre-Dose Week 1 Visit 
The following procedures will be performed prior to dosing (within 3 days) of the Week 1 Visit.  
Please note, Week 1 Visit procedures done at Screening will not need to be repeated if done 
within 3 days of first dose with study drug. 
• Confirmation of eligibility 
• Update medical history 
• Cumulative Illness Rating Scale (CIRS) (for patients ≥65 years of age only) 
• Adverse events 
• Physical examination 
• Disease-related symptoms (no longer required per Amendment 5) 
• Vital signs 
• ECOG performance status 
• Concomitant medications 
• Hematology 
• Serum chemistry 
• Serum immunoglobulins and β2-microglobulin 
• Pre-dose PK sample (ibrutinib arm only) 
• T/B/NK cells 
• Flow cytometry-based immunophenotype assays 
• Predictive biomarkers and mechanisms of resistance 
7.3.2.2. 
Dose Week 1 Visit 
• Administration of ofatumumab or ibrutinib 
7.3.2.3. 
Post-Dose Week 1 Visit 
• Adverse events 
• Concomitant medications 
• Sparse PK sample at 1, 2, 4, and 6 hours (ibrutinib arm only) 
• MRU (no longer required per Amendment 5) 


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7.3.2.4. 
Week 2, 3, 5, 6, and 7 Visits 
The following procedures will be performed, however, patients on the ibrutinib arm may have 
their blood drawn for the central lab submission at the site lab and do not need to return to clinic: 
• Administration of ofatumumab in clinic (ofatumumab arm only) 
• Hematology 
• Flow cytometry-based immunophenotype assays (Weeks 3 & 5 only) 
• Predictive biomarkers and mechanisms of resistance (Weeks 3 & 5 only) 
• Adverse events (by telephone contact for ibrutinib arm patients if not seen in the clinic) 
• Concomitant medications (by telephone contact for ibrutinib arm patients if not seen in 
the clinic) 
• MRU (by telephone contact for ibrutinib arm patients if not seen in the clinic) (no longer 
required per Amendment 5) 
7.3.2.5. 
Week 4-24 Visits, every 4 weeks 
The following procedures will be performed: 
• Administration of ofatumumab or ibrutinib 
• Physical examination 
• Eye-related symptoms (Weeks 12 and 24) 
• Disease-related symptoms (no longer required per Amendment 5) 
• Vital signs 
• ECOG performance status 
• PRO assessments 
• Concomitant medications 
• Adverse events 
• Hematology 
• Serum chemistry 
• Sparse PK sample (ibrutinib arm - Week 4 only) 
• T/B/NK cells (Weeks 12 and 24) 
• Flow cytometry-based immunophenotype assays (Beginning at Week 8) 
• Serum immunoglobulins and β2-microglobulin (Weeks 12 and 24) 
• MRU (no longer required per Amendment 5) 


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7.3.2.6. 
Weeks 36 until Discontinuation of Treatment, every 12 weeks 
The following procedures will be performed: 
• Physical examination 
• Eye-related symptoms (every 12 weeks until 18 months, then once every 24 weeks) 
• Disease-related symptoms (no longer required per Amendment 5) 
• Vital signs 
• ECOG performance status 
• PRO assessments 
• Concomitant medications 
• Adverse events 
• Hematology 
• Serum chemistry 
• Serum immunoglobulins and β2-microglobulin 
• T/B/NK cells 
• Flow cytometry-based immunophenotype assays 
• Predictive biomarkers and mechanisms of resistance 
• MRU (no longer required per Amendment 5) 
7.3.2.7. 
Response Evaluations, every 12 weeks from first dose until progression 
The following procedures will be performed in conjunction with standard visits every 12 weeks 
and then every 24 weeks after 18 months until the patient exhibits disease progression: 
• Radiologic exam by CT, only required every 24 weeks after 12 months, and annually 
after 36 months 
• Overall response assessment 
• Bone marrow biopsy (when appropriate to confirm CR or evaluate cytopenia) 
7.3.2.8. 
End-of-Treatment Visit 
The following will be performed 30 (± 3) days after the discontinuation of treatment with 
study drug: 
• Physical examination 
• Vital signs 
• ECOG performance status 
• Eye-related symptoms 


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• Disease-related symptoms (no longer required per Amendment 5) 
• PRO assessments 
• Concomitant medications 
• Adverse events 
• MRU (no longer required per Amendment 5) 
• Hematology 
• Serum chemistry 
• Flow cytometry-based immunophenotype assays 
• Predictive biomarkers and mechanisms of resistance 
7.3.3. 
Follow-up Phase 
7.3.3.1. 
Post-treatment Phase 
After discontinuation of treatment, the following assessments will be performed every 12 weeks 
(±7 days) until disease progression or study closure, whichever is earlier: 
• Subsequent anticancer therapies 
• Physical examination and ECOG performance status 
• Disease-related symptoms (no longer required per Amendment 5) 
• MRU (no longer required per Amendment 5) 
• PRO assessments 
• Hematology 
• Serum immunoglobulins and β2-microglobulin 
• T/B/NK cells 
• Flow cytometry-based immunophenotype assays 
• Predictive biomarkers and mechanisms of resistance 
Prior to disease progression, response assessment (including CT, CBC and PE) need to be 
continued on a calendar schedule even if the patient receives subsequent anticancer therapy. 
7.3.3.2. 
Post-disease Progression Phase 
Once patient progresses, the following assessments will be assessed every 12 weeks until death, 
withdrawal by patient, lost to follow-up, or study terminated by Sponsor, whichever comes first. 
• Subsequent anticancer therapies 
• MRU (no longer required per Amendment 5) 
• Survival status 


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• Occurrence of any additional malignancy 
• Occurrence of transformation to a more aggressive histology (Richter's transformation)  
7.3.4. 
Treatment with Ibrutinib for Patients on Control Arm  
On 03 January 2014, the DMC determined that the primary endpoint of the study had been met 
and the analysis be considered final. Patients randomized to ofatumumab who meet the criteria 
outlined in Section 7.3.4.1, per the investigator's discretion, can receive next-line therapy with 
ibrutinib and will follow the schedule in Appendix M.  Treatment with ibruntib can be continued 
until disease progression as determined by the investigator, or until they meet the criteria for 
withdrawal in Section 10.  Patients must meet all of the criteria for next-line therapy with 
ibrutinib listed in Section 7.3.4.1.  With Medical Monitor approval, local labs can be used to 
determine appropriateness for next-line ibrutinib. 
7.3.4.1. 
Criteria for Next-line Ibrutinib Therapy 
1. Medical Monitor approval 
2. ECOG Performance Status of ≤3 (Appendix B)  
3. Platelet count ≥25,000/μL   
4. 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)  
5. 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 J), or history of 
myocardial infarction within 6 months prior to first dose with study drug 
6. Recovered from the acute toxicities due to prior chemotherapy, radiotherapy, 
investigational drugs, or experimental treatments (non-hematologic toxicities have 
resolved to a NCI CTCAE [version 4.0] Grade of ≤2) 
7. No known Richter’s transformation 
8. Does not require or receive anticoagulation with warfarin or equivalent vitamin K 
antagonists (eg, phenprocoumon)  
9. Female patient of childbearing potential must have a negative serum or urine pregnancy 
test within 3 days of the first dose of study drug and agree to use highly effective method 
of contraception during the study and for 1 month following the last dose with ibrutinib 
or 12 months following the last dose with ofatumumab.  Post menopausal females 
(>45 years old and without menses for >1 year) and surgically sterilized females are 
exempt from this criterion 


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10. Male patient must use an effective barrier method of contraception during the study and 
for 3 months following the last dose of study drug if sexually active with a female of 
childbearing potential 
11. No history of stroke or intracranial hemorrhage within 6 months 
7.3.4.2. 
Next-line Ibrutinib Therapy Treatment Phase 
Refer to the next-line ibrutinib therapy Schedule of Assessments (Appendix M) for a complete 
list of procedures to be performed at each scheduled study visit. 
8. MAIN EFFICACY EVALUATIONS 
Disease evaluations will include: 
• Physical examination (which will focus on the presence or absence or increase or 
decrease in lymph nodes, liver, and spleen). 
• CBC with measurement of parameters by a central laboratory. 
• Computed tomography (CT) scan of the neck, chest, abdomen, and pelvis (further timing 
is discussed in Section 7.3.2.7 and in the Schedule of Assessments [Appendix A]). 
Efficacy assessments, for the purpose of the study result analyses, will be performed by an IRC 
blinded to study treatment information and independent of Investigators and personnel who are 
involved in the conduct of the study.  The process and convention of the IRC will be detailed in a 
separate charter. 
8.1. 
Definitions 
8.1.1. 
Refractory 
Refractory is defined as treatment failure or progression within 12 months post-treatment. 
8.1.2. 
Relapsed 
Relapsed is defined as a patient who met criteria for CR or PR, but progressed beyond 12 months 
post-treatment. 
8.1.3. 
Treatment Failure 
Treatment failure is defined as best response of progressive disease or SD while on study 
treatment. 
8.1.4. 
Measurable Disease 
Patients must have at least 1 measurable site of disease to participate in this study.  Measurable 
sites of disease are defined as lymph nodes, or lymph node masses.  Each measurable site of 


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disease must be greater than 1.5 cm in the longest diameter.  Measurement must be determined 
by imaging evaluation. 
Tumor lesions that are situated in a previously irradiated area might or might not be considered 
measurable.  If there are tumor lesions in previously irradiated areas and progression has 
occurred, these lesions will be considered measurable.  If tumor lesions in previously irradiated 
areas are present and have been stable, then these lesions are not considered measurable.  
If tumor lesions in previously irradiated areas progress during the study, then disease progression 
will be considered as having occurred provided progression is confirmed by IRC. 
All other sites of disease will be considered assessable.  Assessable disease includes objective 
evidence of disease that is identified by radiological imaging, physical examination, or other 
procedures, as necessary, including peripheral blood counts. 
8.1.5. 
Treatment-related Lymphocytosis 
Treatment-related lymphocytosis, for the purposes of this protocol, is defined as an elevation in 
blood lymphocyte count of ≥50% compared to baseline and ≥5000/µL that occurs in the setting 
of unequivocal improvement in at least one other disease-related parameter including lymph 
node size, spleen size, hematologic parameters (Hgb or platelet count), or disease-related 
symptoms.  Given the known mechanism of action of BCR-inhibiting agents including ibrutinib, 
treatment-related lymphocytosis is an expected and frequent pharmacodynamic phenomenon 
observed with initiation (or re-initiation) of ibrutinib. 
Response assessment in CLL patients treated with novel agents has been clarified by the authors 
of the IWCLL 2008 guidelines and is outlined in the NCCN NHL 2012 guidelines, supporting that 
patients with isolated lymphocytosis in the setting of improvement in other disease parameters 
should not be considered to have progressive disease or treatment failure (Cheson 2012). 
8.1.6. 
Richter’s Transformation 
Richter's syndrome (RS) is lymphomatous transformation to a more aggressive histology in a 
patient with CLL or SLL.  RS is most often characterized by the development of high-grade 
NHL or Hodgkin’s disease.  Symptoms of Richter’s transformation can include new or 
progressive lymphadenopathy or organomegaly, fever, loss of weight and muscle mass, and 
other health problems.  Richter's transformation can be suggested by a CT/PET scan, but should 
be confirmed with a biopsy (eg, lymph node) demonstrating the histologic transformation 
whenever possible. 
8.1.7. 
Minimal Residual Disease (MRD) 
Patients who have achieved a CR should be evaluated for eradication of disease cells as 
determined by flow cytometry on the bone marrow aspiration when available. 


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8.2. 
Radiographic Images Assessment 
Radiological efficacy assessments, for the purpose of the study result analyses, will be performed 
by the IRC, which will be blinded to study treatment information.  The process and convention 
of the review will be detailed in a separate charter. 
The baseline disease assessment will include all areas of known and suspected disease with use 
of the most appropriate and reproducible radiological technique. 
8.3. 
Guidelines for Evaluation 
Table 3 outlines what is required for each parameter at baseline to be evaluable throughout the 
study. 
Table 3: 
Evaluable Parameter Requirements 
Parameter 
Requirements to be Evaluable for Response 
Measurable Disease (required for all patients) 
Lymph Node > 1.5cm 
Splenomegaly 
Enlarged spleen 
Hepatomegaly 
Enlarged liver 
Absolute Lymphocyte Count (ALC) 
≥ 4,000 /µL 
Platelets 
≤100,000 /µL 
Absolute Neutrophil Count (ANC) 
≤ 1500 /µL 
Hgb 
≤ 11.0 g/dL 
8.4. 
Response Categories 
Assessment of response should include physical examination, radiographic imaging, and 
evaluation of blood and marrow per the schedule of assessments (see Appendix A and  
Appendix M) and to confirm CR.  Definition of response for CR, CRi, nPR, PR, PR with 
lymphocytosis, and disease progression will be evaluated by the criteria listed in Table 4.  
Category A criteria define the tumor load and Category B criteria define the function of the 
hematopoietic system. Response must be confirmed by CT and central labs, and must last at least 
2 months without transfusional support or growth factor product to be considered a confirmed 
response. 
8.4.1. 
Complete Response (CR) 
All of the following are required for a CR: 
• No significant lymphadenopathy (>1.5cm) palpable on examination or by CT 
• No hepatosplenomegaly on examination or by CT 


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• No constitutional symptoms (ie, no fever >38ºC for ≥2 weeks, no unintentional ≥10% 
body weight loss within last 6 months, no night sweats for >1 month without other 
evidence of infection, no fatigue interfering with work or usual activities) 
• Neutrophils >1.5 x109/L, platelets >100,000/μL, and Hgb >11g/dL without recent growth 
factor or transfusions 
• ALC <4,000 /µL 
Marrow aspirate and biopsy must be performed after all other criteria meet the definition of CR.  
To define a CR, the marrow sample must be at least normocellular for age, with less than 30% of 
nucleated cells being lymphocytes.  B-lymphoid nodules should be absent. In addition, in 
patients with a CR, MRD by flow cytometry should be performed to evaluate MRD status. 


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Table 4: 
Criteria for Response Categories 
Parameter 
CR 
PR 
PD 
Group A 
Lymphadenopathya 
None; ≤1.5cm 
Decrease ≥50% 
increase ≥50% 
Hepatomegaly 
None 
Decrease ≥50% 
increase ≥50% or new 
hepatomegaly 
Splenomegaly 
None 
Decrease ≥50% 
increase ≥50% or new 
splenomegaly 
Blood lymphocytes 
<4000/µL 
Decrease ≥50% from 
baseline 
increase ≥50% over 
baselinec 
Marrowb 
Normocellular, <30% 
lymphocytes, no B lymphoid 
nodules, Hypocellular defines 
CRi 
 
 
Group B 
Platelet count 
>100,000/µL 
>100,000/µL or increase 
≥50% over baseline 
Decrease of ≥50% from 
baseline secondary to 
CLL 
Hemoglobin 
>11 g/dL 
>11g/dL or increase ≥50% 
over baseline 
Decrease of >2g/dL from 
baseline secondary to 
CLL 
Neutrophils 
>1500/µL 
>1500/µL or increase 
≥50% over baseline 
N/A 
a Sum of the products of multiple lymph nodes (as evaluated by CT scans) or the longest diameter of one target 
lymph node 
b This parameter is not relevant for the PD category unless confirming cytopenic progression. 
c Patients with treatment-related lymphocytosis should remain on study treatment in the absence of other criteria for 
progressive disease (see Section 8.1.5). 
Note: Group A defines the tumor load and Group B defines the function of the hematopoietic system 
CR: all of the criteria need to be met and patients have to lack disease related constitutional symptoms.  
Bone marrow and aspirate is required to confirm CR. 
PR: all abnormal Group A criteria must be met plus 1 of the criteria from Group B must be met.  Note if all PR 
criteria with the exception of ALC are met this is consistent with a PR with lymphocytosis 
SD: the absence of PD and the failure to achieve a CR, CRi, nPR, PR, or PR with lymphocytosis. 
PD: at least 1 of the above criteria from Group A or B are met or development of transformation to a more 
aggressive histology 
Cross reference:  Hallek 2008 and Hallek et al. June 2012 e-letter 


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8.4.2. 
Complete Response with an Incomplete Marrow Recovery (CRi) 
CRi is defined as a CR with an incomplete recovery of the patient’s bone marrow.  Patients who 
have a CRi fulfill all criteria for a CR, but continue to have persistent anemia, thrombocytopenia, 
or neutropenia.  These cytopenias are due to drug toxicity in the bone marrow and are not due to 
any evidence of CLL.  If the marrow is hypocellular, a repeat determination should be performed 
after 4 weeks, or when peripheral blood counts have recovered.  However, this time interval 
should not exceed 6 months. 
8.4.3. 
Nodular Partial Response (nPR) 
nPR is a response where patients meet criteria for a CR, but the bone marrow biopsy shows that 
there are still B-lymphoid nodules, which may represent a clonal infiltrate.  These nodules are 
residual disease and therefore the patient is termed an nPR. 
8.4.4. 
Partial Response (PR) 
A ≥50% drop in lymphocyte count from baseline or ≤4.0 x 109/L is required for a PR and all of 
the following are observed: 
• ≥50% decrease in the sum products of up to 6 lymph nodes, a ≥50% decrease in the 
longest diameter of the single lymph node, or normalization of lymphadenopathy when 
compared to baseline. 
• No new enlarged lymph nodes by physical examination or CT AND no increase in any 
lymph node by CT.  Note:  In a small lymph node <2 cm, an increase of less than 25% is 
not considered to be significant. 
• When abnormal, a ≥50% decrease in the enlargement of the spleen and/or liver from 
baseline or normalization by CT 
Plus a response in at least one of the following evaluable criteria independent of growth factor 
support or transfusion. 
• Neutrophils >1.5 x109/L, or ≥50% improvement over baseline 
• Platelets >100,000/μL or ≥50% improvement over baseline 
• Hgb >11 g/dL or ≥50% improvement over baseline 
* Note: If all criteria are normal, defined as neutrophils >1.5 x109/L, platelets 
>100,000/μL, and Hgb >11g/dL at baseline, they must remain normal to be considered 
consistent with a PR. 
8.4.5. 
PR with Lymphocytosis 
Patient achieved all PR criteria with the exception of lymphocyte criteria. 


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8.4.6. 
Stable Disease (SD) 
Not meeting criteria for CR, CRi, nPR, PR, PR with lymphocytosis, or progressive disease. 
8.4.7. 
Progressive Disease 
A CT scan is required to evaluate all cases of suspected progressive disease for this protocol 
regardless of the modality of disease progression (eg. lymph node, lymphocytosis, 
or transformation).  Progressive disease requires at least ONE of following: 
• New enlarged nodes >1.5 cm, new hepatomegaly or splenomegaly; or other organ 
infiltrates 
• ≥50% increase from nadir in existing lymph node (must reach >1.5 cm in the longest 
diameter) or ≥50% increase from nadir in sum of product of diameters of multiple nodes 
• ≥50% increase from nadir in enlargement of liver or spleen 
• ≥50% increase from baseline in lymphocyte count (and to ≥5 x109/L) unless considered 
treatment-related lymphocytosis (Section 8.1.5) 
• New cytopenia (Hgb or platelets) attributable to CLL.  The progression of any cytopenia 
(unrelated to autoimmune cytopenia, drugs, or bleeding), as documented by a decrease of 
Hgb levels from baseline by more than 20 g/L (2g/dL) or to less than 100 g/L (10g/dL) 
and lower than baseline, or by a decrease of platelet counts from baseline by ≥50% or to 
less than 100 × 109/L (100,000/μL) and lower than baseline in the presence of active 
CLL, defines disease progression ; a marrow biopsy must demonstrate an infiltrate of 
clonal CLL cells if no other evidence of disease progression is present on CT scan. 
• Transformation to a more aggressive histology (eg, Richter’s Transformation).  
Whenever possible, this diagnosis should be established by biopsy. 
Suspected progressive disease must be confirmed by a serial exam at least 2 weeks later.  Please 
see Section 7.1.31 on details regarding suspected PD and IRC confirmation. 
8.5. 
Sustained Hematological Improvement 
In the subset of patients with cytopenia(s) at baseline (Hgb ≤11g/dL, platelets ≤100,000/μL, or 
ANC ≤1500/μL), time to improvement in blood counts and percentage of patients with sustained 
improvement in blood counts, (sustained improvement, defined as improvement in cytopenia by 
≥50%, or Hgb >11g/dL, ANC >1500 cells/μL, platelets >100,000/μL with the duration of 
improvement lasting for at least 2 months without blood transfusion or growth factors), will be 
recorded. 
8.6. 
Resolution of Pretreatment Disease-related Symptoms 
Resolution of pretreatment symptoms including fatigue, weight loss, anorexia, fevers, night 
sweats, or symptoms of splenomegaly will be evaluated. 


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9. ASSESSMENT OF SAFETY 
9.1. 
Safety Monitoring Plan 
The safety of this study will be assessed by an independent DMC.  All enrolled patients will be 
evaluated clinically and using standard laboratory testing during their participation in this study. 
Safety assessments will consist of monitoring and recording AEs and SAEs; measurements of 
protocol-specified hematology, clinical chemistry, and other laboratory variables; measurement 
of protocol-specified vital signs; and other protocol-specified tests that are deemed critical to the 
safety evaluation of the study drug(s). 
9.2. 
Definitions 
9.2.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (ICH-E2A, 1995). 
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 spontaneously offered by the patient and/or observed 
by the Investigator or study staff including laboratory abnormalities of clinical 
significance. 
• Any AEs experienced by the patient through the completion of final study procedures. 
• AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with CLL/SLL that were not 
present before the AE reporting period (see Section 9.3.1) 
• 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 
CRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period. 


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• Pre-planned or elective hospitalization:  A hospitalization planned before signing the 
informed consent form is not considered an SAE, but rather a therapeutic intervention.  
However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE.  
Surgeries or interventions that were under consideration, but not performed before 
enrollment in the study, will not be considered serious if they are performed after 
enrollment in the study for a condition that has not changed from its baseline level.  
Elective hospitalizations for social reasons, solely for the administration of 
chemotherapy, or due to long travel distances are also not SAEs. 
• 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. 
• Asymptomatic Treatment Related Lymphocytosis:  This event should also not be 
considered an AE.  Patients with treatment-related lymphocytosis should remain on study 
treatment and continue with all study-related procedures. 
9.2.2. 
Serious Adverse Event 
Note: The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to the 
grade of an AE (see below).  “Serious” is a regulatory definition. 
A SAE (experience) or reaction 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 patient was at risk 
of death at the time of the event.  It does not refer to an event which hypothetically might 
have caused death if it were more severe.  If either the Investigator or the Sponsor 
believes that an AE meets the definition of life-threatening, it will be considered 
life-threatening. 
• Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the patient’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 patient or patient may 
require intervention to prevent one of the other outcomes listed in this definition.  
Examples of such events are intensive treatment in an emergency department or at home 
for allergic bronchospasm, blood dyscrasias, or convulsion that does not result in 
hospitalization; or development of drug dependency or drug abuse. 
Given that the Investigator’s perspective may be informed by having actually observed the event, 
and the Sponsor is likely to have broader knowledge of the drug and its effects to inform its 
evaluation of the significance of the event, if either the Sponsor or the Investigator believes that 
the event is serious, the event will be considered serious. 


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9.2.3. 
Severity 
Definitions found in the Common Terminology Criteria for Adverse Events version 4.0 
(CTCAE v4.0) will be used for grading the severity (intensity) of nonhematologic AEs.  Refer to 
Appendix D for the grading of hematologic AEs.  The CTCAE v4.0 displays Grades 1 through 5 
with unique clinical descriptions of severity for each referenced AE.  Should a patient experience 
any AE not listed in the CTCAE v4.0, the following grading system should be used to assess 
severity: 
• Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the patient’s daily activities 
• Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the patient, 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 patient’s usual daily activity, and require systemic drug therapy or other 
treatment 
• Grade 4 (Life-threatening or disabling AE) – experiences which cause the patient to be in 
imminent danger of death 
• Grade 5 (Death related to AE) – experiences which result in patient death 
9.2.4. 
Causality 
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. 


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9.2.5. 
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. 
9.3. 
Documenting and Reporting of Adverse and Serious Adverse Events by 
Investigators 
The Investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, as outlined in the prior sections, are recorded on the CRF.  All SAEs also must 
be reported on the SAE Worksheet (see Section 9.3.3). 
9.3.1. 
Adverse Event Reporting Period 
All adverse events will be reported from the time the patient signs the Informed Consent Form 
until 30 days following the last dose of study drug. 
If an SAE is present at the End-of-Treatment Visit, the SAE should be followed to resolution or 
until the Investigator assesses the patient as stable, or the patient is lost to follow-up or 
withdraws consent.  Resolution/stable means the patient has returned to baseline state of health 
or the Investigator does not expect any further improvement or worsening of the event. 
If a death occurs within 30 days after the last dose of study drug, the death must be reported to 
the Sponsor as an SAE. 
Any SAE that occurs more than 30 days after the last dose of the study drug and is deemed 
related to ibrutinib, must be reported to the sponsor.   
9.3.2. 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all patient evaluation timepoints 
during the study.  All AEs and SAEs whether volunteered by the patient, discovered by study 
personnel during questioning, detected through physical examination, clinically significant 
laboratory test, or other means will be recorded in the patient’s medical record and on the AE 
CRF and, when applicable, on the SAE Worksheet. 


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Each recorded AE or SAE will be described by its duration (ie, start and end dates), severity, 
regulatory seriousness criteria (if applicable), suspected relationship to the investigational 
product, and any actions taken. 
9.3.3. 
Expedited Reporting Requirements for Serious Adverse Events 
All SAEs (initial and follow-up information) will be reported on the SAE Worksheet and faxed 
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, fax and email) for the drug safety can be found on the SAE Worksheet form 
and instructions. 
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself.  The primary cause of death on the 
autopsy report or the adverse event/SAE most proximal to death should be the term reported.  
Autopsy and postmortem reports must be forwarded to Pharmacyclics Drug Safety, or designee, 
as outlined above. 
If study drug is discontinued because of an SAE, this information must be included in the SAE 
report. 
9.3.4. 
Events of Special Interest 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities by the Sponsor.  These events will be reported to the Sponsor within 
24 hours of awareness following the procedure described above for SAEs (Section 9.3.3) 
and will require enhanced data collection.  All Events of Special Interest will be submitted 
without a serious criterion selected if no other serious criterion is met. 
9.3.4.1. 
Major Hemorrhage 
Defined as any hemorrhagic event that is Grade 3 or greater in severity, or that results in one of 
the following: intraocular bleeding causing loss of vision, the need for a transfusion of two or 
more units of red cells or an equivalent amount of whole blood, hospitalization or prolongation 
of hospitalization. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 9.3.4 above. 
9.3.4.2. 
Intracranial Hemorrhage 
Any intracranial hemorrhage adverse event, including subdural hematoma/hemorrhage, epidural 
hematoma/hemorrhage and intracerebral hemorrhage, of any grade severity, will be captured as 
an event of special interest according to Section 9.3.4 above. 


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9.3.5. 
Other Malignancies 
In addition to all routine AE reporting, all new malignant tumors including solid tumors, skin 
malignancies and hematologic malignancies are to be reported for the duration of study treatment 
and during any protocol-specified follow-up periods including post-progression follow-up for 
overall survival.   
9.3.6. 
Pregnancy 
Before study enrollment, patients must agree to take appropriate measures to avoid pregnancy.  
However, should a pregnancy occur in a female study patient, 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 patient must immediately inform the investigator if the patient becomes pregnant from 
the time of consent to 30 days after the last dose of ibrutinib or to 12 months following the last 
dose of ofatumumab.  A male patient must immediately inform the investigator if the patient’s 
partner becomes pregnant from the time of consent to 3 months after the last dose of study drug.  
Any female patients receiving ibrutinib capsules who become pregnant must immediately 
discontinue study drug.  The Investigator should counsel the patient, discussing any risks of 
continuing the pregnancy and any possible effects on the fetus. 
Although pregnancy itself is not regarded as an AE, the outcome will need to be documented.  
Report any pregnancy that occurs in a patient or patient’s partner from the time of consent to 
30 days after the last dose of study drug.  Record any occurrence of pregnancy on the Pregnancy 
Report Form Part I and fax to Pharmacyclics Drug Safety, or designee, within 24 hours of 
learning of the event.  With consent the pregnant female 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 an SAE. 
9.3.7. 
Eye-Related Adverse Events 
New or worsening eye-related symptoms that are Grade ≥2 should be evaluated by an 
ophthalmologist whose findings should be reported on the ophthalmic CRF. 
9.4. 
Reporting of Serious Adverse Events by Sponsor 
Regulatory Authorities, IRBs/REBs/IECs, and Investigators will be notified of SAEs in 
accordance with applicable requirements (eg, Good Clinical Practices [GCPs], ICH guidelines, 
national regulations, and local requirements).   


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The Pharmacyclics Pharmacovigilance Committee will review and evaluate accumulating safety 
data from the entire clinical trial database for ibrutinib at appropriate intervals (eg, quarterly) to 
identify new safety signals or increased frequency of events.  This will include an aggregate 
review and comparison to the control group of SAEs that were deemed as “not suspected” of 
being associated with use of ibrutinib because they were likely to have been manifestations of 
underlying disease or that commonly occur in the patient population. 
10. WITHDRAWAL OF PATIENT FROM TREATMENT OR STUDY 
Investigators are encouraged to keep a patient experiencing clinical benefit on study treatment 
unless significant toxicity puts the patient at risk or routine noncompliance puts the study 
outcomes at risk. 
10.1. Discontinuation of Treatment 
If the patient meets any of the following criteria then discontinuation from treatment is mandatory: 
• 
Progressive disease as determined by protocol defined criteria 
• 
Toxicity as defined in dose discontinuation portions of the protocol 
• 
Death 
• 
Withdrawal from treatment by patient including withdrawal of informed consent 
• 
Investigator decision 
• 
Completion of treatment regimen (applies to ofatumumab only) 
• 
Requires prohibited treatment 
• 
Lost to follow-up 
• 
Study terminated by Sponsor 
10.2. Withdrawal from the Study 
A patient may be withdrawn from the study for any of the following reasons including: 
• 
Death 
• 
Lost to follow-up 
• 
Study terminated by Sponsor 
• 
Withdrawal of consent  
o Withdrawal of consent is the primary reason for study termination only if a 
patient refuses any further contact or follow up.  Please contact Medical Monitor 
within 24 hours of any consent withdrawal. 
In case a patient is lost to follow-up, every possible effort must be made by the study site 
personnel to contact the patient and determine the reason for discontinuation.  The measures 
taken to follow-up must be documented in the patient’s records. 
When a patient withdraws before completing the study, the reason for withdrawal must be 
documented in the source documents. 


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10.3. Extension Study 
Patients who were on study drug and did not progress at the time of study closure may enroll into 
a long-term extension study and continue to receive ibrutinib when access to commercial 
ibrutinib is not feasible. 
11. ENDPOINTS 
11.1. Primary 
The primary endpoint of the study is PFS, as assessed by IRC review per IWCLL 2008 criteria 
(Section 8.4). 
11.2. Secondary 
Efficacy 
To compare between the two treatment groups in terms of: 
• OS 
• Overall response rate (ORR) is defined as the proportion of patients who achieve 
complete response (CR), complete response with incomplete bone marrow recovery 
(CRi), nodular partial response (nPR), or partial response (PR) per IWCLL 2008 criteria 
over the course of the study as evaluated by an IRC 
• Patient reported outcome (PRO) as measured by the FACiT-Fatigue. 
o The efficacy measure for the FACiT-Fatigue will be the change in scores from 
baseline to each assessment. 
• Hematological improvement in the subset of patients with cytopenia(s) at baseline 
assessed by time to improvement and percentage of patients with improvement 
Safety 
• To compare the safety and tolerability between the two treatment groups 
11.3. Exploratory 
• Investigator-assessed PFS per IWCLL 2008 criteria 
• Investigator-assessed ORR per IWCLL 2008 criteria 
• Improvement of disease-related symptoms (weight loss, fatigue, fever, night sweats, 
abdominal pain due to splenomegaly, or anorexia). 
• Patient reported outcomes (PRO) as measured by EORTC QLQ-C30 and EQ-5D-5L. 
o The efficacy measure for the EORTC QLQ-C30 will be the change in scores from 
baseline to each assessment for all scales. 


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o The efficacy measure for the EQ-5D-5L will be the change in weighted utility 
score from baseline to each assessment. 
• Medical resource utilization (MRU) associated with the therapy including the number of 
hospitalizations, emergency department visits, blood product transfusions, and use of 
hematopoietic growth factors. 
• PK characteristics of ibrutinib in patients with CLL/SLL and to determine which, if any, 
covariates (eg, age, gender, body size, race) influence exposure to ibrutinib. 
• Exploratory evaluation of predictive biomarkers and/or mechanisms of resistance. 
12. STATISTICAL CONSIDERATIONS 
This section outlines statistical analysis approaches and methods for the study.  Specific details 
for efficacy and safety analyses will be described in the Statistical Analysis Plan (SAP). 
12.1. General Considerations 
12.1.1. 
Independent Review Committee (IRC) 
The IRC will be chaired by a physician with expertise in CLL and SLL and will conduct 
response evaluations in accordance with the IRC charter. 
12.1.2. 
Data Monitoring Committee (DMC) 
The safety of this study will be monitored by an independent DMC. 
An early safety analysis will be performed after approximately 50 patients have been treated for 
approximately 8 weeks.  This analysis will focus on deaths, treatment discontinuations, SAEs, 
and grade 3/4 AEs as well as special events of interest.  This information will be reviewed by the 
Medical Monitor on an ongoing basis until this early safety analysis is conducted.  The chair of 
the DMC, with involvement of the DMC statistician, as needed, will issue a recommendation as 
to whether the study should be interrupted during this period.  If the DMC recommends the trial 
be continued, the DMC will review safety data every 6 months.  Otherwise, the DMC may 
request further safety analyses.  Results from a pre-specified interim analysis will also be 
reviewed by the DMC. 
The independent DMC will be chaired by a physician with expertise in CLL and SLL.  The 
DMC will review data and provide recommendations regarding stopping or continuing the trial 
in accordance with the DMC charter.  The Sponsor may attend only the blinded portion of the 
DMC meetings to answer questions as necessary.  The DMC charter will provide provisions for 
restricted communications between the DMC and the Sponsor in the event the DMC 
recommends stopping the study for safety or superiority.  Following the DMC review of the 
prespecified interim analysis and the unanimous recommendation that the study be stopped early 
and patients on ofatumumab be provided access to ibrutinib – the DMC reviews have concluded.   


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12.2. Randomization 
Two randomization schemes will be generated: one for each geographic region (North America 
versus Rest of World).  Under each scheme, randomization will be stratified using the following 
two stratification factors and patients will be randomized in a 1:1 ratio to receive either 
ofatumumab or ibrutinib within each randomization stratum: 
a) The presence or absence of disease that is refractory to purine analog and anti-CD20 
containing chemoimmunotherapy regimen (at least 2 cycles).  Refractory is defined 
as treatment failure (best overall response of SD or progressive disease on treatment) 
or disease progression within 12 months of the last dose of purine analog. 
b) The presence or absence of 17p del as determined by the assay specification on 
pretreatment FISH or cytogenetics evaluation. 
12.3. Sample Size considerations 
This study is designed to evaluate PFS and is powered based on this endpoint.  Therefore, the 
desired operating characteristics for the PFS endpoint are used to determine the study’s total 
sample size and overall duration.  
With the agreement from the European (Rapporteur and Co-Rapporteurs) and US Health 
Authorities, the overall two-sided significance level for this study is revised from 0.01 to 0.05. 
Given this revision in overall significance level, 176 PFS events provides approximately 90% 
power to detect the target hazard ratio of 0.6 based on a log-rank test and a two-sided overall 
significance level of 0.05 adjusted for one planned interim analysis. 
The sample size and power calculations are based on a two-sided log-rank test for PFS and a 
two-sided log-rank test for OS and were calculated using the software package East 5.4 (Cytel 
Software Corp., Cambridge, MA). 
12.4. Interim Analysis 
A pre-specified interim analysis for both superiority and futility (non-binding) will be performed 
after approximately 117 IRC confirmed PFS events are reported.  Futility will be evaluated by a 
one-sided test. One-hundred and seventeen (117) PFS events correspond to 66.5% of the revised 
planned number of PFS events (176) for the final analysis.  Lan-DeMets spending function with 
O’Brien-Fleming boundary will be used as an early stopping guidance (O'Brien 1979).  At the 
interim analysis, the alpha spending for PFS will be determined based on the actual information 
fraction using O’Brien-Fleming boundary.  Significance level for all secondary endpoints except 
OS will be adjusted with the same significance level as for PFS at the interim analysis.  The two 
sided significance level for OS will be 0.03 at the interim analysis.  The independent DMC will 
review the interim PFS analysis results and make a recommendation accordingly.  Details 
regarding interim efficacy analysis will be described in the DMC charter and the SAP. 


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12.5. Final Analysis 
The final analysis for the PFS will be conducted after approximately 176 PFS events are 
confirmed by the IRC. The two-sided significance level for the final analysis for 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.   
12.6. Analysis Populations 
12.6.1. 
Intent-to-Treat (ITT) Population 
The ITT population is defined as all patients who were randomized.  All efficacy analysis will be 
performed using the ITT population and patients in the ITT population will be analyzed as 
randomized. In addition, ITT population will be used to summarize demographics, and baseline 
and disease characteristics. 
12.6.2. 
Safety Population 
The safety population includes all patients who received at least one dose of study drug.  The 
safety analysis will be performed using the safety population and patients in the safety 
population will be analyzed as treated. 
12.6.3. 
Pharmacokinetic (PK) Evaluable Population 
Pharmacokinetic (PK) evaluable population includes patients who received at least 1 dose of 
study drug and had at least one post-treatment sample obtained. 
12.6.4. 
Biomarker Population 
Biomarker population includes patients whose biomaterial is available and who have consented 
to participate in the study’s biomarker evaluation. 
12.7. Control for Bias 
The following study design components will facilitate the control for bias: 
• Large (approximately 350 patients) 
• Multicenter 
• Randomized 
The randomization code will be controlled through a centralized procedure and will not be 
known to sponsor personnel directly involved with study conduct or data analysis until after the 
interim analysis (if early stopping for superiority) or final analysis.  The unblinding procedure 
will be described in detail in the study unblinding plan. 


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12.8. Efficacy Analyses 
All the stratified analyses will be based on the two randomization stratification factors: 
1) refractory disease (presence versus absence) to purine analog and anti-CD20 containing 
chemoimmunotherapy regimen, and 2) status of 17p del (presence versus absence). 
12.8.1. 
Primary Endpoint and Methods 
The primary efficacy endpoint is PFS, which is defined as the time from the date of 
randomization until disease progression (assessed by the IRC per IWCLL 2008 criteria) or death 
from any cause, whichever occurs first.  Patients who withdraw from the study or are considered 
lost to follow-up without prior documentation of disease progression will be censored on the date 
of the last adequate disease assessment.  For patients without an adequate post-baseline disease 
assessment, PFS will be censored on the date of randomization. 
The primary efficacy analysis will be performed in the ITT population to compare PFS as 
assessed by the IRC for the two treatment arms using a stratified log rank test.  Distribution of 
PFS will be summarized for each treatment arm using median and its corresponding 95% 
confidence interval based on Kaplan-Meier estimates.  The estimate of the hazard ratio and its 
corresponding 95 percent confidence interval will be computed using a Cox Proportional 
Hazards model stratified by the two randomization stratification factors. 
12.8.2. 
Secondary Endpoints and Methods 
12.8.2.1. Overall Survival (OS) and Survival Rate at Landmark Points 
Patients will be followed for survival status until end of study. 
OS is defined as the time from date of randomization until date of death due to any cause.  
Patients who are known to be alive or whose survival status is unknown will be censored at the 
date last known to be alive.  Patients who are completely lost to follow-up for survival will be 
censored at randomization date. 
The analysis methods for overall survival will be similar to those described for PFS. 
In addition, survival rate at landmark points will be summarized for each treatment arm using 
Kaplan-Meier point estimates and compared using the standard normal Z test. 
12.8.2.2. Overall Response Rate 
Overall response rate (ORR) is defined as the proportion of patients who achieve a CR, CRi, 
nPR, or PR over the course of the study as evaluated by the IRC using IWCLL 2008 criteria.  
Patients who do not have any post-baseline response assessment will be considered as 
non-responders.  A Cochran-Mantel-Haenszel chi-square test, stratified by the two 
randomization stratification factors, will be used to compare the two treatment arms. 


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12.8.2.3. Patient-Reported Outcome (PRO) Measures 
PRO as measured by FACiT-Fatigue will be summarized as the change in scores from baseline 
to each assessment. 
12.8.2.4. Hematological Improvements 
In the subset of patients with cytopenia(s) at baseline (Hgb ≤11 g/dL, platelets ≤100,000/μL, or 
ANC ≤1500/μL), time to sustained improvement and percentage of patients with sustained 
hematological improvement will be measured.  Sustained hematological improvement is defined 
as improvement in cytopenia by ≥50%, or Hgb >11 g/dL, ANC >1500/μL, platelets >100,000/μL 
with the duration of improvement lasting for at least 2 months without blood transfusion or 
growth factors. 
• Time to sustained improvement in blood count will be compared using unstratified log 
rank test.  The distribution of the time to sustained improvement will be summarized 
using Kaplan-Meier estimates. 
• Percentage of patients with sustained improvement will be compared using χ2 test. 
12.8.3. 
Exploratory Endpoints and Methods 
12.8.3.1. Investigator-Assessed PFS 
Investigator-assessed PFS is defined as time from randomization until disease progression 
(assessed by the Investigator per IWCLL 2008 criteria) or death from any cause, whichever 
occurs first. 
Analysis methods for Investigator-assessed PFS will be similar to those described for PFS as 
assessed by the IRC. 
12.8.3.2. Investigator-Assessed ORR 
Investigator-assessed ORR will be summarized and analyzed similarly to IRC-assessed ORR. 
12.8.3.3. Improvement of Disease-related Symptoms 
Disease-related symptoms including weight loss, fatigue, fever, night sweats, abdominal pain 
due to splenomegaly, or anorexia) will be assessed by at each assessment compared to baseline.  
Percentage of patients with improvement will be compared using χ2 test. 
12.8.3.4. Patient-Reported Outcome (PRO) Measures 
Patient Reported Outcome (PRO) measures include EORTC QLQ-C30 and EQ-5D-5L. 
For EORTC QLQ-C30, change in scores from baseline to each assessment will be summarized. 


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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. 
12.8.3.5. Biomarker Analysis 
Analyses are to identify biomarkers that are predictive of response (or resistance) to ibrutinib. 
Analyses will be performed within each treatment group in total and stratified by clinical 
covariates or molecular subgroups.  The associations of biomarkers with clinical response or 
time-to-event endpoints will be assessed using the appropriate statistical methods (analysis of 
variance [ANOVA], categorical, or survival model), depending on the endpoint.  Correlation of 
baseline expression levels or changes in expression levels with response or time-to-event 
endpoints will identify responsive (or resistant) subgroups. 
12.8.3.6. Medical Resource Utilization (MRU) Associated with the Therapy 
Parameters collected for MRU associated with the therapy include number of hospitalizations, 
number of emergency department visits, number of blood product transfusions, and number of 
use of hematopoietic growth factors.  Those parameters will be summarized with descriptive 
statistics by treatment arm. 
12.8.3.7. Pharmacokinetic (PK) Analysis 
The plasma concentration data for ibrutinib will be summarized using descriptive statistics at 
each timepoint.  Population PK analysis of plasma concentration-time data of ibrutinib will be 
performed using nonlinear mixed-effects modeling.  Data may be combined with data from other 
studies to support a relevant population PK model.  Available patient characteristics 
(eg, demographics, laboratory variables, genotypes, etc.) will be tested as potential covariates 
affecting PK parameters. Details will be given in a population PK analysis plan and the results of 
the population PK analysis will be presented in a separate report. 
12.9. Safety Analyses 
Safety summaries will include tabulations in the form of tables and listings.  The safety analysis 
will be conducted using the safety population.  Patients will be analyzed according to the actual 
treatment received. 
Study drug exposure including duration and dosage as well as dose modifications of study drug 
including dose reduction, dose delay, missed doses, and dose interruption will be summarized. 


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12.9.1. 
Adverse Events (AEs) 
Adverse events (AEs) will be graded by the Investigator according the NCI CTCAE v4.0 for 
non-hematological AEs.  Hematologic toxicity will be assessed by the IWCLL 2008 criteria for 
grading hematologic toxicity in CLL studies.  Verbatim descriptions of AEs will be coded using 
the current version of the Medical Dictionary for Regulatory Activities (MedDRA).  Adverse 
events that started from the date of the first dose of study drug up to 30 days after the date of the 
last dose of study drug are considered treatment-emergent.  All-treatment emergent AEs will be 
summarized by treatment arm.  The incidence rates of treatment-emergent AEs will be 
summarized by System Organ Class (SOC), preferred term, toxicity grade, and relationship to 
study drug.  In addition, SAEs, Grade 3 or above AEs, AEs leading to study treatment 
discontinuation, delay, reduction, or interruption, AEs leading to death, and events of special 
interest will be summarized.  Multiple occurrence of the same event in a given patient will be 
counted once at the maximum severity and strongest relationship to study drug. 
AEs leading to death and non-fatal SAEs will be listed by patient and tabulated by preferred term. 
12.9.2. 
Laboratory Evaluations 
All laboratory values will be converted to standard international (SI) units and classified as 
normal, low, or high based on normal ranges supplied by the central laboratory.  Hematologic 
parameters including platelet count, hemoglobin, and neutrophils will be assessed by the IWCLL 
2008 criteria for grading hematologic toxicity in CLL studies.  All other gradable laboratory 
parameters will be graded using the NCI CTCAE v4.0. 
Patients with values outside the normal range will be flagged and summarized by treatment arm.  
Selected gradable laboratory parameters will be summarized by treatment arm using shift tables.  
A separate listing and table will be provided to identify and summarize patients with markedly 
abnormal changes.  In addition, changes from baseline in quantitative parameters will be 
summarized descriptively by treatment arm at scheduled timepoints. 
12.9.3. 
Vital Signs 
Vital signs will be classified as normal, low, or high and change from baseline will be 
summarized descriptively by treatment arm at scheduled timepoints.  Patients with markedly 
abnormal changes will be listed and tabulated. 
12.9.4. 
Other Safety Assessments 
Physical examination, ECG, and eye examination results will be listed. 


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13. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
13.1. 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. 
13.2. Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval 
The Investigator will submit this protocol, the ICF, IB, and any other relevant supporting 
information (eg, all advertising materials or materials given to the patient during the study) to the 
appropriate IRB/REB/IEC for review and approval before study initiation.  Amendments to the 
protocol and informed consent form must also be approved by the IRB/REB/IEC before the 
implementation of changes in this study. 
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 patients 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. 
13.3. 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 patient and the patient’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 patient 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 patient’s source record.  Each 
patient 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 patient’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 patient at the 
time that it is signed by the patient. 


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13.4. 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) and with the ICH guidelines on GCP 
(ICH E6). 
13.5. Protected Patient Health Information Authorization 
Information on maintaining patient confidentiality in accordance to individual local and national 
patient privacy regulations must be provided to each patient as part of the informed consent 
process (refer to Section 13.3), either as part of the ICF or as a separate signed document (for 
example, in the US, a site-specific HIPAA consent may be used).  The Investigator or designee 
must explain to each patient that for the evaluation of study results, the patient’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 
patient’s protected health information or disclose it to a third party without applicable patient 
authorization.  It is the Investigator’s or designee’s responsibility to obtain written permission to 
use protected health information from each patient.  If a patient withdraws permission to use 
protected health information, it is the Investigator’s responsibility to obtain the withdrawal 
request in writing from the patient and to ensure that no further data will be collected from the 
patient.  Any data collected on the patient 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 
patient will be respected with strict adherence to professional standards and regulations. 
13.6. Study Files and Record Retention 
The Investigator must keep a record that lists all patients considered for enrollment (including 
those who did not undergo screening) in the study.  For those patients 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 patient confidentiality information), drug dispensing and accountability 
records, shipping records of investigational product and study-related materials, signed 
(electronically), dated and completed CRFs, and documentation of CRF corrections, SAE forms 


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transmitted to Pharmacyclics and notification of SAEs and related reports, source 
documentation, normal laboratory values, decoding procedures for blinded studies, curricula 
vitae for study staff, and all relevant correspondence and other documents pertaining to the 
conduct of the study. 
All essential documentation will be retained by the Investigator for at least 2 years after the date 
the last marketing application is approved for the drug for the indication for which it is being 
investigated and until there are no pending or contemplated marketing applications; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years 
after formal discontinuation of clinical development of the drug. 
The Investigator must notify Pharmacyclics and obtain written approval from Pharmacyclics 
before destroying any clinical study documents or images (eg, scan, radiograph, ECG tracing) at 
any time.  Should an Investigator wish to assign the study records to another party or move them 
to another location, advance written notice will be given to Pharmacyclics.  Pharmacyclics will 
inform the Investigator of the date that study records may be destroyed or returned to 
Pharmacyclics. 
Pharmacyclics must be notified in advance of, and Pharmacyclics must provide express written 
approval of, any change in the maintenance of the foregoing documents if the Investigator 
wishes to move study records to another location or assign responsibility for record retention to 
another party.  If the Investigator cannot guarantee the archiving requirements set forth herein at 
his or her study site for all such documents, special arrangements must be made between the 
Investigator and Pharmacyclics to store such documents in sealed containers away from the 
study site so that they can be returned sealed to the Investigator for audit purposes. 
13.7. Case Report Forms and Record Maintenance 
Case report forms (CRFs) will be used to collect the clinical study data and must be completed for 
each enrolled patient 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, complete, legible, and completed within 5 days of each patient’s visit.  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 patient data (eg, paper, CD, or other appropriate media) for archiving 
at the study site. 
13.8. 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, 
patients, 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-1112-CA) 
2. Patient identification number 
3. Lot number(s) of ibrutinib or comparator dispensed for that patient 
4. Date and quantity of drug dispensed 
5. Any unused drug returned by the patient 
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. 
13.9. 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 patient 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 patients 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 patients 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. 
13.10. 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. 
13.11. 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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13.12. Financial Disclosure 
A separate financial agreement will be made between each Principal Investigator and 
Pharmacyclics or its authorized representative before the study drug is delivered. 
For this study, each Investigator and Subinvestigator (as designated on the Form FDA1572) will 
provide a signed Financial Disclosure Form in accordance with § 21 CFR 54.  Each Investigator 
will notify Pharmacyclics or its authorized representative of any relevant changes during the 
conduct of the study and for 1 year after the study has been completed. 
13.13. 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 patient’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. 
13.14. Protocol Amendments 
Pharmacyclics will initiate any change to the protocol in a protocol amendment document.  The 
amendment will be submitted to the IRB/REB/IEC together with, if applicable, a revised model 
ICF.  Written documentation of IRB/REB/IEC and required site approval must be received by 
Pharmacyclics before the amendment may take effect at each site.  Additionally under this 
circumstance, information on the increased risk and/or change in scope must be provided to 
patients already actively participating in the study, and they must read, understand and sign any 
revised ICF confirming willingness to remain in the trial. 
No other significant or consistent change in the study procedures, except to eliminate an 
immediate hazard, shall be effected without the mutual agreement of the Investigator and 
Pharmacyclics. 


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13.15. 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. 
In most cases, the Investigators at the sites with the highest accruals of eligible patients 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. 
13.16. 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 patients’ interests. 


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14. REFERENCE LIST 
Arzerra® [package insert]. Research Triangle Park, NC:  GlaxoSmithKline; 2011. 
Burger JA, O'Brien S, Fowler N, et al. The Bruton's Tyrosine Kinase Inhibitor, PCI-32765, 
Is well tolerated and demonstrates promising clinical activity in chronic lymphocytic leukemia 
(CLL) and small lymphocytic lymphoma (SLL): an update on ongoing Phase 1 studies. ASH 
Annual Meeting Abstracts) 2010;116(21):57. 
Cella D, Lai J, Chang C, et al.  Fatigue in Cancer Patients Compared with Fatigue in the General 
United States Population. Cancer 2002;94:528–38. 
aChang BY, Huang MM, Francesco M, et al.  The Bruton tyrosine kinase inhibitor PCI-32765 
ameliorates autoimmune arthritis by inhibition of multiple effector cells. Arthritis Res Ther 
2011; 13:R115 (epub). 
bChang BY, Magadala P, Huang, MM, et al. Egress of CD19+CD5+ cells into the Peripheral 
Blood following Treatment with Bruton Tyrosine Kinase Inhibitor, PCI 32765, in Mantle Cell 
Lymphoma Patients, in American Society of Hematology2011. 
aChang BY, Francesco M, De Rooij MF, et al. Egress of CD19+CD5+ cells into peripheral blood 
following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma 
patients. Blood. 2013;122:2412-24. 
bChang BY, Francesco M, Steggerda S, et al. Ibrutinib Inhibits Malignant Cell Adhesion and 
Migration and Reduces Tumor Burden in Lymph Node and Bone Marrow in a Murine Model of 
Mantle Cell Dissemination and Progression. 2013 AACR: Abstract 923. 
Cheson BD, Byrd JC, Rai KR, et al.  Novel targeted agents and the need to refine clinical end 
points in chronic lymphocytic leukemia. J Clin Oncol. 2012;30: 2820-2. 
Child CG, Turcotte JG. Surgery and portal hypertension. In Child CG. The liver and portal 
hypertension. Philadelphia:Saunders. 1964:50-64. 
Coiffier B, Lepretre S, Pedersen LM, et al. Safety and efficacy of ofatumumab, a fully human 
monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic 
lymphocytic leukemia: a phase 1-2 study. Blood. 2008;111:1094-1100. 
Ding W, Zent CS. Diagnosis and management of autoimmune complications of chronic 
lymphocytic leukemia/ small lymphocytic lymphoma. Clin Adv Hematol Oncol. 2007;5:257-61. 
Eichhorst B, Dreyling M, Robak T, Montserrat E, Hallek M; ESMO Guidelines Working Group. 
Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol. 2011 Sep;22 Suppl 6:vi50-4. 
EuroQol Group. EuroQol-A new facility for the measurement of health-related quality of life. 
Health Policy. 1990; 16: 199-208. 
Extermann M, Overcash J, Lyman GH, et al. Comorbidity and functional status are independent 
in older cancer patients. Journal of Clinical Oncology. 1998;16:1582-87. 


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Fayers PM, Aaronson NK, Bjordal K, et al. on behalf of the EORTC Quality of Life Group. 
The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: European Organisation for 
Research and Treatment of Cancer, Brussels 2001. 
http://www.eortc.be/home/qol/files/SCManualQLQ-C30.pdf 
Friedberg JW, Sharman J, Schaefer-Cutillo J, et al. Fostamatinib disodium (FosD), an oral 
inhibitor of Syk, is well-tolerated and has significant clinical activity in diffuse large B-cell 
lymphoma (DLBCL) and chronic lymphocytic leukemia (SLL/CLL). Blood. 2008;112(11). 
Abstract 3. 
Furman RR, Byrd JC, Brown JR, et al. CAL-101, an isoform-selective inhibitor of 
phosphatidylinositol 3-kinase P110, demonstrates clinical activity and pharmacodynamic effects 
in patients with relapsed or refractory chronic lymphocytic leukemia. Blood. 2010;116(21). 
Abstract 55 and oral presentation at: American Society of Hematology Annual Meeting; 
December 4-7, 2010; Orlando, FL. 
Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic 
Leukemia updating the National Cancer Institute-Working Group 1996 guideline Blood. 
2008;111:5446-5456. 
Hallek M, Cheson BD, Catovsky D, et al.  Response assessment in chronic lymphycytic 
leukemia treated with novel agents causing an increase of peripheral blood lymphocytes. 
Blood 2012; e-letter, published June 04, 2012. 
http://bloodjournal.hematologylibrary.org/content/111/12/5446/reply#bloodjournal_el_6920 
Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising 
therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by 
PCI-32765. Blood. 2011; 117:6287-6296. 
Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 
blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell 
malignancy. Proc. Natl Acad. Sci. USA. 2010; 107:13075-13080. 
International Conference on Harmonization (ICH) Guideline for Industry: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting (ICH-E2A).  March 1995. 
International Conference on Harmonization (ICH) Guideline for Industry: E6 Good Clinical 
Practice:Consolidated Guidance (ICH-E6). April 1996. 
Investigator’s Brochure. Ibrutinib. Version 10: 29 August 2016. Pharmacyclics LLC; Janssen 
Research & Development, LLC. 
MacGlashan D, Honigerg LA, Smith A, et al. Inhibition of IgE-mediated secretion from human 
basophils with a highly selective Bruton's tyrosine kinase, BTK, inhibitor. International 
Immunopharmacology. 2011; 11:475-479. 
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in 
Oncology (NCCN Guidelines) Non-Hodgkin’s Lymphomas. Version I.2012. NCCN.org 
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials, Biometrics 1979; 
35:549-556. 


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O'Brien S, Burger JA, Blum KA, et al. The Bruton's Tyrosine Kinase (BTK) Inhibitor PCI-32765 
Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic 
Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study. 
Blood (ASH Annual Meeting Abstracts) 2011;118: Abstract 983 
Oken MM, Creech RH, Tormey DC, et al. (1982) Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655. 
Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton’s 
tyrosine kinase. ChemMedChem; 2007; 2:58–61. 
Pollyea DA, Smith S, Fowler N, et al. A Phase I Dose Escalation Study of the BTK Inhibitor 
PCI-32765 in Relapsed and Refractory B-cell Non-Hodgkin Lymphoma and Use of a Novel 
Fluorescent Probe Pharmacodynamic Assay. Blood (ASH Annual Meeting Abstracts) 2009;114 
(22):3713. 
Ponander S, Chen S-S, Buggy J, et al. The Bruton’s Tyrosine Kinase Inhibitor PCI-32765 
thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. 
Blood 2012 119:1182-9. 
Pugh RN, Murray-Lyon IM, Dawson L. Transection of the oesophagus for bleeding oesophageal 
varices. The British journal of surgery. 1973:60:646-9. 
Smith TJ, Khatcheressian J, Lyman GH, et al.  2006 Update of Recommendations for the Use of 
White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline. Journal of 
Clinical Oncology. 2006:24: 3187-205. 
Teeling JL, French RR, Cragg MS, et al. Characterization of new human CD20 monoclonal 
antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood. 
2004;104:1793-1800. 
Teeling JL, Mackus WJ, Wiegman LJ, et al. The biological activity of human CD20 monoclonal 
antibodies is linked to unique epitopes on CD20. J Immunol. 2006;177:362-371. 
Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in 
fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol.  2010;28:1749-1755. 
Wierda WG, Kipps TJ, Durig J, et al. Chemoimmunotherapy with O-FC in previously untreated 
patients with chronic lymphocytic leukemia. Blood. 2011; 117:6450-6458. 
WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human 
Subjects.  59th WMA General Assembly, Seoul, October 2008. 


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15. APPENDICES 
 


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Appendix A: 
Schedule of Assessments 
 
Treatment Phase 
Follow-Up Phase 
Study Weeks 
Screening 
Phase 
1 
2 
3 
4 
5 
6 
7 
8 
12-24 
q4 weeks 
36 until tx 
term 
q12 weeks 
Response 
Evaluationsc 
q12 weeks  
until PD 
End-of-
Treatment visit 
30 days after last 
dose of study drug 
Post-treatment 
Phasec 
q12 weeks until 
PD 
Post-disease 
Progression 
Phase 
q12 weeks 
Study Windows 
-28 days 
± 3 days 
± 7 days 
± 3 days 
± 7 days 
± 7 days 
Study Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ARM A 
Ofatumumab 300 mg IV 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ofatumumab 2000 mg IV 
 
 
i 
i 
x 
i 
i 
i 
x 
x 
 
 
 
 
 
ARM B 
Ibrutinib 420 mg/day PO 
 
Continuous Daily Dosing 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility & randomize 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam & ECOG status 
x 
x 
 
 
x 
 
 
 
x 
x 
x 
 
x 
x 
 
Vital signs 
x 
x 
 
 
x 
 
 
 
x 
x 
x 
 
x 
 
 
ECG 
x 
 
If clinically indicated (eg, subjects with palpitations, lightheadedness) 
Coagulation (PT, INR, and aPTT) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eye-related symptoms 
x 
 
 
 
 
 
 
 
 
xd 
xc 
 
x 
 
 
PRO assessments 
x 
 
 
 
x 
 
 
 
x 
x 
x 
 
x 
x 
 
Disease-related symptomsg 
 
x 
 
 
x 
 
 
 
x 
x 
x 
 
x 
x 
 
Cumulative Illness Rating Scale (CIRS)a 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
Pregnancy test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serologies 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetic, CLL FISH panel 
x (-90 days*) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
Serum chemistry 
x 
x 
 
 
x 
 
 
 
x 
x 
x 
 
x 
 
 
Serum immunoglobulins & β2-microglobulin 
 
x 
 
 
 
 
 
 
 
xd 
x 
 
 
x 
 
Sparse PK sample collection f 
 
x 
 
 
xe 
 
 
 
 
 
 
 
 
 
 
Genetic & molecular prognostic factors 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T/B/NK cells 
 
x 
 
 
 
 
 
 
 
xd 
x 
 
 
x 
 
Flow cytometry-based immunophenotype assays 
 
x 
 
x 
 
x 
 
 
x 
x 
x 
 
x 
x 
 
Predictive/resistance biomarkers 
 
x 
 
x 
 
x 
 
 
 
 
x 
 
x 
x 
 
CT scans 
x (-6 wks*) 
 
 
 
 
 
 
 
 
 
 
xc 
 
 
 
Medical resource utilization (MRU) g 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Overall response evaluation 
 
 
 
 
 
 
 
 
 
 
 
xc 
 
 
 
Bone marrow biopsy and/or aspirateb 
x (-90 days*) 
 
 
 
 
 
 
 
 
 
 
xb 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Subsequent anticancer therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
i = infusion visit only;  * from randomization   
a. 
Cumulative Illness Rating Scale (CIRS) for patients who are ≥65 years of age. 
b. 
Bone marrow biopsy and aspirate should be obtained to confirm CR and to evaluate cytopenia. 
c. 
Eye-related symptoms and overall response assessment will only need to be performed every 24 weeks after 18 months.  CT scans will only need to be performed every 24 weeks after 12 months 
and annually after 36 months. 
d. 
Weeks 12 and 24 only 
e. 
Week 4 Sparse PK sample collection for ibrutinib arm only. If patient is unable to complete PK assessments at the Week 4 visit, it is acceptable to complete these assessments at the Week 8 visit. 
f. 
Patients  who must take strong or moderate CYP3A4/5 inhibitors while on treatment with ibrutinib, additional PK collections for evaluation of ibrutinib exposure is requested at the following 
scheduled visit after concomitant CYP3A4/5 inhibitor has started and still in use.  Please refer to Section 7.1.21 for the PK collection schedules. 
g. 
Starting from Amendment 5, data collection of disease-related symptoms and MRU will be suspended. 


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Appendix B: 
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., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
5:649-655, 1982. 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed January 4, 2008. 
 


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Appendix C: 
Inhibitors and Inducers of CYP3A 
Inhibitors of CYP3A are defined as follows.  A comprehensive list of inhibitors can be found at the 
following website: http://medicine.iupui.edu/clinpharm/ddis/main-table/.  The general categorization into 
strong, moderate, and weak inhibitors according to the website is displayed below.  Refer to 
Section 6.6.1.1 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 
cobicistat 
rifampin 
boceprevir 
St. John’s Wort 
mibefradil 
troglitazone 
telaprevir 
 
troleandomycin 
 
posaconazole a 
 
Moderate inhibitors: 
 
aprepitant 
 
amprenavir 
 
amiodarone 
 
atazanavir 
 
ciprofloxacin 
 
crizotinib 
 
darunavir/ritonavir 
 
dronedarone 
 
erythromycin 
 
diltiazem 
 
fluconazole 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
voriconazole b 
 
imatinib 
 
Weak inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All other inhibitors: 
 
chloramphenicol 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
Source:  http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
a.      Based on PBPK simulations, up to 9.7-fold increase in AUC and 6.2-fold increase in Cmax could be observed.  If ibrutinib needs to be 
administered with posaconazole, 140 mg ibrutinib will be dosed. 
b.      Based on internal data, 140 mg ibrutinib dosed with voriconazole produces ibrutinib exposures similar to 560 mg ibrutinib dosed alone. 
Therefore, for this study, if ibrutinib needs to be administered with voriconazole, 140 mg ibrutinib will be dosed. 


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Appendix D: 
Hematologic Adverse Event Grading Scheme (Hallek 2008) 
An evaluation of the hematologic toxicity in patients with advanced CLL/SLL must consider the 
high frequency of marrow involvement and previous exposure to chemotherapy with consequent 
medullary compromise at the initiation of therapy.  The standard hematologic grading system for 
solid tumors cannot, therefore, be directly applied.  A substantial proportion of patients would be 
considered to have Grade 2 to 4 hematologic toxicity before any therapy is given.  Therefore, the 
following modified schema will be used to quantitate hematologic deterioration in patients with 
CLL/SLL. 
Hematologic Grading Scheme 
Decrease in Platelets or Hgb 
(Nadir) from Pre-treatment Value, 
% 
ANC/μL (nadir)c 
Toxicity Grade 
0 - 10%a 
≥ 2000 
0 
11 - 24%a,b 
≥ 1500 and < 2000 
1 
25 - 49%a,b 
≥ 1000 and < 1500 
2 
50 - 74%a,b 
≥ 500 and < 1000 
3 
> 75%a,b 
< 500 
4 
a. 
If at any level of decrease, the platelet count falls below 20 × 109/L, toxicity will be considered Grade 4. 
If the baseline platelet count is <20 × 109/L, platelet toxicity cannot be evaluated. 
b. Baseline and subsequent Hgb values must be determined the day of any given transfusion. 
c. 
If the ANC was < 1000/µL before therapy, the patient is not evaluable for toxicity referable to the ANC. 
 


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Appendix E: 
EORTC QLQ-C30 
 


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Appendix F: 
EQ-5D-5L 
 


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Appendix G: 
FACiT-Fatigue 
 
 
 


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Appendix H: 
Cumulative Illness Rating Scale (CIRS) 
CIRS is an indicator of illness severity and comorbidity in older patients (Extermann, 1998)1. 
CIRS scoring is to be performed in the setting of a pretreatment comprehensive history and 
physical by a licensed provider (nurse, PA, MD, or DO) for all patients 65 years and older. 
Instructions: 
The following pages include the CIRS scoring worksheet displaying 14 organ-system categories. 
Write brief descriptions of the medical problem(s) that justified the endorsed score on the line 
following each item. Circle the appropriate score from 0 – 4 based on the rating strategy.  Space 
is provided in each system organ class to provide written descriptions. 
1. Complete each category score as identified by the rating strategy on the worksheet 
2. Each category has room for written comments. If additional room is needed, please 
document on the back of the form 
3. Add the number of Total Categories Endorsed (measured) 
4. Provide the Total Score 
5. Provide the Severity Index (total score divided by total number of categories endorsed) 
6. Provide the number of categories at level 3 severity 
7. Provide the number of categories at level 4 severity 
CLL Rating: 
Please take into account that CLL/SLL diagnosis itself or induced illness or organ damage 
(including cytopenias) are not included in this rating scale.  The goal of this rating scale is to 
assess comorbidity other than CLL/SLL in the patient. 
 
1 Extermann M, Overcash J, Lyman GH, Parr J, Balducci L, Comorbidity and functional status are independent in 
older patients. J Clin Oncol 1998; 16: 1582–87. 


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PCYC 1112-CA Scoring Sheet CIRS(G) 
Cumulative Illness Rating Scale for Geriatrics2 
Patient ID# ________________ Site # _________ Investigator: ______________ 
Rater Name: _______________    Date: ___/___/___ 
*Note Rater must be on delegation of authority log 
Rating Strategy 
Please see specific scoring guidelines below for each organ system. 
0 – No Problem 
1 – Current mild problem or past significant problem 
2 – Moderate disability or morbidity/requires “first line” therapy 
3 – Severe/constant significant disability/”uncontrollable” chronic problems 
4 – Extremely severe/immediate treatment required/end organ failure/severe impairment 
of function 
 
Adapted from 2Extermann M, Overcash J, Lyman GH, Parr J, Balducci L, Comorbidity and functional status are 
independent in older patients. J Clin Oncol 1998; 16: 1582–87. 


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ORGAN SYSTEM 
IF IMPAIRMENT, SPECIFY 
SCORE 
HEART 
 
 
0   1   2   3   4 
VASCULAR 
 
 
0   1   2   3  4 
HEMATOPOETIC 
 
 
0   1   2   3   4 
RESPIRATORY 
 
 
0   1   2   3   4 
ENT/LARYNX 
 
 
0   1   2   3   4 
UPPER GI 
 
 
0   1   2   3   4 
LOWER GI 
 
 
0   1   2   3   4 
LIVER 
 
 
0   1   2   3   4 
RENAL 
 
 
0   1   2   3   4 
GU 
 
 
0   1   2   3   4 
MUSCULOSKELETAL/INTEGUMENT 
 
 
0   1   2   3   4 
NEUROLOGICAL 
 
 
0   1   2   3   4 
ENDOCRINE/METABOLIC/BREAST 
 
 
0   1   2   3   4 
Calculated Ratings 
Total Number Categories Endorsed 
(this is the number of categories above that have a score >0) 
 
Total Score 
(this is the sum of the individual scores above) 
 
Severity Index 
(total score/total number of categories endorsed) 
 
Number of Categories at level 3 severity 
(this is the number of categories above that have a score of 3) 
 
Number of Categories at level 4 severity 
(this is the number of categories above that have a score of 4) 
 


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Appendix I: 
Rai & Binet Staging 
Rai Stage 
Binet* Stage 
0 
Lymphocytes (L) in blood 
(>5000/µL) 
A 
<3 sites involved, Hgb ≥10 g/dL, 
platelets ≥100,000/μL 
I 
L + enlarged lymph nodes 
(LN) 
II 
L + spleen and/or liver 
(LN positive or negative) 
B 
≥3 sites involved, Hgb ≥10 g/dL, 
platelets ≥100,000/μL 
III 
L + anemia 
(Hgb <11g/dL) 
C 
Hgb <10 g/dL  
or 
platelets <100,000/μL 
 
IV 
L + thrombocytopenia 
(platelets <100,000/μL) 
*Involved sites are liver, spleen, and lymph nodes in inguinal, auxiliary, and cervical regions.   
 


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Appendix J: 
New York Heart Association Functional Classification 
Class 
Functional Capacity: How a patient with cardiac disease feels during physical 
activity 
I 
Patients with cardiac disease but resulting in no limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or 
anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity.  They 
are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnea or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be 
present even at rest.  If any physical activity is undertaken, discomfort increases. 
Class 
Objective Assessment 
A 
No objective evidence of cardiovascular disease. No symptoms and no limitation in 
ordinary physical activity. 
B 
Objective evidence of minimal cardiovascular disease. Mild symptoms and slight 
limitation during ordinary activity. Comfortable at rest. 
C 
Objective evidence of moderately severe cardiovascular disease. Marked limitation 
in activity due to symptoms, even during less-than-ordinary activity. Comfortable 
only at rest. 
D 
Objective evidence of severe cardiovascular disease. Severe limitations. Experiences 
symptoms even while at rest. 
 


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Appendix K: 
Definitions for PCYC-1112-CA Eligibility Criteria 
Chemoimmuno-
therapy 
For the purpose of this protocol, a combination treatment regimen that 
contains both a cytotoxic, specifically a purine analog or alkylating agent, 
chemotherapy agent and an anti-CD20 monoclonal antibody 
(eg, rituximab) administered together. 
Autoimmune 
hemolytic anemia 
(AIHA) 
Defined by at least one marker of hemolysis (indirect bilirubin above the 
upper limit of normal (ULN) not due to liver disease, increased lactate 
dehydrogenase (above ULN) without alternative etiology, or increased 
absolute reticulocytosis (above ULN) or bone marrow erythropoiesis in 
the absence of bleeding) AND at least one marker of direct or indirect 
autoimmune mechanism (positive direct antiglobulin for IgG or C3d, cold 
agglutinins) (Ding 2007). 
Immune 
thrombocytopenia 
(ITP) 
Immune thrombocytopenia is defined by platelets ≤100,000/µL and 
increased megakaryocytes on the bone marrow exam. 
Autoimmune 
cytopenia poorly 
responsive to 
therapy 
Autoimmune anemia or thrombocytopenia poorly responsive to treatment 
includes those patients with recurrent autoimmune cytopenias, those 
receiving low dose steroids (≤ 20 mg of prednisone or equivalent) and 
those on intravenous immune globulin (IVIG).  Patients receiving higher 
doses of steroids or experiencing declining platelets or hemoglobin due to 
autoimmune destruction during the 4 weeks prior to the first dose of study 
drug are considered for the purposes of this protocol to have uncontrolled 
autoimmune cytopenias (as defined below) and are not eligible for 
enrollment. 
Autoimmune 
cytopenia, 
uncontrolled 
Uncontrolled autoimmune anemia or thrombocytopenia is defined as those 
patients receiving > 20 mg prednisone (or equivalent) daily or have 
declining platelets or hemoglobin due to autoimmune destruction during 
the 4 weeks prior to the first dose of study drug. 
 
 
 


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


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Appendix M: 
Schedule of Assessments for Patients Treated with Ofatumumab who are 
to Receive Next-line Ibrutinib Therapy 
Study Weeks 
Assessment for 
Next-line Ibrutinib 
Therapy 
Treatment Phase 
Follow-up 
Phase 
Every 4 weeks  
for 24 weeks 
Every 12 weeks  
until PD  
End-of- 
Treatment 
Visit 
Follow-up 
(Every 12 
weeks) 
Study Windows 
±14 d 
±7 d 
±7 d 
30 (±3 d) 
±7 d 
Study Drug Administration 
 
Ibrutinib 420 mg per day PO 
 
Continuous Daily Dosing 
 
 
Procedures 
 
 
 
 
 
Medical Monitor approval 
x 
 
 
 
 
Concomitant medications 
x 
x 
x 
x 
 
Adverse events 
 
x 
x 
x 
 
Physical examination, 
vital signs, ECOG 
x 
x 
x 
x 
 
Hematology 
x 
xe 
x 
x 
 
Serum chemistry 
x 
 
 
 
 
PK sampling if on 
CYP3A4/5 inhibitors d 
 
 
 
 
 
Disease assessment: 
 
 
 
 
 
Investigator assessment of 
response and for 
progressiona 
 
 
x 
 
 
Predictive biomarkers 
 
 
xb 
 
 
Survival status 
 
 
 
 
xc 
Subsequent anticancer 
therapies 
 
 
 
 
xc 
CLL=chronic lymphocytic leukemia; d=day; ECOG=Eastern Cooperative Oncology Group;  
IRC=Independent Review Committee; PD=progressive disease; PO=oral; qd=once daily 
a. 
Efficacy assessments should include CT scan annually until the first disease progression on protocol. For patients who have 
had experienced PD and are crossed over to ibrutinib, CT scans for response assessments may be performed at investigator's 
discretion. 
b. 
Blood samples will be collected at Week 12 Day 1 and at PD 
c. 
By telephone 
d. 
Patients who must take strong or moderate CYP3A4/5 inhibitors while on treatment with ibrutinib, additional PK collections 
for evaluation of ibrutinib exposure is requested at the following scheduled visit after concomitant CYP3A4/5 inhibitor has 
started and still in use.  Please refer to Section 7.1.21 for the PK collection schedules. 
e. 
CBC should be performed weekly for the first 4 weeks  

SAP_001.pdf: 
                                                        NCT Number:  NCT01578707 
 
 
 
 
 
 
 
 
 
Status: 
Approved 
Date: 
25 April 2019 
Prepared by: 
Pharmacyclics LLC 
 
 
 
PHARMACYCLICS LLC 
STATISTICAL ANALYSIS PLAN FOR CSR ADDENDUM 
A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE 3 STUDY OF 
THE BRUTON’S TYROSINE KINASE (BTK) INHIBITOR IBRUTINIB 
VERSUS OFATUMUMAB IN PATIENTS WITH RELAPSED OR 
REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL 
LYMPHOCYTIC LYMPHOMA 
PCYC-1112-CA; PHASE 3 
IMBRUVICA® (IBRUTINIB; PCI-32765)  


 
 
LIST OF ABBREVIATIONS 
CI  
confidence interval 
CLL  
CMH 
chronic lymphocytic leukemia  
Cochran-Mantel-Haenszel 
CR  
complete response 
CRi  
CSR 
complete response with incomplete marrow recovery 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
del17p 
deletion of the short arm of chromosome 17 
DMC  
data monitoring committee 
HR  
hazard ratio 
IRC  
independent review committee 
ITT 
intent to treat 
iwCLL  
International Workshop on CLL 
KM 
MedDRA 
NCI 
Kaplan-Meier 
Medical Dictionary for Regulatory Activities 
National Cancer Institute 
nPR 
nodular partial response 
ORR  
overall response rate 
OS  
overall survival 
PD  
progressive disease 
PFS 
progression-free survival 
PR  
partial response 
SAE 
Serious adverse events 
SAP 
statistical analysis plan 
SLL 
TEAE  
small lymphocytic lymphoma 
Treatment-emergent adverse events 
 
 


 
 
1. INTRODUCTION 
Study PCYC-1112-CA (hereafter referred to as Study 1112) is a randomized, multicenter, open-
label, comparator-controlled Phase 3 study of ibrutinib versus ofatumumab in subjects with 
previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). 
Study 1112 compared the efficacy and safety of orally administered ibrutinib 420 mg/day with 
that of ofatumumab administered intravenously at an initial dose of 300 mg followed by 2000 
mg x 11 doses over a 24-week period. Randomization of subjects into both treatment arms was 
1:1, and subjects received ibrutinib until progressive disease (PD) or unacceptable toxicity was 
observed, whichever occurred first. Two separate randomization schemes were generated for 
each geographic region (North America vs. Rest of World). Under each scheme, randomization 
was stratified using the following factors: 
• 
Presence vs. absence of disease refractory to purine analog and anti-CD20 containing 
combination chemo-immunotherapy regimen. 
• 
Presence vs. absence of deletion of the short arm of chromosome 17 (del17p), as 
defined by assay specification on pre-treatment fluorescence in situ hybridization or 
cytogenetics evaluation. 
The primary endpoint was progression-free survival (PFS) as assessed by the independent review 
committee (IRC) per criteria from the 2008 International Workshop on CLL (iwCLL) with the 
clarification regarding treatment-related lymphocytosis (Hallek et al, 2013). Key secondary 
efficacy endpoints included overall survival (OS) and overall response rate (ORR) (based on the 
IRC assessment). 
Initially, subjects treated with ofatumumab who had experienced PD as confirmed by an IRC 
were allowed to receive ibrutinib if deemed appropriate by the investigator following medical 
monitor approval. Based on the positive results from the interim analysis in December 2013, the 
data monitoring committee (DMC) recommended to allow the remaining subjects originally 
randomized to ofatumumab to be provided with access to ibrutinib therapy. In addition, the DMC 
recommended the interim analysis be the primary analysis for the study and the Clinical Study 


 
 
Report (CSR) was completed on 25 March 2014. After the primary analysis, IRC evaluations 
were discontinued, while efficacy assessments by the investigators continued until study closure. 
Subjects remaining on treatment at the time of study closure will have the option to be rolled 
over to a separate long-term extension study.  
The final analysis will be based on the final data extract from 26 November 2018. This statistical 
analysis plan (SAP) is to describe the final analysis of data in evaluation of efficacy and safety of 
Study 1112.  
2. GENERAL ANALYSIS CONSIDERATION 
2.1. 
ITT Population 
The Intent-to-Treat (ITT) population includes all randomized subjects. Subjects in this 
population will be analyzed according to the treatment to which they were randomized. The ITT 
population will be used for efficacy analyses and to produce subject disposition summaries.  
2.2. 
Safety Population 
All randomized subjects who received at least one dose of study drug will be included in the 
safety population. Subjects in the safety population will be analyzed according to the actual 
treatment received and will be used to summarize the safety (including dosing) data.  
3. SUBJECT INFORMATION 
3.1. 
Duration of Study Follow-up 
Duration of follow-up on the study will be summarized by treatment arm and for the combined 
arms. Median duration will be obtained using Kaplan–Meier methodology with reverse 
censoring. 


 
 
4. EFFICACY ANALYSES 
Analysis of endpoints will be conducted on the ITT population, unless otherwise specified. Table 
1 summarizes the efficacy endpoints and analysis methods to be performed. 
 
The two randomization stratification factors will be used for the stratified analysis/test.  
 
Table 1: Definitions and Analyses for Endpoints 
Endpoint 
Definition 
Analysis Method 
Progression-
free survival 
(PFS) per 
investigator 
Time from date of randomization to date of first 
documentation of PD per investigator response 
assessment or date of death due to any cause, whichever 
occurs first, regardless of the use of subsequent 
anticancer therapy including crossover prior to 
documented PD or death. Subjects who are alive and had 
not progressed will be censored at the date of last 
evidence of non-PD.  
Subjects without a baseline assessment or adequate post 
baseline assessment will be censored at date of 
randomization.  
Kaplan-Meier (KM) will be used to 
estimate median with its 95% 
confidence interval (CI) and selected 
landmark estimates (95% CI). The 
hazard ratio (HR) with its 95% CI, 
will be estimated by Cox regression 
model (with treatment as the only 
covariate) stratified by the two 
randomization stratification factors. 
KM curves and the forest plot of HRs 
for PFS in each subgroup will be 
provided. 
Overall 
survival (OS) 
Time from date of randomization to date of death from 
any cause. Subjects who are known to be alive or whose 
survival status is unknown will be censored at the date 
when they were last known to be alive.  
Subjects who received subsequent anti-neoplastic therapy 
will not be censored at next-line therapy, including 
ofatumumab subjects who received ibrutinib as 
subsequent therapy.  
ITT analysis: The same methods used 
to analyze PFS will be used to 
analyze OS.  
 
Overall 
response rate 
(ORR) per 
investigator 
The proportion of subjects achieving a best overall 
response of CR, CRi, nPR, or PR per investigator 
assessment at or prior to initiation of subsequent anti-
neoplastic therapy.  
P-value is based on Cochran-Mantel-
Haenszel (CMH) chi-square test 
stratified by the two randomization 
stratification factors. 
Sustained 
hemoglobin 
improvement 
Proportion of subjects with hemoglobin increase >= 20 
g/L over baseline continuously for >=56 days without 
blood transfusions or growth factors. 
Analysis for ITT and the subgroup 
with anemia at baseline (hemoglobin 
<= 110 g/L): Chi-square test. 
Sustained 
platelet 
improvement 
Proportion of subjects with platelet increase >= 50% over 
baseline continuously for >=56 days without blood 
transfusions or growth factors. 
Analysis for ITT and the subgroup 
with thrombocytopenia at baseline 
(platelet <= 100 x 109 /L): Chi-square 
test. 


 
 
5. SAFETY ASSESSMENTS 
Safety data will be summarized for the safety population. 
 
Adverse events will be coded by system organ class and preferred term according to the Medical 
Dictionary for Regulatory Activities (MedDRA). Severity of AEs will be graded by the 
investigator according to the National Cancer Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v4.0 for non-hematological AEs and iwCLL 2008 guidelines for 
hematologic toxicity. 
 
Treatment-emergent adverse events (TEAE) are all reported AEs from the first dose of the study 
drug, through the treatment phase and up to 30 days after the last dose of the study drug or 
initiation of subsequent anticancer therapy, whichever came first. TEAE SAEs, TEAE non-SAEs 
and TEAE leading to death will be summarized by treatment arm.