Conditions: Follicular Lymphoma B-cell Lymphoma Non-Hodgkin's Lymphoma
Keywords: Pharmacyclics (PCYC) PCYC Lymphoma Follicular Lymphoma FL Rituximab Ibrutinib Rituxan Non-Hodgkin's Lymphoma (NHL) NHL B-cell Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

Brief summary:
This is an open-label, Phase 2 study designed to assess the efficacy and safety of ibrutinib combined with rituximab in previously untreated subjects with Follicular Lymphoma (FL).

Detailed description:
This is an open-label, Phase 2 study designed to assess the efficacy and safety of ibrutinib combined with rituximab in previously untreated subjects with FL.

There are two study treatment arms.

Subjects enrolled into main study treatment arm will receive ibrutinib continuously until disease progression or unacceptable toxicity. In addition, subjects will receive rituximab once weekly for four doses for the first four weeks of study treatment.

Subjects enrolled into the exploratory study treatment arm will receive ibrutinib continuously as a single agent for the first eight weeks, then ibrutinib concurrently with rituximab once weekly for four doses. After the rituximab treatment, subjects will receive ibrutinib continuously until disease progression or unacceptable toxicity.

Arms:
arm 1: Subjects enrolled into this arm will receive ibrutinib continuously until disease progression or unacceptable toxicity. In addition, subjects will receive rituximab once weekly for four doses for the first four weeks of study treatment. arm 2: Subjects enrolled into this arm will receive ibrutinib continuously as a single agent for the first eight weeks, then ibrutinib concurrently with rituximab once weekly for four doses. After the rituximab treatment, subjects will receive ibrutinib continuously until disease progression or unacceptable toxicity.

Interventions: intervention 1: Ibrutinib intervention 2: rituximab
Intervention descriptions: intervention 1: All subjects will receive 560 mg of Ibrutinib orally. intervention 2: All subjects will receive rituximab 375 mg/m2 intravenously

Protocol document:
Prot_000.pdf: 
Ibrutinib 
 
Protocol PCYC-1125-CA - Amendment 3.0 
IND 102,688 
 
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PROTOCOL
 
 
Title:
A Multicenter, Open-Label, Phase 2 Study of the Bruton’s 
Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination 
with Rituximab in Previously Untreated Subjects with 
Follicular Lymphoma 
Protocol Number: 
PCYC-1125-CA 
IND Number: 
102,688 
Study Drug: 
Ibrutinib 
Sponsor:
Pharmacyclics LLC 
995 East Arques Avenue 
Sunnyvale, CA 94085-4521 
Medical Monitor: 
Jutta K. Neuenburg, MD PhD 
Telephone: 1-408-215-3735 
E-mail: jneuenburg@pcyc.com  
Original Protocol Date:
24 September 2013 
Amendment 1.0 Date: 
12 November 2014 
Amendment 1.1 Date: 
11 December 2014 (Arm 2 Site Only) 
Amendment 2.0 Date: 
01 October 2015 
Amendment 3.0 Date: 
12 September 2016 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document is a confidential communication of Pharmacyclics provided to clinical investigators, study centers, 
associated individuals, and the like under the terms of existing confidentiality agreements. For example, this 
document may be disclosed to appropriate Investigational Review Boards under the condition that they maintain 
confidentiality consistent with their application procedures. Your acceptance and use of this document is subject to 
the condition that no information contained herein will be published or disclosed without first obtaining written 
approval from Pharmacyclics LLC. If you do not agree to this condition, please return the document to 
Pharmacyclics at the above address. 




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STUDY SYNOPSIS 
Title: 
A Multicenter, Open-Label, Phase 2 Study of the Bruton’s Tyrosine 
Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Rituximab in 
Previously Untreated Subjects with Follicular Lymphoma 
Protocol Number: 
PCYC-1125-CA 
Phase:
2 
Indication:
Previously untreated subjects with follicular lymphoma (FL) 
Study Drug and 
Comparator: 
Ibrutinib PO hard gelatin capsule in combination with rituximab; no 
comparator is used in this study.
Objectives: 
Primary
x
To evaluate the efficacy of ibrutinib when combined with 
rituximab (determined by the overall response rate [ORR]) in 
previously untreated subjects with FL 
Secondary
x
To evaluate the efficacy of ibrutinib combined with rituximab in 
subjects with FL as assessed by the duration of response (DOR), 
progression free survival (PFS), and overall survival (OS) 
x
To evaluate the safety and tolerability of ibrutinib combined with 
rituximab in previously untreated subjects with FL 
Exploratory
x
To determine the pharmacokinetics (PK) of ibrutinib when 
combined with rituximab in subjects with FL  
x
To evaluate prognostic and predictive biomarkers relative to 
treatment outcomes 
Study Design: 
This is an open-label, Phase 2 study designed to assess the efficacy and 
safety of ibrutinib combined with rituximab in previously untreated 
subjects with FL.  The study will include approximately 80 subjects 
with two treatment arms. 
Two Treatment Arms   
In Arm 1 (n = 60), subjects will receive ibrutinib 560 mg PO 
continuously until disease progression or unacceptable toxicity.  In 
addition, subjects will receive rituximab 375 mg/m2 intravenous (IV) 
once weekly for 4 doses for the first 4 weeks of study treatment. 
Subjects in Arm 1 will have imaging efficacy assessments every 
12 weeks for the first 8 assessments and then every 24 weeks thereafter. 
In Arm 2 (n = 20), subjects will receive ibrutinib 560 mg PO 
continuously as a single agent for the first 8 weeks, then ibrutinib at 
560 mg will continue concurrently with rituximab 375 mg/m2 IV once 
weekly for 4 doses.  Once treatment with rituximab is complete, 
subjects will continue to receive single-agent ibrutinib continuously 
until disease progression or unacceptable toxicity.  Subjects in Arm 2 
will have imaging efficacy assessments at Week 9, Week 20, and then 
every 12 weeks for 6 assessments after Week 20, and then every 
24 weeks thereafter. 


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One of the purposes of Arm 2 is to identify biomarkers that predict 
sensitivity or resistance to ibrutinib.  Based on Phase 1 clinical data in 
FL it is predicted that approximately half of the subjects treated in this 
arm will show evidence of resistance to single-agent ibrutinib.  By 
providing a lead-in time prior to the initiation of rituximab, pre- and 
post-progression biopsy samples can be collected to address markers of 
drug resistance.  These objectives are exploratory and therefore the 
primary and secondary objectives related to clinical efficacy are 
paramount but will be analyzed separately from Arm 1 since the 
treatment regimen in this arm is different. 
The exploratory objectives are to evaluate prognostic and predictive 
biomarkers relative to treatment outcomes.  For Arm 1, pre-treatment 
and post-progression tumor tissue biopsies are optional.  For Arm 2, 
pre-treatment tumor tissue biopsy is required and post-progression 
tumor tissue biopsies are desired but optional.  Tumor samples may be 
analyzed by gene expression profiling (GEP), whole exome sequencing 
(WES), or other methods. 
Number of Subjects: 
The planned sample size is 80 subjects (60 and 20 subjects in Arms 1 
and 2, respectively) enrolled at multiple sites in the United States (US). 
Inclusion/Exclusion Criteria: 
Inclusion Criteria: 
Subjects must meet all of the following criteria in order to be eligible: 
1.
Histologically documented FL (Grade 1, 2 and 3A)  
2.
Not previously treated with prior anti-cancer therapy for FL  
3.
Stage II, III or IV disease 
4.
At least one measurable lesion 2 cm in longest diameter by CT 
and/or MRI scan (lesions in anatomical locations such as 
extremities or soft tissue lesions that are not well visualized by CT 
may be measured by MRI). 
5.
In the opinion of the investigator would benefit from therapy 
6.
Men and women 18 years of age 
7.
Eastern Cooperative Oncology Group (ECOG) performance status 
of 2 
8.
Life expectancy of more than 3 months, in the opinion of the 
investigator 
9.
Female subjects who are of non-reproductive potential (ie, 
post-menopausal by history - no menses for 2 years; OR history of 
hysterectomy; OR history of bilateral tubal ligation; OR history of 
bilateral oophorectomy).  Female subjects of childbearing potential 
must have a negative serum pregnancy test upon study entry 
10. Male and female subjects who agree to use highly effective 
methods of birth control (eg, condoms, implants, injectables, 
combined oral contraceptives, some intrauterine devices [IUDs], 
sexual abstinence, or sterilized partner) during the period of therapy 
and for 30 days (females) and 90 days (males) after the last dose of 
study drug.  Female subjects who are of non-reproductive potential 
are exempt from this criterion 


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Exclusion Criteria: 
Subjects who meet any of the following criteria are not eligible: 
1.
Medically apparent central nervous system lymphoma or 
leptomeningeal disease  
2.
FL with evidence of large cell transformation 
3.
Any prior history of other hematologic malignancy besides FL or 
myelodysplasia 
4.
History of other malignancies, except 
a)
Malignancy treated with curative intent and with no known 
active disease present for 5 years before the first dose of 
study drug and felt to be at low risk for recurrence by treating 
physician. 
b)
Adequately treated non-melanoma skin cancer or lentigo 
maligna without evidence of disease. 
c)
Adequately treated carcinoma in situ without evidence of 
disease. 
5.
Major surgery within 4 weeks of first dose of study drug 
6.
Any life-threatening illness, medical condition, including 
uncontrolled diabetes mellitus (DM), or organ system dysfunction 
that, in the opinion of the investigator, could compromise the 
subject’s safety or put the study outcomes at undue risk 
7.
Clinically significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure (New York 
Heart Association [NYHA] >Class 2), unstable angina, 
uncontrolled hypertension, or myocardial infarction within 
6 months of screening, or any Class 3 or 4 cardiac disease as 
defined by the NYHA Functional Classification 
8.
Significant screening electrocardiogram (ECG) abnormalities 
including left bundle branch block, 2nd degree atrioventricular (AV) 
block Type II, 3rd degree block, or corrected QT interval (QTc) 
470 msec 
9.
Concurrent systemic immunosuppressant therapy (eg, cyclosporine 
A, tacrolimus, etc., or chronic administration of >20 mg/day of 
prednisone) within 28 days of the first dose of study drug 
10. Known anaphylaxis or IgE-mediated hypersensitivity to murine 
proteins or to any component of rituximab (RITUXAN®) 
11. Recent infection requiring intravenous anti-infective treatment that 
was completed 14 days before the first dose of study drug 
12. Known history of infection with human immunodeficiency virus 
(HIV) or history of active or chronic infection with hepatitis C virus 
(HCV) or hepatitis B virus (HBV), or any uncontrolled active 
systemic infection 
13. Unable to swallow capsules or disease significantly affecting 
gastrointestinal function such as malabsorption syndrome, resection 
of the stomach or small bowel, or complete bowel obstruction 
14. Concurrent use of warfarin or other vitamin K antagonists 


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15. Concurrent use of a strong cytochrome P450 (CYP) 3A inhibitor 
16. Known bleeding diathesis (eg, von Willebrand’s disease) 
or hemophilia 
17. Any of the following laboratory abnormalities:  
a)
Absolute neutrophil count (ANC) <1000 cells/mm3 
(1.0 x 109/L) 
b)
Platelet count <75,000 cells/mm3 (75 x 109/L) independent of 
transfusion support  
c)
Serum aspartate transaminase (AST) or alanine transaminase 
(ALT) 3.0 x upper limit of normal (ULN) 
d)
Creatinine >2.0 x ULN or creatinine clearance (CrCL) 
<30 mL/min  
e)
Hemoglobin <8.0 g/dL 
f)
Bilirubin >1.5 x ULN (unless bilirubin rise is due to Gilbert’s 
syndrome or of non-hepatic origin) 
g)
Prothrombin time (PT)/international normalized ratio (INR) 
>1.5 u ULN and partial thromboplastin time (PTT) 
>1.5 u ULN 
18. Lactating or pregnant 
19. Unwilling or unable to participate in all required study evaluations 
and procedures 
20. Unable to understand the purpose and risks of the study and to 
provide a signed and dated informed consent form (ICF) and 
authorization to use protected health information (in accordance 
with national and local subject privacy regulations) 
Endpoints: 
Primary
Efficacy: 
x
Overall response rate (Complete response [CR] + Partial Response 
[PR]) based on Cheson 2007 as assessed by the investigator 
Secondary
Efficacy: 
x
Duration of response (DOR) 
x
Progression-free survival (PFS) 
x
Overall survival (OS) 
Safety: 
x
Frequency, severity, and relatedness of treatment-emergent adverse 
events (AEs) 
x
Frequency of treatment-emergent AEs requiring discontinuation of 
study drug or dose reductions  
Pharmacokinetic (PK)
x
Plasma PK of ibrutinib in combination with rituximab  
(Arm 1, n = 20 of a total of 60) 
x
Plasma PK of ibrutinib alone and in combination with rituximab 
(Arm 2, n = 20) 


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Exploratory
x
Change in peripheral T/B/natural killer (NK) count and profiling of 
immunophenotypes 
x
Change in secreted protein levels (ie, chemokines, cytokines) 
x
Identification of signaling pathways or biomarkers that predict 
sensitivity or resistance to ibrutinib (ie, gene expression profiling 
[GEP], whole exome sequencing [WES], etc.) 
x
Frequency of tumor mutations (or other molecular markers) 
between pre- and post-treatment tissue that predict acquired 
resistance 
x
Determination of minimal residual disease (MRD) in subjects with 
CR after ibrutinib therapy (peripheral blood [PB] and bone marrow 
[BM]) 
Safety Plan: 
This study will be monitored in accordance with the Sponsor’s 
Pharmacovigilance Committee procedures.  Adverse events (AEs) and 
serious adverse events (SAEs) will be reviewed internally on an 
ongoing basis to identify potential safety concerns.  The Sponsor may 
schedule conference calls with the investigators to discuss study 
progress, obtain investigator feedback, and/or to exchange and discuss 
study-specific issues including AEs and SAEs. 
Study Treatment: 
In Arm 1 (n = 60), subjects will receive 560 mg of ibrutinib each day 
until disease progression or unacceptable toxicity.  Rituximab 
375 mg/m2 will be given IV once weekly for 4 doses for the first 
4 weeks of study treatment.   
In Arm 2 (n = 20), subjects will receive ibrutinib 560 mg PO 
continuously as a single agent for 8 weeks, then ibrutinib at 560 mg 
will continue concurrently with rituximab 375 mg/m2 IV once weekly 
for 4 doses.  Single agent ibrutinib will then continue at 560 mg until 
disease progression or unacceptable toxicity.   
Subjects may receive treatment for up to three years after the first dose 
of the last subject enrolled, until they enroll in an extension study, reach 
the time of the study closure, or discontinue from the study for any 
reason, whichever occurs first. 
Concomitant Therapy and 
Clinical Practice: 
Permitted Concomitant Medications
x
Supportive medications in accordance with standard practice (such 
as for emesis, diarrhea, etc.) are permitted.  Use of neutrophil 
growth factors (granulocyte colony-stimulating factor [G-CSF], eg, 
filgrastim and pegfilgrastim) and red blood cell growth factors 
(erythropoietin) are permitted per institutional policy and in 
accordance with the American Society of Clinical Oncology 
(ASCO) guidelines (Smith 2006).   
x
Transfusions may be given in accordance with institutional policy. 
x
Short courses of corticosteroids (14 days) as treatment for 
non-cancer-related medical reasons (eg, joint inflammation, asthma 
exacerbation, rash, antiemetic use, arthritis, asthma, autoimmune 


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cytopenia, and infusion reactions) at doses that do not exceed 
100 mg per day of prednisone or equivalent are permitted. 
Medications to be Used with Caution
Ibrutinib is metabolized primarily by CYP3A4.  Due to the potential 
increase in ibrutinib exposure, concomitant use of strong CYP3A 
inhibitors should be avoided while the subject is receiving treatment.  
If use of a strong CYP3A inhibitor is indicated, selection of an alternate 
concomitant medication with less potent enzyme inhibition potential is 
strongly recommended.  If ibrutinib must be administered with a strong 
CYP3A inhibitor, the Medical Monitor should be consulted before use, 
and a dose reduction of ibrutinib to 140 mg daily or temporary hold of 
ibrutinib should be considered.  Subjects should be closely monitored 
for potential treatment-related toxicities. 
Prohibited Concomitant Medications
x
Chemotherapy, anticancer immunotherapy, experimental therapy, 
or radiotherapy (except as stated under permitted concomitant 
medications) are prohibited while the subject is receiving ibrutinib.  
x
Corticosteroids for the treatment of the underlying disease are 
prohibited.   
x
Corticosteroids for the treatment of non-cancer related reasons for 
longer than 14 days and/or at doses >100 mg/day of prednisone or 
equivalent are prohibited. 
Statistical Methods: 
Analysis Methods for Arm 1
The primary analysis for all efficacy endpoints will be conducted based 
on the all-treated population.  The all-treated population is defined as 
the subjects who are enrolled in the study and have received at least 
1 dose of study treatment.  
The ORR and its 95% confidence interval (CI) will be calculated using 
normal approximation to the binomial distribution using Wilson’s score 
method.  If the lower bound of the CI around the ORR is greater than or 
equal to 53%, the primary efficacy objective is achieved.  
Duration of response (DOR) is defined as the interval between the date 
of initial documentation of a response of CR or PR, and the date of first 
documented evidence of progressive disease (PD), death, or date of 
censoring if applicable.  The distribution (median, its 95% CI and 
Kaplan-Meier curves) of DOR will be provided using Kaplan-Meier 
estimates for responders in the all-treated population. 
Progression-free survival (PFS) will be assessed and defined as the 
period from the date of first dose of ibrutinib until the date of first 
documented evidence of PD or death, whichever occurs earlier.  
Overall survival (OS) is measured from the date of first dose of 
ibrutinib to the date of the subject’s death from any cause.  PFS and OS 
will be analyzed by the same time-to-event analysis method used for 
DOR.   
 


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Analysis Methods for Arm 2
Overall Response Rate (ORR) and its 95% confidence interval will be 
calculated using normal approximation to the binomial distribution 
using Wilson’s score method. 
Distribution of DOR, PFS and OS will be summarized using the 
Kaplan-Meier estimate of median and its corresponding 95% CI where 
the summaries are possible.    
Analysis for Study Report
The analyses for the clinical study report (CSR) will occur at least 
1 year after the last subject enrolled received the first dose of study 
drug.  
Sample Size Determination: 
The hypotheses test of primary endpoint analysis for Arm 1 in this 
study assumes an underlying response rate of 53% for first-line 
rituximab treatment in subjects with low grade FL (Hainsworth 2002; 
Freedman 2009).  A sample size of approximately 60 eligible subjects 
is needed to exclude a 53% response rate at the 1-sided 0.025 
significance level with at least 80% power, assuming a response rate of 
71% is achieved.  
 
 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...............................................................................................2
STUDY SYNOPSIS .......................................................................................................................3
TABLE OF CONTENTS ............................................................................................................10
LIST OF TABLES .......................................................................................................................13
LIST OF APPENDICES .............................................................................................................13
ABBREVIATIONS AND DEFINITION OF TERMS .............................................................14
1.
BACKGROUND ..............................................................................................................17
1.1
Follicular Lymphoma.........................................................................................................17
1.2
Ibrutinib Background .........................................................................................................18
1.3
Summary of Nonclinical Data ...........................................................................................19
1.3.1
Pharmacology .....................................................................................................19
1.3.2
Toxicology ..........................................................................................................20
1.3.3
Carcinogenesis, Mutagenesis, Impairment of Fertility .......................................20
1.4
Summary of Clinical Studies .............................................................................................21
1.4.1
Pharmacokinetics and Product Metabolism ........................................................21
1.4.2
Summary of Clinical Safety ................................................................................22
1.4.3
Risks ...................................................................................................................23
1.5
Justification of Study Design and Dose Rationale .............................................................25
2.
STUDY OBJECTIVES ....................................................................................................26
2.1
Primary Objective ..............................................................................................................26
2.2
Secondary Objectives .........................................................................................................27
2.3
Exploratory Objective ........................................................................................................27
3.
STUDY DESIGN ..............................................................................................................27
3.1
Description of Study ..........................................................................................................27
3.2
Endpoints ...........................................................................................................................28
3.2.1
Primary Endpoint ................................................................................................28
3.2.2
Secondary Endpoints ..........................................................................................28
3.2.3
Pharmacokinetic (PK) Endpoints........................................................................28
3.2.4
Exploratory Endpoints ........................................................................................28
3.3
Safety Plan .........................................................................................................................29
3.4
Statement of Compliance ...................................................................................................29
4.
SUBJECT SELECTION .................................................................................................29
4.1
Number of Subjects............................................................................................................29
4.2
Inclusion Criteria ...............................................................................................................29
4.3
Exclusion Criteria ..............................................................................................................30
5.
TREATMENT OF SUBJECTS ......................................................................................32
5.1
Enrollment and Blinding ....................................................................................................32


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5.2
Formulation, Packaging and Storage .................................................................................32
5.2.1
Ibrutinib ..............................................................................................................32
5.2.2
Rituximab............................................................................................................32
5.3
Dosage and Administration................................................................................................32
5.3.1
Ibrutinib ..............................................................................................................33
5.3.2
Rituximab............................................................................................................33
5.4
Dose Reduction, Delay and Discontinuation .....................................................................34
5.4.1
Ibrutinib ..............................................................................................................34
5.4.2
Rituximab............................................................................................................35
5.5
Overdose Instructions ........................................................................................................36
5.6
Criteria for Permanent Discontinuation of Study Drug .....................................................36
6.
CONCOMITANT MEDICATIONS/PROCEDURES .................................................37
6.1
Concomitant Medications ..................................................................................................37
6.1.1
Permitted Concomitant Medications ..................................................................37
6.1.2
Medications to be Used with Caution .................................................................37
6.1.3
Prohibited Concomitant Medications .................................................................38
6.2
Guidelines for Ibrutinib Management with Surgeries or Procedures ................................38
7.
STUDY PROCEDURES .................................................................................................39
7.1
Visit Procedures .................................................................................................................39
7.1.1
Screening ............................................................................................................39
7.1.2
Treatment Phase ..................................................................................................40
7.1.3
Follow-Up Phase ................................................................................................49
7.2
Missed Evaluations ............................................................................................................50
7.3
Description of Procedures ..................................................................................................50
7.3.1
Medical History ..................................................................................................50
7.3.2
Physical Examination .........................................................................................50
7.3.3
B-symptoms ........................................................................................................50
7.3.4
Vital Signs, Height and Weight ..........................................................................50
7.3.5
ECOG Performance Status .................................................................................50
7.3.6
Electrocardiogram ...............................................................................................51
7.3.7
Prior/Concomitant Medications ..........................................................................51
7.3.8
Adverse Events ...................................................................................................51
7.3.9
CT/MRI and PET Scans .....................................................................................51
7.3.10
Response Assessment .........................................................................................52
7.3.11
Hematology .........................................................................................................53
7.3.12
Serum Chemistry ................................................................................................53
7.3.13
Coagulation .........................................................................................................53
7.3.14
Hepatitis Serologies ............................................................................................53
7.3.15
Pregnancy Test ....................................................................................................53
7.3.16
Urinalysis ............................................................................................................54


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7.3.17
Bone Marrow Aspirate and Biopsy ....................................................................54
7.3.18
T/B/NK Cell Count .............................................................................................54
7.3.19
Blood Samples for Immunophenotypes, Secreted Proteins, and Other 
Biomarkers ..........................................................................................................54
7.3.20
Pharmacokinetics ................................................................................................54
7.3.21
Pharmacokinetics Sample Collection for Subjects Treated with 
Concomitant CYP3A Inhibitors While on Ibrutinib Treatment .........................55
7.3.22
Tumor Tissue Biopsy ..........................................................................................55
8.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................56
8.1
Completion .........................................................................................................................56
8.2
Treatment Discontinuation .................................................................................................56
8.3
Study Exit/Withdrawal.......................................................................................................56
9.
STATISTICAL METHODS ...........................................................................................57
9.1
General Considerations ......................................................................................................57
9.1.1
Response Assessment .........................................................................................57
9.1.2
Safety Monitoring ...............................................................................................57
9.2
Definition of Analysis Populations ....................................................................................58
9.3
Endpoint Data Analysis .....................................................................................................58
9.3.1
Demographic/Baseline Characteristics and Study Conduct ...............................58
9.3.2
Primary Efficacy Endpoint .................................................................................58
9.3.3
Secondary Efficacy Endpoints ............................................................................59
9.3.4
Safety Analysis ...................................................................................................60
9.3.5
Pharmacokinetics ................................................................................................60
9.3.6
Exploratory Analyses ..........................................................................................61
9.4
Handling of Missing Data ..................................................................................................61
9.5
Determination of Sample Size ...........................................................................................62
9.6
Interim Analysis .................................................................................................................62
9.7
Analysis for Study Report ..................................................................................................62
10.
ADVERSE EVENT REPORTING ................................................................................62
10.1
Adverse Event Definitions and Classifications ..................................................................62
10.1.1
Adverse Events ...................................................................................................62
10.1.2
Serious Adverse Event ........................................................................................63
10.1.3
Unexpected Adverse Events ...............................................................................64
10.1.4
Severity Criteria (Grade 1-5) ..............................................................................64
10.1.5
Causality (Attribution) ........................................................................................65
10.2
Documenting and Reporting of Adverse Events ...............................................................65
10.2.1
Special Reporting Situations ...............................................................................65
10.2.2
Adverse Event Reporting Procedures .................................................................66
10.2.3
Other Malignancies .............................................................................................67
10.2.4
Events of Special Interest ...................................................................................67


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10.2.5
Pregnancy............................................................................................................68
11.
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .................68
11.1
Regulatory and Ethical Compliance ..................................................................................68
11.2
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval .....................................................................................68
11.3
Informed Consent...............................................................................................................69
11.4
Quality Control and Quality Assurance .............................................................................69
11.5
Protected Subject Health Information Authorization ........................................................69
11.6
Study Files and Record Retention......................................................................................70
11.7
Case Report Forms and Record Maintenance ....................................................................71
11.8
Investigational Study Drug Accountability .......................................................................71
11.9
Study Monitoring/Audit Requirements ..............................................................................72
11.10 Investigator Responsibilities ..............................................................................................72
11.11 Sponsor Responsibilities ....................................................................................................73
11.12 Financial Disclosure ...........................................................................................................73
11.13 Liability and Clinical Trial Insurance ................................................................................73
11.14 Protocol Amendments ........................................................................................................74
11.15 Publication of Study Results ..............................................................................................74
11.16 Study Discontinuation ........................................................................................................74
11.17 Study Completion ..............................................................................................................75
12.
REFERENCES .................................................................................................................76
13.
APPENDICES ..................................................................................................................79
LIST OF TABLES 
Table 1:
Dose Modification for Ibrutinib Toxicity ..............................................................35
Table 2:
Dose Modification for Rituximab Toxicity ...........................................................36
Table 3:
Pharmacokinetic Sample Schedule ........................................................................55
 
LIST OF APPENDICES 
Appendix 1:
Schedule of Assessments for Arm 1 ......................................................................80
Appendix 2:
Schedule of Assessments for Arm 2 ......................................................................81
Appendix 3:
Performance Status Scores .....................................................................................82
Appendix 4:
Inhibitors and Inducers of CYP3A ........................................................................83
Appendix 5:
Guidelines for Establishing Response to Treatment ..............................................85
Appendix 6:
Child-Pugh Score ...................................................................................................86


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ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition 
[14C] 
Carbon-14 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AV 
Atrioventricular 
BCR 
B-cell receptor  
BM 
bone marrow 
BR 
bendamustine + rituximab 
BTK 
Bruton’s tyrosine kinase 
C 
Celsius 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
CR 
complete remission (response) 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
dL 
Deciliter 
DM 
diabetes mellitus  
DOR 
duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EU 
European Union 
F 
Fahrenheit 
FCR 
fludarabine + mitoxantrone + rituximab 
FDA 
Food and Drug Administration 
FDG 
[18F]fluorodeoxyglucose 
FL 
follicular lymphoma 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GEP 
gene expression profiling 


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Abbreviation 
Definition 
Hr 
Hour 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
ILD 
interstitial lung disease 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
Intravenous 
Kg 
Kilogram 
LDH 
lactate dehydrogenase 
m 
Meters 
MCL 
mantle cell lymphoma 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm 
millimeter 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose  
NCCN 
National Comprehensive Cancer Network 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer (cells) 
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PCYC 
Pharmacyclics 
PB 
peripheral blood 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
pH 
power of Hydrogen 
PK 
Pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 


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Abbreviation 
Definition 
PO 
per os (oral) 
PR 
partial remission (response) 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QTc 
corrected QT interval 
R-CHOP 
Rituximab + cyclophosphamide + doxorubicin + vincristine sulfate + prednisone 
R-CVP 
Rituximab + cyclophosphamide + vincristine sulfate + prednisone 
REAL 
Revised European American Lymphoma 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SLL 
small lymphocytic lymphoma 
SPD 
sum of the product of the diameters 
TEAEs 
treatment-emergent adverse events 
TLS 
tumor lysis syndrome 
t ½  
half-life 
Tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
US 
United States 
WES 
whole exome sequencing 
WHO 
World Health Organization 
WM 
Waldenstrom’s macroglobulinemia 
 
 


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1.
BACKGROUND
For more detailed and comprehensive background information, please refer to the current 
ibrutinib Investigator’s Brochure (IB). 
1.1
Follicular Lymphoma 
Follicular lymphoma (FL) is one of the most common types of Non-Hodgkin’s Lymphoma 
(NHL) accounting for approximately 22% of cases (NHL Classification Project 1997), and for 
about 70% of indolent lymphomas (NHL Cyber family web site).  Follicular lymphoma is 
characterized by an indolent clinical course, typical morphology, and the presence of a 
chromosomal translocation, t(14;18)(q32;q21) or variant in 85% of patients (Relander 2010).  
The overall incidence of B-cell lymphoid neoplasms in the United States (US) is estimated at 
26.13/100,000 person years (Morton 2006), with FL accounting for 3.18 new cases per 100,000 
persons each year in the US and 5 to 7 new cases per 100,000 persons each year in the European 
Union (EU) (Dreyling 2011).  The neoplastic lymphocytes in FL express pan-B markers CD19, 
CD20, CD22, and CD79a; as well as antigens of the germinal center (including CD10 and 
Bcl-6).  Histologically, the follicular form of NHL is composed mainly of centrocytes with an 
admixture of centroblasts.  Grading is based on the number of large transformed cells in 
10 malignant follicles viewed at high power (Martinez 2007).  Follicular lymphoma is generally 
subdivided into 3 grades (NHL Classification Project 2007).  However, Grade 3 is often further 
divided into 2 subgroups, 3a and 3b; with 3b considered more aggressive (Hans 2003).  
Treatment depends on the stage of the disease, symptoms, patient age, and comorbidities. 
The best time to initiate therapy is a decision of the individual oncologist managing the 
individual patient.  Current guidelines (eg, National Comprehensive Cancer Network [NCCN]) 
are somewhat flexible; therapies and therapy start times are variable.  Some treating oncologists 
especially for patients in earlier stages of disease prefer a watch-and-wait approach in an attempt 
to manage disease symptoms and treatment toxicities (Colombat 2001; Young 1988).  Since FL 
is slow growing, it may take years for the disease to progress, during which time treatment may 
not be necessary.  Depending on a patient’s symptoms, early treatment may not always improve 
overall survival, especially if the disease is not affecting their organs (Colombat 2001). 
Patients with Stage III or IV FL who have involvement of multiple lymph node regions, 
involvement of one or more organs or tissues outside the lymphatic system, and systemic 
symptoms, are candidates for immediate therapy.  When the decision to treat has been made, 
initial therapy may include rituximab as a single agent.  Two single-arm studies have been 
published that form the basis for the NCCN guidelines for rituximab in the first line setting.  
In the first study with 49 patients with low tumor burden where rituximab was given for a total of 
4 weekly doses, patients were eligible for inclusion if they had follicular NHL according to the 
Revised European American Lymphoma (REAL) classification (Harris 1994); disease stage was 
II to IV according to Ann-Arbor classification, and the presence of at least one measurable 
disease site was required (Colombat 2001).  The overall response rate (ORR) was 73% and the 


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time to progression was 50% after the first year (Colombat 2001).  In the second study, 
60 patients were treated with 4 weekly doses of rituximab followed by maintenance therapy at 
6-month intervals until progression (Hainsworth 2002).  Inclusion criteria included biopsy- 
proven indolent B-cell NHL as defined by the REAL classification; disease stage was II to IV or 
disease Stage I or II if relapsed or progressed after radiation therapy (Hainsworth 2002).  The 
ORR was 47% and long-term follow data had a progression-free survival (PFS) of 34 months 
(Hainsworth 2002).   
A third larger study in 349 treatment-naïve patients treated with 4 weekly courses of rituximab 
showed an ORR of 59% (Freedman 2009).  This study included patients with histologically 
confirmed CD20+ FL World Health Organization (WHO) Grade 1 to 3 who had an Eastern 
Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Freedman 2009).  The 
long-term outcome of this study is hard to interpret due to further randomization to an 
experimental regimen. 
In patients with large tumor burdens, rituximab may be combined with 1 or more cytotoxic 
drugs.  Alkylating agents such as cyclophosphamide or bendamustine, in combination with 
rituximab, constitute the mainstay of combination therapy.  The most commonly used 
alkylator-based regimens include BR (bendamustine and rituximab), R-CHOP (rituximab, 
cyclophosphamide, vincristine, doxorubicin, and prednisone), or R-CVP (rituximab, 
cyclophosphamide, vincristine, and prednisone) (Lymphoma Research Foundation 2011).  
Response rates in excess of 85% are observed with many different combinations in the first-line 
setting (Peterson 2003; Hiddeman 2005; Czuczman 2005; Rummel 2005); however these 
treatments are associated with significantly more toxicity than single-agent rituximab.  
Due to the toxicity seen with standard combination treatment regimens in patients who are 
elderly, and for patients that have moderate tumor burdens and non-life threatening disease, an 
initial chemotherapy-free regimen such as rituximab and ibrutinib may be an attractive treatment 
option if found to be well tolerated and have significant anti-tumor activity.   
1.2
Ibrutinib Background 
Ibrutinib (IMBRUVICA®) is a first-in-class, potent, orally administered covalently-binding 
inhibitor of Bruton’s tyrosine kinase (BTK) co-developed by Pharmacyclics LLC and Janssen 
Research & Development LLC for the treatment of B-cell malignancies.  Inhibition of BTK 
blocks downstream B-cell receptor (BCR) signaling pathways and thus prevents B-cell 
proliferation.  In vitro, ibrutinib inhibits purified BTK and selected members of the kinase family 
with 10-fold specificity compared with non-BTK kinases.   
Ibrutinib has been approved in many regions, including the US and EU, for indications covering 
the treatment of patients with mantle cell lymphoma (MCL) who have received at least 1 prior 
therapy, patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma 
(SLL), including CLL with a deletion of the short arm of chromosome 17 (del17p), and patients 


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with Waldenström’s macroglobulinemia.  Ibrutinib is currently under investigation in various 
indications as a single agent and in combinations.  
B-cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release.  B-cells express cell surface 
immunoglobulins comprising the BCR, which is activated by binding to antigen.  Antigen 
binding induces receptor aggregation and the clustering and activation of multiple tyrosine 
kinases, which in turn activate further downstream signaling pathways (Bishop 2003).  
The process of B-cell maturation, including immunoglobulin chain rearrangement and somatic 
mutation, is tightly regulated.  It is thought that B-cell lymphomas and CLL result from 
mutations and translocations acquired during normal B-cell development (Shaffer 2002).  
Several lines of evidence suggest that signaling through the BCR is necessary to sustain the 
viability of B-cell malignancies.   
The role of BTK in BCR signal transduction is demonstrated by the human genetic 
immunodeficiency disease X-linked agammaglobulinemia and the mouse genetic disease 
X-linked immunodeficiency, both caused by a mutation in the BTK gene.  These genetic diseases 
are characterized by reduced BCR signaling and a failure to generate mature B-cells.  The BTK 
protein is expressed in most hematopoietic cells with the exception of T-cells and natural killer 
cells, but the selective effect of BTK mutations suggests that its primary functional role is in 
antigen receptor signaling in B-cells (Satterthwaite 2000).   
Data from Study PCYC-04753 demonstrate that although ibrutinib is rapidly eliminated from the 
plasma after oral administration, once daily dosing with ibrutinib is adequate to sustain maximal 
pharmacodynamic activity for 24 hours postdose at dose levels 2.5 mg/kg.  In Study 
PCYC-04753, the BTK occupancies for the 2.5 mg/kg/day to 12.5 mg/kg/day cohorts and for the 
560 mg continuous dosing cohort, were all above 90% at either 4 or 24 hours after drug 
administration.  
For the most comprehensive nonclinical and clinical information regarding ibrutinib background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to 
the latest version of the ibrutinib IB. 
1.3
Summary of Nonclinical Data 
1.3.1
Pharmacology
Ibrutinib was designed as a selective and covalent inhibitor of the BTK (Pan 2007).  In vitro, 
ibrutinib is a potent inhibitor of BTK activity (IC50 = 0.39 nM).  The irreversible binding of 
ibrutinib to cysteine-481 in the active site of BTK results in sustained inhibition of BTK catalytic 
activity and enhanced selectivity over other kinases that do not contain a cysteine at this position.  
When added directly to human whole blood, ibrutinib inhibits signal transduction from the B-cell 


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receptor and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation 
followed by CD69 expression (Herman 2011).   
Ibrutinib arrested cell growth and induced apoptosis in human B-cell lymphoma cell lines in vitro 
and inhibited tumor growth in vivo in xenograft models (Herman 2011).  Ibrutinib also inhibited 
adhesion and migration of mantle cell lymphoma (MCL) cells in co-culture and reduced tumor 
burden in lymph node and bone marrow in a murine model of MCL dissemination and 
progression (Chang 2013a; Chang 2013b). 
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current IB. 
1.3.2
Toxicology
In safety pharmacology assessments, no treatment-related effects were observed in the central 
nervous system or respiratory system in rats at any dose tested.  Further, no treatment-related 
corrected QT interval (QTc) prolongation effect was observed at any tested dose in a 
cardiovascular study using telemetry-monitored dogs.   
Based on data from rat and dog including general toxicity studies up to 13 weeks duration, 
the greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and in the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation).  Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog).    
In vitro and in vivo genetic toxicity studies showed that ibrutinib is not genotoxic.  In a rat 
embryo-fetal toxicity study, ibrutinib administration was associated with fetal loss and 
malformations (teratogenicity) at ibrutinib doses that result in approximately 6 times and 
14 times the exposure (AUC [area under the curve]) in patients administered the dose of 560 mg 
daily, respectively. 
For the most comprehensive nonclinical and clinical information regarding ibrutinib, please refer 
to the current version of the IB.  
1.3.3
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been conducted with ibrutinib. 
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo 
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. 


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Fertility studies with ibrutinib have not been conducted in animals.  In the general toxicology 
studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects 
on reproductive organs. 
1.4
Summary of Clinical Studies 
Ibrutinib is under late-stage development as an orally administered anticancer agent for patients 
with B-cell malignancies.  As of the 06 April 2014 data cutoff date, there are 26 ongoing and 
9 completed company-sponsored clinical trials investigating the safety, efficacy and 
pharmacokinetics (PK) of ibrutinib in humans as a single agent and in combination with 
chemotherapy and immunotherapy.  Ongoing and completed company-sponsored clinical studies 
of ibrutinib are summarized in the current version of the IB.  
1.4.1
Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging from 1.25 to 12.5 mg/kg/day as well 
as fixed dose levels of 420, 560, and 840 mg/day, exposure to ibrutinib increased as doses 
increased with substantial intersubject variability.  The mean half-life (t1/2) of ibrutinib across 
3 clinical studies ranged from 4 to 9 hours, with a median time to maximum plasma 
concentration (Tmax) of 2 hours.  Administration of 420 mg ibrutinib with a high-fat breakfast in 
subjects with CLL approximately doubled the mean systemic exposure compared to intake after 
overnight fasting with median time to Tmax delayed from 2 to 4 hours.  Ibrutinib was extensively 
metabolized to the dihydrodiol metabolite PCI-45227, a reversible inhibitor of BTK, with 
approximately 15 times lower inhibitory potency compared to ibrutinib.  The metabolite-to-
parent AUC ratio ranged from 0.7 to 3.4.  Steady-state exposure of ibrutinib and PCI-45227 was 
less than 2-fold of first dose exposure. 
The results of a human mass balance study of [14C]-ibrutinib conducted in six healthy male 
subjects demonstrated that less than 10% of the total dose of [14C]-ibrutinib is renally excreted, 
whereas approximately 80% is recovered in feces.  Subjects with mild and moderate renal 
insufficiency (creatinine clearance >30 mL/min) were eligible to enroll in Study PCYC-1102-CA 
in which pharmacokinetic (PK) assessments were included.  No dose adjustment is needed for 
subjects with mild or moderate renal impairment (greater than 30 mL/min creatinine clearance) 
in this study.  There is no data in patients with severe renal impairment or subjects on dialysis.   
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. 


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1.4.2
Summary of Clinical Safety
For more comprehensive safety information please refer to the current version of the IB.  
1.4.2.1
Monotherapy Studies 
Pooled safety data for 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 Investigator’s Brochure 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 
t15% a 
Most frequently reported Grade 3 
or 4 TEAEs t3% b 
Most frequently reported Serious 
TEAEs t2% c 
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Pyrexia 
Hypertension   
 
Anemia 
Diarrhoea    
 
Neutropenia  
Atrial fibrillation 
 
Upper respiratory tract infection 
 
 
Thrombocytopenia    
 
 
Oedema peripheral    
 
 
a Source is Table 6 of IB; b Source is Table 8 of IB; c Source is Table 9 of IB. 
1.4.2.2
Combination Studies 
Pooled safety data for a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in B-cell malignancies.  Therapies used in combination with 
ibrutinib in these studies, included BR (bendamustine and rituximab), FCR (fludarabine, 
cyclophosphamide, and rituximab), ofatumumab, and R-CHOP (rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone).  Data from subjects in Study CLL3001 who crossed 
over from the comparator arm to ibrutinib treatment after progression are not included.  
Most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy (N=423): 


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Most frequently reported TEAEs 
t20% a 
Most frequently reported Grade 3 
or 4 TEAEs t3% b 
Most frequently reported Serious 
TEAEs t2% c 
Neutropenia 
Neutropenia 
Pneumonia          
Diarrhea 
Thrombocytopenia 
Febrile neutropenia     
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Neutrophil count decreased       
Cellulitis              
Anaemia 
Anaemia                          
 
Pyrexia     
Fatigue                          
 
 
Hypertension                     
 
 
Diarrhoea                        
 
a Source is Table 10 of IB;  b Source is Table 12 of IB; c Source is Table 13 of IB. 
1.4.3
Risks 
1.4.3.1
Bleeding-related Events 
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia.  These include minor hemorrhagic events such as contusion, 
epistaxis, and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal 
bleeding, intracranial hemorrhage, and hematuria.  Use of ibrutinib in subjects requiring other 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding.  
Subjects with congenital bleeding diathesis have not been studied.  See Section 6.1.2.4 for 
guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements.  See 
Section 6.2 for guidance on ibrutinib management with surgeries or procedures.   
1.4.3.2
Lymphocytosis and Leukostasis 
Leukostasis 
There were isolated cases of leukostasis reported in subjects treated with ibrutinib.  A high 
number of circulating lymphocytes (>400,000/μL) may confer increased risk.  
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/small lymphocytic lymphoma (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 e.g. 
>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 


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8.0 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.   
1.4.3.3
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 (e.g., 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 5.4.1). 
1.4.3.4
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. 
1.4.3.5
Diarrhea
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy.  Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation.  These events are rarely severe.  Should symptoms be severe or prolonged 
follow the protocol dose modification guidelines (see Section 5.4.1).  
1.4.3.6
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. 
1.4.3.7
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in patients treated with ibrutinib. 
Monitor patients for pulmonary symptoms indicative of ILD.  Should symptoms develop follow 
the protocol dose modification guidelines (see Section 5.4.1). 
1.4.3.8
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. 


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1.4.3.9
Rash
Rash has been commonly reported in subjects treated with either single-agent ibrutinib or in 
combination with chemotherapy.  In a randomized Phase 3 study (PCYC-1112-CA), rash 
occurred at a higher rate in the ibrutinib arm than in the control arm.  Most rashes were mild to 
moderate in severity.  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 erythema, urticaria, angioedema have been reported.   
1.4.3.10
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 
preͲexisting kidney abnormalities. 
1.4.3.11
Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib.  Monitor subjects 
for new onset hypertension or hypertension that is not adequately controlled after starting 
ibrutinib.  Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive 
treatment as appropriate. 
1.5
Justification of Study Design and Dose Rationale
This is an open-label, Phase 2 study designed to assess the safety and efficacy of ibrutinib and 
rituximab in subjects with previously untreated FL. Rituximab, given either as a single agent or 
in combination, is currently a recommended therapy for previously untreated FL.  All subjects 
will receive ibrutinib and rituximab; the study will include two treatment arms with 60 subjects 
in the main study arm and 20 subjects in the exploratory study arm. For the 60 subjects in Arm 1, 
the study will determine clinically meaningful efficacy for the combination of ibrutinib and 
rituximab in untreated FL subjects. Assuming an ORR of 53% for single-agent rituximab, a 
response rate of 71% for the combination of ibrutinib and rituximab implies an 18% 
improvement in ORR over rituximab alone. With a sample size of 60, an 18% change in ORR 
will be detected with 81% power at 1-sided significance level 0.025 (or 2-sided significance 
level 0.05). 
The proposed dose for rituximab is 375 mg/m2 intravenous (IV) administered once weekly for 
4 weeks.  This dose was given in two single-arm published studies that form the basis for the 


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NCCN guidelines for rituximab in the first-line setting (Colombat 2001; Hainsworth 2002) 
and has been used in relapsed/refractory FL (McLaughlin 1998). 
The proposed dose for ibrutinib is 560 mg per day (4 x 140-mg capsules) administered once daily 
without interruption.  In the Phase 1 study (PCYC-04753), the 560 mg dose administered once 
daily appeared safe and favorable responses were seen in subjects with NHL as outlined above.   
Study PCYC-04753 was a first-in-human, Phase 1, dose-escalating study of ibrutinib in subjects 
with recurrent B-cell lymphoma including NHL, CLL, FL, MCL, and WM.  Five sequential 
cohorts of subjects received ibrutinib from 1.25 to 12.5 mg/kg/day for 28 days of a 35-day cycle 
and 2 additional cohorts received a continuous ibrutinib dose of 8.3 mg/kg/day or a 560-mg fixed 
dose. 
Sixty-six (66) subjects were enrolled including 16 subjects with FL.  Of the 16 subjects with FL, 
11 (68.8%) were evaluable for response.  The ORR for these 11 subjects was 45.5%, with 
3 complete responses (CR, 27.3%) and 2 partial responses (PR, 18.2%) and median PFS was 
13.4 months.  Five (45.5%) of the six remaining subjects had stable disease (SD).   
These data imply relevant anti-tumor activity in the indolent lymphoma patient population.  
In Study PCYC-04753, ibrutinib was well tolerated across a broad range of doses (1.25 through 
12.5 mg/kg/day) both when given intermittently and continuously on a 35-day cycle to subjects 
with a variety of lymphoid malignancies.  The most common AEs (>20% of subjects) in this 
population were diarrhea, fatigue, cough, nausea, headache, and pyrexia. AEs were generally 
mild to moderate (Grade 1 or 2) and readily managed or reversible.  There was no apparent 
relationship between the incidences or severity of AEs and dose or schedule of ibrutinib.  
In addition, the maximum tolerated dose of ibrutinib was not reached. Pharmacodynamic studies 
revealed complete BTK active-site occupancy in PBMCs at doses of 2.5 mg/kg and above, 
including the 560 mg continuous dosing cohort.  In addition, because of an expected tissue-to-
plasma concentration ratio of 50% in more distant compartments, such as blood-forming organs 
(bone marrow, spleen, and lymph node) and lymphoid tumor tissue (based on ratio data in the 
range of 0.44 to 0.67 observed in rat), it is reasonable to expect full BTK occupancy in these 
tissues at doses of 5 mg/kg and above. 
Taken together, these data support the proposed doses for the combination of rituximab and 
ibrutinib.  If the combination is effective and well tolerated, further investigation in the 
treatment-naïve FL population will be warranted. 
2.
STUDY OBJECTIVES
2.1
Primary Objective 
The primary objective is to evaluate the efficacy of ibrutinib when combined with rituximab 
(determined by the ORR) in previously untreated subjects with FL. 


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2.2
Secondary Objectives 
The secondary objectives are: 
x
To evaluate the efficacy of ibrutinib combined with rituximab in subjects with FL as 
assessed by the duration of response (DOR), PFS, and overall survival (OS) 
x
To evaluate the safety and tolerability of ibrutinib combined with rituximab in previously 
untreated subjects with FL 
2.3
Exploratory Objective 
The exploratory objectives are: 
x
To determine the pharmacokinetics (PK) of ibrutinib when combined with rituximab in 
subjects with FL 
x
To evaluate prognostic and predictive biomarkers relative to treatment outcomes 
3.
STUDY DESIGN
3.1
Description of Study 
This is an open-label, Phase 2 study designed to assess the efficacy and safety of ibrutinib 
combined with rituximab in previously untreated subjects with FL.  The study will include 
approximately 80 subjects with two treatment arms. 
In Arm 1 (n=60), subjects will receive ibrutinib 560 mg per oral (PO) continuously until disease 
progression or unacceptable toxicity.  In addition, subjects will receive rituximab 375 mg/m2 IV 
once weekly for 4 doses for the first 4 weeks of study treatment. Subjects in Arm 1 will have 
imaging efficacy assessments every 12 weeks for the first 8 assessments and then every 24 weeks 
thereafter.   
In Arm 2 (n=20), subjects will receive ibrutinib 560 mg PO continuously as a single agent for the 
first 8 weeks, then ibrutinib at 560 mg will continue concurrently with rituximab 375 mg/m2 IV 
once weekly for 4 doses.  Once treatment with rituximab is complete, subjects will continue to 
receive single-agent ibrutinib continuously until disease progression or unacceptable toxicity. 
Subjects in Arm 2 will have imaging efficacy assessments at Week 9, Week 20 and then every 
12 weeks for 6 assessments after Week 20, and then every 24 weeks thereafter.  Subjects who 
progress prior to starting rituximab will be discontinued from the study.  Rituximab will not be 
administered prior to the protocol-specified administration. 
One of the purposes of Arm 2 is to identify biomarkers that predict sensitivity or resistance to 
ibrutinib.  Based on Phase 1 clinical data in FL it is predicted that approximately half of the 
subjects treated in this arm will show evidence of resistance to single-agent ibrutinib.  By 
providing a lead-in time prior to the initiation of rituximab, pre- and post-progression biopsy 


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samples can be collected to address markers of drug resistance.  These objectives are exploratory 
and therefore the primary and secondary objectives related to clinical efficacy are paramount but 
will be analyzed separately from Arm 1 since the treatment regimen in this arm is different. 
For Arm 1, pre-treatment and post-progression tumor tissue biopsies are optional.  For Arm 2, 
pre-treatment tumor tissue biopsy is required and post-progression tumor tissue biopsies are 
desired but optional.  Tumor samples may be analyzed by gene expression profiling (GEP), 
whole exome sequencing (WES), or other methods. 
Subjects may receive treatment for up to three years after the first dose of the last subject 
enrolled, until they enroll in an extension study, reach the time of the study closure, or 
discontinue from the study for any reason, whichever occurs first. Reasons for treatment 
discontinuation are outlined in Section 8.2.  
3.2
Endpoints
3.2.1
Primary Endpoint 
Overall response rate (Complete response [CR] + Partial Response [PR]) based on Cheson 2007 
as assessed by the investigator 
3.2.2
Secondary Endpoints 
x
Efficacy: 

Duration of response (DOR) 

Progression-free survival (PFS) 

Overall survival (OS) 
x
Safety: 

Frequency, severity, and relatedness of AEs 

Frequency of AEs requiring discontinuation of study drug or dose reductions 
3.2.3
Pharmacokinetic (PK) Endpoints 
x
Plasma PK of ibrutinib in combination with rituximab (Arm 1, n=20 of a total of 60) 
x
Plasma PK of ibrutinib alone and in combination with rituximab (Arm 2, n=20) 
3.2.4
Exploratory Endpoints 
The exploratory endpoints are as follows: 
x
Change in peripheral T/B/natural killer (NK) count and profiling of immunophenotypes 
x
Change in secreted protein levels (ie, chemokines, cytokines) 


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x
Identification of signaling pathways or biomarkers that predict sensitivity or resistance to 
ibrutinib (ie, GEP, WES, etc.) 
x
Frequency of tumor mutations (or other molecular markers) between pre- and post-treatment 
tissue that are associated with acquired resistance 
x
Determination of minimal residual disease (MRD) in subjects with CR after study treatment 
(peripheral blood [PB] and bone marrow [BM]) 
3.3
Safety Plan 
This study will be monitored in accordance with the Sponsor’s Pharmacovigilance Committee 
procedures.  Treatment-emergent AEs and SAEs will be reviewed internally on an ongoing basis 
to identify safety concerns.  Enrolled subjects will also be evaluated clinically including vital 
signs and standard laboratory test assessment.  The Sponsor may schedule conference calls with 
the investigators to discuss study progress, obtain investigator feedback and exchange, and 
discuss study-specific issues including AEs and SAEs and discontinuations of study drug. 
3.4
Statement of Compliance 
This study will be conducted in compliance with this protocol, principles of International 
Conference on Harmonisation (ICH), Good Clinical Practice (GCP), Declaration of Helsinki, and 
all applicable national and local regulations governing clinical studies. 
4.
SUBJECT SELECTION
4.1
Number of Subjects 
The planned sample size in Arm 1 (main study arm) is 60 subjects enrolled at multiple sites in 
the US.  Other regions may be considered based on overall enrollment. 
The planned sample size in Arm 2 (exploratory study arm) is 20 subjects enrolled at a single site 
in the US. 
4.2
Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the following 
criteria:  
1. Histologically documented FL (Grade 1, 2 and 3A)  
2. Not previously treated with anti-cancer therapy for FL 
3. Stage II, III or IV disease 
4. At least one measurable lesion 2 cm in longest diameter by CT and/or MRI scan 
(lesions in anatomical locations such as extremities or soft tissue lesions that are not well 
visualized by CT may be measured by MRI) 


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5. In the opinion of the investigator would benefit from therapy 
6. Men and women 18 years of age 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 2 
8. Life expectancy of more than 3 months, in the opinion of the investigator 
9. Female subjects who are of non-reproductive potential (ie, post-menopausal by history - 
no menses for 2 years; OR history of hysterectomy; OR history of bilateral tubal 
ligation; OR history of bilateral oophorectomy).  Female subjects of childbearing 
potential must have a negative serum pregnancy test upon study entry. 
10. Male and female subjects who agree to use highly effective methods of birth control 
(eg, condoms, implants, injectables, combined oral contraceptives, some intrauterine 
devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and 
for 30 days (females) and 90 days (males) after the last dose of study drug.  Female 
subjects who are of non-reproductive potential are exempt from this criterion. 
4.3
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Medically apparent central nervous system lymphoma or leptomeningeal disease 
2. FL with evidence of large cell transformation    
3. Any prior history of other hematologic malignancy besides FL or myelodysplasia 
4. History of other malignancies, except 
a.
Malignancy treated with curative intent and with no known active disease present for 
5 years before the first dose of study drug and felt to be at low risk for recurrence 
by treating physician 
b.
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease 
c.
Adequately treated carcinoma in situ without evidence of disease 
5. Major surgery within 4 weeks of first dose of study drug 
6. Any life-threatening illness, medical condition, including uncontrolled diabetes mellitus 
(DM), or organ system dysfunction that, in the opinion of the investigator, could 
compromise the subject’s safety or put the study outcomes at undue risk 
7. Clinically significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure (New York Heart Association [NYHA] >Class 2), 
unstable angina, uncontrolled hypertension, or myocardial infarction within 6 months of 
screening, or any Class 3 or 4 cardiac disease as defined by the NYHA Association 
Functional Classification 
8. Significant screening electrocardiogram (ECG) abnormalities including left bundle 
branch block, 2nd degree atrioventricular (AV) block Type II, 3rd degree block, or QTc 
470 msec 


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9. Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., 
or chronic administration of >20 mg/day of prednisone) within 28 days of the first dose 
of study drug 
10. Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any 
component of rituximab (RITUXAN®) 
11. Recent infection requiring intravenous anti-infective treatment that was completed 
14 days before the first dose of study drug 
12. Known history of infection with human immunodeficiency virus (HIV) or history of 
active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV), 
or any uncontrolled active systemic infection 
13. Unable to swallow capsules or disease significantly affecting gastrointestinal function 
such as malabsorption syndrome, resection of the stomach or small bowel, or complete 
bowel obstruction 
14. Concurrent use of warfarin or other vitamin K antagonists 
15. Concurrent use of a strong cytochrome P450 (CYP) 3A inhibitor 
16. Known bleeding diathesis (eg, von Willebrand’s disease) or hemophilia 
17. Any of the following laboratory abnormalities:  
a.
Absolute neutrophil count (ANC) < 1000 cells/mm3 (1.0 x 109/L) 
b.
Platelet count < 75,000 cells/mm3 (75 x 109/L) independent of transfusion support  
c.
Serum aspartate transaminase (AST) or alanine transaminase (ALT)  3.0 x upper 
limit of normal (ULN) 
d.
Creatinine > 2.0 x ULN or creatinine clearance (CrCL) < 30 mL/min 
e.
Hemoglobin < 8.0 g/dL 
f.
Bilirubin > 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin) 
g.
Prothrombin time (PT)/international normalized ratio (INR) > 1.5 u ULN and partial 
thromboplastin time (PTT) > 1.5 u ULN 
18. Lactating or pregnant 
19. Unwilling or unable to participate in all required study evaluations and procedures 
20. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information 
(in accordance with national and local subject privacy regulations) 


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5.
TREATMENT OF SUBJECTS
5.1
Enrollment and Blinding 
This is an open-label, Phase 2 study with two treatment arms.  Subjects will not be blinded to 
study drug nor will they be randomized.  Enrolled subjects will receive open-label ibrutinib 
capsules in combination with rituximab. 
5.2
Formulation, Packaging and Storage 
5.2.1
Ibrutinib 
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib.  
All formulation excipients are compendial and are commonly used in oral formulations.  
Refer to the ibrutinib IB for a list of excipients.  
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies.  All study 
drug will be dispensed in child-resistant packaging.   
Please refer to the pharmacy manual for additional guidance on study drug preparation, handling 
and storage. 
5.2.2
Rituximab 
Rituximab (RITUXAN®) is indicated for the treatment of patients with relapsed or refractory, 
low-grade or follicular, CD20-positive, B-cell NHL.  In addition, rituximab, given either as a 
single agent or in combination, is currently a recommended therapy for previously untreated 
FL per the NCCN guidelines.  Rituximab is a sterile, clear, colorless, preservative-free liquid 
concentrate for IV administration.  Rituximab is supplied at a concentration of 10 mg/mL in 
either 100 mg (10 mL) or 500 mg (50 mL) single-use vials.  The product is formulated for IV 
administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL 
polysorbate 80, and Sterile Water for Injection.  The pH is adjusted to 6.5. 
Rituximab vials should be stored refrigerated between 2°C to 8°C (36°F to 46°F).  Vials should 
be protected from light. 
Rituximab prescribing information can be found at 
http://www.gene.com/download/pdf/rituxan_prescribing.pdf  
5.3
Dosage and Administration 
Below are specific administration instructions for the agents used within this study.  Subjects 
with an increased risk of TLS should be carefully monitored and treated per institutional 
standards, as appropriate.


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5.3.1
Ibrutinib 
Ibrutinib 560 mg (4 x 140-mg capsules) is administered orally once daily with 8 ounces 
(approximately 240 mL) of water.  The capsules should be swallowed intact and subjects should 
not attempt to open capsules or dissolve them in water.  On the days when subjects receive both 
ibrutinib and rituximab, ibrutinib will be administered first and rituximab will be infused within 
30 min of the ibrutinib dose.  The use of strong CYP3A inhibitors/inducers, and grapefruit and 
Seville oranges should be avoided for the duration of the study (Appendix 4). 
Ibrutinib dosing is continuous (without interruption) throughout the treatment phase.  If a dose of 
ibrutinib is missed, it can be taken as soon as possible on the same day with a return to the 
normal schedule the following day.  No extra capsules to make up missed doses of ibrutinib 
should be taken. 
If rituximab dosing is delayed for toxicity that does not require ibrutinib to be held for toxicity, 
dosing should continue at the investigator’s discretion.  If a rituximab infusion is delayed due to 
scheduling delays, ibrutinib dosing should continue.  
Ibrutinib will be dispensed to subjects in bottles.  All doses of ibrutinib taken in the clinic should 
be taken from the bottle dispensed to the subject.  Unused ibrutinib capsules dispensed during 
previous visits must be returned to the site and drug accountability records (Section 11.8) must 
be updated.  Returned capsules must not be re-dispensed to anyone.  Subjects should return all 
used bottles to the site when they receive new study drug.  For the purpose of drug 
accountability, empty bottles and returned capsules should be kept at the site until after the 
review of the site monitor if allowed by local institution policy. 
Investigators are prohibited from supplying ibrutinib capsules to any subjects not properly 
enrolled in this study or to any physicians or scientists except those designated as 
Subinvestigators on Food and Drug Administration (FDA) Form 1572.  The investigator must 
ensure that subjects receive ibrutinib capsules only from personnel who fully understand the 
procedures for administering the drug. 
Treatment will continue until disease progression or other reason for treatment discontinuation as 
outlined in Section 8.2.  
Dose modifications for toxicity are outlined in Section 5.4. 
5.3.2
Rituximab 
Rituximab is given at 375 mg/m2 IV infusion once weekly for 4 doses. 
Since rituximab, given either as a single agent or in combination, is currently a recommended 
therapy for subjects with previously untreated FL per the NCCN guidelines, the costs for 
administering rituximab are expected to be covered by the individual subject’s insurance.  


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Per Prescribing Information: 
First Infusion:  The rituximab solution for infusion should be administered intravenously at an 
initial rate of 50 mg/hr.  Rituximab should not be mixed or diluted with other drugs. 
If hypersensitivity or infusion reactions do not occur, the infusion rate may be escalated in 
50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.  If a hypersensitivity 
(non-IgE-mediated) or an infusion reaction develops, the infusion should be temporarily slowed 
or interrupted.  The infusion can continue at one-half the previous rate upon improvement of 
subject symptoms. 
Subsequent Infusions:  If the subject tolerated the first infusion well, subsequent rituximab 
infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr 
increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated.  If the subject did 
not tolerate the first infusion well, follow the guidelines for the first infusion. 
Some individual subjects may require close monitoring during the first and all subsequent 
infusions, eg subjects who have pre-existing cardiac or pulmonary conditions, prior clinically 
significant cardiopulmonary AEs or high numbers of circulating malignant cells (25,000/mm3) 
with or without evidence of high tumor burden. 
5.4
Dose Reduction, Delay and Discontinuation 
5.4.1
Ibrutinib 
The ibrutinib dose should be held for any unmanageable, potentially ibrutinib-related toxicity 
that is consistent with the rules outlined in this section.   
Please see Section 10.2.4 for reporting of major hemorrhage and intracranial hemorrhage 
(Section 10.2.4.1). 
The action in Table 1 should be taken for the following ibrutinib-related toxicities: 
x
Grade 4 ANC (<500/μL) for more than 7 days.  The use of neutrophil growth factors is 
permitted per American Society of Clinical Oncology (ASCO) guidelines (Smith 2006) and 
must be recorded in the electronic case report form (eCRF). 
x
Grade 3 thrombocytopenia (<50,000/μL) for subjects with normal platelet count at baseline; 
or for subjects with baseline thrombocytopenia, a platelet decrease of 50% to 74% from 
baseline in the presence of >Grade 2 bleeding 
x
Grade 4 thrombocytopenia (<25,000/μL) for subjects with normal platelet count at baseline; 
or for subjects with baseline thrombocytopenia, a platelet decrease of 75% from baseline or 
<20,000/μL, whichever is higher 
x
Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic and/or 
anti-diarrheal therapy 


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x
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 6.1.2.4).  
Table 1: 
Dose Modification for Ibrutinib Toxicity 
Occurrence 
Action to be Taken 
First 
Withhold ibrutinib until recovery to Grade 1 or baseline; may restart at original dose 
level 
Second 
Withhold ibrutinib until recovery to Grade 1 or baseline; may restart at 1 dose level 
lower (420 mg per day) 
Third 
Withhold ibrutinib until recovery to Grade 1 or baseline; may restart at 1 dose level 
lower (280 mg per day) 
Fourth 
Discontinue ibrutinib 
At the investigator’s discretion, the dose of ibrutinib may be re-escalated after a dose reduction 
in the absence of a recurrence of the toxicity that led to the reduction.  Study treatment should be 
discontinued in the event of a toxicity lasting more than 28 days, unless reviewed and approved 
by the Medical Monitor. 
In the event that the investigator feels deviation from the recommendations above is required, 
please consult the Medical Monitor to discuss for approval. 
Please see Section 6.1.2.1 for guidelines for management of ibrutinib in subjects who require 
treatment with a strong CYP3A inhibitor.  
Dose modifications of ibrutinib must be recorded in the eCRF. 
5.4.1.1 
Dose Modification for Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver.  For subjects who develop mild liver impairment while on 
study (Child-Pugh class A), the recommended dose reduction for ibrutinib is to a level of 280 mg 
daily (two capsules).  For subjects who develop moderate liver impairment while on study 
(Child-Pugh class B), the recommended dose reduction is to a level of 140 mg daily (one 
capsule).  Subjects who develop severe hepatic impairment (Child-Pugh class C) must hold study 
drug until resolved to moderate impairment (Child-Pugh class B) or better.  Monitor subjects for 
signs of toxicity and follow dose modification guidance as needed (Refer to Appendix 6). 
5.4.2
Rituximab 
At the investigator’s discretion, the rituximab dose should be held for any unmanageable, 
potentially rituximab-related toxicity that is consistent with the rules outlined in this section.  


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A missed dose of rituximab on the weekly schedule for any reason will not be made up (the visit 
window for this visit is ± 2 days).  Upon recovery as outlined in Section 5.4, subjects should 
resume the protocol-specified treatment schedule as soon as possible.   
The dose of rituximab should be modified according to the dose modification guidelines in 
Table 2 if any Grade 4 or unmanageable Grade 3 non-hematologic toxicity attributed to rituximab 
occurs. 
Table 2: 
Dose Modification for Rituximab Toxicity 
Occurrence 
Action to be Taken 
First, Second, 
Third 
Withhold rituximab until recovery to Grade 1 or baseline; may restart at original 
dose level 
Fourth 
Discontinue rituximab 
Dose modifications of rituximab must be recorded in the eCRF. 
5.5
Overdose Instructions 
Any dose of study drug administered in excess of that specified in this protocol is considered to 
be an overdose.  Signs and symptoms of an overdose 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 10.2 for further information regarding AE reporting. 
5.6
Criteria for Permanent Discontinuation of Study Drug 
Investigators are encouraged to keep a subject who is experiencing clinical benefit in the study 
unless significant toxicity puts the subject at risk or routine noncompliance puts the study 
outcomes at risk.  For a complete list of criteria for permanent discontinuation of study 
treatment, refer to Section 8.2. 
Subjects who withdraw for any reason other than those specified in Section 8.2 will not be 
replaced.  A Safety Follow-up visit (Section 7.1.3.1) is required for all subjects except for those 
subjects who have withdrawn full consent. 


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6.
CONCOMITANT MEDICATIONS/PROCEDURES
6.1
Concomitant Medications 
6.1.1
Permitted Concomitant Medications 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted.  Use of neutrophil growth factors (granulocyte colony-stimulating factor [G-CSF], 
eg, filgrastim and pegfilgrastim) and red blood cell growth factors (erythropoietin) are permitted 
per institutional policy and in accordance with ASCO guidelines (Smith 2006). Transfusions may 
be given in accordance with institutional policy. 
Short courses of corticosteroids (14 days) as treatment for non-cancer-related medical reasons 
(eg, joint inflammation, asthma exacerbation, rash, antiemetic use, arthritis, asthma, autoimmune 
cytopenia, and infusion reactions) at doses that do not exceed 100 mg per day of prednisone or 
equivalent are permitted. 
6.1.2
Medications to be Used with Caution 
6.1.2.1
CYP3A Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A4.  Avoid co-administration with strong CYP3A4 
(eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, 
itraconazole, and nefazadone) or moderate CYP3A inhibitors and consider alternative agents 
with less CYP3A inhibition.  If a strong CYP3A inhibitor must be used, the Medical Monitor 
should be consulted before use, reduce ibrutinib dose to 140 mg or withhold treatment 
temporarily.  Subjects should be monitored for signs of ibrutinib toxicity.  If a moderate CYP3A 
inhibitor must be used, reduce ibrutinib to 140 mg for the duration of the inhibitor use.  No dose 
adjustment is required in combination with mild inhibitors.  Avoid grapefruit and Seville oranges 
during ibrutinib treatment, as these contain moderate inhibitors of CYP3A (see Section 5.3.1). 
Avoid concomitant use of strong CYP3A inducers (eg, rifampin, carbamazepine, phenytoin, and 
St. John’s Wort).  Consider alternative agents with less CYP3A induction.   
For subjects who must take strong or moderate CYP3A inhibitors while on treatment with 
ibrutinib, additional PK blood samples during concomitant use of ibrutinib with strong or moderate 
CYP3A inhibitors will be requested for ibrutinib exposure confirmation (see Section 7.3.21). 
A list of common CYP3A inhibitors and inducers is provided in Appendix 4; 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. 
For the most comprehensive effect of CYP3A inhibitors or inducers on ibrutinib exposure, please 
refer to the current version of the IB. 


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6.1.2.2
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor (with an IC50 of 2.15 ȝg/mL).  Ibrutinib is not expected to have systemic drug-drug 
interactions with P-gp substrates.  However, it cannot be excluded that ibrutinib could inhibit 
intestinal P-gp after a therapeutic dose.  There is no clinical data available.  Therefore, to avoid a 
potential interaction in the GI tract, narrow therapeutic range P-gp substrates such as digoxin 
should be taken at least 6 hours before or after ibrutinib.  
6.1.2.3
QT Prolongation 
Any medications known to cause QT prolongation should be used with caution; periodic ECG 
and electrolyte monitoring should be considered. 
6.1.2.4
Antiplatelet Agents and Anticoagulant 
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib.  
Supplements such as fish oil and vitamin E preparations should be avoided.  Ibrutinib should be 
used with caution in subjects requiring other anticoagulants or medications that inhibit platelet 
function.  Subjects with congenital bleeding diathesis have not been studied.  For guidance on 
ibrutinib and the use of anticoagulants during procedures/surgeries, see Section 6.2. 
6.1.3
Prohibited Concomitant Medications 
Chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy (except as 
stated under the permitted concomitant medications) are prohibited while the subject is receiving 
ibrutinib. 
Corticosteroids for the treatment of the underlying disease are prohibited.  Corticosteroids for the 
treatment of non-cancer related reasons for longer than 14 days and/or at doses >100 mg/day of 
prednisone or equivalent are prohibited. 
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. 
6.2
Guidelines for Ibrutinib Management with Surgeries or Procedures 
Ibrutinib may increase risk of bleeding with invasive procedures or surgery.  The following 
guidance should be applied to the use of ibrutinib in the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib: 
x
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.   


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x
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.   
x
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.
STUDY PROCEDURES
Before study entry, throughout the study, and at the follow-up evaluation, various clinical and 
diagnostic laboratory evaluations are outlined.  The purpose of obtaining these detailed 
measurements is to ensure adequate safety and tolerability assessments.  Clinical evaluations and 
laboratory studies may be repeated more frequently if clinically indicated.  The Schedules of 
Assessments for Arms 1 and 2 are provided in Appendix 1 and Appendix 2.  
7.1
Visit Procedures 
For a full explanation of all procedures, please refer to Section 7.3. 
7.1.1
Screening
Screening procedures will be performed up to 28 days before Day 1, unless otherwise specified.  
All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF before any 
study-specific screening procedures are performed.  After signing the ICF, completing all 
screening procedures, and being deemed eligible for entry, subjects will be enrolled in the study.  
Procedures that are performed prior to the signing of the ICF and are considered standard of care 
may be used as screening assessments if they fall within the 28-day screening window, with the 
exception of tumor tissue biopsy. 
The following procedures will be performed during Screening: 
x
Informed Consent 
x
Review of eligibility criteria 
x
Medical history and demographics 
x
Complete physical exam  
x
B-symptom collection 
x
ECOG Performance Status 
x
Vitals signs, weight and height  
x
12-lead ECG (in triplicate [1 minute apart]) 
x
Review of prior medications (including over-the-counter drugs, vitamins and herbs)  


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x
Imaging by CT/MRI  
x
Imaging by positron emission tomography (PET)  
x
Bone marrow aspirate and biopsy (including MRD) 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 

Coagulation (PT, PTT, INR) 

Serum pregnancy test (for women of childbearing potential only) 

Hepatitis serologies 

Urinalysis 
x
Research laboratory blood samples for: 

Biomarkers 
x
Tumor tissue biopsy (optional for Arm 1 and required for Arm 2) – may be archival 
7.1.2
Treatment Phase 
7.1.2.1
Arm 1 
7.1.2.1.1
Week 1/Day 1 
Subjects who are deemed eligible will return to the clinic on Week 1, Day 1.  The following 
procedures will be performed: 
Pre-Dose 
x
Confirmation of eligibility 
x
Complete physical exam 
x
ECOG Performance Status 
x
Vital signs and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 
x
Research laboratory blood samples collected 30–60 minutes pre-dose for: 

T/B/NK cell counts 

Biomarkers 
x
Review of concomitant medications 
Dosing and Post-Dose 


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x
Dispense ibrutinib 
x
In-clinic administration of ibrutinib 
x
In-clinic administration of rituximab 
x
Biomarkers (4 hrs [±30 mins] after administration of ibrutinib)  
x
Review of AEs and concomitant medications 
7.1.2.1.2
Week 2/Day 8
The following procedures will be performed on Week 2, Day 8 (±2 days): 
Pre-Dose 
x
Complete physical exam 
x
ECOG Performance Status 
x
Vital signs and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 
x
Review of AEs and concomitant medications 
Dosing and Post-Dose 
x
In-clinic administration of ibrutinib 
x
In-clinic administration of rituximab 
x
Review of AEs and concomitant medications 
7.1.2.1.3
Week 3/Day 15
The following procedures will be performed on Week 3, Day 15: 
Pre-Dose 
x
Complete physical exam 
x
ECOG Performance Status 
x
Vital signs and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 


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x
Research laboratory blood samples collected 30–60 minutes pre-dose for: 
–
PK  
–
T/B/NK cell counts 
–
Biomarkers 
x
Review of AEs and concomitant medications 
Dosing and Post-Dose 
x
In-clinic administration of ibrutinib 
x
In-clinic administration of rituximab 
x
PK (see Section 7.3.20 for timepoints) 
x
Biomarkers (4 hrs [±30 mins] after administration of ibrutinib)  
x
Review of AEs and concomitant medications 
7.1.2.1.4
Week 4/Day 22
The following procedures will be performed on Week 4, Day 22 (±2 days): 
Pre-Dose 
x
Complete physical exam 
x
ECOG Performance Status 
x
Vital signs and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 
x
Review of AEs and concomitant medications 
Dosing and Post-Dose 
x
In-clinic administration of ibrutinib 
x
In-clinic administration of rituximab 
x
Review of AEs and concomitant medications 
7.1.2.1.5
Week 5/Day 29
The following procedures will be performed on Week 5, Day 29 (±2 days): 
x
Complete physical exam 
x
ECOG Performance Status 


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x
Vital signs and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 
x
Review of AEs and concomitant medications 
x
Drug Accountability 
x
Dispense ibrutinib 
7.1.2.1.6
Every 4 Weeks from Week 9 until Treatment Termination
Visits will be performed every 4 weeks (±2 days) starting at Week 9 until completion of the 
Week 49 Visit and then every 12 weeks (±2 days) thereafter.  All visits will be scheduled in 
relation to Day 1.  Visit windows are relative to the Day 1 visit date.  The following procedures 
will be performed: 
x
Complete physical exam 
x
ECOG Performance Status 
x
Vital signs  and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 

Urine pregnancy test (every 12 weeks from Day 1 [or at the closest associated visit] for 
women of childbearing potential only) 
x
Weeks 9 and 13 only - Research laboratory blood samples collected for: 

T/B/NK cell counts 

Biomarkers 
x
Review of AEs and concomitant medications 
x
Drug accountability 
x
Dispense ibrutinib 
7.1.2.2
Arm 2 
7.1.2.2.1
Week 1/Day 1 
Subjects who are deemed eligible will return to the clinic on Week 1, Day 1.  The following 
procedures will be performed: 


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Pre-Dose 
x
Confirmation of eligibility 
x
Complete physical exam 
x
ECOG Performance Status 
x
Vital signs and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 
x
Research laboratory blood samples collected 30–60 minutes pre-dose for: 

T/B/NK cell counts 

Biomarkers 
x
Review of concomitant medications 
Dosing and Post-Dose 
x
Dispense ibrutinib 
x
In-clinic administration of ibrutinib 
x
Biomarkers (4 hrs [±30 mins] after administration of ibrutinib)  
x
Review of AEs and concomitant medications 
7.1.2.2.2
Week 3/Day 15
The following procedures will be performed on Week 3, Day 15: 
Pre-Dose 
x
Complete physical exam 
x
ECOG Performance Status 
x
Vital signs and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 
x
Research laboratory blood samples collected 30–60 minutes pre-dose for: 
–
PK  
–
T/B/NK cell counts 
–
Biomarkers 
x
Review of AEs and concomitant medications 


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Dosing and Post-Dose 
x
In-clinic administration of ibrutinib 
x
PK (See Section 7.3.20 for timepoints) 
x
Biomarkers (4 hrs [±30 mins] after administration of ibrutinib)  
x
Review of AEs and concomitant medications 
7.1.2.2.3
Week 5/Day 29
The following procedures will be performed on Week 5, Day 29 (±2 days): 
x
Complete physical exam 
x
ECOG Performance Status 
x
Vital signs and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 
x
Review of AEs and concomitant medications 
x
Drug Accountability 
x
Dispense ibrutinib 
7.1.2.2.4
Week 9
The following procedures will be performed at Week 9, Day 57 (±2 days, except for imaging): 
Pre-Dose 
x
Imaging by CT/MRI (must be performed within 7 days prior to first dose of rituximab) 
x
Complete physical exam 
x
ECOG Performance Status 
x
Vital signs and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 
x
Research laboratory blood samples collected 30–60 minutes pre-dose for: 
–
T/B/NK cell counts  
–
Biomarkers 
x
Review of AEs and concomitant medications 


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Dosing and Post-Dose 
x
Drug accountability 
x
Dispense ibrutinib 
x
In-clinic administration of ibrutinib 
x
In-clinic administration of rituximab 
x
Review of AEs and concomitant medications 
7.1.2.2.5
Weeks 10, 11, 12
The following procedures will be performed on Weeks 10, 11, 12 (±2 days except Week 11): 
Pre-Dose 
x
Complete physical exam 
x
ECOG Performance Status 
x
Vital signs and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 
x
Week 11 only - Research laboratory blood samples collected 30–60 minutes pre-dose for: 

PK 

T/B/NK cell counts 

Biomarkers 
x
Review of AEs and concomitant medications 
Dosing and Post-Dose 
x
In-clinic administration of ibrutinib 
x
In-clinic administration of rituximab 
x
PK (Week 11 only); see Section 7.3.20 for timepoints 
x
Biomarkers (4 hrs after administration of ibrutinib, Week 11 only) 
x
Review of AEs and concomitant medications 
x
Dispense ibrutinib (Week 12 only) 
7.1.2.2.6
Every 4 Weeks from Week 16 until Treatment Termination
Visits will be performed every 4 weeks (±2 days) starting at Week 16 until completion of the 
Week 56 Visit and then every 12 weeks (±2 days) thereafter.  All visits will be scheduled in 


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relation to Day 1.  Visit windows are relative to the Day 1 visit date.  The following procedures 
will be performed: 
x
Complete physical exam 
x
ECOG Performance Status 
x
Vital signs and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 

Urine pregnancy test (every 12 weeks from Day 1 [or at the closest associated visit] for 
women of childbearing potential only) 
x
Weeks 16 and 20 only - Research laboratory blood samples for: 
–
T/B/NK cell counts  
–
Biomarkers 
x
Drug accountability 
x
Dispense ibrutinib 
x
Review of AEs and concomitant medications 
7.1.2.3
Treatment Termination Visit 
The treatment termination visit should be performed at any time during the study, if based on 
clinical evaluation, the investigator suspects PD, or if the subject discontinues treatment for any 
other reason.  If possible, the visit should be performed within 4 to 24 hours after the subject’s 
previous dose.  If the subject comes in for a regular study visit and the investigator wants to 
discontinue treatment at that time, the regular visit will become the termination visit. Any 
additional procedures that would not be performed for the regular study visit should be 
performed for the treatment termination visit. 
The following procedures will be performed: 
x
Complete physical exam 
x
ECOG Performance Status 
x
Vital signs and weight 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 

Coagulation 


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x
Research laboratory blood samples collected: 
–
T/B/NK cell counts  
–
Biomarkers 
x
CT or MRI (if clinically indicated) 
x
Optional tumor tissue biopsy (if discontinued treatment due to PD) 
x
Drug accountability 
x
Review of AEs and concomitant medications 
7.1.2.4
Response Evaluations 
Response Evaluation visits will be performed at the following timepoints (per Cheson 2007): 
Arm 1:  Every 12 weeks from first dose for the first 8 assessments and then every 24 weeks until 
the subject exhibits disease progression (on or up to 7 days prior to study visit) 
Arm 2:  At Week 9, Week 20, and then every 12 weeks for 6 assessments after Week 20, and 
then every 24 weeks until the subject exhibits disease progression (on or up to 7 days prior to 
study visit) 
The following procedures will be performed in conjunction with standard visits as follows: 
x
Radiologic exam by CT or MRI scan 
x
PET (repeat to confirm CR if positive at screening, PET will only be done to confirm CR and 
will not be required thereafter)  
x
Bone marrow biopsy and/or aspirate for MRD analysis (repeat to confirm CR if positive at 
screening) and possibly for other biomarkers  
x
Overall response assessment 
x
Research laboratory blood samples (when subject achieved CR and/or at PD) for: 

T/B/NK cell counts  

Biomarkers 
If the subject discontinues treatment due to PD and the above research laboratory blood 
samples were collected at the Treatment Termination Visit, the samples do not need to be 
repeated. 
x
B-symptom collection (this assessment should be performed at the clinic visit occurring 
closest to the date of the radiologic exam)   


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7.1.3
Follow-Up Phase 
7.1.3.1
Safety Follow-up 
A Safety Follow-up visit should occur 30 days (±7 days) from the last dose of study drug or 
prior to the start of a new anticancer treatment.  If the subject starts a new anticancer treatment 
less than 7 days after the treatment termination visit, only those procedures not conducted at the 
treatment termination visit should be performed at the Safety Follow-up visit.  
Subjects who withdraw consent to treatment may still participate in Safety Follow-up.  
The following procedures will be performed at the Safety Follow-up visit: 
x
Complete physical exam  
x
ECOG Performance Status 
x
Vital signs and weight 
x
12-lead ECG (in triplicate [1 minute apart]) 
x
Clinical laboratory tests for: 

Hematology 

Serum chemistry 

Coagulation 

Urinalysis 
x
Research laboratory blood samples for: 

Biomarkers 
x
Review of AEs and concomitant medications 
7.1.3.2
Response Follow-Up 
Subjects who discontinue the study for reasons other than PD will be followed every 12 weeks 
(±7 days) from last CT or MRI scan until PD or use of alternative antineoplastic therapy, up to 
3 years after the first dose of the last subject enrolled.  During this period, scans will be done per 
investigator discretion. 
7.1.3.3
Survival Follow-Up 
Once subjects progress or start use of alternative antineoplastic therapy (for subjects who have 
not withdrawn consent), they will be contacted approximately every 12 weeks (±7 days) from 
last dose by clinic visit or telephone to assess survival and the use of alternative antineoplastic 
therapy and stem cell transplant, up to 3 years after the last dose of the last subject enrolled. 
Subjects will be contacted until death, subject withdrawal, lost to follow-up, or study termination 
by the Sponsor, whichever occurs first. 


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7.2
Missed Evaluations 
Missed evaluations should be rescheduled and performed as close to the original scheduled date 
as possible.  An exception is made when rescheduling becomes, in the investigator’s opinion, 
medically unnecessary or unsafe because it is too close in time to the next scheduled evaluation. 
In that case, the missed evaluation should be abandoned. 
7.3
Description of Procedures   
7.3.1
Medical History 
The subject’s complete history through review of medical records and by interview will be 
collected and recorded.  Concurrent medical signs and symptoms must be documented to 
establish baseline severities.  A disease history, including the date of initial diagnosis will be 
recorded.  Smoking history and alcohol use will also be recorded. 
7.3.2
Physical Examination 
The physical examination will include, at a minimum, the general appearance of the subject, 
examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities and 
lymphatic system.  The musculoskeletal system and nervous system may be included in the 
examination if clinically indicated. 
7.3.3
B-symptoms
The subject will be asked about the occurrence of B-symptoms at Screening and at every 
Response Evaluation Visit.  At Screening, collection of B-symptoms will include unexplained 
weight loss >10% within the last 6 months, unexplained fever >38°C for at least 3 consecutive 
days within the last 3 months, and drenching night sweats within the last 3 months.  At every 
Response Evaluation Visit, collection of B-symptoms will include unexplained weight loss 
>10% within the last month, unexplained fever >38°C for at least 3 consecutive days within the 
last month, and drenching night sweats within the last month.  Any new or worsening of a 
pre-existing B-symptom should be recorded as an AE. 
7.3.4
Vital Signs, Height and Weight 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be assessed 
after the subject has rested in the sitting position for approximately 3 minutes.   
Height (screening only) and weight will also be collected. 
7.3.5
ECOG Performance Status 
The ECOG performance index is provided in Appendix 3. 


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7.3.6
Electrocardiogram 
ECGs should be performed at the investigator’s discretion, particularly in subjects with 
arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset dyspnea. 
Subjects should be in supine position and resting for at least 10 minutes before study-related 
ECGs.  During visits in which both ECGs and blood draws are performed, it is recommended 
that ECGs are performed first. 
At Screening and at Safety Follow-up, 12-lead ECGs will be done in triplicate (1 minute apart); 
the calculated QTc average of the 3 ECGs must be <470 msec for eligibility.  
7.3.7
Prior/Concomitant Medications 
All prior/concomitant medications (including over-the-counter, supplements, and herbal 
products) and procedures will be collected from Screening or from 14 days before the start of 
study drug, whichever is longer, through the Safety Follow-up visit. 
7.3.8
Adverse Events 
All AEs whether serious or non-serious, will be documented in the source documents from the 
time signed and dated ICF is obtained until 30 days following the last dose of study drug.  Only 
SAEs will be reported to the Sponsor prior to the first dose of study drug.  From the first dose of 
study drug, AEs/SAEs will be recorded in the eCRFs and will continue until 30 days after the 
last dose of study drug.  
Laboratory abnormalities which result in signs and symptoms, require intervention or follow-up 
and are considered clinically significant should be recorded as AEs.  AEs will be recorded at 
each visit or as reported during the treatment period. 
7.3.9
CT/MRI and PET Scans 
A CT scan (with contrast unless contraindicated) of the neck, chest, abdomen, and pelvis and any 
other disease sites and a PET scan are required for the pretreatment tumor assessment.  
In the case where CT with contrast is contraindicated, an alternative would be MRI of the 
abdomen and pelvis and CT of the chest and neck without contrast.  In this case, neck nodes 
cannot be used as target lesions. 
NOTE:  PET/CT hybrid scanners may be used to acquire the required CT images only if the CT 
produced by the scanner is of diagnostic quality, adheres to the specified slice thickness/scan 
parameters, and includes the use of IV contrast.  Also, the CT images must be separated from the 
PET data prior to submitting the data, and cannot be transmitted as fused CT/PET images.  


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If using a hybrid machine to acquire both PET and CT, the PET must be performed prior to the 
CT with IV contrast as to not compromise PET results.  
If independent CT and PET scanners are used, and the subject is receiving both scans on the 
same day, the PET must be performed prior to the CT with IV contrast. 
The same radiographic technique used for a subject’s pretreatment tumor assessment should be 
used throughout the course of the study and should be mentioned in each radiology report.  
The same imaging equipment should be used for all scans, whenever possible. 
Following the pretreatment tumor assessments, CT/MRI should be performed as per schedule of 
assessments (or more often if clinically indicated) and repeat PET scanning will only be required 
to confirm CR and will be performed only if it was positive at Screening.  PET will only be done 
to confirm CR and will not be required thereafter. 
De-identified copies of all scans and radiology reports (including those from screening) must be 
provided to the Sponsor or designee (eg, central imaging vendor).  At the Sponsor’s discretion, 
the Sponsor or its designee may conduct an independent review of the investigator responses. 
7.3.10
Response Assessment 
Response assessments will be completed by the investigator using Cheson 2007.  At Screening, 
up to six target lesions will be selected and will be followed for the duration of the study.  All 
target lesions must be followed and mentioned in the radiology report at all subsequent response 
assessments (see Appendix 5). 
Information on extranodal involvement (eg, gastric or ocular disease) will also be recorded.  
Lesions in anatomical locations that are not well visualized by CT may be measured by MRI 
instead. 
Caution must be exercised not to confuse a possible tumor flare with progressive disease.  
Delayed responses after a tumor flare have been reported in follicular lymphoma.  In order to 
accommodate the potential for immune flare (pseudoprogression), treatment with ibrutinib may 
continue between the initial assessment and confirmation of progression.  In the absence of 
clinically significant deterioration, a biopsy (if lesion is assessable) should be performed at the 
time of suspected tumor flare (in order to rule out tumor necrosis and/or an inflammatory 
reaction) or the investigator may continue dosing and a CT/MRI scan and/or biopsy should be 
performed at least 4 weeks later to confirm PD.  Subjects with presumed progressive disease 
who, in the Investigator’s opinion, continue to receive clinical benefit from their treatment may 
continue to receive ibrutinib as dictated in the protocol after consultation with the Sponsor and at 
the Investigator’s discretion.  Ibrutinib should be discontinued if there is confirmed progressive 
disease per Cheson 2007 criteria or other clinical data suggest clear evidence of progression.  
such a case, the date of PD will be documented as the evaluation where PD was first suspected. 


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If progressive disease is ruled out, the subject may resume treatment with ibrutinib (if 
interruption was <28 days), and a follow-up radiological assessment is recommended within  
4–6 weeks, if progression was suspected based on imaging studies.  If tumor flare is confirmed 
by biopsy and the study drug interruption is 28 days, subjects may be permitted to continue 
ibrutinib with approval from the Medical Monitor. 
7.3.11
Hematology 
Hematology will be done at each scheduled visit. 
Hematology studies must include complete blood count with differential and platelet counts. 
Testing will be performed at the study center’s local laboratory or other clinical laboratory listed 
on the investigator’s form FDA 1572.   
7.3.12
Serum Chemistry 
Chemistry must include albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea 
nitrogen, calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, 
phosphate, potassium, sodium, total bilirubin, total protein, and uric acid.  Testing will be 
performed at the study center’s local laboratory or other clinical laboratory listed on the 
investigator’s form FDA 1572.   
7.3.13
Coagulation
Coagulation includes PT, PTT and INR.  Testing will be performed at the study center’s local 
laboratory or other clinical laboratory listed on the investigator’s form FDA 1572.   
7.3.14
Hepatitis Serologies 
Hepatitis serologies include Hepatitis C antibody, Hepatitis B surface antigen, Hepatitis B 
surface antibody, and Hepatitis B core antibody.  Testing will be performed at the study center’s 
local laboratory or other clinical laboratory listed on the investigator’s form FDA 1572.   
7.3.15
Pregnancy Test 
A serum pregnancy test will be required at Screening by a local laboratory 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. 
Urine pregnancy tests should be performed every 12 weeks from Day 1 (or at the closest 
associated visit), or as clinically indicated, for women of childbearing potential only. 
Testing will be performed at the study center’s local laboratory or other clinical laboratory listed 
on the investigator’s form FDA 1572. 


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7.3.16
Urinalysis
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  Testing 
will be performed at the study center’s local laboratory or other clinical laboratory listed on the 
investigator’s form FDA 1572.   
7.3.17
Bone Marrow Aspirate and Biopsy 
A unilateral bone marrow aspirate and biopsy will be done at Screening or up to 28 days before 
the first dose of study drug.  Thereafter, bone marrow aspirate and biopsy will only be required 
to confirm CR if it was positive at Screening. 
Standard clinical testing will be performed at the study center’s local laboratory or other clinical 
laboratory listed on the investigator’s form FDA 1572.  Additional samples will be collected for 
biomarkers and other exploratory evaluations such as for evidence of minimal residual disease 
(MRD) if methods are available.  
7.3.18
T/B/NK Cell Count 
The blood sample(s) for T/B/NK cell count (CD3+, CD4+, CD8+, CD19+, CD16/56+) must be 
taken predose.  Percentages and absolute counts of CD3+, CD4+, CD8+, CD19+, CD56+ and 
CD16/56+ cells will be collected.  Thereafter this testing will be done for Arm 1 and Arm 2 per 
schedules of assessment. 
7.3.19
Blood Samples for Immunophenotypes, Secreted Proteins, and Other 
Biomarkers
Samples collected may be used for pharmacodynamic and biomarker assessments including BTK 
and other kinase activity and signaling, expression analysis, sequencing, flow cytometry and 
secreted protein analyses.  Fluids including blood collected during the course of the study may be 
used for, but not limited to, pharmacodynamics and biomarker assessments as noted above. 
7.3.20
Pharmacokinetics
Plasma PK of ibrutinib in combination with rituximab will be collected in 20 of the total 
60 subjects treated in Arm 1.  Plasma PK of ibrutinib alone and in combination with rituximab 
will be collected in all 20 subjects treated in Arm 2. 
Refer to Table 3 for the PK sample schedule for Arm 1 and Arm 2. 


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Table 3: 
Pharmacokinetic Sample Schedule 
Arm 
Ibrutinib 
Rituximab 
Week 
Day 
Predose 
Time After Dosinga
1h ±
15 min
2 h ± 
15 min 
4 h ± 
30 min 
6 h ± 
1 h 
1 
Continuous 
Infusion 3 
3 
15 
x 
x 
x 
x 
x 
2 
Continuous 
NA 
3 
15 
x 
x 
x 
x 
x 
 
Continuous 
Infusion 3 
11 
71 
x 
x 
x 
x 
x 
a 
Record actual time of ibrutinib and rituximab administration and sample collection. 
7.3.21
Pharmacokinetics Sample Collection for Subjects Treated with Concomitant 
CYP3A Inhibitors While on Ibrutinib Treatment 
For subjects who must take strong or moderate CYP3A inhibitors while on treatment with 
ibrutinib, additional PK blood samples for evaluation of ibrutinib exposure is requested at the 
following scheduled visit after concomitant CYP3A inhibitor/inducer has started and is still in 
use.  PK samples will be collected at: 
x
Pre-dose ibrutinib (Sample must be obtained 22–24 hours post the previous day’s dose and 
before dosing on the day of the scheduled visit)  
x
1 hour ± 15 min 
x
2 hours ± 15 min 
x
4 hours ± 30 min 
Refer to the laboratory binder for instructions on collecting and processing these samples.  On 
the day of the sampling visit, the subject will not take a dose before arrival at the clinic.  Study 
drug intake will be observed by clinic staff.  The actual time (versus requested time) that each 
sample is drawn must be recorded using a 24-hour format.  The same clock should be used for 
recording the time of dosing. 
7.3.22
Tumor Tissue Biopsy
For subjects enrolled in Arm 1, pre-treatment and post-progression tumor biopsies are optional. 
For subjects enrolled in Arm 2, pre-treatment biopsy is required and post-progression tumor 
biopsies are optional. 
Tumor samples may be analyzed by GEP, WES, or other methods to define biomarkers that 
predict response or resistance to ibrutinib therapy.


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8.
SUBJECT COMPLETION AND WITHDRAWAL
8.1
Completion 
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost to follow up, or has not withdrawn consent before the end of study. 
8.2
Treatment Discontinuation 
Study treatment will be discontinued in the event of any of the following events: 
x
Confirmed PD 
x
Unacceptable toxicity: an intercurrent illness or AE that prevents further ibrutinib 
administration  
x
Treatment discontinuation by subject 
x
Investigator decision (such as significant protocol deviation, or best interest of the subject) 
x
Subject is significantly or routinely noncompliant with the study procedures and/or 
scheduled evaluations 
x
Subject requires a prohibited concomitant medication 
x
Study termination by Sponsor 
x
Subject becomes pregnant 
All subjects, regardless of reason for discontinuation of study treatment will undergo a treatment 
termination visit and be followed for progression and survival.  
It is recommended that the Investigator notifies the Sponsor prior to discontinuing a subject due 
to any reason. If a subject will be discontinued due to disease progression, the Investigator 
should provide documentation of disease progression for review by the Sponsor’s Medical 
Monitor.  If a subject shows signs of disease progression on physical examination or laboratory 
assessment, the subject may continue study treatment until disease progression is confirmed.  
These subjects should stay in the study to be followed for survival.  
8.3
Study Exit/Withdrawal 
Exit from study (including all follow-up) will occur under the following circumstances: 
x
Withdrawal of consent for follow-up observation by the subject 
x
Lost to follow-up 
x
Study termination by Sponsor 
x
Death 


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If a subject is lost to follow-up, every reasonable effort should be made by the study site 
personnel to contact the subject.  The measures taken to follow up should be documented. 
When a subject withdraws before completing the study, the following information should be 
documented in the source documents: 
x
Reason for withdrawal; 
x
Whether the subject withdraws full consent (ie, withdraws consent to treatment and all 
further contact) or partial consent (ie, withdraws consent to treatment but agrees to 
participate in follow-up visits) 
9.
STATISTICAL METHODS 
9.1
General Considerations 
This is an open-label, Phase 2 study designed to assess the efficacy and safety of ibrutinib 
combined with rituximab in previously untreated subjects with FL.  The study will include 
approximately 80 subjects with two treatment arms, a main study Arm 1 with n=~60 subjects and 
an exploratory Arm 2 with n=~20 subjects.  
For the primary and secondary objectives, Arm 1 and Arm 2 will be analyzed separately. 
One of the purposes of Arm 2 is to identify biomarkers that predict sensitivity or resistance to 
ibrutinib.  Based on Phase 1 clinical data in FL it is predicted that approximately half of the 
subjects treated in this arm will show evidence of resistance to single-agent ibrutinib.  By 
providing a lead-in time prior to the initiation of rituximab, pre- and post-progression biopsy 
samples can be collected to address markers of drug resistance.  These objectives are exploratory 
and therefore the primary and secondary objectives related to clinical efficacy are paramount but 
will be analyzed separately from Arm 1 since the treatment regimen in this arm is different. 
9.1.1
Response Assessment 
Response assessments will be done by the investigators.  The response criteria are based on the 
revised criteria for malignant lymphoma described in the revised International Working Group 
for NHL (Cheson 2007). 
9.1.2
Safety Monitoring 
The study's investigators and data coordinators are responsible for entering the data and safety of 
this study, including implementation of the stopping rules for efficacy. 
All sites are required to use the eCRFs provided by the study sponsor.  All sites will be 
monitored on an ongoing basis by the study sponsor. 


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Safety data is monitored in accordance with the sponsor's Pharmacoviligance Committee 
procedures.  AEs and SAEs will be reviewed internally on an ongoing basis to identify safety 
concerns. 
9.2
Definition of Analysis Populations 
The following definitions will be used for the efficacy and safety analysis sets: 
x
All-Treated Population:  The subjects who are enrolled in the study and have received at 
least 1 dose of study drug. 
x
Response-Evaluable Population:  The subjects in the all treated population who have 
measurable disease at baseline and have at least one adequate post-treatment disease 
assessment by investigator before the start of subsequent anti-cancer therapy.   
x
Safety Analysis Population:  All enrolled subjects who receive at least 1 dose of study drug 
(same as all treated population).   
The all treated population will be used for analyzing efficacy endpoints unless specified 
otherwise, the response evaluable population will be used for sensitivity analysis of efficacy 
endpoints and the safety population will be used for safety analysis. 
9.3
Endpoint Data Analysis 
9.3.1
Demographic/Baseline Characteristics and Study Conduct 
Subject demographics (including age, sex, and race/ethnicity) and other baseline characteristics 
(including ECOG performance status, disease burden, and number of prior therapies) will be 
summarized by study arm.  Summary statistics will include means, standard deviations, and 
medians for continuous variables and proportions for categorical variables. 
Further, compliance parameters (including number of doses taken compared with number of 
doses that should have been taken), the reason for discontinuation, and concurrent treatments 
will also be similarly summarized.   
9.3.2
Primary Efficacy Endpoint 
The primary efficacy endpoint is the overall response rate (CR+PR) as assessed by investigators 
for Arm 1 and Arm 2 separately.  The ORR is defined as the proportion of subjects who achieve 
either a PR or CR as best response as assessed by investigators according to the revised 
International Working Group Criteria for NHL.  Overall response rate will be calculated for the 
all-treated population for Arm 1 and Arm 2 separately.  The corresponding 95% two-sided 
confidence intervals will be derived.   


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9.3.2.1
Analysis Methods for Arm 1 
The primary analysis for all efficacy endpoints will be conducted based on the all treated 
population.  The all treated population is defined as the subjects who are enrolled in the study 
and have received at least 1 dose of study treatment.  Subjects with no evaluable response will be 
considered non-responder. 
The ORR and its 95% confidence interval (CI) will be calculated using normal approximation to 
the binomial distribution using Wilson’s score method.  If the lower bound of the CI around the 
ORR is greater than or equal to 53%, then it will be concluded that the ORR of the treatment 
regimen of Arm 1 is superior to the ORR of 53% given by historical control.  
9.3.2.2
Analysis Methods for Arm 2 
The ORR and its 95% confidence interval will be calculated using normal approximation to the 
binomial distribution using Wilson’s score method.  Subjects with no evaluable post-baseline 
response will be considered as non-responder.   
9.3.3
Secondary Efficacy Endpoints 
9.3.3.1
Duration of Response
For subjects achieving overall response as assessed by investigators, their duration of response as 
assessed by investigators will be calculated to determine durability.  Duration of response will be 
measured from the time by which the measurement criteria are met for CR or PR, whichever is 
recorded first, until death or the first date by which recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  Subjects who had the event after the start of subsequent therapy, 
or are progression-free and alive at the time of clinical cut-off, or have unknown status will be 
censored at the last tumor assessment on or before the start of subsequent therapy and clinical 
cut-off time.  Subjects with no post-baseline disease assessment will be censored on Day 1. 
Data from responders will include subjects who achieve CR or PR based on the revised 
International Working Group Criteria for NHL response criteria (Cheson 2007).  Non-responders 
will be excluded from the analysis for DOR.  Duration of response will be calculated using 
assessments by investigators and by study arm.  Kaplan-Meier methodology will be used to 
estimate event-free curves, median and 95% CI of median. 
9.3.3.2
Progression-free Survival  
Progression-free survival will be measured as time from first study drug administration to the 
first occurrence of lymphoma progression or death from any cause. 


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Data for subjects without disease progression or death will be censored at the date of the last 
tumor assessment that occurs before the initiation of alternative anticancer therapy.  The 
estimates will be formed using the all treated population. 
Progression-free survival will be calculated using assessments by investigators by study arm. 
Kaplan-Meier methodology will be used to estimate event-free curves median and 95% CI of 
median. 
9.3.3.3
Overall Survival 
The duration of OS will be measured from the time of first study drug administration until the 
date of death.  Kaplan-Meier methodology will be used to estimate overall survival curves and 
corresponding quartiles (including the median).   
Data for subjects who have not died or have exited from the study at the time of clinical-cutoff 
will be censored at the date of the last known contact.  The estimates will be formed using the all 
treated population. 
9.3.4
Safety Analysis 
Analysis of safety data will be conducted on the safety population, which includes enrolled 
subjects who receive at least 1 dose of ibrutinib.  Safety summaries will include tabulations in 
the form of tables and listings.  The frequency (number and percentage) of treatment-emergent 
AEs will be reported by the Medical Dictionary for Regulatory Activities (MedDRA®) System 
Organ Class and Preferred Term.  Additional AE summaries will include AE frequency by AE 
severity and by relationship to study drug. 
AEs requiring discontinuation of study drug will be summarized separately, both overall and by 
AE severity and by relationship to study drug. 
Clinically significant abnormal laboratory values will be summarized.  Laboratory shift tables 
containing counts and percentages will be prepared by laboratory parameter.  Summary tables 
will be prepared for each laboratory parameter.  Figures of changes in laboratory parameters over 
time will be generated. 
Safety:  Missing or partial start and end dates for AEs and concomitant medications will be 
imputed according to pre-specified imputation rules.  The rule will be described in a Statistical 
Analysis Plan (SAP).  No other imputation of values for missing data will be performed. 
9.3.5
Pharmacokinetics
Plasma concentrations of ibrutinib and metabolite, for example PCI-45227, will be determined 
using a validated analytical method.  Other potential metabolites of ibrutinib may be explored. 


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x
Bioanalytical data from this study will be used in noncompartmental PK analysis and also 
may be combined with data from other studies performed with ibrutinib in subjects with 
hematologic malignancies as part of a population PK analysis using nonlinear mixed effects 
models.  For the population PK analysis, covariates that could potentially correlate with 
plasma PK parameters will be evaluated.  Pharmacokinetic relationships to 
pharmacodynamic measures of efficacy or toxicity may also be explored.  
x
For subjects who received CYP3A inhibitors, as data permits, a comparison of ibrutinib and 
PCI-45227 plasma concentrations after ibrutinib administration alone and in combination 
with CYP3A inhibitors will be explored. 
9.3.6
Exploratory Analyses 
x
Change in peripheral T/B/NK count and profiling of immunophenotypes 
x
Change in secreted protein levels (ie, chemokines, cytokines, growth factors) 
x
Identification of biomarkers that predict sensitivity or resistance to ibrutinib 
(ie, GEP, WES, etc.) 
Clinically relevant biomarkers may be associated with clinical responses.  A Fisher Exact test or 
other methods may be used to estimate the association between the clinical response rates and 
each biomarker. 
The SAP will provide additional analysis details. 
9.4
Handling of Missing Data 
General Considerations:  Subjects lost to follow-up (or who dropped out) will be included in 
statistical analyses up to the point of their last evaluation or contact. 
Duration of Response and Progression-free Survival:  Data for subjects without disease 
progression or death will be censored at the date of the last tumor assessment and before the date 
of the initiation of alternative anticancer therapy.  Data for subjects who had the event after the 
start of subsequent therapy, or are progression-free and alive at the time of the clinical data 
cut-off, or have unknown status will be censored at the last tumor assessment on or before the 
start of subsequent therapy or clinical cut-off time.  Subjects with no post-baseline disease 
assessment will be censored on Day 1. 
Overall Survival:  Data for subjects who have not died will be censored at the date of the last 
study evaluation or contact when subjects are known to be alive. 
Safety:  Missing or partial start and end dates for AEs and concomitant medications will be 
imputed according to prespecified, conservative imputation rules and will be pre-defined in a 
SAP.  No other imputation of values for missing data will be performed. 


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9.5
Determination of Sample Size 
The planned sample size for this open-label, Phase 2 study is N=60 subjects which will be 
enrolled in Arm 1; 20 additional subjects will be enrolled in Arm 2.  The hypotheses test of 
primary endpoint analysis for Arm 1 in this study assumes an underlying response rate of 53% for 
first-line rituximab treatment in subjects with low grade FL (Hainsworth 2002; Freedman 2009).  
A sample size of approximately 60 eligible subjects is needed to exclude a 53% response rate at 
the 1-sided 0.025 significance level with at least 80% power. 
9.6
Interim Analysis 
No interim analysis is planned.   
9.7
Analysis for Study Report 
The analyses for the Clinical Study Report (CSR) will occur at least 1 year after the last subject 
enrolled  received the first dose of study drug.  Analysis methods will be provided in the SAP. 
10.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the Sponsor, and are mandated by 
regulatory agencies worldwide.  The Sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the Sponsor or its affiliates will be conducted in 
accordance with those procedures. 
10.1
Adverse Event Definitions and Classifications 
10.1.1
Adverse Events 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (ICH-E2A, 1995).  
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions.  
The term “disease progression” should not be reported as an AE term. As an example, "worsening 
of underlying disease" or the clinical diagnosis that is associated with disease progression should 
be reported. 
AEs may include, but are not limited to: 


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x
Subjective or objective symptoms spontaneously offered by the subject and/or observed by 
the investigator or study staff including laboratory abnormalities of clinical significance. 
x
Any AEs experienced by the subject after the ICF is signed and for 30 days following the 
last dose of study drug. 
x
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with FL that were not present 
before the AE reporting period. 
x
Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies). 
The following are NOT considered an AE: 
x
Pre-existing Condition:  A pre-existing condition (documented on the medical history 
eCRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period. 
x
Pre-planned or Elective Hospitalization:  A hospitalization planned before signing the 
ICF is not considered an SAE, but rather a therapeutic intervention.  However, if during the 
pre-planned hospitalization an event occurs, which prolongs the hospitalization or meets any 
other SAE criteria, the event will be considered an SAE.  Surgeries or interventions that 
were under consideration, but not performed before enrollment in the study, will not be 
considered serious if they are performed after enrollment in the study for a condition that has 
not changed from its baseline level.  Elective hospitalizations for social reasons, solely for 
the administration of chemotherapy, or due to long travel distances are also not SAEs. 
x
Diagnostic Testing and Procedures:  Testing and procedures should not to be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported. 
x
Asymptomatic Treatment Related Lymphocytosis:  This event should also not be 
considered an AE.  Patients with treatment-related lymphocytosis should remain on study 
treatment and continue with all study-related procedures. 
10.1.2
Serious Adverse Event 
A SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose: 
x
Results in death (ie, the AE actually causes or leads to death) 
x
Is life-threatening:  “life-threatening” is defined as an AE in which the subject was at risk of 
death at the time of the event.  It does not refer to an event that hypothetically might have 
caused death if it were more severe.  If either the investigator or the Sponsor believes that an 
AE meets the definition of life-threatening, it will be considered life-threatening. 
x
Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization 
x
Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 


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x
Is a congenital anomaly/birth defect 
x
Is an important medical event that may not result in death, be immediately life-threatening 
or require hospitalization, but may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the subject, or subject may require intervention 
to prevent one of the other outcomes listed in this definition.  Examples of such events are 
intensive treatment in an emergency department or at home for allergic bronchospasm, 
blood dyscrasias, or convulsion that does not result in hospitalization; or development of 
drug dependency or drug abuse. 
Given that the investigator’s perspective may be informed by having actually observed the event, 
and the Sponsor is likely to have broader knowledge of the drug and its effects to inform its 
evaluation of the significance of the event, if either the Sponsor or the investigator believes that 
the event is serious, the event will be considered serious. 
10.1.3
Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is 
not listed at the specificity or severity that has been observed.  For example, hepatic necrosis 
would be “unexpected” (by virtue of greater severity) if the Investigator's Brochure referred only 
to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator's 
Brochure/package insert listed only cerebral vascular accidents.  "Unexpected" also refers to AEs 
that are mentioned in the Investigator's Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the study drug under investigation. 
10.1.4
Severity Criteria (Grade 1-5) 
Definitions found in the CTCAE (version 4.03) will be used for grading the severity (intensity) 
of AEs.  The CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of 
severity for each referenced AE.  Should a subject experience any AE not listed in the CTCAE 
v4.03, the following grading system should be used to assess severity: 
x
Grade 1 (Mild AE) – experiences that are usually transient, requiring no special treatment, 
and do not interfere with the subject’s daily activities. 
x
Grade 2 (Moderate AE) – experiences that introduce some level of inconvenience or concern 
to the subject, and that may interfere with daily activities, but are usually ameliorated by 
simple therapeutic measures. 
x
Grade 3 (Severe AE) – experiences that are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment. 
x
Grade 4 (Life-threatening or disabling AE) – experiences that cause the subject to be in 
imminent danger of death. 


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x
Grade 5 (Death related to AE) – experiences that result in subject death. 
10.1.5
Causality (Attribution) 
The investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study drug caused the event) using the following definitions: 
Not Related: 
Another cause of the AE is more plausible; a temporal sequence cannot be 
established with the onset of the AE and administration of the 
investigational product; or, a causal relationship is considered biologically 
implausible. 
Unlikely: 
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely.
Possibly Related: 
There is a clinically plausible time sequence between onset of the AE and 
administration of the investigational product, but the AE could also be 
attributed to concurrent or underlying disease, or the use of other drugs or 
procedures.  Possibly related should be used when the investigational 
product is one of several biologically plausible AE causes. 
Related:
The AE is clearly related to use of the investigational product. 
10.2
Documenting and Reporting of Adverse Events  
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 eCRF.  All SAEs also must 
be reported on an SAE Worksheet as outlined in Section 10.2.2.2.  
10.2.1
Special Reporting Situations 
Safety events of interest on a Sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to: 
x
Overdose of a study drug 
x
Suspected abuse/misuse of a study drug 
x
Inadvertent or accidental exposure to a study drug 
x
Medication error involving a product (with or without subject/patient exposure to the study 
drug, eg, name confusion) 
Special reporting situations should be recorded in the eCRF.  Any special reporting situation that 
meets the criteria of a serious AE should be recorded on the serious AE page of the eCRF. 


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10.2.2
Adverse Event Reporting Procedures 
10.2.2.1
All Adverse Events 
All subjects who receive treatment will be considered evaluable for toxicity.  All serious events 
will be reported from the time a signed and dated ICF is obtained until 30 days following the last 
dose of study drug.  Any SAEs that occur more than 30 days following the last dose of study 
drug should also be reported if considered related to study drug. 
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document.  All records will need to capture the 
details of the duration and the severity of each episode, the action taken with respect to the study 
drug, investigator’s evaluation of its relationship to the study drug, and the event outcome.  
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as "upper respiratory infection").  Investigators must record in the CRF their opinion concerning 
the relationship of the AE to study therapy.  All measures required for AE management must be 
recorded in the source document and reported according to Sponsor instructions. 
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities 
and governing bodies according to the local regulations.  
10.2.2.2
Expedited Reporting Requirements for Serious Adverse Events 
All SAEs occurring during the study must be reported to the Sponsor contact person within 
24 hours of knowledge of the event. 
Information regarding SAEs will be transmitted to the Sponsor using the SAE Form/MedWatch 
or Council for International Organizations of Medical Sciences (CIOMS), which must be 
completed by a physician from the study site, and submitted to the Sponsor within 24 hours of 
when the investigator becomes aware of the event.  
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself.  The primary cause of death on the 
autopsy report should be the term reported.  Autopsy and postmortem reports must be forwarded 
to the Sponsor, or designee, as outlined above. 
If a death occurs within 30 days after the last dose of study drug, the death must be reported to 
the Sponsor as a SAE. 
If study drug is discontinued due to an SAE, this information must be included in the SAE 
report. 


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All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
x
The event resolves 
x
The event stabilizes 
x
The event returns to baseline, if a baseline value/status is available 
x
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
x
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow up after demonstration 
of due diligence with follow-up efforts) 
10.2.3
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. 
10.2.4
Events of Special Interest 
Specific AEs, or groups of AEs, will be followed as part of standard safety monitoring activities 
by the Sponsor.  These events will be reported to the Sponsor within 24 hours of awareness 
irrespective of seriousness (ie, serious and nonserious AEs) following the procedure described 
above for serious AEs and will require enhanced data collection.  All Adverse Events of Special 
Interest (AESI) will be submitted from the clinical site to the Sponsor (or designee).  If no 
serious criterion is met, the site should submit the SAE form by selecting the AESI box. 
10.2.4.1
Major Hemorrhage 
Major hemorrhage is defined as any of the following:  
x
Any treatment-emergent hemorrhagic AEs of Grade 3 or higher*.   
x
Any treatment-emergent serious adverse events of bleeding of any grade 
x
Any treatment-emergent central nervous system hemorrhage/hematoma of any grade 
*All hemorrhagic events requiring transfusion of red blood cells should be reported as Grade 3 or higher AE per 
CTCAE v4.03. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 10.2.4 above. 


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10.2.5
Pregnancy
All initial reports of pregnancy must be reported to the Sponsor by the study-site personnel 
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form.  Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, and congenital 
anomaly) are considered serious AEs and must be reported in a timely fashion.  Any subject who 
becomes pregnant during the study must discontinue further study treatment.  Because the effect 
of the study drug on sperm is unknown, pregnancies in partners of male subjects included in the 
study will also be reported by the study-site personnel within 24 hours of their knowledge of the 
event using the appropriate pregnancy notification form.  The pregnant female will be followed 
for outcome (elective termination of the pregnancy, miscarriage, or delivery) only if she provides 
a separate written consent.  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. 
11.
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS
11.1
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. 
11.2
Institutional Review Board (IRB), Research Ethics Board (REB) and 
Independent Ethics Committee (IEC) Approval 
The Investigator will submit this protocol, the ICF, IB, and any other relevant supporting 
information (eg, all advertising materials or materials given to the subject during the study) to the 
appropriate IRB/REB/IEC for review and approval before study initiation.  Amendments to the 
protocol and informed consent form must also be approved by the IRB/REB/IEC before the 
implementation of changes in this study. 
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 the Sponsor or its authorized representative before 
entering subjects in this study:  (1) a copy of the IRB/REB/IEC letter that grants formal approval; 
and (2) a copy of the IRB/REB/IEC-approved ICF. 


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11.3
Informed Consent 
The ICF and process must comply with the US regulations (§ 21 CFR Part 50) as well as country 
specific national regulations and/or local laws.  The ICF will document the study-specific 
information the Investigator or his/her designee provides to the subject and the subject’s 
agreement to participate.   
The Investigator or designee (designee must be listed on the Delegation of Authority log), must 
explain in terms understandable to the subject the purpose and nature of the study, study 
procedures, anticipated benefits, potential risks, possible AEs, and any discomfort participation 
in the study may entail.  This process must be documented in the subject’s source record.  Each 
subject must provide a signed and dated ICF before any study-related (nonstandard of care) 
activities are performed.  The original and any amended signed and dated consent forms must 
remain in each subject’s study file at the study site and be available for verification by study 
monitors at any time.  A copy of each signed consent form must be given to the subject at the 
time that it is signed by the subject. 
11.4
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).   
11.5
Protected Subject Health Information Authorization 
Information on maintaining subject confidentiality in accordance to individual local and national 
subject privacy regulations must be provided to each subject as part of the informed consent 
process (refer to Section 11.3), either as part of the ICF or as a separate signed document (for 
example, in the US, a site-specific HIPAA consent may be used).  The Investigator or designee 
must explain to each subject that for the evaluation of study results, the subject’s protected health 
information obtained during the study may be shared with the Sponsor and its designees, 
regulatory agencies, and IRBs/REBs/IECs.  The Sponsor will not use the subject’s protected 
health information or disclose it to a third party without applicable subject authorization.  It is the 
Investigator’s or designee’s responsibility to obtain written permission to use protected health 
information from each subject.  If a subject withdraws permission to use protected health 
information, it is the Investigator’s responsibility to obtain the withdrawal request in writing 
from the subject and to ensure that no further data will be collected from the subject.  Any data 
collected on the subject before withdrawal will be used in the analysis of study results. 


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During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations. 
11.6
Study Files and Record Retention 
The Investigator must keep a record of all subjects who have consented to enroll in the study.  
For those subjects subsequently excluded from enrollment, the reason(s) for exclusion is to be 
recorded. 
The Investigator/study staff must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified.  Essential 
documentation includes, but is not limited to, the IB, signed protocols and amendments, 
IRB/REB/IEC approval letters (dated), signed Form FDA 1572 and Financial Disclosures, 
signed ICFs (including subject confidentiality information), drug dispensing and accountability 
records, shipping records of investigational product and study-related materials, signed 
(electronically), dated and completed CRFs, and documentation of CRF corrections, SAE forms 
transmitted to the Sponsor, or designee, 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 the Sponsor and obtain written approval from the Sponsor 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. 
The Sponsor must be notified in advance of, and the Sponsor 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 the Sponsor 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. 


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11.7
Case Report Forms and Record Maintenance 
CRFs will be used to collect the clinical study data and must be completed for each enrolled 
subject with all required study data accurately recorded such that the information matches the 
data contained in medical records (eg, physicians’ notes, nurses’ notes, clinic charts and other 
study-specific source documents).  Authorized study site personnel (ie, listed on the Delegation 
of Authority log) will complete CRFs designed for this study according to the completion 
guidelines that will be provided.  The Investigator will ensure that the CRFs are accurate, 
complete, legible, and completed within 5 days of each subject’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 the Sponsor 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 
will receive a copy of the subject data (eg, paper, CD, or other appropriate media) for archiving 
at the study site. 
11.8
Investigational Study Drug Accountability 
Ibrutinib and any comparator used must be kept in a locked limited access room.  The study drug 
must not be used outside the context of the protocol.  Under no circumstances should the 
Investigator or other site personnel supply ibrutinib or comparator to other Investigators, 
subjects, or clinics or allow supplies to be used other than as directed by this protocol without 
prior authorization from the Sponsor. 
Accountability records for ibrutinib and any comparator must be maintained and readily 
available for inspection by representatives of the Sponsor 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-1125-CA) 
2. Subject identification number 
3. Lot number(s) of ibrutinib or comparator dispensed for that subject 
4. Date and quantity of drug dispensed 
5. Any unused drug returned by the subject 


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At study initiation, the monitor will evaluate and approve the site’s procedure for investigational 
product disposal/destruction to ensure that it complies with the Sponsors’ requirements.  If the 
site cannot meet the Sponsors’ requirements for disposal/destruction, arrangements will be made 
between the site and the Sponsor 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. 
11.9
Study Monitoring/Audit Requirements 
Representatives of the Sponsor or its designee will monitor this study until completion.  
Monitoring will be conducted through personal visits with the Investigator and site staff, remote 
monitoring, as well as any appropriate communications by mail, fax, email, or telephone.  The 
purpose of monitoring is to ensure that the study is conducted in compliance with the protocol, 
standard operating procedures (SOPs), and other written instructions and regulatory guidelines, 
and to ensure the quality and integrity of the data.  This study is also subject to reviews or audits. 
To assure the accuracy of data collected in the CRFs, it is mandatory that the monitor/auditor 
have access to all original source documents, including all electronic medical records (EMR) at 
reasonable times and upon reasonable notice.  During the review of source documents, every 
effort will be made to maintain the anonymity and confidentiality of all subjects during this 
clinical study.  However, because of the experimental nature of this treatment, the Investigator 
agrees to allow the IRB/REB/IEC, representatives of the Sponsor, its designated agents and 
authorized employees of the appropriate regulatory authority to inspect the facilities used in this 
study and, for purposes of verification, allow direct access to the hospital or clinic records of all 
subjects enrolled into this study.  A statement to this effect will be included in the informed 
consent and permission form authorizing the use of protected health information. 
The Sponsor 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, the Sponsor 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. 
11.10
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 


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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. 
11.11
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. 
11.12
Financial Disclosure 
A separate financial agreement will be made between each Principal Investigator and the 
Sponsor 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 the Sponsor or its authorized representative of any relevant changes during the 
conduct of the study and for 1 year after the study has been completed. 
11.13
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, the Sponsor will 
reimburse for reasonable physician fees and medical expenses necessary for treatment of only 
the bodily injury which is not covered by the subject’s medical or hospital insurance, provided 
that the injury is not due to a negligent or wrongful act or omission by the Investigator/study 
staff.  The ICF will include a description of this reimbursement policy, incorporating 
country-specific national regulations and/or local laws.  Financial compensation for lost wages, 
disability or discomfort due to the study is not available. 


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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. 
11.14
Protocol Amendments 
The Sponsor 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 
the Sponsor before the amendment may take effect at each site.  Additionally under this 
circumstance, information on the increased risk and/or change in scope must be provided to 
subjects already actively participating in the study, and they must read, understand and sign any 
revised ICF confirming willingness to remain in the trial. 
No other significant or consistent change in the study procedures, except to eliminate an 
immediate hazard, shall be effected without the mutual agreement of the Investigator and the 
Sponsor. 
11.15
Publication of Study Results 
The Sponsor 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, the Sponsor reserves the right to preview all 
manuscripts and abstracts related to this study, allowing the Sponsor sufficient time to make 
appropriate comments before submission for publication. 
In most cases, the Investigators at the sites with the highest accruals of eligible subjects shall be 
listed as lead authors on manuscripts and reports of study results.  The Medical Monitor, study 
director and/or lead statistician may also be included in the list of authors.  This custom can be 
adjusted upon mutual agreement of the authors and the Sponsor. 
11.16
Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time.  Should this be necessary, both 
the Sponsor and the Investigator will arrange discontinuation procedures.  In terminating the 
study, the Sponsor and the Investigator will assure that adequate consideration is given to the 
protection of the subjects’ interests. 


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11.17
Study Completion 
The study is expected to be completed approximately 3 years after the last subject is enrolled and 
receives the first dose.  Subjects who remain on study treatment may have access to the study 
drug under a long-term protocol or as commercially available product when the study is 
completed. 


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12.
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Lymphoma classification Project. Blood. 1997;89:3909-3918. 
Young RC, Longo DL, Glatstein E, et al. The treatment of indolent lymphomas: watchful 
waiting v aggressive combined modality treatment. Semin Hematol. 1988;25 suppl 2:11-16. 


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13.
APPENDICES


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Appendix 1: Schedule of Assessments for Arm 1 
 
 
Phase
Screening
Study Day
1
8
15
22
29
Q12 weeks for the first 
8 assessments, then 
Q24 weeks thereafter
At any time during the 
study
30 days from last dose 
or prior to subsequent 
antineoplastic therapy
 Q12 weeks 
from last 
CT/MRI 
scan
 Q12 
weeks from 
last dose
Visit Window
-28 days
± 2 days
± 2 days
± 2 days
for CT only: on or up 
to 7 days prior to 
study visit
4-24 hours from 
previous dose
± 7 days
± 7 days
± 7 days
Informed consent
X
Confirm eligibility (Inclusion/exclusion criteria)
X
X
Medical history and demographics
X
Physical exam
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
X
Vital signs and weight (height only at screening)
X
X
X
X
X
X
X
X
12-lead ECG (triplicate)
X
X
Prior and concomitant medications
Adverse events
Hematology
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
Coagulation (PT, PTT, INR)
X
X
X
Hepatitis serologies
X
Pregnancy test  (serum at screening, urine at f/u)
X
Urinalysis
X
X
CT/MRI scan, also as clinically indicated
X 
X
as clnically indicated
X
B-symptom collection
X
X
PET scan
X 
Repeat to confirm CR 
if positive at screening
Bone marrow aspirate and biopsy
(including MRD)
X 
Repeat to confirm CR 
if positive at screening
Survival status and subsequent antineoplastic therapy
X
PK (predose, 1,2,4,6 h)
X
T/B/NK cell counts
X (predose)
X (predose)
When subject achieved 
CR and/or at PD
X
Biomarkers
X
X
(predose & 
4h 
postdose)
X
(predose & 
4h 
postdose)
When subject achieved 
CR and/or at PD
X
X
Tumor tissue biopsy (optional)
X
if discontinued 
treatment due to PD
Dispense ibrutinib
X
X
In-clinic administration of ibrutinib
X
X
X
X
In-clinic administration of rituximab
X
X
X
X
Drug accountability
X
X
Continuous from ICF to 30 days after last dose of study drug
X
X
X
X
As clinically indicated or Q12 weeks from Day 1 at the closest associated visit (± 2 days)
X
Study Drug Administration
Efficacy Assessments
As clinically indicated
X 
(at week 9 & 13 only)
X 
(at week 9 & 13 only)
if taking CYP3A
Research Laboratory Assessments
Response Evaluations
Study Assessments 
X
Clinical Laboratory Assessments
X
9 until Treatment Termination
Treatment
Termination Visit
Continuous from ICF or 14 days prior the first dose of study drug (whichever is greater) to 30 days after last dose of study drug
Treatment
 Q4 weeks until completion of Week 49 Visit and 
then Q12 weeks thereafter
± 2 days
Screening/Administrative
Post-treatment
Study Week
1
2
4
5
3
Response 
Follow-Up 
(Until PD)
Survival 
Follow-up 
(Post PD)
Safety Follow-Up


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Appendix 2: Schedule of Assessments for Arm 2 
 
Phase
Screening
Study Day
1
15
29
57
64
71
78
At Week 9, Week 20, 
and then every 12 
weeks for 6 
assessments after 
Week 20, and then 
Q24 weeks thereafter
At any time during the 
study
30 days from last dose 
or prior to subsequent 
antineoplastic therapy
 Q12 
weeks from 
last dose
 Q12 
weeks from 
last dose
Visit Window
-28 days
± 2 days
± 2 days
except CT
± 2 days
± 2 days
for CT only: on or up 
to 7 days prior to 
study visit
4-24 hours from 
previous dose
± 7 days
± 7 days
± 7 days
Informed consent
X
Confirm eligibility (Inclusion/exclusion criteria)
X
X
Medical history and demographics
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
X
X
X
Vital signs and weight (height only at screening)
X
X
X
X
X
X
X
X
X
X
12-lead ECG (triplicate)
X
X
Prior and concomitant medications
Adverse events
Hematology 
X
X
X
X
X
X
X
X
X
X
Serum chemistry 
X
X
X
X
X
X
X
X
X
X
Coagulation (PT, PTT, INR)
X
X
X
Hepatitis serologies
X
Pregnancy test (serum at screening, urine at f/u)
X
Urinalysis
X
X
CT/MRI scan, also as clinically indicated
X 
X(-7days)
X
As clinical indicated
X
B-symptom collection
X
X
PET scan
X 
Repeat to confirm CR 
if positive at screening
Bone marrow aspirate and biopsy
(including MRD)
X 
Repeat to confirm CR 
if positive at screening
Survival status and subsequent antineoplastic therapy
X
PK (predose, 1,2,4,6 h)
X 
X
T/B/NK cell counts
X 
(predose)
X
(predose)
X
(predose)
X
(predose)
When subject achieved 
CR and/or at PD
X
Biomarkers
X
X
(predose 
& 4h 
postdose)
X
(predose 
& 4h 
postdose)
X
(predose)
X
(predose 
& 4h 
postdose)
When subject achieved 
CR and/or at PD
X
X
Tumor tissue biopsy (optional at PD)
X
if discontinued 
treatment due to PD
Dispense ibrutinib
X
X
X
X
In-clinic administration of ibrutinib
X
X
X
X
X
X
In-clinic administration of rituximab
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
Efficacy Assessments
if taking CYP3A
As clinically indicated or Q12 weeks from Day 1 at the closest associated visit (± 2 days)
X
Research Laboratory Assessments
Study Drug Administration
Treatment
Post-treatment
Study Week
1
Response 
Follow-Up
(Until PD)
Survival 
Follow-Up
(Post PD)
3
9
10
11
12
5
Treatment
Termination Visit
16 until Treatment 
Termination
Safety Follow-Up
Study Assessments 
Continuous from ICF to 30 days after last dose of study drug
X
(at week 16 & 20 only)
Continuous from ICF or 14 days prior the first dose of study drug (whichever is greater) to 30 days after last dose of study drug
As clinically indicated
X
X
X
X
(at week 16 & 20 only)
Clinical Laboratory Assessments
Response Evaluation
Q4 weeks until 
completion of Week 56 
Visit and then Q12 
weeks thereafter
± 2 days
Screening/Administrative


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Appendix 3: Performance Status Scores 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
0
Fully active, able to carry on all predisease performance without restriction. 
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light housework, office work. 
2
Ambulatory and capable of all self-care, but unable to carry out any work activities.  
Up and about more than 50% of waking hours. 
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5
Dead. 
**Oken, 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 04 January 2008. 
 
 


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Appendix 4: Inhibitors and Inducers of CYP3A 
Inhibitors of CYP3A enzymes 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 6.1.2.1 on instructions for concomitant use of CYP3A 
inhibitors or inducers with ibrutinib. 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong Inhibitors: 
carbamazepine 
indinavir 
efavirenz 
nelfinavir 
nevirapine 
ritonavir 
barbiturates 
clarithromycin
glucocorticoids  
itraconazole 
modafinil 
ketoconazole 
oxcarbarzepine 
nefazodone 
phenobarbital 
saquinavir 
phenytoin 
telithromycin 
pioglitazone 
suboxone 
rifabutin 
cobicistat 
rifampin 
boceprevir 
St. John’s Wort 
mibefradil 
troglitazone 
telaprevir 
 
troleandomycin 
 
posaconazole 
 
Moderate Inhibitors: 
 
aprepitant
 
amprenavir 
 
amiodarone 
 
atazanavir 
 
ciprofloxacin 
 
crizotinib 
 
darunavir/ritonavir 
 
dronedarone 
 
erythromycin 
 
diltiazem 
 
fluconazole 
 
fosamprenavir 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
voriconazole a 
 
imatinib 
 
 
 


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Inhibitors of CYP3A 
Inducers of CYP3A 
Weak Inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All Other Inhibitors: 
 
chloramphenicol 
 
delaviridine
 
diethyl-dithiocarbamate
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
a 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. 
Table source: http://medicine.iupui.edu/clinpharm/ddis/main-table/ 


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Appendix 5: Guidelines for Establishing Response to Treatment 
Response 
Definition 
Nodal Masses* 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of all 
evidence of disease 
(a) FDG-avid or PET 
positive prior to therapy; 
mass of any size permitted 
if PET negative 
(b) Variably FDG-avid or 
PET negative; regression 
to normal size on CT 
Not palpable, 
nodules disappeared 
If infiltrate present at 
screening, infiltrate 
cleared on repeat 
biopsy; if 
indeterminate by 
morphology, 
immune-histochemistry 
should be negative 
PR 
Regression of 
measurable disease 
and no new sites 
50% decrease in SPD of 
up to 6 largest dominant 
masses; no increase in size 
of other nodes 
(a) FDG-avid or PET 
positive prior to therapy; 
1 PET positive at 
previously involved site 
(b) Variably FDG-avid or 
PET negative; regression 
on CT 
50% decrease in 
SPD of nodules 
(for single nodule in 
greatest transverse 
diameter); 
no increase in size of 
liver or spleen 
Irrelevant if positive 
prior to therapy; 
cell type should be 
specified 
SD 
Failure to attain 
CR/PR or 
progressive disease 
(a) FDG-avid or PET 
positive prior to therapy; 
PET positive at prior sites 
of disease, and no new 
sites on CT or PET 
(b) Variably FDG avid or 
PET negative; no change 
in size of previous lesions 
on CT 
 
 
CR = complete remission, CT = computed tomography, FDG = [18F]fluorodeoxyglucose, PET = positron emission 
tomography, PR = partial remission, SD = stable disease, SPD = sum of the product of the diameters 
* Change in target lesion measurement by CT, unless MRI used as the assessment modality for lesions in 
anatomical locations not amenable to CT 
Progressive disease for Non-Hodgkin’s lymphoma is characterized by any new lesion or 
increase by 50% of previously involved sites from nadir for example: 
x
Appearance of a new lesion(s) >1.5 cm in any axis, 50% increase in SPD of >1 node, or 
50% increase in longest diameter of a previously identified node >1 cm in short axis 
x
Lesions PET positive if FDG-avid lymphoma or PET positive before therapy 
x
>50% increase from nadir in the SPD of any previous lesions in the liver or spleen 
x
New or recurrent involvement in the bone marrow 
x
An increase of 50% in blood lymphocytes with 5 x 109/L B-cells only in setting of 
enlarging lymph node, liver, or spleen (Note:  an isolated elevation of white blood cell count 
by itself will not be considered progressive disease unless subject becomes symptomatic 
from this). 


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

SAP_001.pdf: 
 
PCYC-1125-CA 
Statistical Analysis Plan 
Page 1 of 14 
 
Version 4.0 
Proprietary and Confidential                                               27 October 2017 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
A Multicenter, Open-Label, Phase 2 Study of the Bruton’s Tyrosine Kinase 
(BTK) Inhibitor, Ibrutinib, in Combination with Rituximab in Previously 
Untreated Subjects with Follicular Lymphoma 
 
 
PCYC-1125-CA 
Prepared by:  Shanhong Guan 
 
27 October 2017 
Version 4.0 
 
 
 
Confidentiality Statement 
The information in this document is considered privileged and confidential by Pharmacyclics LLC., and may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board approval and informed 
consent, or as required by Federal and State Laws.  Persons to whom this information is disclosed must be informed 
that this information is privileged and confidential and that it should not be further disclosed. 
 
 


 
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Revision History 
 
Version 
Number 
Date 
Description 
1.0 
18Feb2014 
Original version 
2.0 
11Feb2016 
Version 2.0: Reason for changes 
x To be consistent with the protocol amendment 2.0 
x To be consistent with the biometrics standard analytical 
methods 
 
3.0 
06Jul2017 
Version 3.0: Reason for changes 
x Updated the latest protocol version and date referenced in the 
introduction section of SAP 
x Updated the language to clarify that PK and biomarker 
analysis are not within the scope of SAP 
x Analysis population: replaced ‘study drug’ by ‘study 
treatment; removed the safety analysis population 
x Extent of exposure: updated the definition of average daily 
dose 
x Analysis of ORR: updated the 95% CI to exact binomial 
(Clopper-Pearson) method 
x In the PFS analysis, subjects who receive subsequent 
antineoplastic therapy before PD or death will not be censored 
at the last evaluable disease assessment prior to the start date 
of the new therapy  
x Updated the definition of hemorrhagic events and major 
hemorrhagic events (Section 5.1.2) 
x Added the following Safety Observations per team discussion: 
Interstitial Lung Disease (ILD), Severe Cutaneous Adverse 
Reaction (SCAR), Cardiac Arrhythmia Excluding A. Fib, and 
rash (Section 5.1.3) 
x T/B/NK data analysis (Section 5.2 in SAP v2.0) is out of the 
scope of SAP and is removed 


 
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4.0 
26Oct2017 
Amendment summary: 
This version applies the latest SAP template; structure and contents 
are updated to align with other studies. Below are the major changes 
made: 
1. Removed the section for objectives of study and add a section 
for endpoints; removed the section for blinding and 
randomization method and refer to the protocol; simplified 
languages where appropriate 
 
 
 


 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .......................................................................................................5 
1. 
INTRODUCTION ..................................................................................................................6 
1.1. 
Study Design ..................................................................................................................6 
1.2. 
Endpoints .......................................................................................................................7 
1.3. 
Statistical Hypotheses ....................................................................................................7 
1.4. 
Sample Size Determination............................................................................................7 
1.5. 
Planned Analyses ...........................................................................................................8 
1.6. 
Testing Procedure and Level of Significance ................................................................8 
2. 
GENERAL ANALYSIS CONSIDERATION ......................................................................8 
2.1. 
Analysis Sets ..................................................................................................................9 
2.2. 
Definition of Subgroups .................................................................................................9 
3. 
SUBJECT INFORMATION..................................................................................................9 
3.1. 
Subject Disposition ........................................................................................................9 
3.2. 
Demographics and Baseline Characteristics ..................................................................9 
3.3. 
Prior and Concomitant Medications ..............................................................................9 
3.4. 
Extent of Exposure to Study Treatment .......................................................................10 
3.5. 
Previous Treatment History and Subsequent Antineoplastic Therapies ......................10 
4. 
EFFICACY AND SAFETY ANALYSES ...........................................................................10 
4.1. 
Efficacy Analyses ........................................................................................................10 
4.2. 
Safety Analyses ............................................................................................................11 
5. 
MODIFICATION OF ANALYSIS TO THE PROTOCOL .............................................14 
6. 
REFERENCES .....................................................................................................................14 
 
 
LIST OF TABLES 
Table 1 Summary of Efficacy Analyses ........................................................................................10 
Table 2 Summary of Safety Analyses ............................................................................................12 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
BSA 
Body Surface Area 
BTK 
Bruton’s Tyrosine Kinase 
CI 
confidence interval 
CR 
complete response. 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
FL 
follicular lymphoma 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities  
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
Pharmacokinetics 
PO 
per os (oral), by mouth 
PR 
partial response 
PT 
preferred term  
SAP 
statistical analysis plan 
SOC 
system organ class 
TEAE 
treatment emergent adverse events 
WBC 
white blood cell 
WHO 
World Health Organization 


 
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1. INTRODUCTION 
This statistical analysis plan (SAP) lays out key elements including definitions and statistical 
methods for analysis of data in evaluation of efficacy and safety for the PCYC-1125-CA study. 
Analyses of pharmacokinetics data and biomarkers will be addressed in separate documents.  
1.1. 
Study Design 
This is an open-label, phase 2 study designed to assess the efficacy and safety of ibrutinib 
combined with rituximab in previously untreated subjects with FL. The study will include 
approximately 80 subjects in two treatment arms. 
 
In Arm 1 (n = 60), subjects will receive ibrutinib 560 mg PO (by mouth) continuously until 
disease progression or unacceptable toxicity.  In addition, subjects will receive rituximab 
375 mg/m2 IV once weekly for 4 doses for the first 4 weeks of study treatment. Subjects in Arm 
1 will have imaging efficacy assessments every 12 weeks for the first 8 assessments and then 
every 16 weeks thereafter.  
 
In Arm 2 (n = 20), subjects will receive ibrutinib 560 mg PO continuously as a single agent for 
the first 8 weeks, then ibrutinib at 560 mg will continue concurrently with rituximab 375 mg/m2 
IV once weekly for 4 doses.  Once treatment with rituximab is complete, subjects will continue 
to receive single-agent ibrutinib continuously until disease progression or unacceptable toxicity. 
Subjects in Arm 2 will have imaging efficacy assessments at the end of 8 weeks and then every 
12 weeks thereafter for 8 assessments and then every 16 weeks thereafter.  Subjects who 
progress prior to starting rituximab will be discontinued from the study.  Rituximab will not be 
administered prior to the protocol-specified administration.   
 
One of the purposes of Arm 2 is to identify biomarkers that predict sensitivity or resistance to 
ibrutinib.  Based on phase 1 clinical data in FL it is predicted that approximately half of the 
subjects treated in this arm will show evidence of resistance to single-agent ibrutinib.  By 
providing a lead-in time prior to the initiation of rituximab, pre- and post-progression biopsy 
samples can be collected to address markers of drug resistance.  These objectives are exploratory 
and therefore the primary and secondary objectives related to clinical efficacy are paramount, but 
will be analyzed separately from Arm 1, since the treatment regimen in this arm is different.  
For Arm 1, pre-treatment and post-progression tumor tissue biopsies are optional. For Arm 2, 
pre-treatment tumor tissue biopsy is required and post-progression tumor tissue biopsies are 
desired but optional.  Tumor samples may be analyzed by gene expression profiling (GEP), 
whole exome sequencing (WES), or other methods.  
Ibrutinib and rituximab are each referred to as a component of study treatment. Study drug and 
study treatment are interchangeable concepts throughout this document. 
 
 


 
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1.2. 
Endpoints 
Primary Endpoints 
Efficacy 
The primary endpoint is ORR (Complete response [CR] + Partial Response [PR]) based on 
Cheson (2007) as assessed by the investigator. 
 
Secondary Endpoints 
Efficacy: 
x 
Duration of response (DOR) 
x 
Progression-free survival (PFS) 
x 
Overall survival (OS) 
 
Safety: 
x 
Frequency, severity, and relatedness of treatment-emergent adverse events (AEs) 
x 
Frequency of treatment-emergent AEs requiring discontinuation of study drug or dose reductions  
 
1.3. 
Statistical Hypotheses 
The primary hypothesis of this study is that the ORR of ibrutinib and rituximab combination 
treatment in low grade FL subjects is equal to or lower than 53%. 
The statistical hypotheses are as follows:  
H0: the ORR of ibrutinib and rituximab combination treatment in low grade FL subjects is equal 
to or lower than 53% 
versus  
H1: the ORR of ibrutinib and rituximab combination treatment in low grade FL subjects is 
greater than 53% 
These hypotheses will be tested using a 2-sided 95% confidence interval that will be calculated 
for ORR based on exact binomial distribution (Clopper-Pearson). 
1.4. 
Sample Size Determination 
Arm 1 


 
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The planned sample size for Arm 1 in this open-label, phase 2 study is 60.  The hypotheses test 
of primary endpoint analysis for Arm 1 in this study assumes an underlying response rate of 53% 
for first-line rituximab treatment in subjects with low grade FL (Hainsworth 2002; Freedman 
2009).   Assuming a true response rate of 71%, a sample size of 60 eligible subjects provides 
greater than 80% power to reject the null hypothesis H0 ≤ 53% at 1-sided 2.5% significance 
level. 
Arm 2 
Twenty (20) subjects will be enrolled in Arm 2.  One of the purposes of Arm 2 is to identify 
biomarkers that predict sensitivity or resistance to ibrutinib.  Due to the exploratory nature of the 
study objective of Arm 2, the sample size was determined without a formal calculation.  The 
sample size of 20 was determined since it was deemed an adequate number to implement 
exploratory evaluation of biomarker activities in relation to ibrutinib treatment.  
 
1.5. 
Planned Analyses 
The primary analysis for the clinical study report (CSR) will occur at least 1 year after the last 
subject enrolled in Arm 1 received the first dose of study treatment. 
 
1.6. 
Testing Procedure and Level of Significance 
The 2-sided significance level for the final analysis of primary endpoint (ORR) will be 0.05.  
Tests of secondary endpoints will be performed using the same significance level.  
2. GENERAL ANALYSIS CONSIDERATION 
Time to event or duration of event endpoints will be based on the actual event date (or censoring 
date) rather than visit number or visit label. Missing efficacy or safety data will not be imputed 
unless otherwise specified. 
In general, the baseline value is defined as the last valid measurement on or prior to the first dose 
of study treatment (ibrutinib/placebo, rituximab). For by-visit analysis, visit windows will be 
used to associate assessment with a scheduled visit and will be created in reference to the date of 
the first dose of study treatment to assign a visit number based on the assessment date. 


 
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2.1. 
Analysis Sets 
All-treated population:  
The subjects who are enrolled in the study and have received at least 1 dose of study treatment.  
Safety and efficacy analyses will be performed using the all-treated population.  
Response-evaluable population:  
The subjects in the all-treated population who have measurable disease at baseline and have at 
least 1 adequate post-treatment disease assessment by the investigator before the start of 
subsequent anti-cancer therapy. 
2.2. 
Definition of Subgroups 
There is no subgroup analysis planned. 
 
3. SUBJECT INFORMATION 
3.1. 
Subject Disposition 
The number of subjects who enrolled and the number of subjects who received study treatment 
(subjects in the safety population) will be summarized by treatment arm. 
Disposition information will be summarized for all-enrolled subjects.  Subject enrollment will be 
summarized by investigator and by treatment arm.  Study termination and treatment 
discontinuation will be summarized by the reason for discontinuation for each arm. 
3.2. 
Demographics and Baseline Characteristics 
Baseline characteristics and demographic information at baseline will be summarized with 
descriptive statistics by treatment arm.  
3.3. 
Prior and Concomitant Medications 
Medications will be coded to a generic name and an Anatomical Therapeutic Chemical (ATC) 
class per the World Health Organization (WHO) drug dictionary. Concomitant medications will 
be summarized by therapeutic class and preferred term and by treatment arm. Concomitant 
medications are defined as medications that were taken at any time on treatment (i.e. from the 
date of the first dose of study treatment through the date of the last dose of study treatment). The 
following concomitant medications will be summarized separately: growth factors, blood 
supportive products and immunoglobulin, CYP3A inhibitors/inducers, anticoagulants and/or 
antiplatelets.  


 
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3.4. 
Extent of Exposure to Study Treatment 
Exposure to study treatment will be summarized by treatment arm. Descriptive statistics will be 
provided for treatment duration and dosing information (e.g. total cumulative dose administered, 
relative dose intensity, dose reduction due to adverse events) for all study treatments.  
3.5. 
Previous Treatment History and Subsequent Antineoplastic Therapies 
Previous treatment history and subsequent FL antineoplastic agents will be summarized 
separately. 
4. EFFICACY AND SAFETY ANALYSES 
4.1. 
Efficacy Analyses 
Efficacy endpoints and analysis methods for the randomized treatment arms (Arms 1 and 2) are 
summarized in Table 1.  
 
Table 1: Summary of Efficacy Analyses  
 
Endpoint 
Definition 
Analysis Methods 
Primary Endpoint 
ORR  
Proportion of subjects achieving the 
best overall responses of CR or PR 
prior to initiation of the next line of 
antineoplastic therapy as assessed by 
investigator per the Cheson (2007) 
criteria. 
Primary 
ORR and its 2-sided 95% CI will be calculated 
using the exact binomial distribution (Clopper-
Pearson), based on the all treated population. 
Sensitivity analysis 
ORR will be performed using the response-
evaluable population. 
Secondary Endpoints 
PFS 
Time from the date of the first dose 
of study treatment to confirmed PD 
or death from any cause, whichever 
occurred first, as assessed by 
investigator. 
For subjects without any baseline or 
post-baseline disease assessment, 
PFS will be censored on the date of 
the first study treatment dose. 
Primary 
Kaplan-Meier method, based on the all treated 
population. 
  


 
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Endpoint 
Definition 
Analysis Methods 
DOR 
Time from the date of the first 
documented response (CR or PR) to 
the first documented evidence of PD 
or death from any cause.  
For subjects with no PD nor death at 
the time of analysis, DOR will be 
censored on the date of the last 
adequate post-baseline disease 
assessment, or on the date of the first 
occurrence of response (CR or PR) 
if there is no disease assessment 
afterwards. 
Primary 
Analysis of DOR will be based on the subjects 
who have achieved a response (CR or PR) prior 
to initiation of the next line of anticancer therapy 
in the all-treated population. The median DOR 
and its 2-sided 95% CI will be obtained using the 
same method as described for PFS. 
 
OS 
Overall survival (OS) is defined as 
the time from the date of the first 
dose of study treatment to the date 
of death due to any cause.  
For subjects who are known to be 
alive or whose survival status is 
unknown at the time of analysis 
and/or study closure, OS data will be 
censored at the date last known 
alive.  Subjects who withdraw 
consent prior to study closure will be 
censored on the date of the consent 
withdrawal. 
Primary 
Based on the all-treated population. KM curves 
will be used to estimate the distribution of OS.  
 
4.2. 
Safety Analyses 
Safety data will be summarized by treatment arm. Table 2 summarizes the safety analyses to be 
performed for all treatment arms. 
Adverse events (AEs) will be coded in accordance with the Medical Dictionary for Regulatory 
Activities (MedDRA). Severity of AEs will be graded by the investigator according the NCI-
CTCAE v4.03.   
All laboratory values will be converted to and reported as international standard (SI) units. In 
general, only data from the central laboratory will be summarized and analyzed. Laboratory 
parameters will be graded using the NCI CTCAE v4.03. 


 
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Unless otherwise specified, only baseline and post-baseline values collected during the 
treatment-emergent period will be included in the safety analysis. In general, the treatment-
emergent period is defined as the period from the date of the first dose of study treatment 
(rituximab, ibrutinib/placebo) up to 30 days after the date of the last dose of study treatment or 
the day before initiation of subsequent antineoplastic therapy (including crossover ibrutinib), 
whichever comes first. The treatment-emergent period for crossover ibrutinib is defined as the 
period from the date of the first dose of ibrutinib after crossover up to 30 days after the date of 
the last dose of ibrutinib or the day before initiation of subsequent antineoplastic therapy, 
whichever comes first. 
The treatment-emergent adverse events (TEAEs) are those events that occur or worsen during 
the treatment-emergent period or that are related to the study treatment.  
Table 2: Summary of Safety Analyses 
 
Safety 
Assessment 
Definition 
Analysis Methods 
 
Safety and 
tolerability 
 
AE: TEAEs, SAEs, grade 3 or 
worse TEAEs, related TEAEs, 
TEAEs leading to treatment 
discontinuation, TEAEs leading to 
dose reduction, TEAEs leading to 
death, protocol- defined events of 
special interest such as 
hemorrhagic events, major 
hemorrhage, and other safety 
observations such as hypertension,  
ILD, SCAR, rash, cardiac 
arrhythmia excluding atrial 
fibrillation), other malignancies 
 
Worst post-baseline toxicity grade 
for selected lab tests: Worst post-
baseline toxicity grade, Hgb, 
creatinine clearance, abnormal 
uric acid, liver function 
abnormalities 
Descriptive summary statistics and/or 
listings 


 
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Safety 
Assessment 
Definition 
Analysis Methods 
 
Vital signs, blood pressure, heart 
rate, temperature, respiratory rate, 
weight 
AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ILD: 
interstitial lung disease; SAE; serious adverse event; SCAR: severe cutaneous adverse reaction; 
TEAE: treatment-emergent adverse event 
 


 
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5. MODIFICATION OF ANALYSIS TO THE PROTOCOL 
Below is a major change made to the analyses described in the protocol: 
x To be consistent with the biometrics standard method of PFS analysis, the censoring 
rule for PFS has been modified where the censor date for subjects without disease 
progression or death is based on the date of the last disease assessment, regardless of 
whether the given subject received alternative anticancer therapy. In the protocol, the 
censor date is based on the last disease assessment prior to the subsequent anti-cancer 
therapy. 
    
6. REFERENCES 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. 
Journal of Clinical Oncology 2007;25:579-586. 
  
Freedman A, Neelapu SS, Nicholas C, et al (2009) Placebo-Controlled Phase III Trial of Patient-
Specific Immunotherapy With Mitumprotimut-T and Granulocyte-Macrophage Colony-
Stimulating Factor After Rituximab in Patients With Follicular Lymphoma. J Clin Oncol 
27:3036-3043. 
 
Hainsworth JD, Litchy S, Burris HA 3rd, Corso SW, Yardley DA, Morrissey L, Greco FA 
(2002), Rituximab as First-Line and Maintenance Therapy for Patients With Indolent Non-
Hodgkin’s Lymphoma. Clin Oncol 15;20(20): 4261-7. 
 
Importance of maintaining the relative dose intensity of CHOP-like regimens combined with 
rituximab in patients with diffuse large B-cell lymphoma, Annals of Hematology, September 
2010, Volume 89, Issue 9, pp 897-904. 
 
Bosly A, Bron D, Van Hoof A, De Bock R, Berneman Z, Ferrat A, Kaufman L, Dauwe M and 
Verhoef G, Achievement of optimal average relative dose intensity and correlation with survival 
in diffuse large B-cell lymphoma patients treated with CHOP, Annals of Hematology, April 
2008, Volume 87, Issue 4, pp 277-283.