Clinical trial NCT01109069
Conditions: B-cell Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Diffuse Well-differentiated Lymphocytic Lymphoma B Cell Lymphoma Follicular Lymphoma Mantle Cell Lymphoma Non-Hodgkin's Lymphoma Waldenstrom Macroglobulinemia Burkitt Lymphoma B-Cell Diffuse Lymphoma
Keywords: PCI-32765 Lymphoma, B-Cell Leukemia, Lymphoid Leukemia, B-Cell Bruton's Tyrosine Kinase
Sponsor: Pharmacyclics LLC.
Start date: 2010-06-01; Completion date: 2019-04-26
Enrollment: 199 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the long-term safety of a fixed-dose, daily regimen of PCI-32765 PO in subjects with B cell lymphoma or chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: PCI-32765
Intervention descriptions: intervention 1: Dose based on parent protocol

Protocol documents:
Prot_000.pdf: 
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PROTOCOL 
TITLE: 
A Long-Term Safety Study of Bruton’s Tyrosine Kinase 
(Btk) Inhibitor PCI-32765 in B Cell Lymphoma and 
Chronic Lymphocytic Leukemia 
PROTOCOL NUMBER: 
PCYC-1103-CA 
STUDY DRUG: 
PCI-32765-00 
IND NUMBER: 
102688 
SPONSOR MEDICAL 
MONITOR: 
Alvina Chu, MD 
Pharmacyclics, Inc. 
Phone: + 1 (408) 215-3027 
Fax: 
+1 (408) 215-3684 
Email: achu@pcyc.com 
SPONSOR: 
Pharmacyclics, Incorporated 
995 East Arques Avenue 
Sunnyvale, CA 94085-4521 
DATE FINAL: 
Original: 
02 April 2010  
Amendment 1: 
04 November 2011  
Amendment 2: 
19 June 2012  
Amendment 3: 
28 September 2012 
Amendment 4: 
16 January 2014 
Amendment 5: 
14 May 2015 
 
 
 
 
 
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, Inc. If you do not agree to this 
condition, please return the document to Pharmacyclics at the above address. 




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TABLE OF CONTENTS 
ABBREVIATIONS AND DEFINITION OF TERMS ...................................................6 
STUDY SYNOPSIS ...........................................................................................................8 
1.0 
BACKGROUND INFORMATION ...................................................................11 
1.1 
Investigational Product Name and Description .....................................................11 
1.2 
Bruton’s Tyrosine Kinase and Lymphoma ............................................................12 
1.3 
Summary of Relevant Nonclinical and Clinical Data ............................................12 
1.3.1  Pharmacology ........................................................................................................12 
1.3.2  Toxicology .............................................................................................................13 
1.3.3  Pharmacokinetics and Product Metabolism ...........................................................14 
1.4 
Summary of Clinical Safety of PCI-32765 ............................................................15 
1.4.1  Monotherapy Studies .............................................................................................15 
1.4.2  Combination Therapy Studies................................................................................16 
1.4.3  Risks .......................................................................................................................16 
1.5 
Justification of Study Design and Dose Rationale .................................................18 
1.6 
Statement on Compliance ......................................................................................19 
2.0 
STUDY OBJECTIVES AND PURPOSE ..........................................................19 
3.0 
STUDY DESIGN ..................................................................................................19 
3.1 
Description of Study ..............................................................................................19 
3.2 
Primary Endpoint ...................................................................................................20 
3.3 
Other Endpoints .....................................................................................................20 
4.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ....................................20 
4.1 
Inclusion Criteria ...................................................................................................20 
4.2 
Exclusion Criteria ..................................................................................................21 
4.3 
Discontinuation of Treatment ................................................................................21 
4.4 
Withdrawal from Study..........................................................................................21 
5.0 
TREATMENT OF SUBJECTS ..........................................................................22 
5.1 
Randomization and Blinding .................................................................................22 
5.2 
Formulation, Packaging, and Storage ....................................................................22 
5.3 
Dosage and Administration of PCI-32765 .............................................................22 
5.4 
Criteria for Adjusting Study Drug Dosage ............................................................23 
5.4.1  Dose Delay .............................................................................................................23 
5.4.2  Dose Reduction and Discontinuation.....................................................................23 
5.4.3  Intrasubject Escalation ...........................................................................................25 
5.4.4  Dose Modification for Hepatic Impaired Subjects ................................................25 
5.5 
Concomitant Therapy.............................................................................................25 
5.5.1  Permitted Concomitant Therapy ............................................................................25 


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5.5.2  Prohibited Concomitant Therapy ...........................................................................25 
5.6 
Medications to be Used with Caution ....................................................................26 
5.6.1  CYP3A Inhibiting/Inducing Agents ......................................................................26 
5.6.2  Drugs That May Have Their Plasma Concentrations Altered by PCI-32765 ........26 
5.6.3  Concomitant Use of QT Prolonging Agents ..........................................................27 
5.6.4  Concomitant Use of Antiplatelet Agents and Anticoagulants ...............................27 
5.6.5  Guidelines for PCI-32765 Management with Surgeries or Procedures .................27 
5.6.6  Reproductive Toxicity ...........................................................................................28 
5.6.7  Overdose Instructions ............................................................................................28 
6.0 
STUDY PROCEDURES .....................................................................................28 
6.1 
Description of Procedures ......................................................................................29 
6.2 
Investigator’s Assessment of Response to Treatment ...........................................32 
6.2.1  Baseline Tumor Assessment ..................................................................................32 
6.2.2  Assessment of Response to Treatment ..................................................................32 
6.3 
Follow-up Phase.....................................................................................................33 
6.3.1  Safety Follow-up Visit ...........................................................................................33 
6.3.2  Post-treatment Phase ..............................................................................................33 
6.3.3  Post-disease Progression Phase..............................................................................33 
6.4 
Missed Evaluations ................................................................................................33 
7.0 
ASSESSMENT OF SAFETY ..............................................................................34 
7.1 
Definitions14,15........................................................................................................34 
7.1.1  Adverse Events ......................................................................................................34 
7.1.2  Serious Adverse Event ...........................................................................................35 
7.1.3  Severity ..................................................................................................................36 
7.1.4  Causality ................................................................................................................36 
7.1.5  Unexpected Adverse Events ..................................................................................37 
7.2 
Documenting and Reporting of Adverse and Serious Adverse Events .................37 
7.2.1  Adverse Event Reporting Period ...........................................................................37 
7.2.2  Assessment of Adverse Events ..............................................................................38 
7.2.3  Expedited Reporting Requirements for Serious Adverse Events ..........................38 
7.2.4  Events of Special Interest.......................................................................................38 
7.2.5  Pregnancy ...............................................................................................................39 
7.2.6  Other Malignancies ................................................................................................39 
7.2.7  Eye-Related Adverse Events ..................................................................................40 
7.3 
Reporting of Serious Adverse Events by Sponsor .................................................40 
8.0 
STATISTICAL CONSIDERATIONS ...............................................................40 
9.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .....40 
9.1 
Institutional Review Board and Independent Ethics Committee ...........................41 


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9.2 
Informed Consent...................................................................................................41 
9.3 
Protected Subject Health Information Authorization ............................................42 
9.4 
Subject Screening Log ...........................................................................................42 
9.5 
Source Documentation Requirements ....................................................................42 
9.6 
Case Report Forms .................................................................................................42 
9.7 
Study Monitoring Requirements ............................................................................43 
9.8 
Investigational Study Drug Accountability ...........................................................44 
9.9 
Financial Disclosure ...............................................................................................45 
9.10 
Availability and Record Retention .........................................................................45 
9.11 
Protocol Amendments ............................................................................................46 
9.12 
Publication of Study Results ..................................................................................46 
9.13 
Liability and Clinical Study Insurance ..................................................................47 
10.0 
REFERENCES .....................................................................................................48 
11.0 
APPENDICES ......................................................................................................50 
 
IN–TEXT TABLES 
Table 1: 
Drug Discontinuation Actions for Subjects on PCI-32765 .................................. 24 
Table 2: 
Intrasubject Dose De-escalation ....................................................................... 24 
 
LIST OF APPENDICES 
Appendix 1. 
Performance Status Scores ................................................................................... 51 
Appendix 2. 
Inhibitors and Inducers of CYP 3A ..................................................................... 52 
Appendix 3. 
Schedule of Assessments ..................................................................................... 53 
Appendix 4. 
Response Assessment Criteria for Chronic Lymphocytic Leukemia (Hallek)9 ... 54 
Appendix 5. 
Response Assessment Criteria for Lymphoma (Cheson 2007)10 ......................... 56 
Appendix 6. 
Response Assessment Criteria for Waldenström's Macroglobulinemia (Kimby 
2006)11 ................................................................................................................. 57 
Appendix 7. 
Child-Pugh Score22,23 ........................................................................................... 58 


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ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BCR 
B cell receptor 
Btk 
Bruton’s tyrosine kinase 
BUN 
blood urea nitrogen 
BW 
body weight 
CLL 
chronic lymphocytic leukemia 
CR 
complete response 
CRF 
case report form 
CRi 
CR with incomplete blood count recovery 
CSSF 
Clinical Supplies Shipping Receipt Form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLBCL 
diffuse large B cell lymphoma  
ECOG 
Eastern Cooperative Oncology Group 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
FDG 
[18F]fluorodeoxyglucose 
GCP 
Good Clinical Practice 
HDPE 
high-density polyethylene 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICF 
informed consent form 
IgH 
immunoglobulin heavy chain 
IRB 
Institutional Review Board 
MCL 
mantle cell lymphoma 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
NHL 
Non-Hodgkins lymphoma 
PBMCs 
peripheral blood mononuclear cells 


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Abbreviation 
Definition 
PCI-32765 
oral formulation of PCI-32765 (study drug) provided in hard gelatin capsules 
also known as “PCI-32765 PO Hard Gelatin Capsule” 
PD 
progressive disease 
PE 
physical examination 
PET 
positron emission tomography 
P-gp 
permeability glycoprotein 
PR 
partial remission (response) 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SD 
stable disease 
SLL 
small lymphocytic lymphoma 
SOC 
standard of care 
SPD 
sum of the product of the diameters 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
WM 
Waldenström's macroglobulinemia  
XLA 
X-linked agammaglobulinemia 


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STUDY SYNOPSIS 
Title: 
A Long-term Safety Study of Bruton’s Tyrosine Kinase (Btk) 
Inhibitor PCI-32765 in B Cell Lymphoma and Chronic 
Lymphocytic Leukemia 
Protocol number: 
PCYC-1103-CA 
Phase: 
Not applicable 
Indication: 
B cell lymphoma and chronic lymphocytic leukemia (CLL) 
Study drug and 
comparator: 
PCI-32765 PO Hard Gelatin Capsule (referred to as PCI-32765) 
No comparator is used in this study. 
Objectives: 
The primary objective is to determine the long-term (> 6 months) 
safety and tolerability of a fixed daily dosing regimen of 
PCI-32765.   
Study design: 
This is an open-label, monotherapy, multicenter, extension study 
open to subjects meeting requirements for roll over from their 
parent protocol and want to continue receiving study drug.  
Subjects from PCYC-04753 who had disease progression may 
enroll in this study at a higher dose level of PCI-32765 (not to 
exceed 840 mg/day) than dose level in PCYC-04753 study. 
Subjects enrolled in this study will receive once daily dosing with 
PCI-32765 at the same dose level they were receiving in the parent 
study.  One cycle is 28 days.  Treatment may be continued as long 
as there is no evidence of progressive disease or unacceptable 
toxicity.   
Safety and efficacy assessments will be performed at a minimum 
of every 3 cycles.  At each visit, adverse events (AEs) of Grade 3 
or 4 in severity, which are either new or represent detectable 
exacerbations of pre-existing conditions, events of special interest 
and ongoing AEs from parent protocol will be recorded.  All 
serious adverse events (SAEs) must be recorded.  Efficacy 
assessments will be performed in accordance with the Guidelines 
for the Diagnosis and Treatment of CLL9 (Appendix 4), 
International Working Group Revised Response Criteria for 
Malignant Lymphoma10 (Appendix 5), and Waldenström's 
Macroglobulinemia (WM)11 (Appendix 6).  If signs and symptoms 
provide evidence of progressive disease (PD), PD must be 
confirmed by CT.  
Upon discontinuation of study treatment, a Safety Follow-up Visit 
(SFU) will be performed prior to the start of a new anticancer 
therapy or approximately 30 (±7) days after the last dose of study 
drug, whichever occurs first.  If a subject discontinues treatment 
for reasons other than disease progression, response assessments 
will be continued approximately every 3 cycles until disease 
progression.   
Once a subject has progressive disease, collect subsequent 
anticancer therapy and subject survival status approximately once 
every 3 months.  At a visit when it is determined that a subject has 


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progressed, collect blood samples for pharmacodynamics and 
pharmacokinetics analyses (e.g., Btk occupancy and B cell 
activation) (refer to Section 6.1.) 
Major inclusion/exclusion 
criteria: 
For the complete list of inclusion/exclusion criteria refer to 
Section 4.0. 
Major Inclusion Criteria: 
1. Men and women with recurrent surface immunoglobulin 
positive B cell non-Hodgkin’s lymphoma (NHL) according to 
WHO classification, (including, but not limited to, CLL/small 
lymphocytic lymphoma [SLL], Waldenström's 
macroglobulinemia [WM], mantle cell lymphoma [MCL], and 
diffuse large B cell lymphoma [DLBCL]) who have met 
requirements for roll over from their parent protocol and want 
to continue study drug.  
2. Female subjects of childbearing potential must have a negative 
serum or urine pregnancy test within 3 days of the first dose of 
study drug and agree to use dual methods of contraception 
during the study and for 90 days following the last dose with 
study drug.  Post menopausal females (>45 years old and 
without menses for >1 year) and surgically sterilized females 
are exempt from this criterion.   
3. Male subjects must use an effective barrier method of 
contraception during the study and for 3 months following the 
last dose if sexually active with a female of childbearing 
potential. 
4. Willing and able to participate in all required evaluations and 
procedures in this study protocol including swallowing 
capsules without difficulty. 
5. Ability to understand the purpose and risks of the study and 
provide signed and dated informed consent and authorization 
to use protected health information (in accordance with 
national and local patient privacy regulations). 
Major Exclusion Criteria: 
1. A life-threatening illness, medical condition or organ system 
dysfunction which, in the investigator’s opinion, could 
compromise the subject’s safety, interfere with the absorption 
or metabolism of PCI-32765, or put the study outcomes at 
undue risk.   
2. Lactating or pregnant. 
Endpoints: 
The primary endpoint of this study is the frequency, severity, and 
relatedness of AEs. 
Other endpoints of this study are: 
• 
Long-term tolerability as measured by treatment-related SAEs 
and discontinuation of study treatment due to AEs.  
• 
PD and death events 
• 
Documented responses 


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Safety plan: 
This study will be monitored in accordance with the sponsor’s 
Pharmacovigilance Committee procedures.  Adverse events and 
serious adverse events (SAEs) will be reviewed internally on an 
ongoing basis to identify safety concerns.  
Study treatment: 
PCI-32765 will be administered orally once daily at the same dose 
level of PCI-32765 as they received in the parent PCI-32765 study. 
Subject from PCYC-04753 who had disease progression may 
enroll in this study at a higher dose level of PCI-32765 (not to 
exceed 840 mg/day) than dose level in PCYC-04753 study.  One 
cycle is 28 days. 
Concomitant therapy and 
clinical practice: 
Concomitant medications which are permitted while on study 
treatment are provided in Section 5.5.1. 
Any chemotherapy (e.g., chlorambucil, bendamustine, 
cyclophosphamide, pentostatin, or fludarabine), anticancer 
immunotherapy (e.g., rituximab, alemtuzumab, or ofatumumab), 
experimental therapy, or radiotherapy are prohibited during the 
Treatment Phase.  Localized, hormonal, or bone sparing treatment 
for non-B-cell malignancies may be considered with approval of 
the medical monitor.   Localized radiotherapy for medical 
conditions other than the underlying B-cell malignancies are 
allowed after consultation and approval by the medical monitor.  
Corticosteroids at dosages equivalent to prednisone >20mg/day 
administered consecutively for 14 days or longer are prohibited.   
For medications to be used with caution refer to Section 5.6. 
Statistical methods: 
No formal statistical tests of hypotheses will be performed as this 
is an open-label, long-term, follow-up study.  This study will 
remain open as long as there are active studies of PCI-32765 with 
subjects who could be eligible for this protocol.   
Demographic characteristics, laboratory parameters, concomitant 
therapy, and AE incidence rates will be summarized using 
descriptive statistics.  All subjects who receive at least 1 dose of 
study drug will be included in the safety and efficacy analyses.   
All available efficacy and safety data will be included in data 
listings and tabulations.  No imputation of values for missing data 
will be performed.  Subjects lost to follow-up will be included in 
statistical analyses to the point of their last evaluation.  All study 
data will be examined using standard data management operating 
procedures. 
 
 


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1.0 
BACKGROUND INFORMATION 
Note: for more detailed and comprehensive background information please refer to the 
PCI-32765 Investigator's Brochure (IB). 
1.1 
INVESTIGATIONAL PRODUCT NAME AND DESCRIPTION 
PCI-32765 (ibrutinib) is a first-in-class, potent, orally administered covalently-binding inhibitor 
of Bruton’s tyrosine kinase (BTK).  Inhibition of BTK blocks downstream B-cell receptor (BCR) 
signaling pathways and thus prevents B-cell proliferation.  In vitro, PCI-32765 inhibits purified 
BTK and selected members of the kinase family with 10-fold specificity compared with non-BTK 
kinases.  PCI-32765 (IMBRUVICA®; ibrutinib) is approved by the U.S. Food and Drug 
Administration (FDA) for the treatment of: 1) mantle cell lymphoma (MCL) in patients who have 
received at least one prior therapy, 2) chronic lymphocytic leukemia (CLL) in patients who have 
received at least one prior therapy, 3) CLL in patients with 17p deletion, and 4) Waldenstrӧm’s 
Macroglobulinemia.  PCI-32765 is currently under investigation in various indications as a single 
agent and in combinations.   
B cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release.  B cells express cell surface 
immunoglobulins comprising the B-cell receptor (BCR), which is activated by binding to antigen.  
Antigen binding induces receptor aggregation and the clustering and activation of multiple 
tyrosine kinases, which in turn activate further downstream signaling pathways. 18  
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. 19  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.1 


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Data from Study PCYC-04753 demonstrate that although PCI-32765 is rapidly eliminated from 
the plasma after oral administration, once daily dosing with PCI-32765 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 PCI-32765 
background, safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of 
PCI-32765, refer to the latest version of the PCI-32765 IB. 
1.2 
BRUTON’S TYROSINE KINASE AND LYMPHOMA 
Several lines of evidence suggest that signaling through the BCR is necessary to sustain 
the viability of B cell malignancies.  First, expression of a functional BCR is maintained 
throughout lymphoma progression even as the non-expressed immunoglobulin heavy chain (IgH) 
is involved in oncogenic translocations and despite prolonged treatment of tumor cells with anti-
idiotype therapies.2,3  In addition, selective knockdown of BCR components by RNA interference 
results in apoptosis in multiple B cell lymphoma cell lines.4 
Recent studies indicate that some large-cell lymphomas have low-level tonic activation of the 
kinases downstream of the BCR and that inhibition of this tonic signaling can induce apoptosis.5  
Primary follicular lymphoma cells have also been found to maintain enhanced signaling from the 
BCR compared with normal B cells.6  In addition, at least 2 drugs that target BCR signaling (the 
Syk inhibitor, R788, and the PKCβ inhibitor, enzastaurin) have shown evidence of anti-tumor 
effects in human B cell lymphomas.7 
1.3 
SUMMARY OF RELEVANT NONCLINICAL AND CLINICAL DATA 
1.3.1 
Pharmacology  
PCI-32765 was designed as a selective and covalently-binding inhibitor of the Btk protein.8  In 
vitro, PCI-32765 is a potent inhibitor of Btk activity (IC50 = 0.39 nM).  The irreversible binding 
of PCI-32765 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, PCI-32765 inhibits signal transduction 
from the B-cell receptor and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-
IgM stimulation followed by CD69 expression.20  


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PCI-32765 arrested cell growth and induced apoptosis in human B cell lymphoma cell lines in 
vitro and inhibited tumor growth in vivo in xenograft models.  In mice, tumor growth inhibition 
was demonstrated at dose levels where no overt toxicity was observed, as measured by body 
weights (BWs).  In addition, PCI-32765 was efficacious in a mouse model of collagen-induced 
arthritis, a disease whose pathogenesis involves B cell activation. 
Binding of PCI-32765 to the active site of Btk (Btk occupancy) was demonstrated in vivo in rat 
and dog blood mononuclear cells, mouse splenocytes, and xenograft tumor cells using a 
pharmacodynamic assay, which uses a specially designed Btk-binding fluorescent probe.  The 
probe binds irreversibly to the active site of Btk, enabling fluorescent detection of labeled Btk 
protein.  The presence of PCI-32765 bound to the Btk active site occludes probe binding thus 
reducing the fluorescence probe signal.  In mice, 50% of the Btk active sites in splenocytes were 
occupied 3 hours after a single oral dose of PCI-32765 at 5 mg/kg.  Mice orally administered 
PCI-32765 30 mg/kg had complete Btk active-site occupancy in splenocytes, which persisted 
about 12 hours post dose.  In dogs, a single oral dose of 10 mg/kg resulted in complete occupancy 
of Btk measured in PBMCs.  The complete occupancy persisted for ≥ 24 hours with partial 
recovery by 48 hours post dose. PCI-32765 added to human blood (ex vivo) leads to complete 
Btk occupancy (IC50 = 100 nM) and inhibition of B cell activation measured by CD69 expression. 
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 PCI-32765 is predicted to be in lymphoid tissues 
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation).  Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog).   
In vitro and in vivo genetic toxicity studies showed that PCI-32765 is not genotoxic.  In a rat 
embryo-fetal toxicity study PCI-32765 administration was associated with fetal loss and 
malformations (teratogenicity) at PCI-32765 doses that result in approximately 6 times and 
14 times the exposure (AUC) in patients administered the dose of 560 mg daily, respectively.  


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1.3.2.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been conducted with PCI-32765. 
PCI-32765 was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo 
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. 
Fertility studies with PCI-32765 have not been conducted in animals. In the general toxicology 
studies conducted in rats and dogs, orally administered PCI-32765 did not result in adverse 
effects on reproductive organs. 
1.3.3 
Pharmacokinetics and Product Metabolism 
Following oral administration of PCI-32765 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 PCI-32765 increased as doses 
increased with substantial intersubject variability.  The mean half life (t1/2) of PCI-32765 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 PCI-32765 with a high-fat breakfast in subjects with 
chronic lymphocytic leukemia (CLL) approximately doubled the mean systemic exposure 
compared to intake after overnight fasting with median time to Tmax delayed from 2 to 4 hours.  
PCI-32765 was extensively metabolized to the dihydrodiol metabolite PCI-45227, a reversible 
inhibitor of Btk, with approximately 15 times lower inhibitory potency compared to PCI-32765.  
The metabolite-to-parent AUC ratio ranged from 0.7 to 3.4.  Steady-state exposure of PCI-32765 
and PCI-45227 was less than 2-fold of first dose exposure. 
The results of human mass balance study of [14C]-PCI-32765 conducted in six healthy male 
subjects demonstrated that less than 10% of the total dose of [14C]-PCI-32765 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 
mild or moderate renal impairment (greater than 30 mL/min creatinine clearance).  There is no 
data in patients with severe renal impairment or patients on dialysis.  In a hepatic impairment 
study, data showed an increase in PCI-3276 exposure.  Following single dose administration, the 
AUC of PCI-32765 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.  The safety of PCI-32765 has not been evaluated in patients 
with hepatic impairment. 


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1.4 
SUMMARY OF CLINICAL SAFETY OF PCI-32765 
For a comprehensive summary of nonclinical and clinical information regarding the efficacy and 
safety of PCI-32765, refer to the current version of the IB. 
1.4.1 
Monotherapy Studies 
Pooled safety data for subjects treated with PCI-32765 monotherapy in 11 nonrandomized studies 
(PCYC-1102-CA, PCYC-1117-CA, PCYC-1112-CA [crossover only], PCYC-1104-CA, 
PCI-32765MCL2001, PCI-32765MCL4001, PCYC-1106-CA, PCYC-1111-CA, 
PCI-32765FLR2002, PCYC-04753, and PCI-32765-JPN-101) has been evaluated.   
The most frequently reported treatment-emergent adverse events (AEs) in more than 10% of 
subjects receiving PCI-32765 as monotherapy in nonrandomized studies (N=1061) were diarrhea 
(35.9%), fatigue (28.6%), nausea (20.2%), cough (17.5%), and anemia (15.2%).  The most 
commonly reported Grade 3 or 4 AEs that were hematologic in nature were neutropenia (10.7%), 
thrombocytopenia (6.2%), and anemia (5.5%). Pneumonia (5.7%), fatigue (2.9%), hypertension 
(2.7%), and atrial fibrillation (2.6%) were the most frequently reported nonhematologic Grade 3 
or 4 AEs.   
The incidence of treatment-emergent SAEs reported was 41.3%. (N=1061); pneumonia (7.0%), 
atrial fibrillation (2.8%), and febrile neutropenia (2.3%) were the most commonly reported 
treatment- emergent SAEs.   
In a randomized Phase 3 study in subjects with CLL/SLL (PCYC-1112-CA)  the most frequently 
reported treatment-emergent AEs in the PCI-32765 arm were diarrhea (47.7%), fatigue (27.7%), 
nausea (26.2%), pyrexia (23.6%), anemia (22.6%), and neutropenia (21.5%). Adverse events 
reported at a higher incidence (>10% difference) in the PCI-32765 arm than in the ofatumumab 
arm included diarrhea (PCI-32765: 47.7%, ofatumumab: 17.8%), arthralgia (17.4%, 6.8%), and 
petechiae (13.8%, 1.0%).   
The most commonly reported Grade 3 or 4 AEs in more than 2% of PCI-32765 treated subjects 
that were hematologic in nature were neutropenia (16.4%), thrombocytopenia (5.6%), and anemia 
(4.6%). Pneumonia (6.7%) was the most frequently reported nonhematologic event.  The most 
frequently reported SAEs in PCI-32765 subjects were pneumonia (8.7%), atrial fibrillation 
(3.1%), pyrexia (3.1%), lung infection (2.6%), lower respiratory tract infection (2.1%) and 
urinary tract infection (2.1%). For more detailed information please refer to the current version of 
the IB.   


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1.4.2 
Combination Therapy Studies 
Pooled safety data for subjects (N=136) treated with PCI-32765 as combination therapy in 3 non-
randomized studies (PCI-32765 + BR or FCR (n=33); PCI-32765 + ofatumumab (n=71), and 
PCI-32765 + R-CHOP (n=32) are summarized below.  The median duration of treatment was 
11.1 months (range: 0.0 to 19.5). 
The most frequently reported treatment-emergent AEs reported in more than 10% of subjects 
were diarrhea (62.5%), nausea (45.6%), neutropenia (37.5%), fatigue (32.4%), peripheral sensory 
neuropathy (30.9%), upper respiratory tract infection (26.5%), vomiting (26.5%), anemia 
(21.3%), and thrombocytopenia (21.3%).  The most commonly reported Grade 3 or 4 AEs were: 
neutropenia (36.0%), pneumonia (8.1%), febrile neutropenia (7.4%), thrombocytopenia (7.4%), 
diarrhea (5.1%), anemia (4.4%), cellulitis (4.4%) and urinary tract infection (4.4%).  
Treatment-emergent SAEs in subjects receiving PCI-32765 as combination therapy (N=136) 
were reported in 39.0% of subjects. The most frequently reported serious AEs were pneumonia 
(8.8%), febrile neutropenia (7.4%), cellulitis (4.4%), and atrial fibrillation (2.9%).   
For more detailed information please refer to the current version of the IB. 
1.4.3 
Risks 
1.4.3.1 
Lymphocytosis and Leukostasis 
Similar to other agents targeting BCR signaling, transient lymphocytosis is a pharmacodynamic 
effect of PCI-32765, in which the inhibition of BTK-mediated cellular homing and adhesion 
results in a mobilization of tumor cells to the peripheral blood.21   
A reversible increase in lymphocyte counts (ie, ≥50% increase from baseline and above absolute 
count 5,000/µL), often associated with reduction of lymphadenopathy has been observed in most 
subjects (approximately 69% to 75%) with CLL/SLL treated with single agent PCI-32765.  This 
effect has also been observed in some subjects (33%) with MCL treated with single agent 
PCI-32765.  This observed transient lymphocytosis is a pharmacodynamic effect and should not 
be considered progressive disease in the absence of other clinical findings.  In both disease types, 
lymphocytosis typically occurs during the first few weeks (median time 1.1 weeks) of PCI-32765 
therapy and typically resolves within a median of 8.0 weeks in subjects with MCL and 
18.7 weeks in subjects with CLL/SLL.   


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Lymphocytosis appeared to occur in lower incidence and at lesser magnitude in subjects with 
CLL/SLL receiving PCI-32765 in combination with chemoimmunotherapy (ie, 27% of subjects 
receiving ibrutinib + bendamustine + rituximab (BR) in Study 1108) or immunotherapy (ie, 55% 
of subjects receiving ibrutinib + ofatumumab in Group 2 of Study 1109).  
A substantial increase in the number of circulating lymphocytes (eg, >400,000/µL) has been 
observed in a subset of subjects.  There have been isolated cases of leukostasis reported in 
subjects treated with PCI-32765.  
1.4.3.2 
Bleeding-related Events 
Major bleeding events including fatal events have occurred in subjects treated with PCI-32765, 
both with and without thrombocytopenia. These include primarily minor hemorrhagic events such 
as contusion, epistaxis, and petechiae; and major hemorrhagic events including gastrointestinal 
bleeding, post procedural hemorrhage, intracranial hemorrhage, and hematuria. 
1.4.3.3 
Rash 
Rash has been commonly reported in subjects treated with either single agent PCI-32765 or in 
combination with chemotherapy.  In a randomized Phase 3 study (PCYC-1112-CA), rash 
occurred at a higher rate in the PCI-32765 arm than in the control arm.  Most rashes were mild to 
moderate in severity.  One case of Stevens-Johnson Syndrome (SJS), with a fatal outcome, was 
reported in a subject with CLL.  The subject received PCI-32765 (420 mg/day) and was also 
receiving various antibiotics and antigout medication (allopurinol) known to be associated with 
SJS.  
1.4.3.4 
Other Malignancies 
Other malignancies, most frequently skin cancers, have occurred in subjects treated with 
PCI-32765.  Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 
3%) have occurred in patients treated with PCI-32765.  The most frequent second primary 
malignancy was non-melanoma skin cancer (range, 4 to 11 %). 
1.4.3.5 
Cardiac  
Atrial fibrillation and atrial flutter have been reported in subjects treated with PCI-32765, 
particularly in subjects with cardiac risk factors, acute infections, and a previous history of atrial 
fibrillation.  In particular subjects with a history of cardiac arrhythmias should be monitored 
closely. 


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1.4.3.6 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with PCI-32765.  
1.4.3.7 
Diarrhea  
Approximately one-third of subjects treated with PCI-32765 monotherapy and two-thirds treated 
with combination therapy reported diarrhea.  Other frequently reported gastrointestinal events 
include nausea, vomiting, and constipation.  These events are rarely severe, with only a small 
number of Grade 3 events, and no Grade 4 events reported to date.  
1.4.3.8 
Infections  
Fatal and non-fatal infections have occurred with PCI-32765 therapy.  At least 25% of subjects 
with MCL and 35% of subjects with CLL had Grade 3 or greater infections per NCI Common 
Terminology Criteria for Adverse Events (CTCAE).  The most commonly reported infections 
include pneumonia, cellulitis, urinary tract infection and sepsis.  Although causality has not been 
established, cases of progressive multifocal leukoencephalopathy (PML) have occurred in 
patients treated with PCI-32765. 
1.4.3.9 
Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with single-
agent PCI-32765 or in combination with chemotherapy.  Subjects at risk of tumor lysis syndrome 
are those with comorbidities and/or risk factors such as high tumor burden prior to treatment, 
increased uric acid (hyperuricemia), elevated LDH, bulky disease at baseline, and pre‐existing 
kidney abnormalities. 
1.5 
JUSTIFICATION OF STUDY DESIGN AND DOSE RATIONALE 
This study is a long-term safety and efficacy extension study.  It allows subjects meeting 
requirements for roll over from their parent protocol and who want to continue receiving study 
drug to continue on study drug.  This reduces the burden of study visits and tests on the subjects 
and allows them to continue to have access to the investigational product.   
The starting dose level for all subjects enrolled in this study will be based on the dose level the 
subject was receiving in the parent study.  Study drug will be administered continuously without 
interruption.  If the subject was in a weight-based dose cohort (subjects from PCYC-04753 


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study), then the fixed dose up to 840 mg/day that most closely approximates the weight-based 
dose will be chosen (refer to Section 5.4.2 for information on dose adjustments).   
1.6 
STATEMENT ON COMPLIANCE 
This study will be conducted in compliance with this protocol, principles of International 
Conference on Harmonisation (ICH) GCP, Declaration of Helsinki, and all applicable national 
and local regulations governing clinical studies. 
2.0 
STUDY OBJECTIVES AND PURPOSE 
The purpose of this study is to determine the long-term safety of a fixed-dose, daily regimen of 
PCI-32765 at dose levels up to 840 mg/day in subjects with B cell lymphoma (including, but not 
limited to, CLL/SLL, Waldenström's macroglobulinemia [WM], mantle cell lymphoma [MCL], 
diffuse large B cell lymphoma [DLBCL], and follicular lymphoma [FL]). 
The primary objective is to determine the long-term (>6 months) safety and tolerability of a fixed 
daily dosing regimen of PCI-32765.   
3.0 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is an open-label, monotherapy, multicenter, extension study open to subjects from prior 
PCI-32765 studies who meet eligibility criteria.  This is an open-label study; as such, no blinding 
measures will be taken.   
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase.   
The Screening Phase will be the last Treatment Phase of the parent protocol.  Subjects will 
complete all safety and efficacy assessments required by the parent protocol, and roll over to this 
extension study to ensure no interruption of treatment with PCI-32765. 
The Treatment Phase will extend from the first dose until study drug discontinuation under this 
protocol.  Subjects roll over from PCI-32765 and chemotherapy combination studies will receive 
PCI-32765 only in this study.  Subjects will receive PCI-32765 once-daily dosing at the dose 
level the subject was receiving in the parent study until disease progression.  Please note that if 
the clinical risk benefit ratio favors continuing PCI-32765 for a brief period of time (e.g. up to 
4 weeks) while salvage anticancer therapy is arranged that this may be considered at the 
Investigators discretion.  Regularly scheduled safety and efficacy assessments are required 
throughout the Treatment Phase.  Further information on dosing is provided in Section 5.3. 


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The Follow-up Phase will comprise of 2 phases; a Post-treatment Phase and a Post-disease 
Progression Phase.  The Post-treatment Phase will extend from the discontinuation of treatment up 
until the subject has PD or other criteria listed in Section 4.3.  A Safety Follow-Up Visit (SFU) 
will be performed prior to the start of a new anticancer therapy or 30 (±7) days after the last dose 
of study drug, whichever occurs first.  If a subject discontinues treatment for reasons other than 
disease progression, response assessments will be continued every 3 cycles until disease 
progression.   
The Post-disease Progression Phase will begin once a subject has progressive disease.  In this 
phase, collection of subsequent anticancer therapy and subject survival status should be 
performed once every 3 months.   
This study will be monitored in accordance with the Sponsor’s Pharmacovigilance Committee 
procedures.  Adverse events and SAEs will be reviewed internally on an ongoing basis to identify 
safety concerns.  This study will remain open as long as there are active studies of PCI-32765 
with subjects who may be eligible for this protocol.  
3.2 
PRIMARY ENDPOINT 
The primary endpoint of this study is the frequency, severity, and relatedness of AEs. 
3.3 
OTHER ENDPOINTS 
Other endpoints of this study are: 
• 
Long-term tolerability as measured by treatment-related SAEs and discontinuation of study 
treatment due to AEs 
• 
PD and death events 
• 
Documented responses 
4.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Eligible subjects will be considered for inclusion in this study if they meet all of the following 
criteria:  
1. Men and women with recurrent surface immunoglobulin positive B cell non-Hodgkin’s 
lymphoma (NHL) according to WHO classification (including, but not limited to, CLL/SLL, 
Waldenström's macroglobulinemia [WM], mantle cell lymphoma [MCL], and diffuse large B 
cell lymphoma [DLBCL]) who have met requirements for roll over from their parent protocol 
and want to continue study drug.   


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2. Female subjects of childbearing potential must have a negative serum or urine pregnancy test 
within 3 days of the first dose of study drug and agree to use dual methods of contraception 
during the study and for 90 days following the last dose with study drug.  Post menopausal 
females (>45 years old and without menses for >1 year) and surgically sterilized females are 
exempt from this criterion.   
3. Male subjects must use an effective barrier method of contraception during the study and for 
3 months following the last dose if sexually active with a female of childbearing potential. 
4. Willing and able to participate in all required evaluations and procedures in this study 
protocol including swallowing capsules without difficulty. 
5. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (in accordance with 
national and local patient privacy regulations). 
4.2 
EXCLUSION CRITERIA 
Subjects will be ineligible for this study if they meet any 1 of the following criteria: 
1. A life-threatening illness, medical condition or organ system dysfunction which, in the 
investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or 
metabolism of oral PCI-32765, or put the study outcomes at undue risk. 
2. Lactating or pregnant. 
4.3 
DISCONTINUATION OF TREATMENT 
If the subject meets any of the following criteria, subject may be discontinued from study 
treatment: 
• 
Progressive disease as determined by histology-specific criteria (refer to Appendix 4, 
Appendix 5, and Appendix 6) 
• 
Adverse event 
• 
Death 
• 
Withdrawal from treatment by subject 
• 
Investigator decision  
• 
Lost to follow-up 
• 
Study terminated by Sponsor 
No subject will be replaced.  Ongoing AEs (see Section 7.0) at time of discontinuation will be 
followed until 30 days after the last dose of PCI-32765.   
4.4 
WITHDRAWAL FROM STUDY 
A subject may be withdrawn from the study for any of the following reasons including: 
• 
Death 


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• 
Lost to follow-up 
• 
Study terminated by Sponsor 
• 
Withdrawal of consent 
In case a subject is lost to follow-up, every possible effort must be made by the study site 
personnel to contact the subject and determine the reason for discontinuation.  The measures 
taken to follow-up must be documented in the subject’s records.   
When a subject withdraws before study closure, the reason for withdrawal must be documented in 
the source documents. 
5.0 
TREATMENT OF SUBJECTS 
5.1 
RANDOMIZATION AND BLINDING 
Subjects enrolled will receive open-label PCI-32765 only.  No randomization or blinding of study 
drug administration will occur during this study. 
5.2 
FORMULATION, PACKAGING, AND STORAGE 
PCI-32765 is provided as a size 0 hard gelatin capsule containing 140 mg of PCI-32765.  The 
capsules are packaged in opaque high-density polyethylene (HDPE) plastic bottles with labels 
bearing the appropriate label text as required by governing regulatory agencies.  The drug product 
is manufactured for Pharmacyclics, Inc. by a contract manufacturer.  All formulation excipients 
are compendial and are commonly used in oral formulations. 
The recommended storage condition for PCI-32765 is room temperature.  If a drug shipment 
arrives damaged, or if there are any other drug complaints, a Product Complaint Worksheet 
should be completed and faxed to Pharmacyclics or designee.  Refer to the IB for additional 
information regarding the drug product to be used in this study. 
5.3 
DOSAGE AND ADMINISTRATION OF PCI-32765 
Subjects will receive daily administration of a fixed dose of PCI-32765.  Subjects will continue 
treatment at the same dose level as in the parent study (up to 840 mg) daily.  Subjects whose dose 
level was previously determined on the basis of weight (PCYC-04753) will receive a fixed dose 
of PCI-32765 (not to exceed 840 mg/day) that is comparable to their prior weight-based dose 
level.  PCI-32765 is intended to be administered orally once daily with 8 ounces (approximately 
240 mL) of water. Avoid grapefruit juice or Seville oranges due to CYP3A inhibition.  The 
capsules should be swallowed intact and subjects should not attempt to open capsules or dissolve 
them in water.   


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Each dose of PCI-32765 should be taken at approximately the same time each day.  If a dose is 
not taken at the scheduled time, it can be taken as soon as possible on the same day with a return 
to the normal schedule the following day.  The subject should not take extra capsules to make up 
the missed dose.  
At any given visit, only enough PCI-32765 to last until the next visit should be dispensed.  
Unused PCI-32765 capsules dispensed during previous visits and all empty bottles should be 
returned and drug accountability records (Section 9.8) updated according to the schedule in 
Appendix 3.  Returned capsules must not be redispensed to the same subject or to another subject.  
Empty bottles should be destroyed at the site or returned to the Sponsor. 
A subject diary will be used to aid with study drug administration compliance.  Investigators are 
prohibited from supplying PCI-32765 to any subjects not properly enrolled in this study or to any 
physicians or scientists except those designated as sub-investigators on form Food and Drug 
Administration (FDA) 1572.  The investigator must ensure that subjects receive PCI-32765 only 
from personnel who fully understand the procedures for administering the drug.  
5.4 
CRITERIA FOR ADJUSTING STUDY DRUG DOSAGE 
5.4.1 
Dose Delay 
Treatment with PCI-32765 should be held for any unmanageable, potentially study drug-related 
toxicity that is Grade 3 or higher in severity.  Subjects who require anticoagulant treatment (e.g., 
heparin and/or warfarin) should have study drug held until stabilized on anticoagulant therapy.  
Study drug may be held for a maximum of 28 consecutive days for toxicity.  Study treatment 
should be discontinued in the event of a toxicity lasting > 28 days, unless reviewed and approved 
by the medical monitor. 
5.4.2 
Dose Reduction and Discontinuation 
At the discretion of the investigator, based upon the recent FDA approvals of IMBRUVICA® 
(PCI-32765) for the treatment of MCL and CLL after having received at least one prior therapy 
and for the treatment of WM, subjects may have their PCI-32765 dose reduced to the approved 
dosage in the absence of toxicity.  Any subsequent dose modifications below the approved label 
dose should follow the dose modification guidelines per protocol for toxicity.  
The actions in Table 1 should be taken for the following toxicities:  
• 
Grade 4 ANC (< 500/µL) for > 7 days (neutrophil growth factors are permitted per 
ASCO guidelines 16 and use must be recorded in CRF). 


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• 
Grade 3 thrombocytopenia (< 50,000/µL) in the presence of clinically significant 
bleeding events. 
• 
Grade 4 thrombocytopenia (< 25,000/µL). 
• 
Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal antiemetic and/or 
anti-diarrheal therapy. 
• 
Any other Grade 4 toxicity or any unmanageable Grade 3 toxicity. 
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of PCI-32765 treatment.  If clinically indicated, the use of anticoagulants or 
antiplatelet agents may be considered for the thromboprophylaxis of atrial fibrillation 
(Section 5.6.4).  
Table 1: 
Drug Discontinuation Actions for Subjects on PCI-32765 
Occurrence 
Action 
1st 
Hold PCI-32765 until recovery to Grade ≤ 1 or baseline; may restart at original 
dose level 
2nd 
Hold PCI-32765 until recovery to Grade ≤ 1 or baseline; restart at one dose 
level lower (140mg less daily)* 
3rd 
Hold PCI-32765 until recovery to Grade ≤ 1 or baseline; restart at one dose 
level lower (140mg less daily)* 
4th 
Discontinue PCI-32765 
* Reference Table 2 for details on dose de-escalation of 420, 560 and 840 mg dose group. 
Changes must be recorded in the Dose Administration eCRF and subject’s records. 
A high number of circulating malignant cells (>400000/mcL) may confer increased risk of 
leukostasis; these subjects should be closely monitored. Administer supportive care such as 
hydration and/or leukophoresis as indicated.  PCI-32765 may be temporarily held, and medical 
monitor should be contacted. 
Table 2: 
Intrasubject Dose De-escalation 
Assigned Daily Dose 
420 mg 
(3 x 140-mg) 
560 mg 
(4 x 140-mg) 
840 mg 
(6 x 140-mg) 
Dose De-escalation Level 1 
280 mg 
(2 x 140-mg) 
420 mg 
(3 x 140-mg) 
700 mg 
(5 x 140-mg) 
Dose De-escalation Level 2 
140 mg 
(1 x 140-mg) 
280 mg 
(2 x 140-mg) 
560 mg 
(4 x 140-mg) 


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5.4.3 
Intrasubject Escalation 
At the Investigator’s discretion, the dose of study drug may be re-escalated after 2 cycles 
following a dose reduction in the absence of a recurrence of the toxicity that led to the reduction.  
Dose changes must be recorded in the Dose Administration eCRF. 
5.4.4 
Dose Modification for Hepatic Impaired Subjects 
PCI-32765 is metabolized in the liver.  For subjects who develop mild liver impairment while on 
study (Child-Pugh class A), the recommended dose reduction for PCI-32765 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 and could be re-treated 
according to resolved hepatic conditions (ie, 140 mg or 280 mg for moderate or mild impairment, 
respectively).  Monitor subjects for signs of toxicity and follow dose modification guidance as 
needed Appendix 7. 
5.5 
CONCOMITANT THERAPY 
5.5.1 
Permitted Concomitant Therapy 
Antiemetics are permitted if clinically indicated.  Standard supportive care medications are 
permitted.  Use of neutrophil growth factors (filgrastim and pegfilgrastim) or red blood cell 
growth factors (erythropoietin) is permitted per the American Society of Clinical Oncology 
(ASCO) guidelines16.  Transfusions may be given in accordance with institutional policy.  
Short courses (≤14 days) of steroid treatment for non-cancer related medical reasons (e.g., joint 
inflammation, asthma exacerbation, rash, antiemetic use and infusion reactions) at doses that do 
not exceed 100 mg per day of prednisone or equivalent are permitted. 
Treatment for autoimmune cytopenias is permitted for <14 days at doses that do not exceed 
100 mg per day of prednisone or equivalent. 
5.5.2 
Prohibited Concomitant Therapy 
Any non-study protocol related chemotherapy, anticancer immunotherapy, experimental therapy, 
or radiotherapy are prohibited during the Treatment Phase.  Localized, hormonal, or bone sparing 
treatment for non-B-cell malignancies may be considered with approval of the medical monitor.  


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Localized radiotherapy for medical conditions other than the underlying B-cell malignancies are 
allowed after consultation and approval by the medical monitor.   
5.6 
MEDICATIONS TO BE USED WITH CAUTION 
5.6.1 
CYP3A Inhibiting/Inducing Agents 
PCI-32765 is metabolized primarily by CYP3A.  Avoid co-administration with strong or 
moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.  Co-
administration of ketoconazole, a strong CYP3A inhibitor, in 18 healthy subjects increased dose 
normalized exposure, Cmax and AUC0-last, of PCI-32765 by 29- and 24-fold, respectively.  The 
maximal observed PCI-32765 exposure (AUC) was ≤2-fold in 37 patients treated with mild 
and/or moderate CYP3A inhibitors when compared with the highest PCI-32765 exposure in 
76 patients not treated concomitantly with CYP3A inhibitors.  Clinical safety data in 66 patients 
treated with moderate (n=47) or strong CYP3A inhibitors (n=19) did not reveal meaningful 
increases in toxicities.  Strong inhibitors of CYP3A (e.g., ketoconazole, indinavir, nelfinavir, 
ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, and nefazadone) should be 
avoided.  If a strong CYP3A inhibitor must be used, reduce the PCI-32765 dose to 140 mg or 
withhold treatment temporarily.  Subjects should be monitored for signs of PCI-32765 toxicity.  If 
a moderate CYP3A inhibitor must be used, reduce PCI-32765 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 PCI-32765 treatment, as these contain moderate inhibitors 
of CYP3A (see Section 5.3). 
Co-administration of PCI-32765 with a strong CYP3A inducer, rifampin, in healthy subjects 
decreases PCI-32765 plasma concentrations by approximately 10-fold.  Avoid concomitant use of 
strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin, and St. John’s Wort).  
Consider alternative agents with less CYP3A induction. 
A list of common CYP3A inhibitors and inducers is provided in Appendix 2; a comprehensive 
list of inhibitors, inducers, and substrates may be found at http://medicine.iupui.edu/clinpharm/ 
ddis/table.aspx.  This website is continually revised and should be checked frequently for updates.  
5.6.2 
Drugs That May Have Their Plasma Concentrations Altered by PCI-32765 
In vitro studies indicated that PCI-32765 is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor (with an IC50 of 2.15 μg/mL).  PCI-32765 is not expected to have systemic drug-drug 
interactions with P-gp substrates.  However, it cannot be excluded that PCI-32765 could inhibit 


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intestinal P-gp after a therapeutic dose.  There are no clinical data available.  Therefore, to avoid a 
potential interaction in the GI tract, narrow therapeutic range P-gp substrates such as digoxin 
should be taken at least 6 hours before or after PCI-32765. 
5.6.3 
Concomitant Use of QT Prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; periodic 
electrocardiogram (ECG) and electrolyte monitoring should be considered.  
5.6.4 
Concomitant Use of Antiplatelet Agents and Anticoagulants 
Warfarin or vitamin K antagonists should not be administered concomitantly with PCI-32765.  
Supplements such as fish oil and vitamin E preparations should be avoided.  Use PCI-32765 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 PCI-32765 
and the use of anticoagulants during procedures/surgeries see Section 5.6.5.  
Subjects requiring the initiation of therapeutic anticoagulation therapy (e.g., atrial fibrillation), 
consider the risks and benefits of continuing PCI-32765 treatment.  If therapeutic anticoagulation 
is clinically indicated, treatment with PCI-32765 should be held and not be restarted until the 
subject is clinically stable and has no signs of bleeding.  No dose reduction is required when 
study drug is restarted. 
5.6.5 
Guidelines for PCI-32765 Management with Surgeries or Procedures 
PCI-32765 may increase risk of bleeding with invasive procedures or surgery.  The following 
guidance should be applied to the use of PCI-32765 in the peri-operative period for subjects who 
require surgical intervention or an invasive procedure while receiving PCI-32765.   
5.6.5.1 
Minor Procedures 
For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis) PCI-32765 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 PCI-32765, it is not necessary to hold PCI-32765 for these procedures.   
5.6.5.2 
Major Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, PCI-32765 should 
be held at least 7 days prior to the intervention and should be held at least 7 days after the 


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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. 
5.6.5.3 
Emergency Procedures 
For emergency procedures (unscheduled/urgent), PCI-32765 should be held for a minimum of 
7 days after the urgent surgical procedure and until the surgical site is reasonably healed. 
5.6.6 
Reproductive Toxicity 
Reproductive toxicity studies have not been done with PCI-32765.  Therefore, women of child-
bearing potential who are sexually active must use highly effective contraception during the study 
and for 90 days after the last dose of PCI-32765.  Men who are sexually active, must use highly 
effective contraception during the study and for 90 days (3 months) after the last dose of 
PCI-32765.  Subjects should promptly notify the investigator if they, or their partner, become 
pregnant during this period.  If a female subject becomes pregnant during the treatment period, 
she must discontinue PCI-32765 immediately.  Pregnancy in a female subject or a male subject’s 
partner must be reported in the same manner as a SAE (refer to Section 7.2.3). 
5.6.7 
Overdose Instructions 
Any dose of study drug 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 
an SAE in the appropriate time frame and documented as clinical sequelae to an overdose.  There 
is no specific antidote for ibrutinib.  In the event of an overdose, subjects should be closely 
monitored and given appropriate supportive treatment. 
6.0 
STUDY PROCEDURES 
The Schedule of Assessments is shown in Appendix 3.  Descriptions of the scheduled evaluations 
are outlined below and complete information on study drug and dosing is provided in Section 5.0. 
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.  All results from these 
evaluations must be captured in the provided electronic case report forms (eCRFs). 


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6.1 
DESCRIPTION OF PROCEDURES 
Informed Consent 
Screening 
The subject must read, understand and sign the IRB-approved informed consent form (ICF) 
confirming his or her willingness to participate in this study before initiating any screening 
activity that is not standard of care.  Subjects must also grant permission to use protected health 
information.  
Medical History 
Screening 
Medical history, concomitant medications, and any ongoing signs or symptoms from the prior 
PCI-32765 protocol must be recorded in the site’s source documentation. 
Adverse Events 
At all visits (except Post-treatment and Post-PD follow up assessments) 
The accepted regulatory definition for an AE is provided in Section 7.1.  Adverse events that 
meet the criteria for SAEs, events of special interest (Section 7.2.4), and AEs of grade 3 or higher 
in severity will be recorded from the subject's first dose of study drug until 30 days after study 
drug discontinuation or start of a new anticancer therapy.  Important additional requirements for 
reporting SAEs are explained in Section 7.2. 
Concomitant Medication Use  
At screening visit and during study when associated with protocol specified AE or SAE. 
Verify concomitant medication use to ensure subjects' eligibility to remain on study and when 
associated with a protocol specified AE/SAE.  See Section 7.0 for further AE/SAE details.  
Confirmation of Eligibility 
Screening 
Perform all necessary procedures and evaluations to document that the subject meets each 
eligibility criterion.  Screening evaluations must be completed within 14 days before the subject’s 
first dose of PCI-32765 under this protocol. 
Physical Examination and Vital Signs 
At all visits (except Post treatment and Post PD follow up assessments) 
The screening physical examination will include, at a minimum, the general appearance of the 
subject, height (screening only) and weight, and examination of the skin, eyes, ears, nose, throat, 
lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic 
system. 


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Symptom-directed physical exams will be done during the treatment period and at the Safety 
Follow-up Visit. 
Vital signs will include blood pressure, pulse, respiratory rate, and body temperature.  Vital signs 
and weight will be measured at every visit.  Screening vital signs and weight do not need to be 
repeated if performed on prior PCI-32765 protocol within 14 days before the first administration 
of study drug on this protocol. 
Eye-related Symptom Assessment 
At Screening and all physical exams while on Treatment and Safety Follow-up.  
The subjects will be asked about eye-related symptoms at Screening and with all subsequent 
physical exams while on treatment. 
If there are any eye-related symptoms of severity Grade ≥2 at Screening or if the subject develops 
any eye-related symptoms of severity Grade ≥2 while on study treatment, an ophthalmologic 
evaluation/consult must be performed and the outcome must be reported on the ophthalmologic 
eCRF.  
ECOG Performance Status 
Treatment Phase and Safety Follow-up Visit 
The ECOG performance index is provided in Appendix 1. 
Hematology 
Screening, Treatment Phase and Safety Follow-up Visit 
Hematology 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.  Screening hematology does not need to be repeated if performed 
on prior PCI-32765 protocol within 14 days before the first administration of study drug on this 
protocol.  Subjects who roll into PCYC-1103-CA Study with < 12 months of study drug exposure 
will need to have hematology performed every 30 days (±7 days) until completion of 12 months 
on study drug and then hematology will be extended to every 3 months (±7 days). 
Serum Chemistry 
Screening, Treatment Phase and Safety Follow-up Visit 
Serum chemistry must include glucose, calcium, albumin, total protein, sodium, potassium, CO2, 
chloride, blood urea nitrogen (BUN), creatinine, alkaline phosphatase, ALT, AST, and total 
bilirubin.  Testing will be performed at the study center’s local laboratory or other clinical 
laboratory listed on the investigator’s form FDA 1572.  Screening chemistry does not need to be 
repeated if performed on prior PCI-32765 protocol within 14 days before the first administration 
of study drug on this protocol. 


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Urine Pregnancy Test 
Screening and Safety Follow-up Visit 
Pregnancy tests are required only for women with childbearing potential.  Testing will be 
performed at the study center’s local laboratory or other clinical laboratory listed on the 
investigator’s form FDA 1572. 
ECG 
Treatment Phase and Safety Follow-up Visit 
ECGs should be performed at the investigator's discretion, particularly in subjects with 
arrhythmic symptoms (e.g., 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, ECGs should be 
performed first. 
Pharmacodynamics and Pharmacokinetics 
Only when subject progresses 
At a visit when it is determined that a subject has progressed, collect blood samples for 
pharmacodynamic and pharmacokinetics analyses (e.g., Btk occupancy and B cell activation).  
• 
Pharmacodynamic sample should be collected 4 hours post last dose of PCI-32765.  
• 
Pharmacokinetic samples should be collected pre-dose and 4 hours post last dose of 
PCI-32765.   
If Pharmacodynamic and Pharmacokinetic samples cannot be collected at specified timepoints, 
draw a random sample and capture time of collection and time of last PCI-32765 dose. 
Refer to the laboratory binder for instructions on collecting and processing these samples. 
If available, tumor samples should also be collected at the visit when disease progression is 
determined. 
Predictive Biomarkers and Mechanisms of Treatment Resistance 
Treatment Phase 
Blood samples will be collected and assessed or maintained centrally to evaluate potential 
biomarkers related to response to therapy and/or to investigate potential mechanisms of treatment 
resistance.  These samples may be later characterized by technologies such as gene expression 
profiling, mutational analysis by sequencing, or proteomic assays.  Inhibition of BTK and other 
related kinases may also be explored in these cells.  It is expected that these efforts may identify 
genes and pathways associated with primary or later development of resistance to PCI-32765 by 
comparison of subjects with variable outcomes which could potentially generate biomarkers that 
could assist with future development of this compound. 


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Disease Assessment 
Treatment Phase and Post-treatment Follow-up Phase 
Disease assessments, as outlined by histology-specific guidelines, should be performed every 
3 cycles (±7 days) while on study treatment.  Disease assessments will include physical 
examination, disease-related symptoms, CBC, radiologic exam by computed tomography (CT) 
scan or positron emission tomography (PET), and/or bone marrow biopsy (refer to Section 6.2 for 
response assessment guidelines).  Data from bone marrow examinations, including analysis for 
minimal residual disease (MRD) (bone marrow or peripheral blood if bone marrow is unavailable 
or considered inappropriate), will be collected and should be performed if subject meets all other 
criteria for CR.   
Study Drug Accountability 
At all visits (except Follow-up Phase) 
Refer to Section 9.8. 
6.2 
INVESTIGATOR’S ASSESSMENT OF RESPONSE TO TREATMENT  
The investigator must evaluate the subject’s response to treatment based on Guidelines for the 
Diagnosis and Treatment of CLL9 (Appendix 4), International Working Group Revised Response 
Criteria for Malignant Lymphoma 10 (Appendix 5), and Waldenström's Macroglobulinemia 
(WM)11 (Appendix 6).   
6.2.1 
Baseline Tumor Assessment 
As this is a long-term extension study, the baseline tumor assessments are derived from the 
baseline tumor assessment from the prior PCI-32765 protocol.   
The exception is those subjects from PCYC-04753 who had disease progression and enrolled in 
this study to receive higher dose level.  Their baseline tumor assessment must be done within 
30 days of starting on this protocol. 
6.2.2 
Assessment of Response to Treatment  
Objective response will be categorized as complete response (CR), complete response with 
incomplete marrow recovery (CRi), nodular partial response (nPR), partial response (PR), partial 
response with lymphocytosis (PRL), stable disease (SD), or progressive disease (PD) based on 
the guidelines of each histology (refer to Appendix 4, Appendix 5, and Appendix 6).  The 
response assessments will be performed once every 3 cycles (±7 days) during the Treatment 
Phase.  All responses must be maintained for at least 2 months to be considered confirmed.  To 
facilitate lymph node, liver, and spleen assessments in subjects, obtain a CT scan of the chest, 


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abdomen, and pelvis, every 3 cycles for the first 18 cycles from the subject’s first dose of study 
drug in the parent study, then every 6 cycles up to cycle 36, then every 12 cycles (annually) 
thereafter.   
• 
Progressive Disease (PDs) must be confirmed by CT scan.  
• 
Complete responses (CRs) must be confirmed by bone marrow biopsy/aspirate.  For 
subjects who obtain complete response (CR), subsequent scans are only required to 
confirm disease progression. 
6.3 
FOLLOW-UP PHASE 
After study Treatment Phase is completed, all subjects will enter the Follow-up Phase.  The 
Follow-up Phase will comprise of the following:  
• 
Safety Follow-up Visit  
• 
Post-treatment Phase  
• 
Post-disease Progression Phase   
6.3.1 
Safety Follow-up Visit 
The Safety Follow-up Visit will be conducted prior to the start of a new anticancer treatment or 
30 (±7) days after the last PCI-32765 dose, whichever occurs first, to monitor for ongoing AEs 
(refer to Section 7.0) and to document the occurrence of any new AEs.  The Schedule of 
Assessments (Appendix 3) describes the procedures required for the Safety Follow-up Visits. 
6.3.2 
Post-treatment Phase 
The Post-treatment Phase will extend from the discontinuation of treatment up until the subject 
has progressive disease or other criteria listed in Section 4.3.  Subjects will be followed 
approximately every 3 months (±7 days) for disease progression and initiation of any subsequent 
anticancer therapy. 
6.3.3 
Post-disease Progression Phase 
After disease progression, follow subject for survival status (including cause of death) by clinic 
visit or phone contact, as well as collection of subsequent anticancer therapy once every 3 months 
(±7 days) until the end of study.   
6.4 
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, 


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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. 
7.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording Grade 3 or 4 AEs, SAEs, AEs of 
special interest (Section 7.2.4) and measurements of protocol-specified physical exam; and other 
tests to ensure patient safety. 
7.1 
DEFINITIONS14,15 
7.1.1 
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 an 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. 
For the purposes of this clinical study, AEs include only grade 3 or 4 events which are either new 
or represent detectable exacerbations of pre-existing conditions or events of special interest (see 
protocol Section 7.2.4).   
The following are exceptions that will be collected as AE’s regardless of severity grade:   
• 
AE leading to dose reduction  
• 
AE leading to treatment discontinuation  
• 
SAE  
• 
Other malignancies 
• 
Eye-related adverse events Grade 2 or higher 
Disease progression is not an adverse event; rather it may be the cause of an adverse event.  
Adverse events that occur due to disease progression must be reported as all other treatment-
emergent adverse events.  “Disease progression” should never be an adverse event term. 
Adverse events may include, but are not limited to: 
• 
Subjective or objective symptoms provided by the subject and/or observed by the 
investigator or study staff including laboratory abnormalities of clinical significance. 
• 
Any AEs experienced by the subject through 30 days after last dose of study drug. 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
were not present before the AE reporting period (refer to Section 7.2.1). 


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• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies). 
The following are NOT considered an AE: 
• 
Pre-existing condition: A pre-existing condition (documented on the medical history 
case report form [CRF]) is not considered an AE unless the severity, frequency, or 
character of the event worsens during the study period. 
• 
Preplanned or elective hospitalization: A hospitalization planned before signing the 
informed consent form is not considered an SAE, but rather a therapeutic intervention.  
However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE.  
Surgeries or interventions that were under consideration but not performed before 
enrollment in the study will not be considered serious if they are performed after 
enrollment in the study for a condition that has not changed from its baseline level.  
Elective hospitalizations for social reasons, solely for the administration of 
chemotherapy, or due to long travel distances are also not SAEs. 
• 
Diagnostic Testing and Procedures: Testing and procedures should not to be reported 
as AEs or SAEs, but rather the cause for the test or procedure should be reported. 
• 
Asymptomatic Treatment-Related Lymphocytosis: This event should also not be 
considered an AE.  Subjects with treatment-related lymphocytosis should remain on 
study treatment and continue with all study-related procedures.  
7.1.2 
Serious Adverse Event 
The terms “severe” and “serious” are not synonymous. Severity (or intensity) refers to the grade 
of an AE (see below). “Serious” is a regulatory definition.  
An SAE (experience) or reaction is any untoward medical occurrence that at any dose: 
• 
results in death (i.e., the AE actually causes or leads to death) 
• 
is life-threatening (“life-threatening” is defined as an AE in which the subject was at risk 
of death at the time of the event.  It does not refer to an event which hypothetically might 
have caused death if it were more severe. If either the investigator or the Sponsor believes 
that an AE meets the definition of life-threatening, it will be considered life-threatening.) 
• 
requires inpatient hospitalization >24 hours or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event that may not result in death, be immediately 
life-threatening or require hospitalization, but may be considered an SAE when, based 
upon appropriate medical judgment, the event may jeopardize the patient, or patient may 
require intervention to prevent one of the other outcomes listed in this definition.  
Examples of such events are intensive treatment in an emergency department or at home 
for allergic bronchospasm, blood dyscrasias, or convulsion that does not result in 
hospitalization; or development of drug dependency or drug abuse. 


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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. 
7.1.3 
Severity 
Definitions found in the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 will 
be used for grading the severity (intensity) of AEs.  The CTCAE v4.03 displays Grades 1 through 
5 with unique clinical descriptions of severity for each referenced AE.  Should a subject 
experience any AE not listed in the CTCAE v4.03, the following grading system should be used 
to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities. 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures. 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment. 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death. 
• 
Grade 5 (Death related to AE) – experiences which result in subject death. 
7.1.4 
Causality 
The investigator is to assess the causal relation (i.e., whether there is a reasonable possibility that 
the study drug caused the event) using the following definitions: 
Unrelated: 
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. 
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. 


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Definitely Related: 
The AE is clearly related to use of the investigational product. 
7.1.5 
Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the IB or is not listed at the specificity or 
severity that has been observed.  For example, hepatic necrosis would be “unexpected” (by virtue 
of greater severity) if the IB referred only to elevated hepatic enzymes or hepatitis.  Similarly, 
cerebral thromboembolism and cerebral vasculitis would be “unexpected” (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents.  "Unexpected" also refers to AEs that 
are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
study drug under investigation. 
7.2 
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS 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 CRFs.  All SAEs also must 
be reported on the SAE Worksheet. 
7.2.1 
Adverse Event Reporting Period 
The AE reporting period for this study begins when the subject takes the first dose of study drug 
and ends 30 days after the last dose of study drug.  Ongoing AEs from parent protocol must be 
followed to resolution or until the investigator assesses the subject as stable, or the subject is lost 
to follow-up or withdraws consent.  SAEs occurring after 30 days following the last dose of study 
drug should also be reported if considered related to study drug.  If an SAE is present at the 
Safety Follow-up Visit, the SAE (and associated AEs and concomitant medications) should be 
followed to resolution or until the investigator assesses the subject as stable, or the subject is lost 
to follow-up or withdraws consent.  Resolution/stable means the subject has returned to baseline 
state of health or the investigator does not expect any further improvement or worsening of the 
event. 
If a death occurs within 30 days after the last dose of study drug the death must be reported to the 
Sponsor as an SAE. 


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7.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time points 
during the study.  All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through physical examination, clinically significant 
laboratory test, or other means will be recorded in the subject’s medical record and on the AE 
eCRF and, when applicable, on a SAE Worksheet.   
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), severity, 
regulatory seriousness criteria, if applicable, suspected relationship to the investigational product 
(see following guidance), and any actions taken. 
7.2.3 
Expedited Reporting Requirements for Serious Adverse Events 
All SAEs (initial and follow-up information) will be reported on a SAE Worksheet and faxed to 
Pharmacyclics Drug Safety, or designee, within 24 hours of the discovery of the event or 
information.  Pharmacyclics may request follow-up and other additional information from the 
investigator (e.g., hospital admission/discharge notes, laboratory results).  
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 Pharmacyclics Drug Safety, or designee, as outlined above.   
If study drug is discontinued because of an SAE, this information must be included in the SAE 
report. 
7.2.4 
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 
following the procedure described above for SAEs (Section 7.2.3) and will require enhanced data 
collection.  All Events of Special Interest will be submitted without a serious criterion 
selected if no other serious criterion is met.   
7.2.4.1 
Major Hemorrhage 
Major hemorrhage is defined as any of the following:  
• 
Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher.a.  
• 
Any treatment-emergent serious adverse events of bleeding of any grade 


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• 
Any treatment-emergent central nervous system hemorrhage/hematoma of any grade 
a. 
All hemorrhagic events requiring transfusion of red blood cells should be reported as 
grade 3 or higher AE per CTCAE. 
Events meeting the definition of major hemorrhage will be captured as an event of special interest 
according to Section 7.2.4 above. 
7.2.5 
Pregnancy 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy.  
However, should a pregnancy occur, consent to provide follow-up information regarding the 
outcome of the pregnancy and the health of the infant until 30 days old will be requested. 
A female subject must immediately inform the investigator if the subject becomes pregnant from 
the time of consent to 30 days after the last dose of study drug.  A male subject must immediately 
inform the investigator if the subject’s partner becomes pregnant from the time of consent to 
3 months after the last dose of study drug.  Any female subjects receiving PCI-32765 who 
become pregnant must immediately discontinue study drug.  The investigator should counsel the 
subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus.   
Although pregnancy itself is not regarded as an AE, the outcome will need to be documented.  
Any pregnancy occurring in a subject or subject’s partner from the time of consent to 30 days 
after the last dose of study drug must be reported.  Record any occurrence of pregnancy on the 
Pregnancy Report Form Part I and fax to Pharmacyclics Drug Safety, or designee, within 
24 hours of learning of the event.  The pregnant female will be followed for outcome, which is 
defined as elective termination of the pregnancy, miscarriage, or delivery of the fetus.  For 
pregnancies with an outcome of live birth, the newborn infant will be followed until 30 days old 
by completing the Pregnancy Report Form Part II.  Any congenital anomaly/birth defect noted in 
the infant must be reported as a SAE.   
7.2.6 
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. 


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7.2.7 
Eye-Related Adverse Events 
New or worsening eye-related symptoms that are Grade 2 or higher, or a symptom that was 
Grade 2 or higher at baseline worsens, should be evaluated by an ophthalmologist whose findings 
should be reported on the ophthalmologic eCRF. 
7.3 
REPORTING OF SERIOUS ADVERSE EVENTS BY SPONSOR 
Regulatory Authorities, Institutional Review Boards/ Independent Ethics Committees 
(IRBs/IECs), and Principal Investigators will be notified of SAEs in accordance with applicable 
requirements (eg, GCPs, ICH guidelines, national regulations, and local requirements).   
Pharmacyclics has a Pharmacovigilance Committee that will review and evaluate accumulating 
safety data from the entire clinical study database PCI-32765 at appropriate intervals (e.g., 
quarterly) to identify new safety signals or increased frequency of events.  This will include an 
aggregate review and comparison to the control group of SAEs that were deemed as “not 
suspected” of being associated with use of the study drug because they were likely to have been 
manifestations of underlying disease or that commonly occur in the patient population.   
8.0 
STATISTICAL CONSIDERATIONS 
No formal statistical tests of hypotheses will be performed as this is an open-label, long-term 
extension study.  This study will remain open as long as there are active studies of PCI-32765 
with subjects who could be eligible for this protocol.   
Demographic characteristics, laboratory parameters, concomitant therapy, and AE incidence rates 
will be summarized using descriptive statistics.  PD and deaths will be presented using a listing.  
Documented responses will be provided in a listing.  All subjects who receive at least 1 dose of 
study drug in study PCYC-1103-CA will be included in the safety and efficacy analyses.  All 
available efficacy and safety data will be included in data listings and tabulations.  No imputation 
of values for missing data will be performed.  Subjects lost to follow-up will be included in 
statistical analyses to the point of their last evaluation.  All study data will be examined using 
standard data management operating procedures.  
9.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
Pharmacyclics retains the right to terminate the study and remove all study materials from a study 
site at any time.  Specific circumstances that may precipitate such termination are: 
• 
Unsatisfactory subject enrollment with regard to quality or quantity (e.g., <12 subjects 
enrolled within 12 months of starting the study) 


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• 
Significant or numerous deviations from study protocol requirements, such as failures to 
perform required evaluations on subjects and maintain adequate study records 
• 
Inaccurate, incomplete and/or late data recording on a recurrent basis 
• 
The incidence and/or severity of AEs in this or other studies indicating a potential health 
hazard caused by the study drug 
9.1 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE 
The investigator will submit this protocol, the informed consent, IB, and any other relevant 
supporting information (e.g., all advertising materials or materials given to the subject during the 
study) to the appropriate IRB/IEC for review and approval before study initiation.  Amendments 
to the protocol must also be approved by the IRB/IEC and local regulatory agency, as 
appropriate, before the implementation of changes in this study. 
The investigator is responsible for providing the IRB/IEC with any required information before or 
during the study, such as SAE expedited reports or study progress reports. 
The IRB/IEC must comply with current United States (US) regulations (§21 CFR 56) as well as 
country-specific national regulations and/or local laws. 
The following documents must be provided to Pharmacyclics or its authorized representative 
before entering subjects in this study: (1) a copy of the IRB/IEC letter that grants formal 
approval; and (2) a copy of the IRB/IEC-approved ICF. 
9.2 
INFORMED CONSENT  
The informed consent form (ICF) and process must comply with the United States 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, the study 
procedures, anticipated benefits, potential risks, the possible adverse effects, and any discomfort 
participation in the study may entail.  Each subject must provide a signed and dated informed 
consent before any study–related (nonstandard of care) activities are performed (such as 
screening).  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. 


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9.3 
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 9.2), either as part of the informed consent form or as a separate signed 
document (for example, in the US, a site-specific Health Insurance Portability and Accountability 
Act [HIPAA] consent may be used).  The investigator or designee must explain to each subject 
that for the evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with Pharmacyclics and its designees, regulatory agencies, and 
IRBs/IECs.  As the study sponsor, Pharmacyclics will not use the subject’s protected health 
information or disclose it to a third party without applicable subject authorization.  It is the 
investigator’s or designee’s responsibility to obtain written permission to use protected health 
information from each subject.  If a subject withdraws permission to use protected health 
information, it is the investigator’s responsibility to obtain the withdrawal request in writing from 
the subject and to ensure that no further data will be collected from the subject.  Any data 
collected on the subject before withdrawal will be used in the analysis of study results. 
During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations. 
9.4 
SUBJECT SCREENING LOG 
The investigator must keep a record that lists all subjects considered for enrollment (including 
those who did not undergo screening) in the study.  For those subjects subsequently excluded 
from enrollment, record the reason(s) for exclusion. 
9.5 
SOURCE DOCUMENTATION REQUIREMENTS 
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.  Source 
documentation for this study will include, but not be limited to, worksheets, hospital and/or clinic 
or office records documenting subject visits including study and other treatments or procedures, 
medical history and physical examination information, laboratory and special assessments results, 
pharmacy records, drug accountability records, and medical consultations (as applicable). 
9.6 
CASE REPORT FORMS 
Electronic case report forms will be used to collect the clinical study data and must be completed 
for each enrolled subject with all required study data accurately recorded such that the 
information matches the data contained in medical records (e.g., physicians’ notes, nurses’ notes, 


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clinic charts and other study-specific source documents).  Authorized study site personnel (i.e., 
listed on the Delegation of Authority form) will complete eCRFs designed for this study 
according to the completion guidelines that will be provided.  The investigator will ensure that the 
eCRFs are accurate, complete, legible, and completed in a timely manner.  At all times, the 
investigator has final responsibility for the accuracy and authenticity of all clinical data. 
The eCRFs exist within an electronic data capture (EDC) system with controlled access managed 
by Pharmacyclics or its authorized representative for this study.  Study staff will be appropriately 
trained in the use of eCRFs and application of electronic signatures before the start of the study 
and before being given access to the EDC system.  Original data and any changes of data will be 
recorded using the EDC system, with all changes tracked by the system and recorded in an 
electronic audit trail.  The investigator attests that the information contained in the eCRFs is true 
by providing electronic signature within the EDC system.  After database lock, the investigator 
will receive a copy of the subject data (e.g., paper, CD-ROM or other appropriate media) for 
archiving at the study site. 
9.7 
STUDY MONITORING REQUIREMENTS 
Representatives of Pharmacyclics or its designee will monitor this study until completion.  
Monitoring will be conducted through personal visits with the investigator and site staff 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 endure 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 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/IEC, representatives of 
Pharmacyclics, its designated agents, and authorized employees of the appropriate regulatory 
agencies 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. 


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Pharmacyclics or its authorized representative may perform an audit at any time during or after 
completion of this study.  All study-related documentation must be made available to the 
designated auditor.  In addition, a representative of the FDA or other Regulatory Agencies may 
choose to inspect a study site at any time before, during, or after completion of the clinical study. 
In the event of such an inspection, Pharmacyclics will be available to assist in the preparation.  
All pertinent study data should be made available as requested to the Regulatory Authority for 
verification, audit, or inspection purposes. 
9.8 
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY 
PCI-32765 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 PCI-32765 to other investigators, subjects, or clinics or allow supplies to be 
used other than as directed by this protocol without prior authorization from Pharmacyclics. 
PCI-32765 accountability records must be maintained and readily available for inspection by 
representatives of Pharmacyclics and are open to inspections by regulatory authorities at any 
time.  
Each shipment of PCI-32765 will contain a Clinical Supplies Shipping Receipt form (CSSR) that 
must be appended to the site’s drug accountability records.  Additionally a Drug Re-order Form 
for requesting more PCI-32765 is provided in the pharmacy binder.  If it is used, the Drug Re-
order Form must also be included in the site’s drug accountability records.   
Contents of each shipment must be visually inspected to verify the quantity and document the 
condition of PCI-32765.  Then the designated recipient completes and signs the CSSR.  A copy of 
the signed CSSR must be faxed or mailed to Pharmacyclics at the fax number/mailing address 
listed on the form. 
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-1103-CA) 
2. subject identification number 
3. lot number(s) of PCI-32765 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 Pharmacyclics’ requirements.  If the 
site cannot meet Pharmacyclics’ requirements for disposal/destruction, arrangements will be 
made between the site and Pharmacyclics or its representative, for return of unused 
investigational product. Before disposal/ destruction, final drug accountability and reconciliation 
must be performed by the monitor. 
All study supplies and associated documentation will be regularly reviewed and verified by the 
monitor. 
9.9 
FINANCIAL DISCLOSURE 
A separate financial agreement will be made between each principal investigator and 
Pharmacyclics or its authorized representative before the study drug is delivered. 
For this study, each investigator and sub-investigator (as designated on the form FDA 1572) will 
provide a signed Financial Disclosure Form in accordance with § 21 CFR 54.  Each investigator 
will notify Pharmacyclics or its authorized representative of any relevant changes during the 
conduct of the study and for 1 year after the study has been completed. 
9.10 
AVAILABILITY AND RECORD RETENTION 
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study.  Essential documentation includes, but is not limited to, the 
IB, signed protocols and amendments, IRB/IEC approval letters (dated), signed form FDA 1572 
and Financial Disclosure, 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 Pharmacyclics and notification of SAEs and related 
reports, source documentation, normal laboratory values; decoding procedures for blinded 
studies; curricula vitae for study staff, all relevant correspondence and other documents 
pertaining to the conduct of the study. 
Subject identity information will be maintained for 15 years.  All other essential documentation 
will be retained by the investigator for at least 2 years after the date the last marketing application 
is approved for the drug for the indication for which it is being investigated and until there are no 
pending or contemplated marketing applications; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after formal discontinuation of 
clinical development of the drug. 


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Pharmacyclics must be notified in advance of, and Pharmacyclics must provide express written 
approval of, any change in the maintenance of the foregoing documents if the investigator wishes 
to move study records to another location or assign responsibility for record retention to another 
party.  If the investigator cannot guarantee the archiving requirements set forth herein at his or her 
study site for all such documents, special arrangements must be made between the investigator 
and Pharmacyclics to store such documents in sealed containers away from the study site so that 
they can be returned sealed to the investigator for audit purposes. 
9.11 
PROTOCOL AMENDMENTS 
Pharmacyclics will initiate any other change to the protocol in a protocol amendment document.  
The amendment will be submitted to the IRB/IEC together with, if applicable, a revised model 
ICF.  Written documentation of IRB/IEC approval must be received by Pharmacyclics before the 
amendment may take effect at each site.  Additionally under this circumstance, information on the 
increased risk and/or change in scope must be provided to subjects already actively participating 
in the study, and they must read, understand and sign any revised ICF confirming willingness to 
remain in the study. 
No other significant or consistent change in the study procedures, except to eliminate an 
immediate hazard, shall be effected without the mutual agreement of the investigator and 
Pharmacyclics. 
9.12 
PUBLICATION OF STUDY RESULTS 
Pharmacyclics may use the results of this clinical study in registration documents for regulatory 
authorities in the United States or abroad.  The results may also be used for papers, abstracts, 
posters or other material presented at scientific meetings or published in professional journals or 
as part of an academic thesis by an investigator.  In all cases, to avoid disclosures that could 
jeopardize proprietary rights and to ensure accuracy of the data, Pharmacyclics reserves the right 
to preview all manuscripts and abstracts related to this study, allowing Pharmacyclics sufficient 
time to make appropriate comments before submission for publication. 
In most cases, the principal investigators at the sites with the highest accruals of eligible subjects 
shall be listed as lead authors on manuscripts and reports of study results.  The medical monitor, 
study director and/or lead statistician may also be included in the list of authors.  This custom can 
be adjusted upon mutual agreement of the authors and Pharmacyclics. 


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9.13 
LIABILITY AND CLINICAL STUDY INSURANCE 
In the event of a side effect or injury, appropriate medical care as determined by the investigator/ 
designee will be provided. 
If a bodily injury is sustained, resulting directly from the use of the study drug, Pharmacyclics 
will reimburse for reasonable physician fees and medical expenses necessary for treatment of 
only the bodily injury which is not covered by the subject’s medical or hospital insurance, 
provided that the injury is not due to a negligent or wrongful act or omission by the investigator/ 
study staff.  The ICF will include a description of this reimbursement policy, incorporating 
country-specific national regulations and/or local laws.  Financial compensation for lost wages, 
disability or discomfort due to the study is not available. 
Clinical study 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. 


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10.0 
REFERENCES 
1. 
Satterthwaite AB,Witte O. The role of Bruton’s tyrosine kinase in B-cell development and 
function: a genetic perspective. Immunological Reviews 2000;175:120-127. 
2. 
Küppers R. Mechanisms of B cell lymphoma pathogenesis. Nature Reviews Cancer 2005; 
5:251-262. 
3. 
Meeker T, Lowder J, Cleary ML, et al. Emergence of idiotype variants during treatment of 
B-cell lymphoma with anti-idiotype antibodies. New England Journal of Medicine 
1985;312:1658-1665. 
4. 
Gururajan M, Jennings CD, Bondada S. Cutting edge:  Constitutive B cell receptor signaling 
is critical for basal growth of B lymphoma. Journal of Immunology 2006;176: 5715-5719. 
5. 
Chen L, Monti S, Juszczynski P, et al. SYK-dependent tonic B-cell receptor signaling is a 
rational treatment target in diffuse large B-cell lymphoma. Blood 2008;111:2230-2237. 
6. 
Irish JM, Czerwinski DK, Nolan GP, Levy R. Altered B-cell receptor signaling kinetics 
distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells. 
Blood 2006;108:3135-3142. 
7. 
Robertson MJ, Kahl BS, Vose JM, et al. Phase II study of enzastaurin, a protein kinase C 
beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. Journal 
of Clinical Oncology 2007;25:1741-1746. 
8. 
Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's 
tyrosine kinase. ChemMedChem 2007;2:58-61. 
9. 
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 
guidelines. Blood 2008;111:5446-5456. 
10. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. Journal of Clinical Oncology 2007;25:579-586. 
11. Kimby E, Treon SP, Anagnostopoulos A, et al. Update on recommendations for assessing 
response from the Third International Workshop on Waldenstrom's Macroglobulinemia. Clin 
Lymphoma Myeloma 2006;5:380-383. 
12. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. 
In: MacLeod CM, editor. Evaluation of chemotherapeutic agents. New York: Columbia 
University Press; 1949. p 196. 
13. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5:649-655. 
14. International Conference on Harmonization (ICH) Guideline for Industry: Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting (ICH-E2A). March 
1995. 
15. Food and Drug Administration (FDA). Guidance for Industry and Investigators: Safety 
Reporting Requirements for INDs and BA/BE Studies (Draft Guidance). September 2010. 


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16. Smith, TJ, Khatcheressian J, Lyman GH, et al.  2006 update of recommendations for the use 
of white blood cell growth factors: an evidence based clinical practice guideline. J of 
Clinical Oncology 2006;24:3187-3205. 
17. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
Accessed 19 September 2011. 
18. Bishop GA, et al. Antigen-specific B-lymphocyte activation. Crit Rev Immunol 2003; 
23:165–197. 
19. Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: The dark side of B cell 
differentiation. Nat Rev Immunol 2002;2:920–932. 
20. Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising 
therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted 
by PCI-32765. Blood 2011; 117:6287-6296. 
21. Stevenson FK, Krysov S, Davies AJ, et al. B-cell receptor signaling in chronic lymphocytic 
leukemia. Blood 2011;118: 4313–4320. 
22. Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal 
hypertension. Philadelphia:Saunders. 1964. pp. 50-64.   
23. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R . Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60:646-9. 
 


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11.0 
APPENDICES 


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Appendix 1. 
Performance Status Scores 
% 
Karnofsky Performance 
Status12 
Status 
Eastern Cooperative Oncology Group 
(ECOG) 
Performance Status13 
100 
Normal; no complaints; no 
evidence of disease. 
0 
Fully active, able to carry on all 
predisease performance without 
restriction. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
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. 
70 
Care for self.  Unable to carry 
on normal activity or do active 
work. 
60 
Requires occasional assistance 
but is able to care for most of 
his or her needs. 
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. 
50 
Requires considerable 
assistance and frequent medical 
care. 
40 
Disabled, requires special care 
and assistance. 
3 
Capable of only limited self-care, 
confined to bed or chair more than 50% of 
waking hours. 
30 
Severely disabled; 
hospitalization is indicated 
though death not imminent. 
20 
Hospitalization necessary; very 
sick; active supportive treatment 
necessary. 
4 
Completely disabled.  Cannot carry on 
any self-care.  Totally confined to bed or 
chair. 
10 
Moribund; fatal processes 
progressing rapidly. 
0 
Dead. 
5 
Dead. 
 
 
 


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Appendix 2. 
Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A are defined as follows.  A comprehensive list of inhibitors can 
be found at the following website:  http://medicine.iupui.edu/clinpharm/ddis/table.aspx17 .  
The general categorization into strong, moderate, and weak inhibitors according to the website is 
displayed below: Refer to Section 5.6.1 on instructions for concomitant use of CYP3A inhibitors 
and inducers with PCI-32765. 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
Carbamazepine 
INDINAVIR 
Efavirenz 
NELFINAVIR 
Nevirapine 
RITONAVIR 
Barbiturates 
CLARITHROMYCIN 
Glucocorticoids 
ITRACONAZOLE 
Modafinil 
KETOCONAZOLE 
Oxcarbarzepine 
NEFAZODONE 
Phenobarbital 
SAQUINAVIR 
Phenytoin 
SUBOXONE 
Pioglitazone 
TELITHROMYCIN 
Rifabutin 
Moderate inhibitors: 
Rifampin 
Aprepitant 
St. John’s Wort 
Erythromycin 
Troglitazone 
diltiazem  
 
Fluconazole 
 
grapefruit juice 
 
Seville orange juice 
 
Verapamil 
 
Weak inhibitors: 
 
Cimetidine 
 
All other inhibitors: 
 
Amiodarone 
 
NOT azithromycin 
 
Chloramphenicol 
 
Boceprevir 
 
Ciprofloxazin 
 
Delaviridine 
 
diethyl-dithiocarbamate 
 
Fluvoxamine 
 
Gestodene 
 
Imatinib 
 
Mibefradil 
 
Mifepristone 
 
Norfloxacin 
 
Norfluoxetine 
 
star fruit 
 
Telaprevir 
 
Voriconazole 
 
Source: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx.17 


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Appendix 3. 
Schedule of Assessments 
 
Screeninga 
Treatment Phase 
Follow-up Phase 
 
 
Safety and Efficacy 
Every 3 Cycles (84 days)   
±7 days 
Safety Follow-up 
Prior to anticancer tx or  
30 (±7) days after last dose 
Post-treatment Follow-up  
every 3 cycles (84 days) 
±7 days until  PDb 
Post-PD Follow-up 
every 3 months  
(±7 days) 
Informed consent 
X 
 
 
 
 
Confirm eligibility 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
PEc/Vital signsd/Weightd 
X 
X 
X 
 
 
  Eye-related symptoms 
 X 
X 
X 
 
 
ECOG status 
 
X 
X 
 
 
Lab assessments: 
 
 
 
 
 
Urine pregnancy teste 
X 
 
X 
 
 
Hematologyf 
X 
X 
X 
 
 
Serum chemistryg 
X 
X 
X 
 
 
Pharmacodynamics & Pharmacokineticsl 
 
Will only be collected when a subject progresses 
 
  Predictive biomarkers & mechanisms of resistance 
 
  Approximately once per year 
 
 
 
  ECG 
 
 If clinically indicated (eg, subjects with palpitations, lightheadedness) 
 
Dispense study drugh 
 
X 
 
 
 
Study drug compliance 
 
X 
 
 
 
Disease assessmenti 
 
X 
 
X 
 
Concomitant medicationsj 
X 
X 
X 
 
 
New anti-cancer treatmentm 
 
 
X 
X 
X 
Adverse eventsk 
X 
X 
X 
 
 
Survival 
 
 
 
 
X 
a. 
Screening tests should be performed within 14 days before the first administration of study drug, unless otherwise indicated. 
b. 
Subjects who did not progress on treatment, but discontinued study drug will be followed every 3 cycles for disease progression. 
c. 
The screening PE will include, at a minimum, the general appearance of the subject, height (screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, 
extremities, musculoskeletal system, nervous system, and lymphatic system.  Symptom-directed physical examinations will be performed thereafter. 
d. 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) will be assessed.  Screening vital signs and weight do not need to be repeated if performed during a prior PCI-32765 protocol within 
14 days before the first administration of study drug during the current protocol. 
e. 
Women of childbearing potential only.  If positive, pregnancy must be ruled out by ultrasound to be eligible.  
f. 
Hematology includes complete blood count with differential and platelet count.  Screening hematology does not need to be repeated if performed on prior PCI-32765 protocol within 14 days before the first 
administration of study drug on this protocol.  Subjects who roll into PCYC-1103-CA Study with < 12 months of study drug exposure will need to have hematology performed every 30 days (±7 days) till 
completion of 12 months on study drug and then hematology will be extended to every 3 cycles (±7 days) while on study treatment.  
g. 
Serum chemistry includes glucose, calcium, albumin, total protein, sodium, potassium,  CO2, chloride, blood urea nitrogen (BUN), creatinine, alkaline phosphatase, ALT, AST, and total bilirubin.  
Screening chemistry does not need to be repeated if performed on prior PCI-32765 protocol within 14 days before the first administration of study drug on this protocol.  Serum chemistry will be performed 
every 3 cycles while on study treatment. 
h. 
One cycle is once daily administration for 28 days.  Dispense sufficient study drug until the next scheduled visit. 
i. 
Objective response will be categorized as complete response (CR), partial response (PR), stable disease, or progressive disease based on the guidelines of each histology (refer to Appendix 4, Appendix 5 
and Appendix 6.  The response assessments will be performed once every 3 cycles during the Treatment Phase.  All responses must be maintained for at least 2 months to be considered confirmed.  
Complete responses (CRs) must be confirmed by bone marrow biopsy/aspirate.  Progressive disease (PD) must be confirmed by CT. To facilitate lymph node, liver, and spleen assessments in subjects, 
obtain a CT scan of the chest, abdomen, and pelvis, every 3 cycles for the first 18 cycles from the subject’s first dose of study drug in the parent study, then every 6 cycles up to cycle 36, then every 
12 cycles (annually) thereafter.   
j. 
Verify concomitant medication use to ensure subjects' eligibility to remain on study. Record concomitant medications at screening visit and when associated with protocol specified AEs and with SAEs.    
k. 
Grade 3 and 4 AEs as well as all SAEs, exceptions (refer to Section 7.1.1) and events of special interest to be collected (refer to Section 7.2.4 
l. 
Pharmacodynamic and Pharmacokinetic samples to be collected at the visit when it is determined that the subject has PD. 
m. 
Once a subject has progressive disease and discontinues study treatment, attempts to collect subsequent anti-cancer therapy should be performed approximately once every 3 months 
 


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Appendix 4. 
Response Assessment Criteria for Chronic Lymphocytic Leukemia (Hallek)9 
Response 
Peripheral Bloodf 
Bone Marrow 
Nodes, Liver, and Spleena,e 
CR 
Lymphocytes < 4 x 109/L 
ANC > 1.5 x 109/Lb 
Platelets > 100 x 109/Lb 
Hemoglobin > 11.0 g/dL 
(untransfused)b 
Normocellular 
< 30% 
lymphocytes 
No B-lymphoid 
nodulesd 
Normal  
(e.g., no lymph nodes > 1.5 cm) 
CRi 
Lymphocytes < 4 x 109/L 
Persistent anemia, 
thrombocytopenia, or 
neutropenia related to drug 
toxicity 
Hypocellular 
< 30% 
lymphocytes 
Normal  
(e.g., no lymph nodes > 1.5 cm) 
PR 
Lymphocytes ≥ 50% decrease 
from baseline or  
ALC < 4 x 109/L 
AND 
ANC > 1.5 x 109/L 
Or 
Platelets > 100 x 109/L or 
 50% improvement over 
baselineb 
Or 
Hemoglobin > 11.0 g/dL or 
50% improvement over 
baseline (untransfused)b 
Not required 
≥ 50% reduction in lymphadenopathyc 
and/or in spleen or liver enlargement 
PR with 
lymphocytosis 
Subjects who achieved a PR by IWCLL 2008 criteria in all parameters except lymphocyte 
count will be considered PR with lymphocytosis.  Subjects with a PR with lymphocytosis 
will not be considered to have achieved a PR until there is a 50% reduction in ALC from 
baseline was achieved or ALC <4 x 109/L 
SD 
Failure to attain CR/PR or 
progressive disease 
Not required 
No significant increase or decrease 
ANC = absolute neutrophil count; CR = complete remission;  
CRi = CR with incomplete blood count recovery; PR = partial remission 
 
a. 
Computed tomography (CT) scan of abdomen, pelvis, and chest is required for this evaluation 
b. 
Without need for exogenous growth factors 
c. 
In the sum products of ≤ 6 lymph nodes or in the largest diameter of the enlarged lymph node(s) 
detected before therapy and no increase in any lymph node or new enlarged lymph nodes 
d. 
Subjects meeting all criteria for a CR with B-lymphocyte nodules on bone marrow exam will be 
considered nodular partial response (nPR). 
e. 
The investigator will assess response in subjects with limited tumor burden at baseline using only the 
parameters that were abnormal at baseline.   
f. 
If all hematological parameters were normal at baseline (eg,  Hbg >11g/dL, Plt >100 x 109/L, ANC  
>1.5 x 109/L), they must remain normal for the subjects to be considered to have achieved a response. 
  
 
 


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Progressive disease for CLL is characterized by ≥ 1 of the following: 
• 
Appearance of any new lesion, such as enlarged lymph nodes (> 1.5 cm), de novo 
appearance of hepatomegaly or splenomegaly, or other organ infiltrates 
• 
An increase of ≥ 50%  
• 
in longest diameter of any previous site  
• 
in the previously noted enlargement of the liver or spleen 
• 
in blood lymphocytes with ≥ 5 x 109/L B cells only in setting of enlarging lymph node, 
liver, or spleen (note: isolated elevation of WBC by itself will not be considered 
progressive disease unless subject becomes symptomatic from this) 
 
 


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Appendix 5. 
Response Assessment Criteria for Lymphoma (Cheson 2007)10  
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, 
immuno- 
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 
 
 
Abbreviations: CR = complete response, CT = computed tomography, FDG = [18F]fluorodeoxyglucose, 
PET = positron-emission tomography, PR = partial remission, SD = stable disease, SPD = sum of the product of the 
diameters 
 
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: 
• 
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 
• 
Lesions PET positive if FDG-avid lymphoma or PET positive before therapy 
• 
> 50% increase from nadir in the SPD of any previous lesions in the liver or spleen 
• 
New or recurrent involvement in the bone marrow 
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:  isolated elevation of WBC by itself will not be considered 
progressive disease unless subject becomes symptomatic from this) 
 
 


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Appendix 6. 
Response Assessment Criteria for Waldenström's Macroglobulinemia 
(Kimby 2006)11 
Response 
Definition 
CR 
A disappearance of serum and urine monoclonal protein determined by 
immunofixation, absence of malignant cells in bone marrow determined by 
histologic evaluation, resolution of adenopathy/organomegaly, (confirmed by 
computed tomography [CT] scan), and no signs or symptoms attributable to WM.  
Recommendation of the CR status is required ≥ 6 weeks later with a second 
immunofixation.  
PR 
A ≥ 50% reduction of serum monoclonal IgM concentration determined by 
protein electrophoresis, ≥ 50% decrease in adenopathy/organomegaly on physical 
examination or on CT scan, and no new symptoms or signs of other active 
disease. 
SD 
A < 25% reduction and < 25% increase of serum monoclonal IgM determined by 
electrophoresis without progression of adenopathy/organomegaly, cytopenias, or 
clinically significant symptoms caused by disease and/or signs of WM. 
PD 
A ≥ 25% increase in serum monoclonal IgM by protein electrophoresis confirmed 
by a second measurement or progression of clinical significant findings caused by 
disease (eg, anemia, thrombocytopenia, leukopenia, or bulky adenopathy/ 
organomegaly) or symptoms (eg, unexplained recurrent fever ≥ 38.4°C, drenching 
night sweats, ≥ 10% weight loss, hyperviscosity, neuropathy, or symptomatic 
cryoglobulinemia) attributable to WM.  
Abbreviations: WM=Waldenström's Macroglobulinemia, CR = complete response,  
CT = computed tomography, PR = partial response, SD = stable disease, PD=progressive 
disease 
 
 
 


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Appendix 7. 
Child-Pugh Score22,23 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L 
(mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or 
suppressed with 
medication) 
Grade III-IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C