An Open-label Study to Assess the Long-term Safety and Efficacy of ONO/GS-4059 in Subjects With Relapsed/Refractory B-cell Malignancies
Phase: PHASE1
Conditions: Relapsed/Refractory B-cell Malignancies
Sponsor: Gilead Sciences

Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Indication: 
Protocol ID: 
Clinical Program 
Manager: 
Gilead Medical Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
An Open-label Study to Assess the Long-term Safety and 
Efficacy of Tirabrutinib (ONO/GS-4059) in Subjects with 
Relapsed/Refractory B-cell malignancies 
Gilead Sciences, Inc. 
This is a non-IND study 
2015-001404-58 
Relapsed/Refractory B-cell malignancies 
GS-US-401-1787 
Naine: 
Telephone: 
Naine: 
Telephone: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
Amendment 5: 
19 May 2015 
24 J aimary 2017 
12 May 2017 
30 November 2017 
23 J aimary 2019 
29 October 2019 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee. The infonnation is only to be 
used by you in connection with authorized clinical studies of the investigational drug 
described in the protocol. You will not disclose any of the infonnation to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessary to obtain 
infonned consent from those persons to whom the drug may be administered. 

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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................10
1.
INTRODUCTION ..............................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.2.
Tirabrutinib ............................................................................................................................................15
1.2.1.
General Information .............................................................................................................15
1.2.2.
Tirabrutinib Preclinical Pharmacology and Toxicology.......................................................19
1.2.3.
Clinical Trials of Tirabrutinib ..............................................................................................21
1.3.
Rationale for This Study ........................................................................................................................21
1.4.
Compliance ............................................................................................................................................21
2.
OBJECTIVES.....................................................................................................................................................22
3.
STUDY DESIGN................................................................................................................................................23
3.1.
Endpoints ...............................................................................................................................................23
3.2.
Study Design..........................................................................................................................................23
3.3.
Study Treatments ...................................................................................................................................23
3.4.
Duration of Treatment............................................................................................................................23
3.5.
Criteria for Discontinuation of Study Drug............................................................................................23
3.6.
Source Data............................................................................................................................................24
4.
SUBJECT POPULATION..................................................................................................................................25
4.1.
Number of Subjects and Subject Selection ............................................................................................25
4.2.
Inclusion Criteria....................................................................................................................................25
4.3.
Exclusion Criteria...................................................................................................................................25
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................26
5.1.
Enrollment and Treatment Assignment..................................................................................................26
5.2.
Description and Handling of Tirabrutinib..............................................................................................26
5.2.1.
Tirabrutinib ..........................................................................................................................26
5.3.
Dosage and Administration of Tirabrutinib ...........................................................................................27
5.4.
Prior and Concomitant Medications.......................................................................................................28
5.5.
Accountability for Tirabrutinib ..............................................................................................................28
6.
STUDY PROCEDURES ....................................................................................................................................29
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................30
6.2.
Description of Study Procedures............................................................................................................30
6.2.1.
Written Informed Consent....................................................................................................30
6.2.2.
Recording Medical History ..................................................................................................30
6.2.3.
Medication History...............................................................................................................30
6.2.4.
Physical Examination...........................................................................................................30
6.2.5.
Vital Signs............................................................................................................................30
6.2.6.
Electrocardiogram................................................................................................................31
6.2.7.
Laboratory Assessments.......................................................................................................31
6.2.8.
Pharmacokinetic Samples.....................................................................................................32
6.2.9.
Bone Marrow Examination ..................................................................................................32

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6.4. 
6.5. 
6.6. 
6.7 
Treatment Response Assessment ......................................................................................... 32 
ECOG Performance Status ................................................................................................... 32 
Tumor Imaging CT ............................................................................................................ 32 
Assessments for Premature Discontinuation from Study ....................................................................... 34 
End of Study ........................................................................................................................................... 34 
Tirabrutinib Dose interruption and adjustment ...................................................................................... 35 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 36 
7. I. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 36 
7.1.1. 
Adverse Events ..................................................................................................................... 36 
7 .1.2. 
Serious Adverse Events ........................................................................................................ 36 
7.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ......................................................................... 37 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 38 
7 .2.1. 
Assessment of Causality for Study Drugs and Procedures ................................................... 38 
7 .2.2. 
Assessment of Severity ........................................................................................................ 38 
7.3. 
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead ....................................................................................................................... 38 
7.4. 
Gilead Reporting Requirements ............................................................................................................. 40 
7.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events .......................................................................................................................... 40 
7.6. 
Toxicity Management ............................................................................................................................ 40 
7.6.1. 
Warnings and Precautions .................................................................................................... 41 
7.7. 
Special Situations Reports ...................................................................................................................... 41 
7.7.1. 
Definitions of Special Situations .......................................................................................... 41 
7.7.2. 
lnstmctions for Reporting Special Situations ....................................................................... 42 
8. 
STATISTICAL CONSIDERA TIONS ................................................................................................................ 44 
8.1. 
8.2. 
8.3. 
8.4. 
8.5. 
8.6. 
8.7. 
8.8. 
"O. 
8.11. 
Analysis Objectives and Endpoints ........................................................................................................ 44 
8.1.1. 
Analysis Objectives .............................................................................................................. 44 
8.1.2. 
Primary Endpoint ................................................................................................................. 44 
8.1.3. 
Secondary Endpoint ............................................................................................................. 44 
Analysis Sets .......................................................................................................................................... 44 
8.2.1. 
Rollover Analysis Set ........................................................................................................... 44 
8.2.2. 
Full Analysis Set .................................................................................................................. 45 
8.2.3. 
Pharmacokinetics Anal sis Set.. ........................................................................................... 45 
-
Data Hand mg onventtons ................................................................................................................... 45 
Subject Disposition ................................................................................................................................ 45 
Subject Characteristics ........................................................................................................................... 45 
Efficacy Analysis ................................................................................................................................... 46 
Safety Analysis ....................................................................................................................................... 46 
8.7.1. 
Extent of Exposure and Compliance .................................................................................... 46 
8.7.2. 
Adverse Events ..................................................................................................................... 46 
8.7.3. 
Laboratory Evaluations ........................................................................................................ 47 
Pharmacokinetic Anal sis ...................................................................................................................... 48 
amp e tze ............................................................................................................................................ 4 
Data Monitoring Committee .................................................................................................................. 48 
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9.
RESPONSIBILITIES..........................................................................................................................................49
9.1.
Investigator Responsibilities ..................................................................................................................49
9.1.1.
Good Clinical Practice..........................................................................................................49
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................49
9.1.3.
Informed Consent.................................................................................................................49
9.1.4.
Confidentiality......................................................................................................................50
9.1.5.
Study Files and Retention of Records ..................................................................................50
9.1.6.
Case Report Forms...............................................................................................................51
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................52
9.1.8.
Inspections............................................................................................................................52
9.1.9.
Protocol Compliance............................................................................................................52
9.2.
Sponsor Responsibilities ........................................................................................................................52
9.2.1.
Protocol Modifications.........................................................................................................52
9.2.2.
Study Report and Publications .............................................................................................53
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................53
9.3.1.
Payment Reporting...............................................................................................................53
9.3.2.
Access to Information for Monitoring..................................................................................53
9.3.3.
Access to Information for Auditing or Inspections ..............................................................54
9.3.4.
Study Discontinuation..........................................................................................................54
10.
REFERENCES ...................................................................................................................................................55
11.
APPENDICES ....................................................................................................................................................61
Appendix 1.
Investigator Signature Page....................................................................................................62
Appendix 2.
Study Procedures Table..........................................................................................................63
Appendix 3.
Definitions of Response for Waldenstrom’s Macroglobulinemia ..........................................65
Appendix 4.
Modified International Workshop on Chronic Lymphocytic Lymphoma Leukemia 
(IWCLL) Criteria for Response Assessment..........................................................................66
Appendix 5.
Follicular Lymphoma, Marginal Zone Lymphoma, and Small Lymphocytic 
Lymphoma Response Assessment..........................................................................................73
Appendix 6.
ECOG status...........................................................................................................................79
Appendix 7.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03....................................80
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................81
LIST OF IN-TEXT TABLES
Table 5-1.
Examples of Concomitant Medications Prohibited in this Study ...........................................28
Table 6-1.
Analytes..................................................................................................................................31
LIST OF IN-TEXT FIGURES
Figure 1-1.
Inhibition of the BCR Pathway by Tirabrutinib .....................................................................17
Figure 6-1.
Initial Study Procedures .........................................................................................................29

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
An Open-label Study to Assess the Long-term Safety and Efficacy of 
Tirabrutinib in Subjects with Relapsed/Refractory B-cell 
malignancies
IND Number:
EudraCT Number:
This is a non-IND study
2015-001404-58
Study Centers 
Planned:
Initially, 6 sites in the EU will participate in this study; the number of 
sites and countries will be expanded as additional tirabrutinib studies 
are initiated
Objectives:
The primary objective of this study is:

To determine the long-term safety and tolerability of tirabrutinib
in subjects in a prior tirabrutinib study and whose disease had not 
progressed on the parent study 
The secondary objective of this study is: 

To determine the long term efficacy of tirabrutinib
Study Design:
An open-label study for subjects who have tolerated and achieved 
stable disease or have improved with tirabrutinib treatment while 
enrolled in a prior tirabrutinib study 
Number of 
Subjects Planned:
The number of subjects enrolled will be determined by the number of 
subjects who complete a prior tirabrutinib study without disease 
progression, wish to continue therapy with tirabrutinib and meet the 
study entry criteria
Target Population:
Subjects who complete a prior tirabrutinib study without disease 
progression
Duration of 
Treatment:
Subjects will continue on tirabrutinib for a maximum duration of 
5 years from the start of this study.

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Diagnosis and 
Eligibility 
Criteria:
Inclusion Criteria:
1) Currently enrolled in a prior tirabrutinib Study 
2) Did not discontinue treatment with tirabrutinib for any reason 
other than to enroll in this study
3) Eastern Cooperative Oncology Group (ECOG) performance status 
of 0, 1, or 2 at enrollment in this study
4) Any Grade 3 or 4 non-hematologic toxicity that the investigator 
considers related to previous tirabrutinib use must have resolved, 
reverted to Grade 1, or reverted to the baseline of the prior study 
prior to Day 1 of this study
5) Negative serum and urine pregnancy test is required for female 
subjects (unless surgically sterile or greater than 2 years 
post-menopausal)
6) Male subjects and female subjects of childbearing potential who 
engage in heterosexual intercourse must agree to use protocol 
specified method(s) of contraception as described in Appendix 8.
7) Lactating females must agree to discontinue nursing before the 
study drug is administered
8) Ability and agreement to attend protocol-specified visits at the 
study site
9) Able to comprehend and willing to sign the informed consent 
form
Exclusion Criteria:
1) Known hypersensitivity to tirabrutinib, its metabolites, or 
formulation excipients
Study Procedures/
Frequency:
Procedures performed at a regular follow-up visit on subject’s 
previous tirabrutinib study may be used to fulfill screening criteria 
and to establish any new medical history on this study.
At Day 1, the starting dose of tirabrutinib capsules/tablets will be 
identical to the dose administered in the prior tirabrutinib study. All 
subjects will self-administer tirabrutinib capsules/tablets.

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The initial study procedures to be conducted for each subject enrolled 
in this study are presented in the following figure:
Initial Study Procedures

Steps 1 through 5 may occur on the same or different days, but 
must occur sequentially 

The maximum amount of time allowed from Step 1 to Step 5 is 
30 days 

Results from laboratory assessments and procedures performed up 
to 30 days prior to Step 5 (eg, results from procedures performed 
during the previous study or as part of the subject’s routine care 
[if documentation is available] may be utilized for determining 
eligibility)
Study visits consisting of clinical, laboratory, and disease assessments 
will be completed every 28 days up to Cycle 22, then every 12 weeks. 
All study required laboratory assessments will be performed by a 
laboratory and ECG assessments will be performed and interpreted by 
local departments. Following treatment, subjects will be followed for 
safety and disease status for a period of 30 days.
Test Product, Dose, 
and Mode of 
Administration:
Tirabrutinib oral capsules are brown, opaque, hard capsules and 
contain 10 mg, 25 mg, or 100 mg of tirabrutinib per capsule. 
Tirabrutinib oral tablets are supplied as either 20 mg blue, 
plain-faced, round, film-coated tablets, 80-mg yellow, plain-faced, 
modified capsule-shaped, film-coated tablets or 100 mg white, 
plain-faced, round, film-coated tablets.
The dosing regimen will be once or twice daily based on the prior 
dosing regimen from the parent study. The capsules/tablets are 
packaged in blister packs; the capsule blister packs are also within an 
aluminum foil pouch. The tirabrutinib tablets are also packaged in 
white, high density polyethylene (HDPE) bottles.
Reference Therapy, 
Dose, and Mode of 
Administration:
n/a
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  

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Criteria for 
Evaluation:
Safety: The primary endpoint for this study is safety. Safety will be 
evaluated by the incidence and severity of adverse events (AEs) and 
clinical laboratory abnormalities.
Efficacy: Efficacy endpoints are considered secondary and will 
include:

Overall response rate (ORR): defined as the proportion of subjects 
who achieve partial response (PR) or complete response (CR)

Duration of response (DOR): defined as the interval from 
first documentation of CR or PR to the earlier of the first 
documentation of definitive disease progression or death from any 
cause

Progression-free survival (PFS): defined as the interval from date 
of the first dose of tirabrutinib on the parent study to the earlier of 
the first documentation of definitive disease progression or death 
from any cause

Overall survival (OS): defined as the interval from date of the 
first dose of tirabrutinib on the parent study until death from any 
cause.
Pharmacokinetics: The pharmacokinetic (PK) Analysis Set will 
consist of all enrolled subjects who have at least 1 evaluable PK 
sample.
Statistical Methods:
Analysis Methods
The Rollover Study Analysis Set consists of all subjects who are 
enrolled into this study. This analysis set will be used for the 
summary of subject characteristics, disposition, and study drug 
treatment administration.
The Full Analysis Set (FAS) consists of all subjects who are enrolled 
and treated in the parent study. This analysis set will be used for the 
summary of safety and efficacy endpoints. 
Subject characteristics and disposition will be summarized using 
descriptive statistics. In general, continuous variables will be 
summarized by sample size, mean, standard deviation (StD), median, 
minimum, and maximum and categorical variables by counts and 
percentages. Baseline data are defined as the data collected prior to 
dosing on the parent study. 

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Tumor response will be based on investigator assessment. ORR will 
be estimated and its associated 95% confidence interval will be 
calculated using the exact method. All time-to-event endpoints 
(DOR, PFS, and OS) will be analyzed using the Kaplan-Meier 
method. The medians and associated 95% confidence intervals for 
these endpoints will be provided if the medians can be estimated. 
AEs will be summarized by system organ class, high level term, and 
preferred term and by severity and relationship to study treatment. 
Clinical laboratory tests, vital signs, and their changes from baseline 
will be summarized descriptively.
Sample Size
No formal hypothesis testing is planned for this study. The number of 
subjects enrolled will be determined by the number of subjects who
rollover from prior tirabrutinib studies.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
ADME
absorption, distribution, metabolism, elimination
AE
adverse event
ALT
alanine transaminase
AM
morning
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
aPTT
activated partial thromboplastin
AST
aspartate transaminase
AUC
area under the plasma/serum/peripheral mononuclear cell concentration versus time 
curve 
AUC0-last
area under the concentration verses time curve from time 0 to the last quantifiable 
concentrations
AUCinf
area under the concentration versus time curve extrapolated to infinite time, calculated 
as AUC0-last + (Clast/λz)
AUCτ
area under the concentration versus time curve over the dosing interval 
BCRP
breast cancer resistance protein
BSC
best supportive care
BSEP
bile salt export pump
BUN
blood urea nitrogen
C1D1
Cycle 1 Day 1
CBC
complete blood count
CEA
carcinoembryonic antigen
CFR
Code of Federal Regulations 
CI
confidence interval
Clast
last observed quantifiable plasma concentration of drug
CLL
chronic lymphocytic leukemia
CL/F
apparent oral clearance after administration of the drug:
CL/F= Dose/AUCinf
where “dose” is the dose of the drug
Cmax
maximum observed serum/plasma concentration of drug
CMH
Cochran-Mantel-Haenszel
Conmed
concomitant medication
CR
complete response
CrCL
creatinine clearance
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CRP
c-reactive protein

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CSR
clinical study report
CT
computed tomography/ computed axial tomography scan
CTCAE
Common Terminology Criteria for Adverse Events
CYP450
cytochrome P450
DDI
drug-drug interaction
DLT
dose limiting toxicity 
DMC
data monitoring committee
DLBCL
diffuse large B-cell lymphoma
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form(s)
EOT
end of treatment
eSAE
electronic serious adverse event
ET
essential thrombocythemia
EudraCT
European clinical trials database
EU
European Union
FAS
Full Analysis Set
FDA
(United States) Food and Drug Administration
5-FU
5-fluorouracil
FL
follicular lymphoma
GCP
Good Clinical Practice (Guidelines)
GGT
gamma-glutamyl transpeptidase
GLP
Good Laboratory Practice
GSI
Gilead Sciences, Inc.
H
hour
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
IC50
inhibitory concentration 50
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IL
interleukin 
IND
Investigational New Drug
INR
international normalized ratio
IMP
investigational medicinal product
IRB
Institutional Review Board

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ITT
intent-to-treat
IUD
intrauterine device(s)
Kg
kilogram
KM
Kaplan-Meier
KRAS
Kirsten rat sarcoma viral oncogene homolog
LDH
lactate dehydrogenase
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MF
myelofibrosis
µM
micromole
msec
millisecond
MRD
maximum recommended dose
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
N
number enrolled
NOAEL
no observed adverse effect level
NHL
non-Hodgkin’s lymphoma
OAT
organic anion transporter
OCT
organic cation transporter
OS
overall survival
ORR
overall response rate
PD
progressive disease
PE
physical exam
PFS
progression-free survival
P-gp
permeability glycoprotein
PK
pharmacokinetic
PP
per-protocol
PR
partial response
PRO
patient-reported outcome(s)
PT
prothrombin time
PTT
partial thromboplastin time
PV
polycythemia vera
PVE
Pharmacovigilance and Epidemiology
QTc
corrected QT interval
RAF
rapidly accelerated fibrosarcoma
RBC
red blood cell
RECIST
Response Evaluation Criteria In Solid Tumor
RNA
ribonucleic acid
RP2D
recommended phase 2 dose 
SADR
serious adverse drug reaction(s)

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SAE
serious adverse event(s)
SAP
statistical analysis plan
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvate transaminase
SOP
standard operating procedure
STAT
Signal Transducer and Activator of Transcription
StD
standard deviation
SUSAR
suspected unexpected serious adverse reaction(s)
T1/2
an estimate of the terminal elimination half-life of the drug in serum/plasma, calculated 
by dividing the natural log of 2 by the terminal elimination rate constant (z)
Tlast
the time (observed time point) of Clast
Tmax
the time (observed time point) of Cmax
TBK1
TANK-binding kinase 1
TTR
time to response
TYK2
tyrosine kinase 2
ULN
upper limit of normal 
WBC
white blood cell
WM
Waldenstrom’s macroglobulinemia
z
terminal elimination rate constant, estimated by linear regression of the terminal 
elimination phase of the serum, plasma concentration of drug versus time curve

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1.
INTRODUCTION
1.1.
Background
Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of malignancies arising from 
lymphoid tissue, with varied clinical and biological features. In 2008, there were an estimated 
356,000 new cases of NHL and 192,000 deaths from NHL worldwide {Ferlay 2010}. NHL is the 
eighth most commonly diagnosed cancer in men and the 11th in women. Diffuse large B-cell 
lymphoma (DLBCL) is the most common type of NHL accounting for approximately 30% to 
40% of all new patients {Sweetenham 2007}, whereas follicular lymphoma (FL) and mantle cell 
lymphoma (MCL) account for approximately 20% to25% and 6% to10% of new lymphomas, 
respectively {Dreyling 2007}. B-cell chronic lymphocytic leukemia (CLL) is the most common 
of the chronic leukemias in adults with approximately 8500 new cases per year in the 
European Union and the United States (US) {Kristinsson 2009}. Approximately 90% of 
lymphomas are NHL and nearly 95% of NHLs are of B-cell origin; > 90% of CLL is of B-cell 
origin {Morton 2006}. 
B-cell NHL and CLL arise from the accumulation of monoclonal B lymphocytes in lymph nodes 
and often in organs such as blood, bone marrow, spleen, and liver. This group includes 
histopathologic varieties such as FL, MZL, MCL, CLL, small lymphocytic lymphoma (SLL), 
Waldenstrom’s macroglobulinemia (WM), and DLBCL. These disorders are characterized by 
lymphadenopathy, cytopenias, and sometimes induce life-threatening organ dysfunction. Patients 
may also have constitutional symptoms (fevers, night sweats, and/or weight loss) and fatigue 
{Diehl 2004, Dighiero 2008, Salles 2007, Williams 2010}.
Few patients with B-cell malignancies are cured with available therapies. The 3-year 
progression-free survival (PFS) is only 40% with activated B-cell (ABC) DLBCL compared to 
74% with GCB-DLBLC. For patients who are refractory to primary therapy or progress and are 
not transplant candidates, few therapeutic options exist {Roschewski 2014}. For patients with 
the indolent B-cell malignancies, such as iNHL (FL and MZL), MCL, CLL, SLL, and WM, the 
goal of first and subsequent line therapies is to induce tumor regression and delay tumor 
progression in order to control disease-related complications and potentially extend life. Patients 
who require treatment are commonly given chemotherapeutic and/or immunotherapeutic agents 
{Eichhorst 2010, Friedberg 2011, Gribben 2011, Hoppe 2008, Jost 2007, Zelenetz 2011}. 
Although patients with iNHL and CLL can achieve durable remissions with front-line 
combination therapies, most patients will eventually experience disease relapse {Hallek 2010, 
Lenz 2005, Recher 2011, Santoro 1987, Schulz 2007}. Despite use of agents with differing 
mechanisms of action, progressive resistance to treatment develops. {Di Bella 2010, Friedberg 
2011, Goy 2009, Hess 2009, Keating 2002, Moskowitz 2009, Wierda 2010}.

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1.2.
Tirabrutinib
1.2.1.
General Information
Tirabrutinib (also known as GS-4059, ONO/GS-4059, ONO-4059HCL, ONO-1973, and 
ONO-WG-307) is a potent small molecule inhibitor of Bruton’s tyrosine kinase (BTK) that is 
being jointly developed by Gilead Sciences, Inc. (Gilead) and Ono Pharmaceutical Co, Ltd. 
(ONO) for oral administration in the treatment of B-cell malignancies. 
BTK was originally identified in 1993 as a non-receptor intracellular protein tyrosine kinase that 
is defective in the inherited immunodeficiency disease X-linked agammaglobulinaemia (XLA) 
{Tsukada 1993, Vetrie 1993}. XLA is characterized by low levels of immunoglobulin 
production and the absence of peripheral B cells, indicating a specific role for BTK in B-cell 
development and function. BTK is a member of the TEC family of tyrosine protein kinases. BTK 
is primarily expressed in hematopoietic cells, particularly in B cells, but not in plasma cells or 
T cells {de Weers 1993, Genevier 1994, Smith 1994}. BTK is also found in specific cells of the 
myeloid lineage, including monocytes, macrophages, neutrophils, and mast cells, where its 
biological role remains to be fully explored. 
BTK plays a crucial role in the development and activation of B cells through its activation via 
the B-cell receptor (BCR) {Aoki 1994, Hendriks 2014, Honigberg 2010}. Signaling through the 
BCR regulates cellular proliferation and activation and promotes survival, differentiation, and 
clonal expansion of B cells (Figure 1-1) {Rickert 2013}. In addition to BCR signaling, BTK is 
activated by Toll-like receptors (TLR) which contribute to B-cell activation {Jefferies 2003}. 
BTK also plays a critical role in signaling pathways triggered by the C-X-C chemokine receptor 
type 4 and type 5 (CXCR4 and CXCR5) which mediate homing of B cells to lymph nodes and 
bone marrow and control integrin-mediated adhesion and B-cell survival to vascular adhesion 
molecule 1 (VCAM1) and fibronectin {de Rooij 2012, Hendriks 2014}.
Signaling through the BCR has been established as a key oncogenic driver in many B-cell 
malignancies, including (CLL, SLL, ABC-DLBCL, MCL, and WM). A first in class BTK 
inhibitor, ibrutinib (Imbruvica®), has demonstrated clinical benefit to patients with CLL, MCL 
and WM {Pharmacyclics Inc. 2015}. Additionally, transient clinical responses were observed in 
a pilot study of relapsed DLBCL, primarily in the non-GCB subtype {Wilson 2012}. 
Tirabrutinib is an orally administered, potent and selective inhibitor of BTK initially evaluated in 
a Phase 1 single agent dose escalation study, ONO-4059POE001, conducted in the United 
Kingdom (UK) and France. This study is completed and has enrolled and treated 90 subjects 
with relapsed CLL, non-GCB DLBCL, MCL, SLL, and other indolent non-Hodgkin’s 
lymphomas (iNHLs). Tolerability and efficacy were demonstrated in subjects with CLL at doses 
ranging from 40 to 600 mg once daily with no maximum tolerated dose (MTD) identified. 
Responses were observed in subjects in the NHL cohort at doses from 40 to 480 mg. Dose 
limiting toxicities (DLTs) of rash and non-immune reaction were observed at 600 mg once daily 
in the NHL cohort.

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Additional adverse events (AEs) have been observed during Study ONO-4059POE001, 
including: hematological disorders such as neutropenia, anemia, and thrombocytopenia; bleeding 
disorders such as petechiae, purpura, and hemorrhage; pyrexia and concomitant infections; 
gastrointestinal disturbances such as nausea, diarrhea, and abdominal pain; rash and irritation 
such as acne, urticarial, petechial or purpuric rash, dry skin, pruritus, and eye pruritus; asthenia; 
and fatigue. The most commonly reported serious adverse events (SAEs) were infections. Please 
refer to the current edition of the tirabrutinib Investigator’s Brochure (IB) for additional safety
information.
Another BTK inhibitor, ibrutinib, which is approved in the US for CLL, MCL, and WM, has 
identified warnings and precautions for hemorrhagic events, infections, cytopenias, atrial 
fibrillation, second primary malignancies including skin cancers and other carcinomas, tumor 
lysis syndrome, and embryo-fetal toxicity. The most common AEs observed with ibrutinib in 
patients with B-cell malignancies were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, 
musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash. As these 
reported events may be related to target BTK inhibition, clinical trial subjects will be monitored 
for these events

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Figure 1-1.
Inhibition of the BCR Pathway by Tirabrutinib
Adapted from Herrera and Jacobsen (2014) {Herrera 2014}
Chronic Lymphocytic Leukemia
Signaling through BTK plays a key role in the maintenance of CLL as demonstrated by the 
efficacy achieved in CLL by ibrutinib, a first in class BTK inhibitor {Byrd 2014}. In a Phase 3 
trial in relapsed or refractory CLL or SLL, ibrutinib-treated patients experienced a rapid and 
sustained decrease in lymphadenopathy accompanied by lymphocytosis, suggesting that CLL 
cells are mobilized from lymphoid tissue to blood. CLL cells from the blood, bone marrow, and 
lymph nodes of patients treated with ibrutinib show reduced proliferation and expression of 
NF-κB regulated genes and surface activation markers such as CD69 and CD86 {Herman 2014}. 
Ibrutinib (Imbruvica®) is approved in the US for the treatment of CLL in patients who have 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

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received at least one prior therapy and for patients with 17p deletion based on an overall 
response rate (ORR) of 42.6% and improved PFS and overall survival (OS) compared to 
ofatumumab {Pharmacyclics Inc. 2015}. In Study ONO-4059POE001, with a median follow-up 
of 26.4 months, tirabrutinib demonstrated an ORR of 85.7% (n  28); 7 subjects (25.0%) had a 
complete response (CR), and 17 subjects (60.7%) had a partial response (PR). The Kaplan Meier 
(KM) estimate of median duration of response (DOR), median progression-free survival (PFS) 
and median overall survival (OS) was not reached.
Diffuse Large B-Cell Lymphoma
At present there are no approved drugs for relapsed refractory DLBCL in patients who are 
not candidates for high dose combination chemotherapy and stem cell transplant. 
National Comprehensive Cancer Network (NCCN) Guidelines recommend either a clinical trial, 
palliative radiation therapy or 1 of the following options with or without rituximab:
bendamustine, CEPP (cyclophosphamide, etoposide, procarbazine, prednisone), CEOP 
(cyclophosphamide, etoposide, vincristine, prednisone), DA-EPOCH (dose adjusted etoposide, 
prednisone, vincristine, cyclophosphamide, doxorubicin), GDP (gemcitabine, dexamethasone, 
cisplatin), Gem-Ox (gemcitabine, oxaliplatin), or lenalidomide {National Comprehensive Cancer 
Network (NCCN) 2015}. ORRs with these regimens in this patient population range from 28%
to 63%, with median PFS of 3 to 7 months. The activated B-cell (ABC) -DLBCL subtype, 
identified by gene expression profiling has been identified retrospectively as a poor prognostic 
indicator for PFS and OS for patients treated with first line rituximab, cyclophosphamide, 
doxorubicin, vincristine, prednisone (R-CHOP) chemotherapy, although not at the time of 
relapse, when all patients have a poor prognosis {Lenz 2008}. 
ABC-DLBCL cells are dependent on NF-κB signaling for survival and proliferation {Davis 
2010}. The sensitivity of ABC-DLBCL to NF-κB inhibition can be explained by the chronic 
activation of BCR and/or TLR signaling mediated in 50% of cases by activating mutations in 
components of the BCR such as CD79B (18% of ABC-DLBCL) or myeloid differentiation 
primary response 88 (MYD88) (29% of ABC-DLBCL) and caspase recruitment domain family, 
member 11 (CARD11) (10% of ABC-DLBCL). Inhibition of BTK inhibits proliferation and 
induces apoptosis in a subset of ABC-DLBCL; tirabrutinib and ibrutinib have demonstrated 
evidence of short-term efficacy in the relapsed setting in the non-GCB DLBCL subgroup 
(41% ORR [12/29] with ibrutinib and ORR 41% [7/17] with tirabrutinib). Median PFS was short 
with both inhibitors, at approximately 4 months. 
Mantle Cell Lymphoma
MCL is a rare type of B-cell non-Hodgkin’s lymphoma (approximately 6% of NHL) which, at 
presentation, can be indolent or aggressive. Cure is uncommon and there is no standard front-line 
regimen, although common therapies are rituximab, cyclophosphamide, doxorubicin, vincristine, 
dexamethasone (R-HyperCVAD), variations on R-CHOP, rituximab-bendamustine, and the 
Nordic regimen {Geisler 2008}. Consolidation with autologous transplant in first remission may 
prolong PFS. If and when patients relapse, the goal of therapy is similar to the other relapsed 
B cell malignancies; to induce tumor regression and delay tumor progression in order to control 
disease-related complications and potentially extend life. Options at relapse include ibrutinib, 

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bortezomib, rituximab-bendamustine, and lenalidomide. Similar to CLL, a large proportion of 
cells from patients with MCL, harbor a stereotypic BCR repertoire, indicating a crucial role for 
BCR stimulation in this disease {Hadzidimitriou 2011}. In addition, constitutive activation of 
NF-κB and the PI3K pathways is observed in MCL, reflecting chronic activation of BCR, TLR, 
and/or tumor necrosis factor receptors (TNFR) in this disease {Colomer 2014, Jares 2012}. 
Ibrutinib is approved for use in patients with MCL who have received at least 1 prior therapy, 
based on an ORR of 65.8% (complete responses [CR] 17.1%) and median PFS of 13.9 months 
{Wang 2013}. In Study ONO-4059POE001, tirabrutinib demonstrated a similar ORR in a small 
number of subjects; (60% [6/10]). 
Waldenstrom’s Macroglobulinemia
In WM, activating mutations in MYD88 are prevalent (67% to 100% of cases), leading to 
constitutive activation of BTK and NF-κB downstream of TLR {Treon 2012, Yang 2013}. In 
WM cell lines and primary cells, ibrutinib, reduced NF-κB activation and triggered apoptosis. 
Ibrutinib is approved for use in WM with a reported ORR of 61.9% (39/63) without any CRs, 
and duration of response (DOR) ranging from 2.8 to 18.8 months {Pharmacyclics Inc. 2015}. In 
Study ONO-4059POE001, 1 of 2 subjects with WM responded to tirabrutinib.
For further information on tirabrutinib, refer to the current edition of the tirabrutinib IB.
1.2.2.
Tirabrutinib Preclinical Pharmacology and Toxicology
1.2.2.1.
Nonclinical Pharmacology
Primary pharmacology studies in enzyme-based and cell-based systems indicate that tirabrutinib
is a potent inhibitor of BTK. BTK inhibition by tirabrutinib resulted in inhibition of proliferation 
and survival in ABC-DLBCL and MCL-derived cell lines, and in primary cells from CLL 
subjects. 
Tirabrutinib is a potent and selective inhibitor of BTK relative to 3 other non-receptor tyrosine 
kinases which function in B-cell and T-cell activation: human FYN, LCK, and LYNa. The IC50
values of tirabrutinib against recombinant human BTK, FYN, LCK, and LYNa were 2.10, 2220, 
788, and 3490 nM, respectively, demonstrating tirabrutinib to be 1060-, 375-, and 1660-fold 
more selective for BTK relative to FYN, LCK, and LYNa, respectively. Selectivity was also 
demonstrated by evaluating the binding affinity (Kd) of tirabrutinib for BTK, BLK, BMX, CSK, 
ERBB2, HUNK, LCK, MAP2K5, RIPK2, TEC, and TXK. tirabrutinib was demonstrated to be
21- to > 3500-fold more selective for BTK than for other kinases that are structurally or 
functionally related, with the exception of similar binding affinity to the tyrosine-protein kinase 
TEC.
Tirabrutinib demonstrated in vitro cellular activity on BTK autophosphorylation in human 
B lymphocytes from peripheral blood monocyte cells and whole blood in ABC-DLBCL-derived 
cell lines. The maximum inhibitory activity and potency of tirabrutinib increased with length of 
exposure and decreased after 24 hours following washout of tirabrutinib from the media. The 
in vitro inhibitory activity of tirabrutinib on 2 ABC-DLBCL lymphoma cell lines, TMD-8 and 
U-2932 demonstrated inhibition of P-BTK in a dose dependent manner.

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These data collectively demonstrate that tirabrutinib is a potent inhibitor of BTK tyrosine kinase 
activity in primary human B lymphocytes from peripheral blood mononuclear cells and in 
ABC-DLBCL-derived cell lines.
For further information on tirabrutinib, refer to the current edition of the IB.
1.2.2.2.
Absorption, Distribution, Metabolism and Elimination (ADME)
The bioavailability of tirabrutinib was 15.5% following a single oral administration of 
tirabrutinib at 5 mg/kg to fasted male rats. Following repeated oral daily administration of 
tirabrutinib for 28 days to non-fasted male rats, the maximum observed concentration (Cmax) and 
area under the concentration-time curve from time 0 to 24 h (AUC24h) increased proportionally 
with doses ranging from 3 to 100 mg/kg/day. There was no obvious accumulation of tirabrutinib
after 28 days repeated dosing. 
Following a single oral administration of [14C]-ONO-4059HCL at 5 mg/kg to fasted male rats, 
the radioactivity concentrations in several tissues were 2.1 to 26 fold that found in plasma at 
0.5 h post-dose with radioactivity concentrations decreasing in all tissues to 7.0% of Cmax or 
lower by 168 h post-dose. The elimination half-life (t1/2) of the radioactivity in the eyeball in 
pigmented rats (130 h) was longer than that in albino rats (79 h), suggesting that tirabrutinib or 
its metabolites binds to melanin. The primary binding protein of tirabrutinib in human serum is 
albumin; protein binding of [14C]-ONO-4059HCL at 0.5μg/mL in rat, monkey, and human serum 
was 98.2%, 90.7%, and 92.3%, respectively. 
Species differences were observed in the main metabolites in in vitro metabolism analysis; 
however, all metabolite peaks detected in cultured human hepatocytes were also detected in 
cultured hepatocytes of rat or monkey. The primary cytochrome P450 (CYP) iso-form 
responsible for tirabrutinib metabolism is CYP3A4/5, but CYP2D6 also metabolizes tirabrutinib
though to a lesser degree. Tirabrutinib is not a CYP inducer. Tirabrutinib inhibited CYP2C8, 
2C9 and 2C19, the respective inhibition constant (Ki) values were 7.02, 8.31, and 14.4μmol/L. 
Tirabrutinib resulted in mechanism based inhibition of CYP3A4/5 at 10μmol/L. Tirabrutinib is a 
P-glycoprotein (P-gp) substrate, whereas tirabrutinib inhibited human P-gp with an IC50 value of 
26.8μmol/L. In addition, tirabrutinib showed inhibitory potential for several other transporters 
including OAT3, OATP1B1, MATE1, OCT1, and OCT2.
Refer to the tirabrutinib IB for additional information.
1.2.2.3.
Nonclinical Toxicology
In the single dose toxicity studies in rats and monkeys, doses of tirabrutinib ranged from 1 to 
2000 mg/kg and 1 to 1000 mg/kg, respectively. The lethal dose was 2000 mg/kg in rats and 
1000 mg/kg in monkeys. In the 4-week repeated oral dose toxicity studies, 8/44 mortalities at
1000 mg/kg/day were observed in rats. These 8 rats showed spontaneous activity decrease along 
with bradypnea, stool volume decrease, lacrimation and a severe body weight decrease. At 
100 mg/kg/day in monkey, one animal was moribund. This single monkey exhibited 
somnolence, ataxia and prone position before showing moribund condition. The primary target 
organs of tirabrutinib were pancreas islets at doses of 10 mg/kg/day or higher in rats and CNS 

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effects at 100 mg/kg/day in monkeys. In the 4-week repeated oral dose toxicity study in rats, 
fibrosis of the centre/periphery of the pancreatic islets was observed at doses at 10 mg/kg/day or 
higher as well as eosinophilic changes and hypertrophy of the hepatocytes, hypertrophy of the
zona fasciculate and glomerulosa cells accompanied with an increase in lipid in the adrenal at 
doses 100 mg/kg/day or higher.
In the 4-week repeated oral dose toxicity study in monkeys, Berlin blue staining positive
pigment-laden macrophages in the medullary sinus were observed at 3 mg/kg/day or higher as 
well as angiectasis and/or haemorrhage in pancreatic islets and lobules at 10 mg/kg/day or 
higher. Surviving animals at 100 mg/kg/day showed CNS effects which were weaker than that of 
moribund animal. The no observed-adverse-effect-levels (NOAEL) in rats and monkeys are 
estimated to be 3 mg/kg/day and less than 3 mg/kg/day, respectively. The severe toxic dose in 
10% (STD 10) in rats and the highest non-severe toxic dose (HNSTD) in monkeys were 
determined to be 600 mg/kg/day and 30 mg/kg/day, respectively.
A more detailed summary of findings from studies in rats and dogs is available in the IB for 
tirabrutinib.
1.2.3.
Clinical Trials of Tirabrutinib
As of 1 October 2017, 6 clinical studies of tirabrutinib are ongoing.
Updated clinical information regarding completed and ongoing clinical studies may be found in 
the tirabrutinib IB.
1.3.
Rationale for This Study
Based on the analysis of Study ONO-4059POE001, subjects obtained a clinical benefit from 
treatment with tirabrutinib as demonstrated by response rate. As of the completion of the study, 
86% of CLL subjects and 39% of NHL subjects demonstrated an objective response.
Tirabrutinib appears to have been well tolerated overall and with prolonged administration in 
Study ONO-4059POE001. 
1.4.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.

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2.
OBJECTIVES
The primary objective of this study is:

To determine the long-term safety and tolerability of tirabrutinib in subjects in a prior 
tirabrutinib study and whose disease had not progressed on the parent study 
The secondary objective of this study is: 

To determine the long term efficacy of tirabrutinib

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3.
STUDY DESIGN
3.1.
Endpoints
The endpoints of this study are described in Section 8.
3.2.
Study Design
This study is an open-label rollover study for subjects who have tolerated and achieved stable 
disease or improved with tirabrutinib treatment while enrolled in a prior tirabrutinib study.
3.3.
Study Treatments
Subjects who meet eligibility criteria will receive a single dose of tirabrutinib on Study Day 1 
(Cycle 1, Day 1). Each cycle will consist of 28 days of therapy. If there is no evidence of disease
progression by clinical assessment or by CT (or MRI), a subject may continue receiving 
tirabrutinib until disease progression (clinical or radiographic), unacceptable toxicity, withdrawal
of consent, or other reasons specified in Section 3.5.
In subjects who have a tumor flare after the discontinuation of therapy or are at a high risk of 
such an event, treatment may be reinstituted or continued following progression until initiation of 
subsequent therapy.
3.4.
Duration of Treatment
Subjects will continue on tirabrutinib for a maximum duration of 5 years from the start of this 
study. After discontinuation of treatment, subjects will be followed for safety for 30 days.
3.5.
Criteria for Discontinuation of Study Drug
Study medication may be discontinued in the following instances:

Documented progression of malignant disease

Pregnancy

Investigator discretion

Non-compliance with study drug

Initiation of other anti-cancer or experimental therapy

Protocol violation

Withdrawal of consent

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
Lost to follow-up

Study termination by the sponsor

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Unacceptable toxicity, as defined in the toxicity management section of the protocol 
(Section 7.6), or toxicity that, in the judgment of the investigator, compromises the ability to 
continue study-specific procedures or is considered to not be in the subject’s best interest
3.6.
Source Data
The subject identification numbers assigned by the Sponsor or captured by the interactive 
voice/web response system (IXRS) will be considered source data. 

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
All subjects enrolled in a prior tirabrutinib study who are still alive and have not had disease 
progression may be eligible to participate in this extension study.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Currently enrolled in a prior tirabrutinib study 
2) Did not discontinue treatment with tirabrutinib for any reason other than to enroll in this 
study
3) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at enrollment 
4) Any Grade 3 or 4 non-hematologic toxicity that the investigator considers related to previous 
tirabrutinib use must have resolved, reverted to Grade 1 or reverted to the baseline of the 
prior study prior to Day 1 of this study
5) Negative serum and urine pregnancy test is required for female subjects (unless surgically 
sterile or greater than 2 years post-menopausal)
6) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in
Appendix 8.
7) Lactating females must agree to discontinue nursing before the study drug is administered
8) Ability and agreement to attend protocol-specified visits at the study site
9) Able to comprehend and willing to sign the informed consent form
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Known hypersensitivity to tirabrutinib, the metabolites, or formulation excipient

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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible for the study prior to 
enrollment. Subjects will be assigned a unique screening number at the time of consent.
An interactive web response system (IWRS) will be employed to manage the conduct of the trial. 
The IWRS will be used to maintain a central log documenting screening and enrollment, to
manage dose modifications, to assess current inventories of study drug, to initiate any necessary
resupply of study drug, and to document discontinuation of treatment.
Once eligibility is confirmed subjects will be assigned a unique subject number. This is an 
open-label study.
All baseline tests and procedures must be completed prior to the administration of the first dose 
of tirabrutinib on Day 1. Once a subject number is assigned to a subject, it will not be reassigned 
to another subject.
5.2.
Description and Handling of Tirabrutinib
5.2.1.
Tirabrutinib
5.2.1.1.
Formulation
Tirabrutinib capsules are brown, opaque hard HPMC capsules. Each capsule contains the 
equivalent of 10 mg, 25 mg, or 100 mg tirabrutinib as the hydrochloride salt (GS-4059-01). The 
capsules contain the following inactive ingredients: microcrystalline cellulose, and magnesium 
stearate. Each capsule shell contains carrageenan, potassium chloride, titanium dioxide, red iron 
oxide, and hypromellose.
Tirabrutinib film-coated tablets, 20 mg, contain the equivalent of 20 mg tirabrutinib as the
hydrochloride salt (GS-4059-01). The 10% drug load formulation tablet is a blue, plain-faced,
round, film-coated tablet. The tirabrutinib film-coated tablets, 20 mg, contain the following
inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal
silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol,
talc, and FD&C blue #2/indigo carmine aluminum lake.
Tirabrutinib film-coated tablets, 80 mg, contain the equivalent of 80 mg tirabrutinib as the
hydrochloride salt (GS-4059-01). The 33% drug load formulation tablet is a yellow, plain-faced,
modified capsule-shaped, film-coated tablet. The tirabrutinib film-coated tablets, 80 mg, contain 
the following inactive ingredients: lactose monohydrate, microcrystalline cellulose,
crospovidone, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide,
polyethylene glycol, talc, and iron oxide yellow.

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Tirabrutinib film-coated tablets, 100 mg, contain the equivalent of 100 mg tirabrutinib as the 
hydrochloride salt (GS-4059-01). The 33% drug load formulation tablet is a white, plain-faced, 
round, film-coated tablet. The tirabrutinib film-coated tablets, 100 mg, contain the following 
inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal 
silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, 
and talc.
5.2.1.2.
Packaging and Labeling
Tirabrutinib (ONO/GS-4059) capsules, 10 mg, 25 mg, and 100 mg are packaged in polyvinyl 
chloride (PVC) blisters with aluminum foil lidding and placed within an aluminum foil pouch.
Tirabrutinib (ONO/GS-4059) tablets 20 mg and 100 mg are packaged in blister strips made of 
polyvinyl chloride/ polychlorotrifluoroethylene (Aclar) film and have aluminum foil lidding 
materials that are then placed in a blister card. 
Tirabrutinib (GS-4059) tablets 80 mg and 100 mg are also packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 30 tablets, silica gel desiccant and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child-resistant 
polypropylene screw cap with an induction sealed and aluminum-faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products, Feb. 2010), and/or other local regulations.
5.2.1.3.
Storage and Handling
Tirabrutinib packaged drug product should be stored at controlled room temperature until 
required for administration. Controlled room temperature is defined as 25C (77F); excursions 
are permitted between 15C and 30C (59F to 86F).
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling tirabrutinib.
5.3.
Dosage and Administration of Tirabrutinib
Tirabrutinib capsules/tablets will be provided by Gilead and will be taken orally. Initiation of 
treatment with the study drug will take place after enrollment and cohort assignment. Subjects 
will self-administer tirabrutinib capsules 10 mg, 25 mg, or 100 mg capsules or tirabrutinib tablets 
20 mg, 80 mg or 100 mg orally once or twice daily from prior dosing regimen on parent study.
To reduce variability in drug absorption, subjects will be instructed to take tirabrutinib at least
1 hour before or 2 hours after a meal.

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If the subject misses a dose, he/she should be instructed to take the study drug as soon as he/she 
remembers, unless more than 8 hours has elapsed since the scheduled time of the missed dose. In 
this case, the subject should be instructed to wait and take the next dose at the regularly 
scheduled time. 
5.4.
Prior and Concomitant Medications
In vitro data indicate tirabrutinib is a substrate of CYP3A4. Co-administration of CYP3A4 
inhibitors may increase tirabrutinib exposure. However, preliminary PK data from Study 
GS-US-401-1757 demonstrate that idelalisib, a CYP3A4 inhibitor, does not cause a clinically 
relevant increase in tirabrutinib exposure, indicating tirabrutinib is not a sensitive CYP3A4 
substrate. As such, co-administration of strong CYP3A4 inhibitors is allowed in this study, but 
caution should be exercised. Co-administration of the strong CYP3A4 and P-gp inducer rifampin 
resulted in a significant decrease in tirabrutinib exposure (~70%). As such, potent CYP3A4 and 
P-gp inducers are prohibited while subjects are receiving tirabrutinib and ≥2 weeks prior to 
study drug administration. Examples of strong CYP3A4 and P-gp inducers are provided in the 
Table 5-1. 
In vitro data indicate tirabrutinib has the potential to inhibit several CYPs and transporters. 
Therefore, tirabrutinib may affect the plasma concentrations of their substrates. Caution should 
be exercised when co-administering concomitant medications that are metabolized by CYP3A4/5 
and transported by OAT3, OATP1B1, MATE1, OCT1, OCT2, or P-gp. 
Examples of strong CYP3A4/P-gp inducers are provided in Table 5-1.
Table 5-1.
Examples of Concomitant Medications Prohibited in this Study
Strong
CYP3A4/P-gp Inducer
carbamazepine, phenytoin, rifampin, St. John’s Wort, enzalutamide rifabutin, 
phenobarbital, mitotane, avasimibe
5.5.
Accountability for Tirabrutinib
The investigator is responsible for ensuring adequate accountability of all used and unused IMP.
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
Tirabrutinib accountability records will be provided to each study site to:

Record the date received and quantity of tirabrutinib

Record the date, subject number, subject initials, the tirabrutinib blister number dispensed

Record the date, quantity of used and unused tirabrutinib returned, along with the initials of 
the person recording the information.
The methods of tirabrutinib return and destruction are described in Section 9.1.7.

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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
Procedures performed at a regular follow-up visit on subject’s previous tirabrutinib study may be 
used to fulfill screening criteria and to establish any new medical history on this study.
At Day 1, the starting dose of tirabrutinib capsules/tablets will be identical to the dose 
administered in the prior tirabrutinib study. All subjects will self-administer tirabrutinib
capsules/tablets.
The initial study procedures to be conducted for each subject enrolled in the study are presented
in Figure 6-1.
Figure 6-1.
Initial Study Procedures

Steps 1 through 5 may occur on the same or different days, but must occur sequentially

The maximum amount of time allowed from Step 1 to Step 5 is 30 days 

Results from laboratory assessments and procedures performed up to 30 days prior to Step 5
(eg, results from procedures performed during the previous study or as part of the subject’s 
routine care [if documentation is available] may be utilized for determining eligibility) 
Study visits consisting of clinical, laboratory, and disease assessments will be completed every 
28 days up to Cycle 22, then every 12 weeks. All study required laboratory assessments will be 
performed by a local laboratory and ECG assessments will be performed and interpreted by local 
departments. Following treatment, subjects will be followed for safety and disease status for a 
period of 30 days.
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  

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6.1.
Subject Enrollment and Treatment Assignment
A subject will be considered enrolled once enrolled in IXRS. It is the responsibility of the 
investigator to ensure that each subject is eligible for the study before enrollment. Details 
regarding treatment assignment and dosing are provided in Section 5.3.
6.2.
Description of Study Procedures 
During the treatment period, all visits may be performed within the specified window for that 
study visit (see Appendix 2).
6.2.1.
Written Informed Consent
All subjects must personally sign and date the institutional review board / independent ethics 
committee (IRB/IEC) approved informed consent form before any study procedures are 
performed (Section 9.1.3).
6.2.2.
Recording Medical History
Medical history from the previous study will not be reported in the electronic case report form 
(eCRF) for this study. Any ongoing AE from the previous study at the time of enrollment in this 
study will be considered medical history on this study and should be reported in the eCRFs and 
followed to resolution.
6.2.3.
Medication History
A current list of ongoing medications will be obtained prior to enrollment and recorded on the 
eCRF.
6.2.4.
Physical Examination
The Investigator or qualified designee will perform a physical examination at Screening and time 
points outlined in the Study Procedures Tables (Appendix 2). Screening and End of Treatment 
will be a complete physical examination. Beginning at Cycle 1 Day 1, a modified physical 
examination will be a performed to monitor for any changes (eg, lymph nodes, lung, cardiac, 
abdomen, skin, neurologic, and any systems, as clinically indicated). Abnormal findings prior to 
first dose of study treatment will be reported on the medical history page of the eCRF. Any 
changes from the prior to first dose of study treatment baseline physical examination which 
represent a clinically significant deterioration will be documented on the AE page of the eCRF.
Weight (without shoes) should be measured with each physical examination.
Height (without shoes) should be measured at Screening only.
6.2.5.
Vital Signs
Vital signs will include pulse, systolic and diastolic blood pressure, and body temperature. They 
should be collected per institutional guidelines.

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6.2.6.
Electrocardiogram
Twelve (12) lead ECGs will be obtained at the time points outlined in the Study Procedures 
Tables (Appendix 2). Subjects should be resting quietly for 5 minutes prior to ECG collection.
The Investigator or qualified designee will review all ECGs. The ECG tracings will be 
maintained in the source documentation of each subject and the appropriate data reported on the 
eCRF. 
6.2.7.
Laboratory Assessments
All samples collected in this study for laboratory assessments will be sent to local laboratories
with the exception of urine pregnancy test which may be completed at the site. Screening 
laboratory samples should be obtained within 30 days prior to the first dose of tirabrutinib taken 
on this study.
The local laboratory will be responsible for chemistry, CBC, coagulation, urinalysis, and serum 
pregnancy testing per Table 6-1. Any samples collected per the Schedule of Assessments 
(Appendix 2) may be analyzed for any tests necessary to ensure subject safety. The date and time 
of sample collection will be reported to the local laboratory.
Table 6-1.
Analytes
Chemistry
Urinalysis
Hematology and Coagulation
Other Analytes
Albumin
Alkaline phosphatase
ALT
AST
Amylase
Bicarbonate
BUN
Calcium
Chloride
Creatininea
GGT
Glucose
LDH
Lipase
Magnesium
Phosphorus
Potassium
Sodium
Total bilirubin
Direct bilirubin
Total protein
Uric acid
Color and appearance
Specific gravity
pH
Occult blood
Protein
Glucose
Bilirubin
Leukocyte esterase
Ketones
Nitrite
Urobilinogen
Microscopicc
Urine beta hCGb
Hematology
RBC
Hemoglobin
Hematocrit
Platelets
WBC
Differential
Neutrophils
Bands
Eosinophils
Basophils
Lymphocytes
Monocytes
% blasts
ANC
Coagulation
PT (INR)
PTT
Serum beta hCGb
Total IgA, IgG, IgM 
Immunoglobulin 
electrophoresis
ALT  alanine aminotransferase; AST  aspartate aminotransferase; BUN  blood urea nitrogen; 
GGT
gamma glutamyl transpeptidase; LDH  lactate dehydrogenase; PT  prothrombin time; 
PTT
partial thromboplastin time; RBC  red blood cell; WBC  white blood cell; hCG human chorionic gonadotropin
Note: Additional components, abnormal, and/or atypical cells will also be reported if present
a
Estimated creatinine clearance/glomerular filtration rate will be calculated based on the Cockroft Gault formula
b
If applicable, serum and urine pregnancy test should be obtained
c
Reflex testing based on other abnormalities

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6.2.8.
Pharmacokinetic Samples
Plasma samples for pharmacokinetics (PK) will be collected pre-dose (Cycles 2 and 3 only) and 
concentrations of tirabrutinib will be determined. Plasma concentrations of tirabrutinib
metabolites may be determined.
6.2.9.
Bone Marrow Examination
Bone marrow examination (core biopsy and/or aspirate as per local standard of care) will be 
performed for follow-up only (for both NHL and CLL subjects) if previously positive and/or to 
confirm CR, if physical examination and CT-scans demonstrate a CR.
6.2.10.
Treatment Response Assessment 
The determination of disease response and progression will be based on standardized criteria 
{Cheson 2007, Hallek 2008, Owen 2013}. During the course of the study, investigators will 
periodically assess the status of each subject’s disease. Treatment decisions by the investigator in 
this study will be based on these assessments. All relevant radiographic and clinical information 
required to make each tumor status assessment must be made available for source verification.
6.2.11.
ECOG Performance Status
The Eastern Cooperative Oncology Group (ECOG) performance status is an investigator 
assessment of the impact of the disease on the subject’s activities of daily living. ECOG will be 
scored using the scale index in Appendix 6.
6.2.12.
Tumor Imaging (CT)
CT with contrast or MRI (for subjects who cannot tolerate CT contrast) will be obtained to 
document disease, in accordance with the NHL and CLL response assessment guidelines 
{Cheson 1999, Hallek 2008}. If not performed in the previous 90 days prior to Cycle Day 1 on 
this study, imaging of the neck, chest, abdomen and pelvis by CT scan with contrast or MRI will 
be performed between C1D1 and C1D28, and at approximately week 12 and then every 
24 weeks. The timing of all scan should be regardless of cycle number or dose interruption.
Scans taken as part of procedures performed at a regular follow-up visit on subject’s previous 
tirabrutinib study may be used to fulfill the screening criteria up to 90 days prior to first dose of 
tirabrutinib. During the treatment, scans may be performed at time points other than specified, as 
clinically indicated to assess tumor progression. For subjects who stop study treatment in the 
absence of disease progression (eg, experienced unexpected toxicity), scans should continue to 
be collected approximately every 24 weeks until disease progression or initiation of systemic 
anti-tumor therapy other than the study treatment (whichever is earlier). Assessment of 
progression will be as determined by the investigator.

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As this is an extension protocol from ONOPOE00l [EudraCT Number: 2011-005033-39], the 
same imaging procedure and specifications ( eg, contrast agent, scaimer, slice thickness, etc.) 
used to define measurable target and non-target lesions from the time of initiation of treatment 
should be used throughout the study for each subject. 
CT scans may not be perfonned at sites or in countries where additional radiology approval is 
required, unless that approval is sought and granted. 
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Unscheduled visits 
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Unscheduled procedures, including, but not limited to, vital signs, 12-lead ECG, and CT or MRI, 
will be recorded on the applicable eCRFs. 
6.5. 
Assessments for Premature Discontinuation from Study 
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perfonn the required study-related 
follow-up and procedures (see Section 3.5, Criteria for Discontinuation of Study Drug). If this is 
not possible or acceptable to the subject or investigator, the subject may be withdrawn from the 
study. 
6.6. 
End of Study 
End of study for a subject is defined as the date of the last study-related procedures or the date of 
death for an on-study subject or when a subject has reached the end of the study duration. 
See Section 9.3.4. 
Subjects will be contacted by phone 30 days ( ± 7 days) after the last dose of tirabrutinib to assess 
for AEs. For subjects who come off study for reasons other than disease progression, the site 
should also obtain infonn ation post-study anti-cancer therapies, surgeries, and date of definitive 
disease progression (if known). 
All treatment-emergent AEs and laboratory abnonnalities present at the end of study are to be 
followed until resolution or the event is detennined to be irreversible by the investigator. 
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6.7
Tirabrutinib Dose interruption and adjustment
The following are the guidelines for tirabrutinib dose interruption. 
Interruption of tirabrutinib administration of up to 28 days will be acceptable to allow for any 
reversal of toxicity. If the toxicity does not resolve to CTC Grade ≤ 2 or to baseline within 
2 weeks, tirabrutinib will be permanently discontinued. Additionally, tirabrutinib should be 
permanently discontinued if any Grade 4 study drug- related adverse event is observed. No dose 
reductions will be allowed.
If, in the opinion of the investigator, a subject who has been tolerating therapy well demonstrates 
a loss of clinical response, the dose of tirabrutinib may be increased to the MTD (600 mg for 
CLL and 480 mg for NHL). To be considered for a dose increase, the subject must not ever have
had a previous dose reduction of tirabrutinib due to a drug related adverse event or any Grade 3 
or higher drug related adverse event. It must be noted, that no data is available to inform whether 
a higher dose of tirabrutinib will overcome resistance to tirabrutinib and therefore an increased 
dose is allowed if thought to be in the best interest of the patient by the investigator, but not 
recommended.

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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an AE and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
first dose of study drug on the previous study, are considered medical history. If they 
occurred during the previous study, prior to the first dose of tirabrutinib on this study, but 
have not resolved, they are considered medical history on this study

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.2.1.
Protocol-Specific Serious Adverse Event Instructions
Protocol-specific SAEs, in this study, is to be considered medically important and therefore 
“serious.” To maintain the integrity of the study, the following events that are assessed as 
unrelated to IMP will not be considered as SAEs:

Progression of malignancy being studied

Death due to malignancy being studied
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the study drugs caused or contributed to the disease 
progression (ie, by a means other than lack of effect). Unrelated disease progression and death 
should be captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.

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7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the IMP. For SAEs, an alternative 
causality must be provided (eg, pre-existing condition, underlying disease, intercurrent 
illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE occurred as a result of protocol procedures (eg, venipuncture).
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the CTCAE Version 4.03. For each episode, the highest 
severity grade attained should be reported.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on eCRF: all SAEs and AEs related to protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. Gilead may 
request that certain AEs be followed beyond the protocol defined follow up period.

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All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the infonned consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead Phannacovigilance and Epidemiology (PYE) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures perfonned after infonned 
consent is signed. 
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period. 
However, if the investigator learns of any SAEs that occur after study participation has 
concluded and the event is deemed relevant to the use of IMP, he/she should promptly docmnent 
and report the event to Gilead PYE. 
• 
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Electronic Serious Adverse Event ( eSAE) Reporting Process 
• 
Site perso1mel record all SAE data in the eCRF database and from there transmit the SAE 
infonnation to Gilead PYE within 24 hours of the investigator's knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infonnation electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious AE reporting fonn and 
submit within 24 hours to: 
Gilead PVE 
Fax: 
E-mail: 
IPIPD 
IPIPD 
• 
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been reported via a paper fonn because the eCRF database has been locked, 
no further action is necessary. 
• 
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a docmnent to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
reports. 
• 
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject's eCRF and the event description section of the SAE fonn. 
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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the tirabrutinib IB. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (eg, clinical chemistry, hematology, and urinalysis) that require medical or surgical 
intervention or lead to tirabrutinib interruption or discontinuation must be recorded as an AE, as 
well as an SAE, if applicable. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (ie, anemia) not the laboratory result (ie, decreased hemoglobin).
Severity should be recorded and graded according to the CTCAE Version 4.03.
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
7.6.
Toxicity Management 
Dosing requirements for certain toxicities are specified in Section 5.3. The investigator may 
contact the medical monitor to review toxicities that are not directly discussed in the protocol. 
Laboratory abnormalities identified at Screening/Baseline and during study participation should 
be treated at the investigator’s discretion.

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7.6.1.
Warnings and Precautions
7.6.1.1.
Hemorrhage
Bleeding events have occurred in subjects with relapsed/refractory CLL and relapsed/refractory 
NHL who received tirabrutinib as monotherapy. These include minor hemorrhagic events such as 
contusion, hematoma, purpura, and petechiae, and major hemorrhagic events such as small 
intestinal hemorrhage and subdural hematoma. Subjects should be monitored for signs of 
bleeding and treated appropriately. Consider interrupting treatment with tirabrutinib for up to 
7 days prior to surgery or other interventions associated with a significant risk of bleeding and 
resuming treatment once hemostasis is achieved.
7.6.1.2.
Infections 
Infections, some with fatal outcome, have occurred in subjects with CLL and NHL who received 
tirabrutinib as monotherapy. Monitor subjects for fever and infections and treat appropriately.
7.6.1.3.
Hypersensitivity Reaction 
Hypersensitivity reactions (including an allergic reaction) have been observed in a small number 
of subjects who received tirabrutinib. If a subject experiences a hypersensitivity reaction, 
consider interruption or discontinuation of tirabrutinib.
7.6.1.4.
Embryo-Fetal Toxicity
Based on findings in animals, tirabrutinib may cause fetal harm when administered to a pregnant 
woman. Reproductive failure and embryo-fetal toxicity have been observed in rats and rabbits. In 
rabbits, post-implantation loss was observed at systemic exposures approximately 63 times 
greater than the expected exposure in rheumatoid arthritis (RA) subjects receiving 20 mg 
tirabrutinib once daily and approximately 4 times the mean exposure in CLL subjects receiving 
320 mg tirabrutinib once daily.
Women of childbearing potential should be advised of the risk of fetal harm during exposure to 
tirabrutinib. They should use highly effective contraception and have pregnancy testing during 
exposure to tirabrutinib. Women of childbearing potential should be advised to contact their 
physician immediately if they become pregnant or suspect they may be pregnant.
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of AEs associated with product complaints, and pregnancy reports regardless of an associated 
AE. 
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.

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Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead PVE using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead PVE.

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Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to or Gilead PVE using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead PVE.
Gilead PVE contact information is as follows: Fax number 
 or 
email
Refer to Appendix 8 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to the eCRF completion guidelines for full instructions on the mechanism of special 
situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
PPD
PPD

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is to determine the long-term safety and tolerability of 
tirabrutinib in subjects who received tirabrutinib in the prior tirabrutinib study and whose disease 
had not progressed on the parent study.
The secondary objective of this study is to determine the long-term efficacy of tirabrutinib.
8.1.2.
Primary Endpoint
The primary endpoint is safety. Safety will be evaluated by the incidence and severity of AEs
and clinical laboratory abnormalities, as defined by Common Terminology Criteria for 
CTCAE v4.03.
8.1.3.
Secondary Endpoint
Secondary endpoints will include:

ORR: defined as the proportion of subjects who achieve PR or CR

DOR: defined as the interval from first documentation of CR or PR to the earlier of the 
first documentation of definitive disease progression as assessed by the investigator, or death 
from any cause

PFS: defined as the interval from date of the first dose of tirabrutinib on the parent study to 
the earlier of the first documentation of definitive disease progression as assessed by the 
investigator, or death from any cause

OS: defined as the interval from date of the first dose of tirabrutinib on the parent study until 
death from any cause.
8.2.
Analysis Sets
8.2.1.
Rollover Analysis Set
The Rollover Study Analysis Set consists of all subjects who are enrolled into this study. This 
analysis set will be used for the summary of subject characteristics, disposition, and study drug 
treatment administration.

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The Full Analysis Set consists of all subjects who are enrolled and treated in the parent study. 
This analysis set will be used for the smmnary of safety and efficacy endpoints. 
8.2.3. 
Pharmacokinetics Analysis Set 
The Phannacokinetic Analysis Set consists of all enrolled subjects who have at least 1 evaluable 
PK sample. 
-
8.3. 
Data Handling Conventions 
By-subject listings will be created for important variables from each eCRF module. Summary 
tables for continuous variables will contain the following statistics: N (nmnber in population), 
n (number with data), mean, standard deviation, 95% confidence intervals (Cls) on the mean, 
median, minimum, and maximum. Smmnary tables for categorical variables will include: N, n, 
percentage, and 95% Cls on the percentage. Unless otherwise indicated, 95% Cls for binary 
variables will be calculated using the binomial distribution ( exact method). Data will be 
described and summarized by phase and dose level, analysis set, and time point. As appropriate, 
changes from baseline to each subsequent time point will be described and summarized. 
Graphical techniques (eg, waterfall plots, Kaplan-Meier curves, line plots) may be used when 
such methods are appropriate and infonnative. 
The baseline value used in each analysis will be the last (most recent) pre-treatment value on the 
parent study. Data from all sites will be pooled for all analyses. Analyses will be based upon the 
observed data unless methods for handling missing data are specified. If there is a significant 
degree of non-normality, analyses may be perfonned on log-transfonned data or nonparametric 
tests may be applied, as appropriate. 
8.4. 
Subject Disposition 
The nmnber and percentage of subjects who received study drug, completed each parent study, 
entered this study and discontinued from this study will be smmnarized. A smmnary of the 
reasons of the discontinuation from the study treatment will be provided separately for each 
study. 
8.5. 
Subject Characteristics 
Demographic and baseline measurements will be captured from parent study and smmnarized 
using standard descriptive methods. Demographic smmnaries will include sex, race/ethnicity, 
and age. Baseline data will include a smmnary of baseline ECOG perfonnance status and 
selected patient and disease characteristics. 
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8.6.
Efficacy Analysis
Subjects’ efficacy data will be integrated with the parent study. The efficacy analysis will be 
based on full analysis set defined based on the parent study. 
Tumor response will be based on investigator assessment. ORR will be estimated and its 
associated 95% confidence interval will be calculated using the exact method. Subjects who do 
not have sufficient baseline or on study tumor assessment to characterize response will be 
counted as non-responders.
DOR, PFS, and OS will be analyzed using Kaplan-Meier (KM) methods. The median will be 
provided along with the corresponding 95% CI. Additionally, the 25% and 75% percentiles for 
these endpoints will also be provided.
The data for DOR and PFS will be censored on the date of the last available disease assessment 
for subjects who are not known to have relapsed or died by the end of the study follow-up. The 
data for OS will be censored on the date of last known alive for subjects who are not known to 
have died by the end of the study follow-up.
8.7.
Safety Analysis
All safety data collected on or after the date tirabrutinib was first dispensed up to the date of 
last dose of tirabrutinib will be summarized by patient cohort and dose levels. 
8.7.1.
Extent of Exposure and Compliance
Descriptive information will be provided by phase and dose level regarding the number of doses 
of study treatment prescribed, the total number of doses taken, duration of treatment, and the 
number and timing of prescribed dose reductions and interruptions.
Tirabrutinib compliance will be described in terms of the proportion of study treatment actually 
taken based on returned pill count relative to the amount that was dispensed (taking into account 
physician-prescribed reductions and interruptions).
8.7.2.
Adverse Events
All AEs will be listed. The focus of AE summarization will be on treatment-emergent AEs. 
A treatment-emergent AE is defined as an AE that occurs or worsens in the period from the 
first dose of study treatment in the parent study to 30 days after the last dose of study treatment
in the rollover study.
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA)
(http://www.meddramsso.com) with descriptions by System Organ Class (SOC), High-Level 
Group Term (HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term
(LLT). The severity of AEs will be graded by the investigator according to the CTCAE,
Version 4.03, whenever possible. If a CTCAE criterion does not exist for a specific type of AE, 
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the maximum intensity of the AE: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the AE to the study treatment
will be categorized as related or unrelated.
Treatment-emergent AEs will be summarized by cohort. Summary tables will be presented to 
show the number of subjects reporting treatment-emergent AEs by severity grade and 
corresponding percentages. A subject who reports multiple treatment-emergent AEs within the 
same PT (or SOC) is counted only once for that PT (or SOC) using the worst severity grade. AE
descriptions will be presented in alphabetical order of System Organ Class, then by decreasing 
frequency in the “overall” column for a given Preferred Term. Separate listings and summaries 
will be prepared for the following types of treatment emergent AEs:

Study-drug-related AEs

AEs that are Grade ≥ 3 in severity

AEs leading to study treatment interruption and/or dose modification

AEs leading to study treatment discontinuation

SAEs
8.7.3.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data 
and will be reported using conventional units. The focus of laboratory data summarization will 
be on treatment-emergent laboratory abnormalities. A treatment emergent laboratory abnormality 
is defined as an abnormality that, compared to baseline, worsens by ≥1 grade in the period from 
the first dose of study treatment on the parent study to 30 days after the last dose of study 
treatment on the rollover study. If baseline data are missing, then any graded abnormality 
(ie, an abnormality that is Grade ≥in severity) will be considered treatment emergent. 
Laboratory abnormalities that occur before the first dose of study treatment or > 30 days after the 
last dose of study treatment will be included in data listings.
Hematological, serum biochemistry, and urine data will be programmatically graded according 
to CTCAE severity grade, when applicable. For parameters for which a CTCAE grade does not 
exist, reference ranges from the local laboratory will be used to determine programmatically if a 
laboratory parameter is below, within, or above the normal range for the subject’s age, sex, etc.
Hematological and serum biochemistry and their changes from baseline will be summarized. 
Summary tables will be presented for each relevant assay to show the number of subjects by 
CTCAE severity grade with corresponding percentages. For parameters for which a CTCAE 
grade does not exist, the frequency of subjects with values below, within, and above the normal 
ranges will be summarized. Subjects will be characterized only once for a given assay, based on 
their worst severity grade observed during a period of interest (eg, during the study or from 
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Shift tables for hematology and serum biochemistry will also be presented by showing change in 
CTCAE severity grade from baseline to each visit. For parameters for which a CTCAE grade 
does not exist, shift tables will be presented showing change in results from baseline 
(nonnal, low and high [ or abnonnal] to each visit (nonnal, low and high [ or abnonnal]). Tables 
will be prepared to show frequencies adjusted for baseline values; for this frequency, subjects 
with the same or worse toxicity grade at baseline are not considered. 
8.8. 
Pharmacokinetic Analysis 
The concentration of tirabrutinib and, if applicable, metabolite(s) will be summarized by nominal 
sampling time using descriptive statistics. Population PK and exposure-response may be 
explored. 
8.10. 
Sample Size 
No fonnal hypothesis testing is plaimed for this study. The number of subjects enrolled will be 
detennined by the nmnber of subjects who completed a prior tirabrutinib study .. 
8.11. 
Data Monitoring Committee 
A Data Monitoring Co1mnittee will not be used in this study. 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/EC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB or IEC-approved consent form for documenting 

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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or 
local requirements. The consent form will inform subjects about genomic testing and sample 
retention, and their right to receive clinically relevant genomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The 
investigator must keep a screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. Subject data will be processed in accordance 
with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the IMP, and any other study information, remain the 
sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator 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. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, and 
governmental approval with correspondence, informed consent, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

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
Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all AEs and other safety parameters (start and end date, and including causality 
and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in the 
audit trail of the system. Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that 

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the forms have been reviewed, and that the entries accurately reflect the information in the 
source documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (eg, data entry 
error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy of
the data entered by that site. This archive must be stored in accordance with the records retention 
requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB or IEC 
in accordance with local requirements and receive documented IRB or IEC approval before 
modifications can be implemented.

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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:the results of the study 
in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, 
manuscript, or presentation form or the study has been completed at all study sites for at least 
2 years.
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.

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9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.

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10.
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Definitions of Response for Waldenstrom’s Macroglobulinemia
Appendix 4.
Modified International Workshop on Chronic Lymphocytic Lymphoma Leukemia 
(IWCLL) Criteria for Response Assessment
Appendix 5.
Follicular Lymphoma, Marginal Zone Lymphoma, and Small Lymphocytic 
Lymphoma Response Assessment
Appendix 6.
ECOG status
Appendix 7.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements

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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
An Open-label Study to Assess the Long-term Safety and Efficacy of Tirabrutinib 
(ONO/GS-4059) in Subjects with Relapsed/Refractory B-cell Malignancies 
GS-US-401-1787, Protocol Amendment 5, 29 October 2019 
This protocol has been approved by Gilead Scie ce,sJ ncJbe_folJo:wj niu;j1VJature_documents 
this a 
roval. 
Name (Printed) 
Author 
Date 
' 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 62 
29 October 2019 

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Appendix 2.
Study Procedures Table
Study Phase
Screening/
Enrollmenta
C1D1 a
(Baseline)
Day 1 of Each Cycle 
up to and including 
Cycle 22 (28 days)
Every 12 weeks 
starting with Cycle 
22 until EOT
60 Month Visit/
EOT/Early 
Withdrawal
30-Day Safety 
Follow-up Visit
Window (Days)
- 30
± 3
± 7
± 14
± 7
Informed Consent
X
General and Safety Assessments
Medication History
X
Physical Examinationb
X
X
X
X
X
Vital Signs
X
X
X
X
X
12-lead ECG
X
X
AE/Concomitant Medication
X
X
X
X
X
X
Disease Assessments
Response Assessment
X
X
X
X
X
ECOG
X
X
X
X
X
CT scan (neck, chest, 
abdomen, Pelvis) & Tumor 
Measurementsc
X
Xc
X
Bone Marrow Examinationd
X
Xd
X
Laboratory Assessments
Serum / Urine Pregnancy 
Teste
X
X
X
X
Chemistry
X
X
X
X
X
CBC and Differential
X
X
X
X
X
Coagulation
X
X

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Study Phase
Screening/
Enrollmenta
C1D1 a
(Baseline)
Day 1 of Each Cycle 
up to and including 
Cycle 22 (28 days)
Every 12 weeks 
starting with Cycle 
22 until EOT
60 Month Visit/
EOT/Early 
Withdrawal
30-Day Safety 
Follow-up Visit
Window (Days)
- 30
± 3
± 7
± 14
± 7
Total IgA, IgG, IgM 
Immunoglobulin 
electrophoresis
X
Xf
X
Urinalysis 
X
Xf
X
X
Sparse PKg
Xg
Investigational Product
Tirabrutinib Accountability 
and Dispensing 
Xh
X
X
X
Xi
a
Results from laboratory assessments and procedures performed up to 30 days prior may be utilized to determine eligibility and serve as study baseline
b
A complete physical examination will be performed at Screening and End of Treatment visit. Starting C1D1 a modified physical examination may be performed
c
For subjects who have not had tumor imaging in the 90 days prior to C1D1, a scan should be performed at baseline (between day 1 and day 28), at approximately 12 weeks
and then every 24 weeks (± 2 weeks). For subjects who have undergone tumor imaging within 90 days prior to C1D1, scan should be performed at approximately 12 weeks 
then every 24 weeks (± 2 weeks)
d
To confirm clinical response if physical exam and CT scan demonstrate possible CR
e
Pregnancy testing only in women per Appendix 8
f
Total IgA, IgG, IgM Immunoglobulin electrophoresis and Urinalysis every 3 cycles
g
PK samples collected pre dose on C2D1 and C3D1 only
h
Dispensing only
i
Accountability only
CCI

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Appendix 3.
Definitions of Response for Waldenstrom’s Macroglobulinemia

Complete response (CR): Absence of serum monoclonal IgM protein by immunofixation, 
Normal serum IgM level and complete resolution of extramedullary disease, i.e., 
lymphadenopathy and splenomegaly if present at baseline. Morphologically normal bone 
marrow aspirate and trephine biopsy.

Very good partial response: Monoclonal IgM protein is detectable. ≥ 90% reduction in serum 
IgM level from baseline. Complete resolution of extramedullary disease, i.e., 
lymphadenopathy and splenomegaly if present at baseline. No new signs or symptoms of 
active disease.

Partial response (PR): Monoclonal IgM protein is detectable. ≥ 50% but < 90% reduction in 
serum IgM level from baseline. Reduction of extramedullary disease, i.e., lymphadenopathy 
and splenomegaly if present at baseline. No new signs or symptoms of active disease.

Minor response: Monoclonal IgM protein is detectable. ≥ 25% but < 50% reduction in serum 
IgM level from baseline. No progression in extramedullary disease, i.e., 
lymphadenopathy/splenomegaly. No new signs or symptoms of active disease.

Stable disease: Monoclonal IgM protein is detectable. < 25% reduction and < 25% increase 
in serum IgM level from baseline. No new signs or symptoms of active disease.

Progressive disease: ≥ 25% increase in serum IgM level from lowest nadir 
(requires confirmation) and/or progression in clinical features attributable to the disease.

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Appendix 4.
Modified International Workshop on Chronic Lymphocytic 
Lymphoma Leukemia (IWCLL) Criteria for Response Assessment
The determination of CLL response and progression will be based on standardized International 
Workshop on CLL (IWCLL) Criteria {Hallek 2008}, as specifically modified for this study to 
reflect current recommendations which consider the mechanism of action of tirabrutinib, and 
similar drugs.
Note: As this is an extension protocol from ONO-POE001 (EudraCT Number: 
2011-005033-39), please monitor the same index and nodal index lesions that were 
previously identified at the initiation of treatment.
1.
Identification and Measurement of Tumor Lesions and Organomegaly
1.1
Index Lesions
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should be 
located in disparate regions of the body. Only peripheral nodes need be selected as index lesions. 
However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever 
these sites are involved.
Index lesions will be measured and recorded at baseline and at the stipulated intervals during 
treatment. The cross-sectional dimensions (the largest cross-sectional diameter, ie, the 
longest diameter (LD) × the longest perpendicular diameter (LPD) will be recorded (in cm) for 
each index lesion. The product of the perpendicular diameters (PPD) for each index lesion and 
the sum of greatest perpendicular diameters (SPD) for all index lesions will be calculated and 
recorded. The baseline SPD will be used as references by which objective tumor response will be 
characterized during treatment. The nadir LD of individual lesions and the nadir SPD will be 
used as references by which CLL progression will be characterized. All LD and LPD diameters 
will be reported in centimeters and all PPDs and SPDs will be reported in centimeters squared.
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.5 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm.
Index lesions measuring > 1.5 cm in the LD and > 1.0 cm in the LPD, will be prioritized during 
baseline index lesion selection.
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index lesions 
will be considered. Because nodal index lesions that have one or both diameters > 0 cm and 
1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned for each 
diameter that meets these criteria and the resulting PPD will be used in SPD calculations. Based 
on this convention, a CR may be achieved even if an SPD value is > 0 cm2, (ie, if all lymph 
nodes measure < 1.0 cm2).

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A new node that measures > 1.5 cm in the LD and > 1.0 cm in the LPD will be considered 
progressive disease (PD).
In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression of the lesion 
will be based on the SPD of sub-components. Lesion sub-components will have the true PPDs 
calculated. Similarly, lesion sub-components that are visible but neither abnormal nor 
measurable will have the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.
1.2
Spleen and Liver
Both the spleen and liver will be should be assessed by CT/MRI scan at baseline and at the 
stipulated intervals during treatment. The baseline and nadir values for the longest vertical 
dimension (LVD) of each organ will be used as reference to further characterize the objective 
tumor response of the measurable dimensions of the CLL during treatment.
The spleen will be considered enlarged if it is > 12 cm in LVD {Asghar 2011, Bezerra 2005}, 
with the LVD being obtained by multiplying the number of sections on which the spleen is 
visualized by the thickness of the sections (eg, if the spleen is seen in 14 contiguous 
cross-sectional images with 0.5-cm thickness, the LVD is recorded as 7 cm). 
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of 
the spleen at baseline or nadir, not changes relative to the total splenic LVD. 
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or 
decrease to 12 cm in the LVD is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by 50% (minimum increase of 2 cm) from 
nadir is required for declaration of splenic progression. 
The liver will be considered enlarged if it is > 18 cm in LVD {Erturk 2006}.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver in its LVD or to 
18 cm in the LVD is required for declaration of a hepatomegaly response. Conversely, an 
increase in liver enlargement by 50% (minimum increase of 2 cm) from nadir is required for 
declaration of hepatic progression. .
1.3
Non-Index Lesions
Any other measurable and abnormal nodal lesions not selected for quantitation as index lesions 
may be considered non-index lesions. In addition, non-measurable evidence of CLL such as 
nodal lesions with both diameters < 1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal 
masses that are not confirmed and followed by imaging techniques, cystic lesions, 
previously irradiated lesions, lesions with artifacts may be considered as non-index disease.

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The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-index lesions should be recorded. 
The non-index disease at baseline will be used as a general reference to further characterize 
regression or progression of CLL during assessments of the objective tumor response during 
treatment. Measurements are not required and these lesions should be followed as “present” or 
“absent”.
1.4
Definitions of Disease Response and Progression
Responses will be categorized by the Investigator as CR, PR, SD, or PD. In addition, a response 
category of non-evaluable (NE) is provided for situations in which there is inadequate 
information to otherwise categorize response status. A response category of ND is included for 
situations in which there is no evidence of tumor either at baseline or on treatment.
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until PD/recurrence (taking as reference for PD the 
smallest measurements recorded since treatment started). Subjects with a best overall response of 
NE or ND will be included in the denominator in the analyses of disease response.
1.4.1. Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

ALC in peripheral blood of < 4 x 109/L

Regression of all index lesions to normal size 1.5 cm in the LD 

Normal spleen and liver size

Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease

Morphologically negative bone marrow defined as < 30% of nucleated cells being 
lymphoid cells and no lymphoid nodules in a bone marrow sample that is normocellular for 
age

Peripheral blood counts meeting all of the following criteria:
ANC > 1.5 x 109/L without need for exogenous growth factors (eg, G-CSF)
Platelet count 100 x 109/L without need for exogenous growth factors
Hemoglobin 110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin)

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1.4.2. Partial Response
To satisfy criteria for a PR, all of the following criteria must be met: 

No evidence of new disease

A change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; (2) Only 
lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below: 
In a subject with baseline lymphocytosis (ALC 4 x 109/L), a decrease in peripheral 
blood ALC by 50% from baseline or a decrease to < 4 x 109/L
A decrease by 50% from the baseline in the SPD of the index nodal lesions
In a subject with enlargement of the spleen at baseline, a splenomegaly response as 
defined in Section 1.2
In a subject with enlargement of the liver at baseline, a hepatomegaly response as defined 
in Section 1.2
A decrease by 50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules

No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting 1 of the following criteria:
ANC 1.5 x 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
Platelet count 100 x 109/L or 50% increase over baseline without need for exogenous 
growth factors
Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood 
cell transfusions or need for exogenous growth factors (eg, erythropoietin)
1.4.3. Stable Disease
To satisfy criteria for SD, the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD

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1.4.4. Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD: 

Evidence of any new disease:
A new node that measures > 1.5 cm in the LD and > 1.0 cm in the LPD 
New or recurrent splenomegaly, with a minimum LVD of 14 cm
New or recurrent hepatomegaly, with a minimum LVD of 20 cm
Unequivocal reappearance of an extra-nodal lesion that had resolved
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities related to 
CLL)

Evidence of worsening of index lesions, spleen or liver, or non-index disease: 
Increase from the nadir by 50% in the SPD of index lesions
Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass 
that now has an LD of > 1.5 cm and an LPD of > 1.0 cm
Splenic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm)
Hepatic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm)
Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
lymph node or other tissue biopsy, or fluid cytology (with the biopsy or fluid cytology 
date being considered the date of CLL progression if the subject has no earlier objective 
documentation of CLL progression). 

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
Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells
The current platelet count is < 100 x 109/L and there has been a decrease by > 50% from 
the highest on-study platelet count 
The current hemoglobin is < 110 g/L (11.0 g/dL) and there has been a decrease by 
> 20 g/L (2 g/dL) from the highest on-study hemoglobin 
1.4.5. Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE: 

There are no images or inadequate or missing images

Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have undergone 
splenectomy).
Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or non-index 
lesions. Missing non-index lesions will not impact the ability to assess for response or disease 
progression.
1.4.6. No Disease
Subjects have a status of ND if all of the following conditions occur: 

Index disease absent at both baseline and on-treatment. 

Non-index disease absent at both baseline and on-treatment.

Enlargement of the liver and spleen absent at both baseline and on-treatment

Abnormalities of peripheral blood counts (elevated ALC and abnormally low ANC, platelet 
count, and hemoglobin) and evidence of CLL in bone marrow (if available) absent at both 
baseline and on treatment
1.4.7. Lymphocytosis During Therapy

tirabrutinib, and other agents in class can mobilize CLL cells from tissues into the peripheral 
blood. This characteristic pharmacological action can be prominent early in therapy but can 
persist over time and should not be confused with disease progression in subjects who have 
persistent control of other CLL-related signs and symptoms.

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
In the absence of other objective evidence of disease progression, the occurrence of 
lymphocytosis will not preclude subjects from meeting the criteria for a PR if other criteria 
for PR are met and will not be considered evidence of CLL progression if occurring in 
isolation.

Subjects with lymphocytosis should be continued on tirabrutinib until the occurrence of 
definitive disease progression (ie, disease progression that is manifest by worsening 
CLL-related signs other than lymphocytosis alone), or the occurrence of another reason to 
discontinue study treatment as described in Section 3.5.
1.5
Definitive CLL Progression
Assessment of response and progression will be by the investigator. Subjects who progress will 
be discontinued from the study. 

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Appendix 5.
Follicular Lymphoma, Marginal Zone Lymphoma, and Small 
Lymphocytic Lymphoma Response Assessment
The determination of FL, MZL, and SLL response and progression will be based on standardized 
response criteria for malignant lymphoma {Cheson 2007}.
1.
Identification and Follow-up of Tumor Lesions and Organomegaly
Note: As this is an extension protocol from ONO-POE001 (EudraCT Number: 
2011-005033-39), please monitor the same index and nodal index lesions that were 
previously identified at the initiation of treatment.
1.1.
Index Lesions
Up to 6 lesions (eg, lymph nodes, liver or spleen nodules, and/or other circumscribed extra-nodal 
masses) should be selected as index lesions that will be used to quantitate the status of the 
disease during study. Ideally, the index lesions should be located in disparate regions of the body 
and include mediastinal, abdominal, and retroperitoneal areas of disease whenever these sites are 
involved. 
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The 
cross-sectional dimensions LD × LPD will be recorded (in cm) for each index lesion. Using the 
LD and LPD, the product of the PPD for each index lesion will be calculated. The SPDs for all 
index lesions will be calculated and recorded. The baseline SPDs will be used as references by 
which objective tumor response will be characterized during treatment. The nadir LDs of 
individual lesions and the nadir SPDs will be used as references by which objective tumor 
progression will be characterized during study. All PPD and SPD measurements will be reported 
in centimeters squared.
1.2.
Nodal Index Lesions
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.0 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm. 
Abnormal, measurable nodal lesions will be subcategorized as either large or small. 

Large nodal lesions have an LD that is > 1.5 cm and an LPD that is 1.0 cm. 

Small nodal lesions have an LD that is > 1.0 cm and 1.5 cm and an LPD that is > 1.0 cm.
Index lesions measuring > 1.5 cm in the LD, regardless of the measurement of the LPD, will be 
prioritized during baseline index lesion selection.

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At follow-up time points, the SPD of all nodal index lesions will be considered. Because nodal 
index lesions that have one or both diameters > 0 cm and 1.0 cm cannot be reliably measured, 
a default value of 1.0 cm will be assigned for each diameter that meets these criteria and the 
resulting PPD will be used in SPD calculations. Based on this convention, a CR may be achieved 
even if an SPD value is > 0 cm2 (ie, if all lymph nodes measure < 1.0 cm2).
New or enlarging nodal lesions that are still 1.0 cm by 1.0 cm will not be considered to 
represent recurrent disease or PD. A new node that measures > 1.5 cm in any diameter or a 
new node that measures > 1.0 cm to 1.5 cm in the LD and measures > 1.0 cm in the LPD will 
be considered PD.
In cases in which a large lymph node mass has split into multiple components, only those 
elements that are > 1.0 cm in at least 1 diameter will be considered abnormal and used in 
calculating the SPD. Components that are ≤1.0 cm in the LD are assumed to be normal lymph 
node structures. PD will not be based on the growth of a lesion sub-component until it meets the 
criteria for abnormal. Lesion sub-components that are abnormal (> 1.0 cm in 1 diameter) will 
have the true PPDs calculated with the result used only for calculating an accurate nadir. Lesion 
sub-components that are normal (1.0 cm in the LD) will have the default PPD of 1.0 cm2
(1.0 cm x 1.0 cm) stored only for the purposes of calculating the nadir value. 
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.
1.3.
Extra-Nodal Index Lesions 
An extra-nodal mass may be selected as an index lesion if it is both abnormal and measurable at 
baseline. An extra-nodal mass of any size is considered abnormal. It is considered measurable at 
baseline if it has 2 perpendicular diameters that can be accurately measured in cross section with 
the LD being 1.0 cm and the LPD also being 1.0 cm.
At follow-up time points, the PPD of each single extra-nodal index lesion and the SPD of all 
extra-nodal index lesions will be considered. Because extra-nodal index lesions that have one or 
both diameters > 0 cm and < 1.0 cm cannot be reliably measured, a default value of 1.0 cm will 
be assigned for each diameter that meets these criteria and the resulting PPD will be used in 
SPD calculations. If an extra-nodal lesion is no longer clearly visible, it will be considered 
resolved and its PPD will be defined as 0 cm2. 
If an extra-nodal lesion that had resolved (ie, had a PPD of 0 cm2) subsequently reappears 
unequivocally, the subject will be considered to have PD. A new unequivocal extra-nodal lesion 
of any size that appears at a site that was not previously involved with lymphoma and is 
discernible to the radiologist by CT scan will be considered PD.

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1.4.
Non-Index Lesions
Any other measurable and abnormal nodal or extra-nodal lesions not selected for quantitation as 
index lesions may be considered non-index lesions. In addition, non-measurable evidence of 
iNHL such as abnormal, non-measurable nodal lesions, extra-nodal lesions with both diameters 
< 1.0 cm, bone lesions, leptomeningeal disease, ascites, pleural or pericardial effusions, 
lymphangitis of the skin or lung, abdominal masses that are not confirmed and followed by 
imaging techniques, cystic lesions, previously irradiated lesions, or lesions with artifacts may be 
considered as non-index disease. 
If present at baseline, up to 6 non-index lesions should be recorded. Measurements are not 
required. 
Non-index disease will be used as a general reference to further characterize regression or 
progression of lymphoma during assessments of the objective tumor response during treatment. 
These lesions should be followed as “present” or “absent”.
1.5.
Definitions of Tumor Response and Progression
Responses will be categorized as CR, PR, SD, or PD. In addition, a response category of NE is 
provided for situations in which there is inadequate information to otherwise categorize response 
status. A response category of ND is included for situations in which there is no evidence of 
tumor both at baseline and on-treatment.
The best overall response will be determined. The best overall response is the best response 
recorded from the start of study drug until PD/recurrence (taking as reference for PD the 
smallest measurements recorded since study drug started). Subjects with a best overall response 
of NE or ND will be included in the denominators in calculations of tumor response rate.
1.5.1. Complete Response
To satisfy criteria for CR, all of the following criteria must be met:

No evidence of new disease

Regression of all index nodal lesions to normal size (≤1.5 cm in the LD for nodes that were 
considered large at baseline and < 1.0 cm in the LD and ≤1.0 cm in the LPD for nodes that 
were considered small at baseline) (see Section 1.2 for definitions of large and small nodes)

Regression to normal of all nodal non-index disease 

Disappearance of all detectable extra-nodal index and non-index disease

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
Normal spleen and liver size by imaging studies, no hepatic or splenic lymphoma nodules, 
and no new liver or spleen enlargement

Morphologically negative bone marrow based on an adequate unilateral core biopsy 
(> 20 mm unilateral core); if the sample is indeterminate by morphology, it should be 
negative by immunohistochemistry 

If PET performed (not required), no evidence of residual disease
1.5.2. Partial Response
To satisfy criteria for PR, all of the following criteria must be met except for subjects with WM 
as noted below:

No evidence of new disease

A 50% decrease from baseline in the SPD of the index lesions 

No increase in the size of non-index disease

No increase in the size of the liver or spleen and no new liver or spleen enlargement

Persistence of bone marrow involvement in a subject who meets other criteria for CR based 
on the disappearance of all nodal and extra-nodal masses

If PET performed (not required): 
Typically FDG-avid lymphoma: if no baseline PET scan or if the PET scan was positive 
before initiating study drug(s), the on-treatment PET is positive in 1 previously 
involved site. If baseline PET was performed and was negative, there is no new PET 
evidence of disease
Variably FDG-avid lymphoma/FDG-avidity unknown: if no pretreatment PET scan or if 
the pretreatment PET scan was negative for lymphoma, CT criteria should be used in 
assessing the tumor during study. If the PET scan was positive before initiating study 
drug(s), the on-treatment PET is positive in 1 previously involved site.
1.5.3. Stable Disease
To satisfy criteria for SD, all of the following criteria must be met:

No evidence of new disease

Neither sufficient tumor shrinkage from baseline to qualify for PR nor sufficient evidence of 
tumor growth to qualify for PD

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1.5.4. Progressive Disease
The occurrence of any of the following events indicates PD:

Evidence of any new disease that was not present at baseline:
A new node that measures > 1.5 cm in LD and > 1.0 cm in the LPD
A new node that measures > 1.0 cm to < 1.5 cm in the LD and > 1.0 cm in the LPD
Unequivocal reappearance of an extra-nodal lesion that had resolved (ie, had previously 
been assigned a PPD of 0 cm2)
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities) of any size 
unequivocally attributable to lymphoma (usually requires PET, biopsy, cytology, or other 
non-radiologic confirmation to confirm disease attributable to lymphoma). 
New or recurrent bone marrow involvement with iNHL if the last prior bone marrow 
biopsy performed as part of the study (baseline or on-study) was negative for iNHL

Evidence of worsening of nodal or extra-nodal index lesions:
Increase from the nadir by 50% in the SPD of index lesions
Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass 
that now has an LD of > 1.5 cm and an LPD of > 1.0 cm 

Unequivocal increase in the size of non-index disease

Transformation to a more aggressive NHL histology as established by lymph node biopsy or 
cytology.

If PET performed (not required):The appearance of any new lesion compatible with 
lymphoma with confirmation by other radiographic or histological modalities
The reappearance of any activity in a pre-existent lesion that meets size criteria for a new 
lesion on CT
1.5.5. Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE:

There are no images or inadequate or missing images.

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1.5.6. No Disease
In a subject who does not have evidence of PD, the occurrence of all of the following conditions 
indicates a response status of ND: 

Index disease absent at both baseline and on-study

Non-index disease absent at both baseline and on-study

Enlargement of the liver and spleen absent at both baseline and on-study

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Appendix 6.
ECOG status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg,, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
{Oken 1982}

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Appendix 7.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
CTCAE v4.03 can be accessed from the below link:
http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf

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Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
The risks of treatment with tirabrutinib during pregnancy have not been evaluated. There is no 
data available at this time to exclude the possibility that tirabrutinib has a drug-drug interaction 
(DDI) with hormones used for contraception. There is insufficient data to exclude the possibility 
of a clinically relevant interaction of tirabrutinib with hormonal contraception that results in 
reduced contraception efficacy. Therefore, contraceptive steroids are not recommended as a 
contraceptive method either solely or as a part of a contraceptive regimen. Please refer to the 
latest version of the tirabrutinib IB for additional information.
b) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must also not rely on hormone-containing contraceptives as a form 
of birth control during the study. They must have a negative serum pregnancy test at Screening 
and a negative pregnancy test on the Baseline/Day 1 visit prior to randomization. Pregnancy tests 
will be performed at each visit thereafter. Female subjects must agree to one of the following 
from Screening until 30 days following the end of relevant systemic exposure.

Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.

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Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
for countries where it’s available
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure.
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid. Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 90 days after the 
end of relevant systemic exposure. Additional contraception recommendations should also be 
considered if the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the end of relevant systemic exposure.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM). Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 7.7.2.1.

amd-5-prot-GS-US-401-1787
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
29-Oct-2019
17:05:18
Clinical Research eSigned
30-Oct-2019
21:51:39
PPD
PPD