A Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib (ONO/GS-4059) in Combination With Other Targeted Anti-cancer Therapies in Subjects With B-cell Malignancies
Phase: PHASE1
Conditions: B-cell Malignancies
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib 
(ONO/GS-4059) in Combination with other Targeted Anti-cancer Therapies 
in Subjects with B-cell Malignancies 
Sponsor: 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
IND Number: 
EudraCT Number: 
Clinical Trials.gov Identifier: 
125473 
2015-000834-30 
NCT02457598 
Indication: 
B-cell malignancies
Protocol ID: 
GS-US-401-1757
Clinical Program Manager: 
Name: 
 
Telephone: 
Email: 
Gilead Medical Monitor: 
Name: 
 
Telephone: 
Fax: 
Mobile: 
Email: 
Protocol Version/Date: 
Original: 
19 March 2015 
Amendment 1: 
07 May 2015 
Amendment 2: 
01 September 2015 
Amendment 3: 
25 March 2016 
Amendment 3.1 (UK Specific): 
12 May 2016 
Amendment 4: 
13 July 2016 
Amendment 5: 
20 December 2016 
Amendment 5.1: (UK Specific) 
17 January 2017 
Amendment 6: 
22 September 2017 
Amendment 6.1 (UK Specific): 
11 October 2017 
Amendment 7: 
14 December 2018 
Amendment 7.1 (UK Specific): 
11 January 2019 
Amendment 8: 
05 November 2019 
Amendment 8.1 (UK Specific): 
05 November 2019 
Amendment 9: 
12 March 2020 
Amendment 9.1 (UK Specific): 
19 Mar 2020 
Amendment 10: 
01 May 2020 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or under control of 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 information 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 information to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from 
those persons to whom the drug may be administered. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
(r) GILEAU 

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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 5 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 5 
PROTOCOL SYNOPSIS .............................................................................................................................................. 6 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 29 
1. 
INTRODUCTION .............................................................................................................................................. 33 
1.1. 
Background ............................................................................................................................................ 33 
1.2. 
Tirabrutinib ............................................................................................................................................ 34 
1.2.1. 
General Information ............................................................................................................. 34 
1.2.2. 
Tirabrutinib Nonclinical Pharmacology and Toxicology ..................................................... 38 
1.2.3. 
Clinical Trials of Tirabrutinib .............................................................................................. 41 
1.3. 
Idelalisib ................................................................................................................................................. 43 
1.4. 
Entospletinib .......................................................................................................................................... 44 
1.4.1. 
Nonclinical Pharmacology ................................................................................................... 44 
1.4.2. 
Nonclinical ADME .............................................................................................................. 45 
1.4.3. 
Nonclinical Toxicology ........................................................................................................ 46 
1.4.4. 
Clinical Trials ....................................................................................................................... 47 
1.5. 
Obinutuzumab ........................................................................................................................................ 48 
1.6. 
Rationale for This Study ........................................................................................................................ 49 
1.6.1. 
Dose Rationale ..................................................................................................................... 50 
1.6.2. 
Risk/Benefit Assessment for the Study ................................................................................ 53 
1.6.3. 
Potential Benefits ................................................................................................................. 56 
1.7. 
Compliance ............................................................................................................................................ 56 
2. 
OBJECTIVES ..................................................................................................................................................... 57 
3. 
STUDY DESIGN ................................................................................................................................................ 59 
3.1. 
Endpoints ............................................................................................................................................... 59 
3.2. 
Study Design .......................................................................................................................................... 59 
3.2.1. 
Dose Escalation .................................................................................................................... 59 
3.2.2. 
Dose Expansion .................................................................................................................... 63 
3.2.3. 
Long-Term Safety Monitoring ............................................................................................. 64 
3.3. 
Study Treatments ................................................................................................................................... 64 
3.4. 
Duration of Treatment ............................................................................................................................ 67 
3.5. 
Dose Limiting Toxicities ........................................................................................................................ 68 
3.6. 
Criteria for Discontinuation of Study Drug and Study ........................................................................... 68 
3.7. 
Criteria for Removal from Study ........................................................................................................... 69 
4. 
SUBJECT POPULATION .................................................................................................................................. 70 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 70 
4.2. 
Inclusion Criteria .................................................................................................................................... 70 
4.3. 
Exclusion Criteria ................................................................................................................................... 72 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................................... 74 
5.1. 
Randomization, Blinding and Treatment Codes .................................................................................... 74 
5.1.1. 
Enrollment ............................................................................................................................ 74 
5.2. 
Description and Handling of Study Drugs ............................................................................................. 74 
5.2.1. 
Tirabrutinib .......................................................................................................................... 74 
5.2.2. 
Idelalisib ............................................................................................................................... 76 

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5.2.3. 
Entospletinib ........................................................................................................................ 77 
5.2.4. 
Obinutuzumab ...................................................................................................................... 78 
5.3. 
Dosage and Administration of Study Drugs ........................................................................................... 78 
5.3.1. 
Dosage and Administration of Obinutuzumab ..................................................................... 80 
5.3.2. 
Prior and Concomitant Medications ..................................................................................... 83 
5.3.3. 
Tirabrutinib .......................................................................................................................... 84 
5.3.4. 
Idelalisib ............................................................................................................................... 84 
5.3.5. 
Entospletinib ........................................................................................................................ 84 
5.3.6. 
Obinutuzumab ...................................................................................................................... 86 
5.4. 
Accountability for Study Drugs ............................................................................................................. 86 
5.4.1. 
Investigational Medicinal Product Return or Disposal ......................................................... 87 
6. 
STUDY PROCEDURES .................................................................................................................................... 88 
6.1. 
Subject Enrollment and Treatment Assignment ..................................................................................... 88 
6.2. 
Study Procedure Descriptions ................................................................................................................ 88 
6.2.1. 
Informed Consent ................................................................................................................. 88 
6.2.2. 
Medical and Medication History .......................................................................................... 89 
6.2.3. 
Physical Examination ........................................................................................................... 89 
6.2.4. 
Vital Signs ............................................................................................................................ 89 
6.2.5. 
Electrocardiogram Assessment ............................................................................................ 89 
6.2.6. 
ECOG Performance Status ................................................................................................... 90 
6.2.7. 
Prior and Concomitant Medications ..................................................................................... 90 
6.2.8. 
Adverse Events ..................................................................................................................... 90 
6.2.9. 
Radiology Assessment ......................................................................................................... 91 
6.2.10. 
Tumor Status Assessments ................................................................................................... 92 
6.2.11. 
Blood and Urine Samples ..................................................................................................... 93 
6.2.12. 
Biomarker Samples to Address the Study Objectives .......................................................... 94 
 
 
 
.
 
6.2.15. 
Pregnancy Test for Females of Childbearing Potential ........................................................ 96 
6.2.16. 
Pharmacokinetic Samples ..................................................................................................... 96 
6.2.17. 
Pharmacodynamic Samples .................................................................................................. 98 
6.2.18. 
Unscheduled Procedures .................................................................................................... 100 
6.3. 
Post-treatment Assessments ................................................................................................................. 100 
6.3.1. 
Post-Study Phone Call ........................................................................................................ 100 
6.4. 
Criteria for Discontinuation of Study Treatment .................................................................................. 100 
6.5. 
Dose Interruption and Reduction ......................................................................................................... 100 
6.6. 
End of Study ......................................................................................................................................... 108 
6.7. 
Post Study Care .................................................................................................................................... 108 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................. 109 
7.1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ............................... 109 
7.1.1. 
Adverse Events ................................................................................................................... 109 
7.1.2. 
Serious Adverse Events ...................................................................................................... 109 
7.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ....................................................................... 110 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ............................................................... 111 
7.2.1. 
Assessment of Causality for Study Drugs and Procedures ................................................. 111 
7.2.2. 
Assessment of Severity ...................................................................................................... 111 
7.3. 
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead ..................................................................................................................... 112 
7.4. 
Gilead Reporting Requirements ........................................................................................................... 114 
7.5. 
Toxicity Management .......................................................................................................................... 114 
7.5.1. 
Warnings and Precautions .................................................................................................. 114 
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7.6. 
Special Situations Reports .................................................................................................................... 120 
7.6.1. 
Definitions of Special Situations ........................................................................................ 120 
7.6.2. 
Instructions for Reporting Special Situations ..................................................................... 120 
8. 
STATISTICAL CONSIDERATIONS .............................................................................................................. 122 
8.1. 
Analysis Endpoints ............................................................................................................................... 122 
8.1.1. 
Primary Endpoint ............................................................................................................... 122 
8.1.2. 
Secondary Endpoints .......................................................................................................... 122 
 
 
8.2. 
Analysis Sets ........................................................................................................................................ 123 
8.2.1. 
All Enrolled Analysis Set ................................................................................................... 123 
8.3. 
Data Handling Conventions ................................................................................................................. 124 
8.4. 
Demographic Data and Baseline Characteristics ................................................................................. 124 
8.5. 
Efficacy Analysis ................................................................................................................................. 124 
8.5.1. 
Primary Analysis ................................................................................................................ 124 
8.6. 
Safety Analysis .................................................................................................................................... 125 
8.6.1. 
Extent of Exposure ............................................................................................................. 125 
8.6.2. 
Adverse Events ................................................................................................................... 125 
8.6.3. 
Laboratory Evaluations ...................................................................................................... 126 
8.7. 
Pharmacokinetic Analysis .................................................................................................................... 127 
8.8. 
Biomarker Analysis .............................................................................................................................. 127 
8.9. 
Sample Size .......................................................................................................................................... 127 
8.10. 
Timing of Analyses .............................................................................................................................. 128 
8.10.1. 
Interim Analysis ................................................................................................................. 128 
8.10.2. 
Final Analysis ..................................................................................................................... 128 
9. 
RESPONSIBILITIES ........................................................................................................................................ 129 
9.1. 
Investigator Responsibilities ................................................................................................................ 129 
9.1.1. 
Good Clinical Practice........................................................................................................ 129 
9.1.2. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval ......................................................................................................... 129 
9.1.3. 
Informed Consent ............................................................................................................... 130 
9.1.4. 
Confidentiality .................................................................................................................... 130 
9.1.5. 
Study Files and Retention of Records ................................................................................ 130 
9.1.6. 
Case Report Forms ............................................................................................................. 132 
9.1.7. 
Investigational Medicinal Product Accountability and Return ........................................... 132 
9.1.8. 
Inspections .......................................................................................................................... 132 
9.1.9. 
Protocol Compliance .......................................................................................................... 133 
9.2. 
Sponsor Responsibilities ...................................................................................................................... 133 
9.2.1. 
Protocol Modifications ....................................................................................................... 133 
9.2.2. 
Study Report and Publications ........................................................................................... 133 
9.3. 
Joint Investigator/Sponsor Responsibilities ......................................................................................... 133 
9.3.1. 
Payment Reporting ............................................................................................................. 133 
9.3.2. 
Access to Information for Monitoring ................................................................................ 134 
9.3.3. 
Access to Information for Auditing or Inspections ............................................................ 134 
9.3.4. 
Study Discontinuation ........................................................................................................ 134 
10. REFERENCES ................................................................................................................................................. 135 
11. APPENDICES .................................................................................................................................................. 142 
 
Appendix 1. 
Investigator Signature Page .................................................................................................. 143 
Appendix 2. 
Study Procedures Table (Dose Escalation and Dose Expansion) ......................................... 144 
Appendix 3. 
Study Procedures Table (Long-Term Safety Monitoring) .................................................... 149 
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Appendix 4. 
Waldenstrom’s Macroglobulinemia Assessment .................................................................. 151 
Appendix 5. 
Modified International Workshop on Chronic Lymphocytic Lymphoma Leukemia 
(IWCLL) Criteria for Response Assessment ........................................................................ 152 
Appendix 6. 
Follicular Lymphoma, Marginal Zone Lymphoma, Small Lymphocytic Lymphoma, 
Diffuse Large Cell Lymphoma and Mantle Cell Lymphoma Response Assessment ........... 158 
Appendix 7. 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 .................................. 163 
Appendix 8. 
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements................................................................................................. 164 
Appendix 9. 
Eastern Cooperative Oncology Group (ECOG) Performance Status ................................... 167 
LIST OF IN-TEXT TABLES 
Table 1. 
Dose Escalation for Combination I (Tirabrutinib + Idelalisib) ............................................... 11 
Table 2. 
Dose Escalation for Combination II (Tirabrutinib + Entospletinib) ....................................... 11 
Table 3. 
Dose Evaluation for Triplet Combinations (Combination III and IV) .................................... 13 
Table 3-1. 
Dose Escalation for Combination I (of Tirabrutinib + Idelalisib) .......................................... 60 
Table 3-2. 
Dose Escalation for Combination II (Tirabrutinib + Entospletinib) ....................................... 61 
Table 3-3. 
Dose Evaluation for triplet combinations (Combination III and IV) ...................................... 62 
Table 3-4. 
Dose escalation/ DLT Guidelines ........................................................................................... 63 
Table 5-1. 
Guidance on the management of infusion-related reactions (IRRs) ....................................... 83 
Table 5-2. 
Dosing restrictions for HMB-CoA reductase inhibitors for subjects receiving 
entospletinib ........................................................................................................................... 85 
Table 5-3. 
Examples of Concomitant Medications Prohibited in this Study ........................................... 85 
Table 6-1. 
Blood and Urine Samples Collected During the Course of the Studyef .................................. 99 
Table 6-2. 
Dose Adjustments, Withholding and Discontinuation Related to Idelalisib and/or 
Tirabrutinib ........................................................................................................................... 101 
Table 6-3. 
Restarting Doses of Tirabrutinib after Treatment Interruption for Drug-related 
Grade 3 or 4 Toxicity* ......................................................................................................... 104 
Table 6-4. 
Restarting Doses of Idelalisib after Treatment Interruption for Drug-related Grade 3 
or 4 Toxicity*† ..................................................................................................................... 104 
Table 6-5. 
Dose Adjustments, Withholding and Discontinuation Related to Entospletinib 
and/or Tirabrutinib................................................................................................................ 105 
Table 6-6. 
Restarting Doses of Entospletinib after Treatment Interruption for Drug-related 
Grade 3 or 4 Toxicity* ......................................................................................................... 107 
Table 6-7. 
Dose Adjustment Guidelines for Subjects Receiving Obinutuzumab .................................. 107 
Table 7-1. 
Grading of Adverse Event Severity ...................................................................................... 112 
Table 8-1. 
Probability of Dose Escalation (N=3+3) .............................................................................. 127 
LIST OF IN-TEXT FIGURES 
Figure 1-1. 
Inhibition of the BCR Pathway by Tirabrutinib ..................................................................... 36 
Figure 3-1. 
Dosing Schema for Dose Escalation (Combination I and II) ................................................. 65 
Figure 3-2. 
Dosing Schema for Dose Expansion (Combination III and IV) ............................................. 66 
Figure 7-1. 
Kaplan-Meier Time to Diarrhea or Colitis ........................................................................... 116 

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PROTOCOL SYNOPSIS 
 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
 
 
 
Study Title:  
A Phase 1b Dose Escalation and Dose Expansion Study of 
Tirabrutinib (ONO/GS-4059) in Combination with other Targeted 
Anti-cancer Therapies in Subjects with B-cell Malignancies 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
125473 
2015-000834-30 
NCT02457598 
Study Centers 
Planned: 
Approximately 25 centers worldwide 
As of Amendment 9, all subjects currently on the study will transition into long-term safety 
monitoring. Subjects from the ongoing Study GS-US-401-1787 and subjects who came off 
Study GS-US-401-1757 or Study GS-US-401-1787 but continued to receive treatment via 
named patient use will be enrolled into Group VI in this study to participate in long-term 
safety monitoring. 
Objectives: 
The primary objectives of the study are:  
For the dose escalation phase:  
• To characterize the safety and tolerability of tirabrutinib 
combined with idelalisib or entospletinib (also known as ENTO, 
and GS-9973) in subjects with relapsed or refractory B-cell 
lymphoproliferative malignancies  
• To characterize the safety and tolerability of tirabrutinib 
combined with obinutuzumab and idelalisib or entospletinib in 
subjects with relapsed or refractory B-cell lymphoproliferative 
malignancies 
For the dose expansion phase: 
• To evaluate the preliminary efficacy of tirabrutinib combined 
with idelalisib or entospletinib in B-cell lymphoproliferative 
malignancies (subtype[s] to be determined based on the dose 
escalation phase) 

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• To evaluate the preliminary efficacy of tirabrutinib combined 
with obinutuzumab and idelalisib or entospletinib in subjects 
with relapsed or refractory B-cell lymphoproliferative 
malignancies 
• To evaluate the preliminary efficacy of tirabrutinib alone 
administered at 80 mg once daily in subjects with relapsed or 
refractory chronic lymphocytic leukemia (CLL) 
For long-term safety monitoring phase: 
• To evaluate the long-term safety of tirabrutinib as a 
monotherapy, and in combination with idelalisib or 
entospletinib, with or without obinutuzumab, in subjects with 
relapsed or refractory B-cell lymphoproliferative malignancies. 
The secondary objectives of the study are: 
For the dose escalation phase: 
• To evaluate the preliminary efficacy of tirabrutinib combined 
with idelalisib or entospletinib in subjects with relapsed or 
refractory B-cell lymphoproliferative malignancies 
• To evaluate the preliminary efficacy of tirabrutinib combined 
with obinutuzumab and idelalisib or entospletinib in subjects 
with relapsed or refractory B-cell lymphoproliferative 
malignancies 
• To evaluate the pharmacokinetics (PK) of tirabrutinib 
administered alone and in combination with idelalisib or 
entospletinib in subjects with relapsed or refractory B-cell 
lymphoproliferative malignancies 
For the dose expansion phase: 
• To further characterize the safety and tolerability of tirabrutinib 
combined with idelalisib or entospletinib in subjects with a 
specific tumor subtype (to be determined) 
• To further characterize the safety and tolerability of tirabrutinib 
combined with obinutuzumab and idelalisib or entospletinib in 
subjects with a specific tumor subtype (to be determined) 
• To characterize the safety and tolerability and evaluate the 
preliminary efficacy of single-agent tirabrutinib in subjects with 
relapsed or refractory CLL 

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Study Design: 
This is a Phase 1b, open-label, multicenter, sequential 
dose-escalation study to evaluate the safety, tolerability, PK, 
pharmacodynamics, and efficacy of tirabrutinib in combination with 
idelalisib or entospletinib, with or without obinutuzumab, in 
subjects with relapsed or refractory B-cell lymphoproliferative 
malignancies. Tirabrutinib may also be evaluated as a single-agent 
to obtain additional safety, tolerability, and efficacy data at the 
maximum tolerated dose (MTD) equivalent dose.  
The study will consist of 3 parts. The first part is a dose-escalation 
phase to evaluate safety, tolerability, PK, and pharmacodynamics of 
tirabrutinib combination therapies. Subjects with B-cell 
lymphoproliferative malignancies who have refractory or relapsed 
disease will be enrolled in a standard 3 + 3 dose escalation study 
design, to receive oral tirabrutinib combined with idelalisib or 
entospletinib. 
Once a dose level of tirabrutinib combined with idelalisib or 
entospletinib has been deemed safe and tolerable, additional cohorts 
of subjects will be enrolled to receive the triplet combination of 
obinutuzumab, tirabrutinib and idelalisib or entospletinib. Up to 
2 dose levels for each triplet combination may be evaluated. 
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The second part of the study is an expansion phase to evaluate the 
preliminary efficacy of tirabrutinib combined with idelalisib or 
entospletinib in a specific B-cell malignancy subtype (eg, CLL) and 
non-germinal center B-cell-like diffuse large B cell lymphoma 
(non-GCB-DLBCL). The iNHL expansion may be grouped into one 
expansion cohort or divided into more specific subgroups such as 
mantle cell lymphoma (MCL), follicular lymphoma (FL), 
Waldenstrom's macroglobulinemia (WM) and marginal zone 
lymphoma (MZL). The expansion phase may also include subjects 
who receive the triplet combination of obinutuzumab, tirabrutinib, 
and idelalisib or entospletinib in specific B-cell malignancies 
(eg, CLL). An expansion arm of single-agent tirabrutinib 80 mg 
once daily in subjects with relapsed or refractory CLL may also be 
included. 
Each expansion arm will enroll up to approximately 30 subjects. 
The choice of enrolling a subject into a specific cohort will be based 
on the treatment slots open at the time of screening, 
inclusion/exclusion enrollment criteria and at the discretion of the 
investigator. 
The third part of the study is long-term safety monitoring to 
evaluate the long-term safety of tirabrutinib both as a monotherapy 
and in combination with other anti-cancer therapies. As of 
Amendment 9, all subjects currently on the study who have no 
clinical evidence of disease progression will transition into 
long-term safety monitoring. Subjects from the ongoing 
Study GS-US-401-1787 and subjects who came off 
Study GS-US-401-1757 or Study GS-US-401-1787 but continued 
to receive treatment via named patient use (or individual expanded 
use) will be enrolled into Group VI to participate in long-term 
safety monitoring. 
Combination I: Tirabrutinib and Idelalisib 
Initially, 3 subjects will enroll in Cohort 1A of Combination I; the 
starting dose will be 20 mg once daily of tirabrutinib and 50 mg 
twice daily of idelalisib (Table 1). If a dose-limiting toxicity (DLT) 
occurs within 28 days from Cycle 1, Day 1 in Cohort 1A, this 
cohort will be expanded to enroll 3 additional subjects. If ≥ 2 DLTs 
occur in Cohort 1A, (ie, ≥ 2 subjects experience DLTs) 
development of the combination of tirabrutinib and idelalisib will 
discontinue. 

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If no DLT occurs in 3 subjects or < 2 DLTs occur in up to 
6 subjects in Cohort 1A, then Cohort 2A will open. Cohort 2A will 
enroll 3 subjects with tirabrutinib dosed at 40 mg once daily and 
idelalisib 50 mg twice daily. Once enrollment is complete in 
Cohort 2A, Cohort 2B will enroll 3 subjects with tirabrutinib dosed 
at 20 mg twice daily and idelalisib 50 mg twice daily. Cohorts 2A 
and 2B will dose escalate independently; if no DLT occurs in 
3 subjects or < 2 DLTs occur in up to 6 subjects in Cohort 2A and 
Cohort 2B has completed enrollment, then the next 3 subjects will 
be enrolled in Cohort 3A with tirabrutinib dosed at 80 mg once 
daily and idelalisib 50 mg twice daily. Similarly, if no DLT occurs 
in 3 subjects or < 2 DLTs occur in up to 6 subjects in Cohort 2B, 
Cohort 3B will enroll 3 subjects with tirabrutinib dosed 40 mg 
twice daily and idelalisib 50 mg twice daily. Subsequent cohorts 
will enroll if no DLTs in 3 subjects or < 2 DLTs occur in up to 
6 subjects are observed. If a second DLT is observed in any cohort, 
the MTD of tirabrutinib combined with idelalisib will have been 
exceeded and the prior cohort will be the MTD. The MTD for 
tirabrutinib once-daily will be determined separately from the MTD 
for tirabrutinib twice-daily. 
A new cohort will not open for enrollment until the last subject has 
completed the 28-day safety period for the prior cohort. All 
available safety, tolerability, and PK data will be reviewed prior to 
proceeding to the next cohort. The design will be adaptive, with 
cohorts for reduced or intermediate doses added based on emerging 
safety, PK, pharmacodynamics, and efficacy results. Additionally, 
either tirabrutinib once daily or tirabrutinib twice daily cohorts may 
be discontinued based on emerging safety and efficacy data. If there 
is no evidence of clear benefit of twice daily dosing of tirabrutinib 
compared with once daily dosing based on available tolerability, 
efficacy, PK and pharmacodynamic data, dose escalation in the 
twice daily dosing arm may be terminated prior to identifying an 
MTD. Accordingly, as of 25 March 2016, enrollment in the cohorts 
evaluating twice daily dosing of tirabrutinib combined with 
idelalisib was discontinued due to 2 of 5 subjects reporting Grade 4 
neutropenia (1 DLT with associated fever and infection and 1 DLT 
without) within the first 28 days of dosing in Cohort 2B. 
Subjects will return to the clinic for frequent evaluation and 
monitoring as per Appendix 2. 
The doses for each cohort are shown in the following Table 1. 

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Table 1. 
Dose Escalation for Combination I 
(Tirabrutinib + Idelalisib) 
Dose 
Level 
Combination I-A 
Combination I-B 
Tirabrutinib 
Idelalisib 
Tirabrutinib 
Idelalisib 
 
A 
B 
1 
20 mg QD 
50 mg BID 
— 
— 
2 
40 mg QD 
50 mg BID 
20 mg BID 
50 mg BID 
3 
80 mg QD 
50 mg BID 
— 
— 
4 
80 mg QD 
100 mg QD 
— 
— 
5 
160 mg QD 
100 mg QD* 
— 
— 
QD = Once daily dosing, BID = Twice daily dosing * Dose Level 5 (Combination I-A) 
will be limited to DLBCL only 
Once the MTD of the combination of tirabrutinib of idelalisib 
twice daily has been determined, based on safety and efficacy, 
additional cohorts may be enrolled at up to the MTD of tirabrutinib 
combined with 100 mg of idelalisib once daily  
Combination II: Tirabrutinib and Entospletinib  
Initially 3 subjects will enroll in Cohort 1A of Combination II; the 
starting dose will be 40 mg once daily of tirabrutinib and 200 mg 
once daily of entospletinib (Table 2). If 1 DLT occurs within 
28 days from Cycle 1, Day 1 in Cohort 1A of Combination II, this 
cohort will be expanded to enroll 3 additional subjects. If ≥ 2 DLTs 
occur in Cohort 1A of Combination II, (ie, ≥ 2 subjects experience 
DLTs), development of the combination of tirabrutinib and 
entospletinib will discontinue. If no DLTs in 3 subjects or < 2 DLTs 
in up to 6 subjects are observed, then the dose will be escalated to 
dose Level 2. 
Table 2. 
Dose Escalation for Combination II 
(Tirabrutinib + Entospletinib) 
Dose 
Level 
Combination II-A 
Combination II-B 
Tirabrutinib 
Entospletinib 
Tirabrutinib 
Entospletinib 
1 
40 mg QD 
200 mg QD 
— 
— 
2 
80 mg QD 
200 mg QD 
40 mg QD 
400 mg QD 
3 
150 mg QD 
200 mg QD 
80 mg QD 
400 mg QD 
4 
— 
— 
160 mg QD 
400 mg QD* 
QD = Once daily dosing BID = Twice daily dosing * Dose Level 4 (Combination II-B) 
will be limited to DLBCL only 

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Dose Level 2 will consist of 2 cohorts: Cohort 2A with tirabrutinib 
80 mg once daily and entospletinib 200 mg once daily and 
Cohort 2B with tirabrutinib 40 mg once daily and entospletinib 
400 mg once daily. The first 3 subjects enrolled in Dose Level 2 
will be assigned to Cohort 2A; the next 3 subjects will be assigned 
to Cohort 2B. 
Cohorts 2A and 2B will dose escalate independently; if 1 DLT 
occurs in Cohort 2A, then Cohort 2A will be expanded to enroll 3 
additional subjects. Similarly, if 1 DLT occurs in Cohort 2B, then 
Cohort 2B will be expanded to enroll 3 additional subjects. If no 
DLT occurs in 3 subjects or < 2 DLTs occur in up to 6 subjects in 
Cohort 2A then Cohort 3A may begin enrollment. Similarly, if no 
DLT occurs in 3 subjects or < 2 DLTs occur in up to 6 subjects in 
Cohort 2B then Cohort 3B may begin enrollment. 
If ≥ 2 DLTs are observed in Cohort 2A and < 2 DLTs occur in up to 
6 subjects in Cohort 2B, then the MTD of tirabrutinib combined 
with entospletinib is 40 mg once daily. Cohort 3A will not be 
enrolled, however, Cohort 3B may continue with enrollment. 
Similarly, if ≥ 2 DLTs are observed in Cohort 2B and < 2 DLTs 
occur in up to 6 subjects in Cohort 2A, then the MTD of 
entospletinib combined with tirabrutinib is 200 mg once daily. 
Cohort 3B will not be enrolled, however, Cohort 3A may continue 
with enrollment. 
A new cohort within arm A and arm B will not open for enrollment 
until the last subject has completed the 28-day safety period for the 
prior cohort, (ie only one entospletinib/GS-4059 cohort will be 
open at any time in the A and B groups. All available safety, 
tolerability, and PK data will be reviewed prior to proceeding to the 
next cohort. 
The maximum dose to be tested will be 160 mg total daily dose of 
tirabrutinib and 400 mg total daily dose of entospletinib, however, 
the dose escalation will be adaptive, with cohorts for reduced 
dosing, intermediate dosing, or different schedule (QD vs BID) 
added based on emerging safety, PK, pharmacodynamics, and 
efficacy results. Dose level 5 (Combination I-A) and Dose level 4 
(Combination II-B) are limited to subjects with non-GCB DLBCL 
only. 

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Combination III and Combination IV: The addition of 
obinutuzumab to Combination I or II 
Once a dose escalation cohort in Combination I or II has completed 
a 28-day safety review, an additional cohort of 3 (+3) subjects may 
be enrolled at this Dose Level with the addition of obinutuzumab. 
Up to 2 dose levels for each triplet combination may be evaluated. 
Initially 3 subjects each will enroll at the chosen dose level(s) in 
Combination III and Combination IV in parallel (see Table 3). If 
1 DLT occurs within 28 days from Cycle 1 in Combination III, the 
Combination III cohort will be expanded to enroll 3 additional 
subjects. Similarly, if 1 DLT occurs within 28 days from Cycle 1 in 
Combination IV, the Combination IV cohort will be expanded to 
enroll 3 additional subjects. If ≥ 2 DLTs occur in Combination III 
or IV, (ie, ≥ 2 subjects experience DLTs), development of the 
specific Combination (III or IV) will be discontinued. 
Based on the results for Combination I and Combination II, the 
dose levels for each triplet combination (III and IV) will be 
determined. 
If multiple dose levels of tirabrutinib plus idelalisib or entospletinib 
are chosen in Combination III or IV, they will be conducted in a 
staggered manner (lowest dose level first), similar to the dose levels 
in Combination I and II, with the same stopping rules applied. 
Table 3. 
Dose Evaluation for Triplet Combinations 
(Combination III and IV)  
Dose Level 
Combination III 
Combination IV 
Tirabrutinib + 
idelalisib 
Obinutuzumab 
Tirabrutinib + 
Entospletinib 
Obinutuzumab 
A 
Triplet Dose 
Level 1 
Dose determined 
by results of 
Combination I 
Dose Escalation 
(Table 1) 
1000 mg IV 
infusion 
x 
8 doses 
Dose determined 
by results of 
Combination II 
Dose Escalation 
(Table 2) 
1000 mg IV 
infusion 
x 
8 doses 
B 
Triplet Dose 
Level 2  
Dose determined 
by results of 
Combination I 
Dose Escalation 
(Table 1) 
1000 mg IV 
infusion 
x 
8 doses 
Dose determined 
by results of 
Combination II 
Dose Escalation 
(Table 2) 
1000 mg IV 
infusion 
x 
8 doses 
 
 

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A DLT is a toxicity (defined below) which occurs during the DLT 
assessment window (Cycle 1, Day 1 through Cycle 1, Day 28) in 
each cohort: 
1) All Grade ≥ 4 hematological toxicities persisting for > 7 days 
2) All Grade ≥ 3 non-hematological toxicities (except for tumor 
lysis syndrome or alopecia, or Grade 3 nausea, vomiting, 
diarrhea, or constipation that resolves within 72 hours with 
medical intervention) 
3) All Grade ≥ 4 non hematologic laboratory abnormalities 
4) Febrile Neutropenia (defined as ANC < 1.0 x 109/L with a 
single temperature > 38.3oC [101 oF] or sustained temperature 
≥ 38oC [100.4 oF] for more than 1 hour) 
5) Grade ≥ 2 non-hematologic treatment-emergent adverse event 
(TEAE) that in the opinion of the investigator is of potential 
clinical significance such that further dose escalation would 
expose subjects to unacceptable risk 
All adverse events (AEs) should be considered relevant in 
determining DLTs and to reporting unless the event can clearly be 
determined to be unrelated to tirabrutinib and/or idelalisib or 
entospletinib. Lymphocytosis will not be considered a DLT. 
For certain toxicities, such as laboratory assessments without a 
clear clinical correlate, a discussion between the investigator and 
medical monitor, may take place to determine if this AE should be 
assessed as a DLT and necessitate dose interruption or dose 
reduction.  
During the DLT assessment window, subjects who fail to complete 
at least 21 total days of tirabrutinib and idelalisib or entospletinib 
for reasons other than DLT will not be evaluable for DLT 
assessment and additional subjects may be enrolled to that cohort in 
order to provide adequate safety data for dose escalation decisions. 
Expansion phase cohort(s) and dose selection will be based on 
emerging safety, PK, pharmacodynamics, and efficacy results from 
the dose escalation. Dose expansion may occur after the next higher 
dose cohort has opened in the dose escalation. Dose expansion may 
proceed at a lower dose than the MTD. 
Group V: Tirabrutinib single agent 
Additionally, a cohort of up to approximately 30 subjects with 
relapsed or refractory CLL may be enrolled to receive single-agent 
tirabrutinib 80 mg once daily to provide preliminary safety and 
efficacy data at this recommended Phase 2 combination dose level. 

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Long-Term Safety Monitoring 
As of Amendment 9, all subjects currently on the study will 
transition into long-term safety monitoring. Subjects from the 
ongoing Study GS-US-401-1787 and subjects who came off 
Study GS-US-401-1757 or Study GS-US-401-1787 but continued 
to receive treatment via named patient use will be enrolled into 
Group VI to participate in long-term safety monitoring. Subjects 
enrolled in Group VI will continue the same treatment regimen in 
Study GS-US-401-1787 or named patient use starting from 
Long-Term Safety Monitoring Cycle 1 Day 1.  
Subjects from the ongoing Study GS-US-401-1787 who enroll into 
Group VI in this study should have their Study GS-US-401-1787 
end of treatment (EOT) visit, Study GS-US-401-1757 Screening, 
and Long-Term Safety Monitoring Cycle 1 Day 1 visit on the same 
day. Subjects on named patient use who enroll into Group VI in this 
study should have their Study GS-US-401-1757 Screening and 
Long-Term Safety Monitoring Cycle 1 Day 1 visit on the same day.  
All active subjects who have no clinical evidence of disease 
progression will transition to long-term safety monitoring and will 
continue the same treatment regimen. Study visits will be 
completed every 12 weeks for the first 12 months, and then every 
24 weeks during the long-term safety monitoring phase.  
Number of Subjects 
Planned: 
Up to 98 subjects in the dose escalation phase and up to 
270 subjects in the dose expansion phase will be enrolled.  
As of Amendment 9, all subjects currently on this study will 
transition into long-term safety monitoring. Up to 6 additional 
subjects in the United Kingdom (UK) from the ongoing 
Study GS-US-401-1787 and up to 2 additional subjects in total in 
the United States (US) and UK who came off 
Study GS-US-401-1757 or Study GS-US-401-1787 but continued 
to receive treatment via named patient use will be enrolled into 
Group VI to participate in long-term safety monitoring.  
Therefore, up to 376 subjects may be enrolled in the study. 
Target Population: 
Adults with relapsed or refractory FL, marginal zone lymphoma 
(MZL), CLL, small lymphocytic lymphoma (SLL), MCL, 
Waldenstrom’s macroglobulinemia (WM), or non-GCB DLBCL 
who have measurable disease per standard criteria and require 
therapy for their cancers.  

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As of Amendment 9, subjects previously enrolled in the ongoing 
Study GS-US-401-1787, and subjects who came off 
Study GS-US-401-1757 or Study GS-US-401-1787 but continued 
to receive treatment via named patient use who are clinically 
deriving benefit from their therapy and have not experienced 
progression of disease. 
Duration of 
Treatment: 
Treatment will continue in the absence of disease progression 
(clinical or radiographic), unacceptable toxicity, pregnancy, and 
substantial noncompliance with study procedures or study drug, 
initiation of another anti-cancer or experimental therapy, study 
discontinuation, or withdrawal from study. As of Protocol 
Amendment 8, the maximum participation in the treatment period 
for any subject is an additional 6 years from the date of that 
amendment (ie, until November 2025).  
As of Amendment 9, entospletinib will be provided until 
31 December 2020 to subjects enrolled in Combination II and IV 
who are currently receiving entospletinib. Subjects treated with 
entospletinib as part of a combination regimen with tirabrutinib will 
stop receiving entospletinib by 31 December 2020 but may 
continue to be treated with tirabrutinib monotherapy. 
Tirabrutinib is supplied as 40 mg, 80 mg, and 100 mg until study 
completion. Idelalisib is supplied as 50 mg tablets until 
31 December 2020 and 100 mg tablets until study completion. 
Subjects assigned to the 50 mg once daily idelalisib dose will be 
given the option, at the investigator’s discretion, to switch to 
100 mg once daily idelalisib dose leading to an increase in total 
daily dose from 50 mg to 100 mg idelalisib, or to discontinue from 
the study by 31 December 2020 and transition to standard of care 
treatment. Subjects receiving 50 mg once daily of idelalisib must 
not experience any ≥ Grade 3 AEs related to idelalisib to be eligible 
for this dose increase. Following the dose increase, if the subjects 
experience any ≥ Grade 3 toxicity, they will discontinue idelalisib 
and be given the option to continue tirabrutinib monotherapy, at the 
investigator’s discretion.  
Subjects assigned to the 50 mg twice daily idelalisib dose will be 
given the option, at the investigator’s discretion, to switch to the 
100 mg once daily idelalisib dose with no change to the total daily 
dose, or to discontinue from the study by 31 December 2020 and 
transition to standard of care treatment. 

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Diagnosis and Main 
Eligibility Criteria: 
Inclusion Criteria: 
Subjects must meet all of the following inclusion criteria to be 
eligible for participation in this study: 
1) Male or female ≥18 years of age 
2) Diagnosis of FL, MZL, SLL, CLL (meeting IWCLL Criteria 
2008), MCL, WM, or non-GCB DLBCL as documented by 
medical records and with histology based on criteria established 
by the World Health Organization (WHO). 
a) FL Grades 1, 2, or 3a 
b) SLL with absolute lymphocyte count of < 5 x 109/L at initial 
diagnosis 
c) MZL (splenic, nodal, or extra-nodal) 
d) WM, measurable disease defined as serum monoclonal IgM 
> 0.5 g/dL or meeting at least 1 of the recommendations 
from the Second International Workshop on Waldenstrom’s 
Macroglobulinemia for requiring treatment (Appendix 4) 
3) Prior treatment for FL, MZL, SLL, MCL or WM with ≥ 2 or for 
CLL or non-GCB DLBCL with ≥1 chemotherapy-based or 
immunotherapy-based regimen who are not transplant eligible 
and have had either documented disease progression or no 
response (stable disease) to the most recent treatment regimen. 
4) For diseases other than WM, presence of radiographically 
measurable lymphadenopathy or extra-nodal lymphoid 
malignancy (defined as the presence of ≥ 1 lesion that measures 
≥2.0 cm in the longest dimension [LD] and ≥1.0 cm in the 
longest perpendicular dimension [LPD] as assessed by 
computed tomography [CT] or magnetic resonance imaging 
[MRI]). 
5) All acute toxic effects of any prior antitumor therapy resolved to 
Grade ≤1 before the start of study therapy (with the exception of 
alopecia [Grade 1 or 2 permitted], or bone marrow parameters 
[any of Grade 1 or 2 permitted]). 
6) Eastern Cooperative Oncology Group (ECOG) Performance 
Status (PS) ≤ 2 
7) Adequate organ function defined as follows: 
a) Hematologic: Platelets ≥ 50 x 109/L; Hemoglobin 
≥ 8.0 g/dL; ANC ≥ 1.0 x 109/L (without platelet transfusion 
or any growth factors within previous 7 days of the 
hematologic laboratory values obtained at screening visit) 

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b) Hepatic: Aspartate transaminase (AST) / Alanine 
transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) 
Total or conjugated bilirubin ≤ 1.5 x ULN 
c) Renal: Serum Creatinine ≤ 1.5 x ULN or creatinine clearance 
(CrCl) ≥ 60 mL/min as calculated by the Cockcroft-Gault 
method 
8) For female subjects of childbearing potential, willingness to 
abstain from heterosexual intercourse or use a protocol 
specified method of contraception as described in Appendix 8. 
9) Male subjects of reproductive potential who engage in 
heterosexual intercourse must agree to use protocol specified 
method(s) of contraception as described in Appendix 8 
10) Able and willing to provide written informed consent to 
participate in the study  
11) Willingness and ability to comply with protocol-specified 
Pneumocystis jirovecii pneumonia (PJP) prophylaxis 
Group VI only (Numbers 12-18): 
12) Currently enrolled in Study GS-US-401-1787 or previously 
enrolled in Study GS-US-401-1757 or Study GS-US-401-1787 
and currently receiving continued treatment via named patient 
use 
13) Continuing to benefit from the current treatment regimen in the 
opinion of the investigator/treating physician 
14) Negative urine pregnancy test is required for female subjects of 
childbearing potential as described in Appendix 8 
15) 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. 
16) Lactating females must agree to discontinue nursing before the 
study drug is administered 
17) Ability and agreement to attend protocol-specified visits at the 
study site 
18) Able to comprehend and willing to sign the informed consent 
form 

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Exclusion Criteria: 
Subjects who meet any of the following exclusion criteria are not to 
be enrolled in this study: 
1) History of lymphoid malignancy other than those allowed per 
the inclusion criteria. 
2) Known active central nervous system or leptomeningeal 
lymphoma. Imaging documentation of the absence or presence 
of central disease is not required. 
3) History of myelodysplastic syndrome. 
4) History of or current Richter’s transformation. 
5) History of a non-lymphoid malignancy except for the following: 
adequately treated local basal cell or squamous cell carcinoma 
of the skin, cervical carcinoma in situ, superficial bladder 
cancer, asymptomatic prostate cancer without known metastatic 
disease and with no requirement for therapy or requiring only 
hormonal therapy and with normal prostate-specific antigen for 
≥1 year prior to start of study therapy, or any other cancer that 
has been in complete remission for ≥ 5 years. 
6) Less than 21 days since receiving treatment with biologic, small 
molecule, immunotherapy, chemotherapy, radiation, or other 
agent for lymphoid malignancy including other investigational 
products. 
7) Ongoing liver injury, alcoholic liver disease, non-alcoholic 
steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic 
obstruction caused by cholelithiasis, cirrhosis of the liver, or 
portal hypertension 
8) Hepatitis B surface antigen (HBsAG) positive or hepatitis B 
core antibody positive 
9) Hepatitis C virus (HCV) antibody positive 
10) Known human immunodeficiency virus (HIV) infection  
11) Ongoing CMV infection, treatment, or prophylaxis within the 
past 28 days prior to the screening test for active CMV 
(subjects may receive CMV prophylaxis on study) 
12) Ongoing symptomatic pneumonitis 
13) Ongoing inflammatory bowel disease 
14) Pregnancy or breastfeeding 

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15) History of prior therapy with any inhibitor of serine/threonine 
protein kinase (AKT), Bruton tyrosine kinase (BTK), 
phosphatidylinositol 3-kinase (PI3K) (including idelalisib, 
GS-9820, GS-9901), Janus Kinase (JAK), mammalian target of 
rapamycin (mTOR), or spleen tyrosine kinase (SYK) except for 
Group V (single-agent tirabrutinib), for which only prior BTK 
treatment is excluded. 
16) Ongoing immunosuppressive therapy, including systemic 
corticosteroids for treatment of lymphoid malignancy. Subjects 
may use topical, enteric, or inhaled corticosteroids as therapy 
for comorbid conditions and systemic steroids for autoimmune 
anemia and/or thrombocytopenia. Ongoing use of low-dose 
systemic corticosteroids (≤5 mg/day of methylprednisolone or 
equivalent) is permitted. During study participation, subjects 
may receive systemic or other corticosteroids as needed for 
treatment-emergent comorbid conditions 
17) Life expectancy < 4 months as per investigator assessment. 
18) Concurrent participation in another therapeutic clinical trial. 
19) History of long QT syndrome or whose correct QT interval 
(QTc) measured (Fridericia method) at screening is prolonged 
(> 450 ms). 
20) History of stroke or intracranial hemorrhage within 12 months 
prior to enrollment. 
21) Use of strong CYP3A4 and P-gp inducers within 2 weeks prior 
to the first dose of study drug 
22) For subjects enrolling in the entospletinib combination arms 
only: 
a) Use of strong CYP3A4 or CYP2C9 inducers or moderate 
CYP2C9 inducers within 2 weeks prior to the first dose of 
study drug. 
b) Use of a proton pump inhibitor during the screening 
window. H2 receptor antagonists are allowed. 
23) History of sensitivity or intolerance to any of the excipients of 
the drug to be administered based on the study arm (tirabrutinib, 
idelalisib, entospletinib, or obinutuzumab) 
24) For subjects enrolling in the idelalisib combination arms only: 
History of serious allergic reaction including anaphylaxis and 
toxic epidermal necrolysis 

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25) For subjects enrolling in the obinutuzumab arms: prior 
treatment with obinutuzumab and/or the presence of any active 
infection 
Group VI only (Numbers 26-27):  
26) History of sensitivity or intolerance to any of the excipients of 
the drug to be administered based on the study arm (tirabrutinib, 
idelalisib, or entospletinib) 
27) Evidence of clinical or radiological disease progression 
Study Procedures/ 
Frequency: 
Screening: 
Screening will commence with obtaining the subject’s signed 
informed consent and will occur up to 28 days prior to the 
first dosing of study drug on Cycle 1, Day 1. Screening procedures 
will include the following: medical history review, physical exam, 
vital signs, 12-lead electrocardiogram (ECG), ECOG Performance 
Status, prior/concomitant medication review, chemistry, hematology 
and coagulation, AE assessment, and CT or MRI (scans that meet 
protocol requirements that are obtained as part of standard medical 
practice up to 28 days prior to Cycle 1, Day 1 are acceptable) and 
for WM, serum evaluation for IgM. Baseline tumor assessment 
according to disease type will be measured and characterized prior 
to Cycle 1, Day 1 to assess the subject’s disease status prior to 
beginning treatment.  
For Group VI, urine pregnancy testing performed up to 30 days and 
imaging performed up to 90 days prior to enrollment may be used 
to fulfill eligibility criteria. 
Dose Escalation Arms: 
Subjects who meet eligibility criteria will receive a single dose of 
tirabrutinib on Cycle 1, Day 1 and then initiate idelalisib or 
entospletinib in combination with tirabrutinib on Cycle 1, Day 2. 
The first cycle will consist of 28 days (1 day of single agent 
tirabrutinib and 27 days of combination treatment), and each 
subsequent cycle will be 28 days of combination treatment. The 
assigned combination drug will remain consistent throughout the 
subject’s study participation, there will be no dose escalation or 
crossover permitted on study. Safety and efficacy assessments will 
occur on an outpatient basis including assessment of tumor 
response, physical exam, vitals, ECG, collection of blood samples 
(for routine safety labs, tirabrutinib and idelalisib or entospletinib PK, 
pharmacodynamics, and biomarkers at applicable visits), and 
assessment of AEs. In addition, subjects will undergo a CT (or MRI) 
scan every 12 weeks, except DLBCL and CLL. Subjects with 

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DLBCL will have an additional scan at week 6. Subjects with CLL 
will only undergo scans at baseline, 24 weeks, and at the time of 
progression. As of Amendment 7, CT/MRI scans will no longer be 
performed and will only be performed at the time of disease 
progression or at study discontinuation. 
Obinutuzumab will be initiated on Study Day 1 with a test dose of 
100 mg. If this dose is tolerated well, the remainder of the full dose 
may be subsequently administered on Study Day 1. Alternatively, 
the remaining 900 mg will be administered on Study Day 2. 
Subsequent infusions of obinutuzumab will be administered on 
Cycle 1, Day 6 (+/- 2 days), Cycle 1, Day 13 (+/- 2 days), Cycle 2, 
Day 1 (+/- 3 days) and then every 28 days (+/- 3 days) until 
Cycle 6, Day 1 (+/- 3 days) for up to 8 intravenous infusions of 
1000 mg each. 
Treatment with the combination of tirabrutinib with idelalisib or 
entospletinib will be administered in combination with 
obinutuzumab 1-2 days after Study Day 1. The first day of dosing 
these oral agents is considered Cycle 1, Day 1. The combination of 
oral targeted agents will continue to be taken daily on a schedule 
(once daily or twice daily) as determined by the results of the 
Combination I and II dose escalations. The 28-day window for DLT 
evaluation will start with the initiation of the oral agent 
combination. Subjects who withdraw or discontinue study after 
only receiving obinutuzumab will not be considered evaluable for 
the purposes of DLT determination and will be replaced.  
A subject who does not show evidence of disease progression by 
clinical assessment or by CT (or MRI) may continue receiving study 
drugs until disease progression (clinical or radiographic), 
unacceptable toxicity, withdrawal of consent, or other reasons 
specified in Section 3.6. 
Dose Expansion Arms: 
Subjects enrolling in expansion arms will follow the same treatment 
and evaluation schedule with sparse PK sampling.  
After discontinuation of treatment, subjects will be followed for 
safety for 30 days. 
Long-Term Safety Monitoring: 
As of Amendment 9, all subjects currently on the study will 
transition into long-term safety monitoring and will continue the 
same treatment regimen. Subjects enrolled in Group VI will receive 
the same treatment regimen administered in 
Study GS-US-401-1787 or named patient use. Only study 

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procedures for the long-term safety monitoring phase are to be 
conducted for each subject enrolled, as presented in Appendix 3. 
Screening procedures will only apply to Group VI. Subjects from 
the ongoing Study GS-US-401-1787 who enroll into Group VI in 
this study should have their Study GS-US-401-1787 EOT visit, 
Study GS-US-401-1757 Screening, and Long-Term Safety 
Monitoring Cycle 1 Day 1 visit on the same day. Subjects on named 
patient use who enroll into Group VI in this study should have their 
Study GS-US-401-1757 Screening and Long-Term Safety 
Monitoring Cycle 1 Day 1 visit on the same day. Clinical 
evaluations and laboratory assessments will be performed every 
12 weeks for the first 12 months, and then every 24 weeks during 
the long-term safety monitoring phase per institutional standard of 
care. 
PK and Pharmacodynamics Sampling (As of Amendment 7, 
Pharmacodynamics samples will no longer be collected)  
Dose Escalation (Combination I and II): 
PK samples will be collected on Cycle 1, Day 1 at pre-dose and 0.5, 
1, 2, 3, 4, 6, 8, and 
 post-dose of tirabrutinib and 
Cycle 1, Days 2 and 8 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 
 
 and 24 hours post-dose of tirabrutinib and idelalisib or 
entospletinib. 
 
 
 and the 24-hour 
sample should be collected 24 hours post-dose relative to the 
morning dose. PK samples will be collected in all cohorts at 
pre-dose and between 1-6 hours post-dose on Cycle 1 Day 15. A 
sparse PK sample will also be collected anytime on the first day of 
Cycles 2 to 6. 
Blood samples for pharmacodynamics will be collected on Cycle 1, 
Day 1 at pre-dose, 2, and 6 hours post-dose; on Cycle 1, Days 2 and 
8 at pre-dose, 2, 6, and 24 hours post-dose; and at the end of 
treatment or disease progression. When study drug is administered 
twice daily, the 24 hour sample will be collected 24-hours postdose 
relative to the morning dose. The collection of some or all of these 
samples may not be feasible at the site due to shipment logistics 
depending on their geographic location. In addition, sampling time 
points may be eliminated or modified based upon emerging data. 
CCI
CCI
CCI
-
I 

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Dose Expansion (Combinations I and II): 
A PK sample will be collected on Cycle 1, Day 1 between 1.5and 
4 hours (inclusive) post-dose of tirabrutinib. On Cycle 1, Day 8 and 
Cycle 2, Day 1, a PK sample will be collected at pre-dose and 
between 1.5 and 4 hours post-dose of tirabrutinib and idelalisib or 
entospletinib. A sparse PK sample will also be collected anytime on 
the first day of Cycles 3 to 5 and at pre-dose on the first day of 
Cycle 6. 
Pharmacodynamic samples will be collected on Cycle 1, Day 1 at 
pre-dose and between 1.5 and 4 hours post-dose of tirabrutinib. On 
Cycle 1, Day 8 and Cycle 2, Day 1, a pharmacodynamic sample 
will be collected at pre-dose and between 1.5 and 4 hours post-dose 
of tirabrutinib and idelalisib or entospletinib and at the end of 
treatment or disease progression.  
Dose Escalation and Dose Expansion Combinations III and IV:  
A PK sample will be collected on Cycle 1, Day 1 between 1.5 and 
4 hours post-dose of tirabrutinib. On Cycle 1, Day 8 and Cycle 2, 
Day 1, a PK sample will be collected at pre-dose and between 1.5 
and 4 hours post-dose of tirabrutinib and idelalisib or entospletinib. 
A PK sample will also be collected anytime on the first day of 
Cycles 3 to 5 and at pre-dose on the first day of Cycle 6. 
Pharmacodynamic samples will be collected on Cycle 1, Day 1 at 
pre-dose and between 1.5 and 4 hours post-dose of tirabrutinib. On 
Cycle 1, Day 8 and Cycle 2, Day 1, a pharmacodynamics sample 
will be collected at pre-dose and between 1.5 and 4 hours post-dose 
of tirabrutinib and idelalisib or entospletinib and at the end of 
treatment or disease progression. 
Dose Expansion Group V: 
A PK sample will be collected on Cycle 1, Day 1 between 1.5 and 
4 hours post dose of tirabrutinib. On Cycle 1, Day 8 and Cycle 2, 
Day 1, a PK sample will be collected at pre-dose and between 1.5 
and 4 hours post-dose of tirabrutinib. A sparse PK sample will also 
be collected anytime on the first day of Cycles 3 to 5 and at 
pre-dose on the first day of Cycle 6. 
Pharmacodynamic samples in these same subjects will be collected 
at Cycle 1, Day 1 pre-dose and between 1.5-4 hours post-dose of 
tirabrutinib. Cycle 1, Day 8 at pre-dose and 4 hours and at the end 
of treatment or disease progression. 

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Long-Term Safety Monitoring: 
No PK or pharmacodynamics samples will be collected. 
Test Product, Dose, 
and Mode of 
Administration: 
Tirabrutinib will be self-administered orally once or twice daily 
depending on cohort, beginning on Cycle 1, Day 1 of the study and 
thereafter at approximately the same time each day until end of 
treatment. In the tirabrutinib and idelalisib arm, idelalisib will be 
self-administered orally twice daily, beginning on Cycle 1, Day 2 
and at approximately the same time as tirabrutinib. In the 
tirabrutinib and entospletinib arm, entospletinib will be 
self-administered orally as per assigned treatment group, beginning 
on Cycle 1, Day 2. Tirabrutinib is supplied as 10 mg and 25 mg 
capsules or as 20 mg, 40 mg, 75 mg, 80 mg, or 100 mg tablets. 
Idelalisib is supplied as 50 mg and 100 mg tablets. Entospletinib is 
supplied as 200 mg tablets.  
As of Amendment 9, tirabrutinib is supplied as 40 mg, 80 mg, and 
100 mg until study completion. Idelalisib is supplied as 50 mg 
tablets until 31 December 2020 and 100 mg tablets until study 
completion. Entospletinib is supplied as 200 mg tablets until 
31 December 2020. 
Obinutuzumab: 
Obinutuzumab will be administered as 8 intravenous infusions of 
1000 mg each over approximately 21 weeks. A test dose of 100 mg 
will be administered on Study Day 1. If the dose is tolerated well, 
the remaining 900 mg may be administered. Alternatively, the 
remaining 900 mg may be given the next day, on Study Day 2. 
Subsequent infusions of obinutuzumab will be administered on 
Cycle 1 Day 6, Cycle 1 Day 13 Cycle 2, Day 1 and then every 
4 weeks until Cycle 6, Day 1. 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Not applicable 
CCI
CCI

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Criteria for 
Evaluation 
 
Safety: 
Safety will be evaluated by assessment of clinical laboratory tests, 
physical examination, 12-lead ECG, vital signs measurements, and 
the documentation of AEs  
As of Amendment 9, long-term safety will be evaluated by the 
assessment of AE/serious adverse events (SAEs). 
Efficacy: 
In subjects who do not have CLL, overall response rate (ORR) 
defined as the proportion of subjects who achieve a complete 
response (CR) or partial response (PR) at Week 12 and at any time 
point. 
In subjects with CLL, the endpoint will be evaluated at Week 24. 
(Proportion of subjects with CLL achieving CR and negative 
minimal residual disease (MRD) will also be evaluated).  
Progression free survival (PFS) defined as the interval from the 
start of the study therapy to the earlier of the first documentation of 
definite disease progression or death from any cause. 
Duration of response (DOR) defined as the interval from the 
first documentation of CR or PR to the earlier of the first 
documentation of definite disease progression or death from any 
cause. 
Time to response (TTR) defined as the interval from start of 
treatment to the first documentation of CR or PR. Response criteria 
for each disease is included in Appendix 4, Appendix 5, and 
Appendix 6. 
Pharmacokinetics: 
In the dose escalation phase, PK parameters for tirabrutinib, 
idelalisib, idelalisib metabolite GS-563117, and entospletinib will 
be calculated, as applicable: Cmax, AUCtau, Ctau, Tmax, and t1/2. PK of 
other tirabrutinib, idelalisib or entospletinib metabolites may be 
explored. 
Statistical Methods: 
The All Enrolled Analysis Set will include all subjects who are 
enrolled in the study. The Safety Analysis Set will include all 
subjects who receive at least 1 dose of study treatment. The 
Pharmacokinetic Analysis Set will include subjects who receive at 
least 1 dose of study treatment and have the necessary baseline and 
on-study measurements to provide interpretable results for the 
specific parameters of interest. 

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Subject characteristics and study results will be described and 
summarized by phase (escalation and expansion) and dose level for 
the relevant analysis sets. Descriptive summaries will be prepared 
to show sample size, mean, standard deviation (StD), 
95% confidence intervals (CIs) on the mean, median, minimum, 
and maximum for continuous variables and counts, percentages, 
and 95% exact CIs on the percentage for categorical variables. 
Based on the Safety Analysis Set, information regarding study 
treatment administration, study drug compliance, safety variables, 
and post-study therapies will be described and summarized. Study 
drug plasma concentrations will also be described and summarized 
using the Pharmacokinetics Set. 
Tumor response will be based on investigator’s assessment. ORR 
and CR will be estimated for each dose level or expansion arm 
where appropriate and their associated 95% confidence intervals 
will be calculated using the exact method. Duration of response and 
PFS will be analyzed using the Kaplan-Meier method. The median 
and quartiles and their associated 95% confidence intervals for 
these endpoints will be provided if estimable.  
Adverse events will be coded using the current MedDRA and 
graded using the NCI-CTCAE criteria and will be summarized by 
system organ class 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 Calculation 
The trial employs the standard National Cancer Institute (NCI) 
definition of MTD (starting dose associated with DLT in < 33.3% 
of subjects during the DLT assessment window) to determine dose 
escalation. The cohort size and dose-escalation rules establish a low 
probability of increasing the dose if the true rate of DLT is high 
while there is a high likelihood of escalating or proceeding to the 
next cohort of the study if the true underlying probability of DLT is 
low. For example, if the true underlying probability of DLT is low 
(eg, < 10%) at the current dose level, there is a high probability 
(> 0.91) of dose escalation to the next dose level. Conversely, if the 
true underlying proportion of DLT is high (eg, > 60%) at the 
current dose level, there is a low probability (< 0.08) of escalation 
to the next dose level. 

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It is estimated that approximately 90 evaluable subjects will be 
needed for the planned dose-escalation phase of the study. Under 
the assumption that ~10% of enrolled subjects may not be evaluable 
for DLT, approximately 98 subjects will be enrolled during the 
2 dose escalation phases. During the dose expansion phase, up to 
270 subjects will be enrolled under the assumption that up to 
4 disease types and/or dose levels will be evaluated in the idelalisib 
combination, and up to 4 disease types and/or dose levels in the 
entospletinib combination. 
The sample size of the expansion cohort is determined based on 
Simon’s 2-stage optimal design. If 3 or fewer out of the 
first 11 subjects achieve response, then the expansion of the cohort 
will be stopped; otherwise the enrollment will continue to 
30 subjects. The design will have approximately 83% power to rule 
out that ORR is below 25% based on a 1-sided binomial test at 
0.05 significance level with assumed response rate of 50%. 
In addition, as of Amendment 9, up to 8 additional subjects from 
Study GS-US-401-1787 or previously enrolled in 
Study GS-US-401-1757 or Study GS-US-401-1787 who are 
currently receiving continued treatment via named patient use may 
be enrolled for long-term safety monitoring. 
Therefore, up to 376 subjects may be enrolled in the study. 
 
 
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 
ABC-DLBCL 
activated B cell-like diffuse large B cell lymphoma  
ADME 
absorption, distribution, metabolism, and excretion  
ADP 
adenosine 5’-diphosphate sodium salt  
AE 
adverse event 
Akt 
serine/threonine protein kinase 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
aPTT 
activated partial thromboplastin time 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase  
AUC0-24h 
mean exposure 
AUC24h 
area under the concentration-time curve from time 0 to 24 h 
AUClast 
area under the plasma/serum concentration versus time curve from time zero to the 
last quantifiable concentration 
AUCtau 
area under the plasma/serum concentration versus time curve over the dosing interval 
BA 
Bioavailability 
BCR 
B-cell receptor 
BHCG 
Beta-human chorionic gonadotropin 
BID 
twice daily 
BTK 
Bruton tyrosine kinase 
BUN 
Blood urea nitrogen 
CARD11 
caspase recruitment domain family, member 11 
CBC 
complete blood count 
CH50 
50% hemolytic complement activity 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed plasma/serum concentration of drug 
CMV 
cyotmegalovirus 
CNS 
central nervous system 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
Ctau 
observed drug concentration at the end of the dosing interval 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CYP 
cytochrome P450 enzyme 

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CYP 
cytochrome P 
DDI 
drug-drug interaction  
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EC50 
estimated concentration of drug for a half maximal response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
ENTO 
Entospletinib, GS-9973 
EOT 
end of treatment 
eSAE  
electronic Serious Adverse Event 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FL 
follicular lymphoma 
FSH  
follicle stimulating hormone 
GCB  
germinal center B-cell lymphoma 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HDPE 
high density polyethylene  
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
HSP 
hysterosalpingogram 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization (of Technical Requirements for Registration 
of Pharmaceuticals for Human Use) 
ICxx 
concentration that results in xx% inhibition 
IEC 
independent ethics committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IMP 
investigational medicinal product 
iNHL 
indolent non-Hodgkin lymphoma 
INR  
international normalized ratio 
IP 
investigational product 

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IRC 
Independent review committee 
JAK 
Janus kinase 
LD 
longest dimension 
LPD 
longest perpendicular dimension 
LDH 
lactate dehydrogenase 
MAPK 
mitogen-activated protein kinase 
MCL 
mantle cell lymphoma 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
MZL 
marginal zone lymphoma 
ND 
no disease 
NA 
not applicable 
NCI 
National Cancer Institute 
ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PFS 
progression free survival 
PI3K 
phosphatidylinositol 3-kinase 
PLCγ 
phospholipase C gamma 
PJP 
Pneumocystis jirovecii pneumonia 
PK 
pharmacokinetics 
PS 
performance status 
PR 
partial response 
PT 
prothrombin time 
PVE 
Pharmacovigilance and Epidemiology 
QT  
electrocardiographic interval between the beginning of the Q wave and termination of 
the T wave, representing the time for both ventricular depolarization and repolarization 
to occur 
QTc 
corrected QT 
RBC 
red blood cell 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SD 
stable disease 
SLL 
small lymphocytic lymphoma  
SOP 
standard operating procedure 
SPD 
sum of the products of greatest perpendicular diameters 
SRT 
safety review team 
StD 
standard deviation 

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STD10 
severely toxic dose in 10% of animals 
SUSAR 
suspected unexpected serious adverse reaction 
SYK 
spleen tyrosine kinase 
t1/2 
estimate of the terminal elimination half-life of the drug in plasma/serum, calculated by 
dividing the natural log of 2 by the terminal elimination rate constant (lz) 
TEAE 
treatment-emergent adverse event 
TLR 
Toll-like receptor 
Tmax 
time (observed time point) of Cmax 
TNFR 
tumor necrosis factor receptors  
TTR 
time to response 
ULN 
upper limit of normal 
US 
United States 
UK 
United Kingdom 
WBC 
white blood cell 
WHO 
World Health Organization 
WM 
Waldenstrom's macroglobulinemia 
 

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1. 
INTRODUCTION 
1.1. 
Background 
Non-Hodgkin lymphomas (NHL) 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 
8th 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% to 25% and 6% to 10% of new lymphomas, 
respectively {Dreyling 2007}. B-cell chronic lymphocytic leukemia (CLL) is the most common 
of the chronic leukemias in adults with approximately 20,000 new cases per year in the 
European Union (EU) 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, SLL, 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 PFS is only 
40% with activated B-cell (ABC) DLBCL compared to 74% with GCB-DLBCL. 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 (formerly 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 LLC 2016}. 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. As of January 2015, this study 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.  
Another BTK inhibitor, ibrutinib, which is approved in the US and EU 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, they are considered potential risks for 
tirabrutinib.  
Preliminary in vitro data from ABC-DLBCL, MCL, and CLL samples have shown additive or 
synergistic growth inhibition when combining the BTK inhibitor tirabrutinib and the 
phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor idelalisib, and additive growth inhibition 
when combining the tirabrutinib with the spleen tyrosine kinase (SYK) inhibitor entospletinib, 
suggesting the potential for improved and more durable responses with combination treatment. 
Based on these data, tirabrutinib is being evaluated in combination with idelalisib or 
entospletinib for the treatment of the B-cell lymphoproliferative malignancies, including CLL, 
MCL, WM, FL, SLL, MZL, and non-GCB DLBCL. 

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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 and SLL in the EU for 
adult CLL patients who are previously untreated of have received at least 1 prior therapy. 
{Pharmacyclics LLC 2016}. 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), 17 subjects (60.7%) had a partial response (PR), and overall response 
was missing for 1 subject (3.6%). The Kaplan Meier (KM) estimate of median duration of 
response (DOR), median progression-free survival (PFS) and median overall survival (OS) was 
not reached.  
Cell 
mombran 
ento-
s letinb 
8-cell 
proliferation, 
dlff r ntl tlon, 
nd surviv I 
rch 

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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}. Overall response rates with these regimens in this patient population range from 
28% to 63%, with median PFS of 3 to7 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 progression-free survival. 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, 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]).  

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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 
complete responses, and duration of response ranging from 2.8 to 18.8 months {Pharmacyclics 
LLC 2016}. In Study ONO-4059POE001, 1 of 2 subjects with WM responded to tirabrutinib. 
1.2.2. 
Tirabrutinib Nonclinical Pharmacology and Toxicology 
 
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. Potentiation of tirabrutinib activity was achieved in combination with other BCR 
inhibitors, idelalisib and entospletinib, and with a BCL-2 inhibitor. tirabrutinib efficacy in an 
in vivo model of ABC-DLBCL was enhanced when combined with anti-CD20 therapeutic 
monoclonal antibodies. Thus, evaluation in nonclinical models of B-cell malignancies 
demonstrated the nonclinical activity of tirabrutinib for inhibiting BCR- induced signaling, and 
suppressing the growth and survival of malignant B cells in vitro and in vivo. 
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. 
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 (PBMCs) 
and in ABC-DLBCL-derived cell lines. 
For further information on tirabrutinib, refer to the current edition of the Investigator’s Brochure 
(IB). 
1.2.2.1. 

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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]-tirabrutinib 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]-tirabrutinib 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 was found to be a substrate for the hepatic update 
transporters OATP1B1 and OATP1B3. Tirabrutinib is not a CYP inducer. Tirabrutinib inhibited 
CYP2C8, 2C9 and 2C19, the respective inhibition constant (Ki) values were 7.02, 8.31 and 
14.4 μmol/L. Tirabrutinib resulted in mechanism based inhibition of CYP3A4/5 at 10 μmol/L. 
Tirabrutinib is a P-glycoprotein (P-gp) substrate, whereas tirabrutinib inhibited human P-gp, with 
an IC50 value of 26.8 μmol/L. In addition, tirabrutinib showed inhibitory potential for several 
other transporters including OAT3, OATP1B1, MATE1, OCT1 and OCT2. 
Refer to the IB for additional information on tirabrutinib. 
 
Nonclinical Toxicology 
Nonclinical safety pharmacology studies of tirabrutinib showed no significant adverse effects on 
central nervous, respiratory or cardiovascular system functions at the exposure observed at 
tirabrutinib 320 mg once daily in humans.  
Nonclinical safety pharmacology parameters measured in the single dose and 28-day repeat dose 
tirabrutinib studies in rats and cynomolgus monkeys showed no significant adverse effects on 
central nervous, respiratory, or cardiovascular system functions at the projected exposure of the 
human target dose of 320 mg once daily. In rats, CNS signs prior to death or euthanasia in 
moribund condition included decreased spontaneous activity, decreased respiratory rate 
(bradypnea), decreased stool volume, lacrimation and severe body weight decreases at a dose of 
≥ 1000 mg/kg/day. In monkeys, morbidity and mortality was seen at doses of 1000mg/kg/day 
and 1 monkey was euthanized in moribund condition at a dose of 100 mg/kg/day CNS signs 
1.2.2.2. 
1.2.2.3. 

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ataxic gait, increased grooming, abnormal posture (sitting or prone position), decreased 
spontaneous activity, and/or somnolence. No microscopic correlates were identified in central or 
peripheral nervous system tissues or skeletal muscle. The no-observed-adverse-effect level 
(NOAEL) for CNS effects was 100 mg/kg in rats and 30 mg/kg in monkeys. 
Increased risk of QT prolongation is not expected based on hERG studies, but subjects will be 
monitored closely for QT changes through frequent ECGs at or around Cmax throughout this 
Phase 1 trial. 
The following target organs/systems were identified in the nonclinical toxicology studies: 
pancreas in rats and monkeys, adrenal glands in rats, and lesser effects on the liver and thyroid 
gland in rats. Lesser effects on the liver and thyroid gland in rats are consistent with induction of 
metabolic enzymes in hepatocytes and compensatory hypertrophy of the thyroid gland in rats and 
of limited significance to humans.  
In the pancreas, fibrosis in the islets of Langerhans and intra-islet regions and/or lobules, often 
accompanied by inflammation and hemorrhage were seen in rats after 4 weeks of repeated daily 
oral administration of doses ≥ 10 mg/kg/day tirabrutinib. The frequency of pancreatic findings 
increased with increasing dosing duration through 26 weeks of daily dosing. Microscopic 
findings were at least partially reversible after a 4- or 8-week non-dosing recovery period 
following up to 26 weeks of repeated daily dosing. There was no effect on exocrine pancreatic 
function as measured by blood amylase and lipase concentrations. Fasting insulin concentrations 
were decreased after 12 and 26 weeks of daily oral dosing with 300 mg/kg/day tirabrutinib, but 
were fully reversible after a 4 to 8 week non-dosing recovery period. In monkeys, focal 
interstitial hemorrhage in the pancreas and angiectasis in the islets were seen after 4-weeks of 
repeated daily administration of doses ≥ 10 mg/kg/day and at doses of ≥ 3 mg/kg in males 
and ≥ 1 mg/kg in females after 13 weeks of repeated daily administration. These findings were 
unassociated with inflammation or fibrosis in monkeys, unassociated with decreases in fasting 
insulin levels, reversible after a 4-week non-dosing recovery period.  
Tirabrutinib inhibited the production of several pro-inflammatory cytokines by human immune 
cells ex vivo (eg, IL-6, TNF-α, MCP-1, MIP-1α, IL-1β, IL-8, and IFN-γ) but did not inhibit the 
production of pro-inflammatory cytokines including by isolated rat pancreatic islet cells in 
primary culture. In contrast, tirabrutinib increased the production of selected pro-inflammatory 
cytokines IL-1β and IFN-γ in rats and TNF-α and IL-8 monkey immune cells ex vivo. For this 
reason, it is considered unlikely that tirabrutinib administration will produce inflammatory 
changes in the human pancreas as compared with changes seen in the pancreas of rats and 
monkeys. 
The NOAEL for pancreatic toxicity was 3 mg/kg/day in rats, 1 mg/kg/day in male monkeys, and 
less than 1 mg/kg/day in female monkeys. Mean exposure (AUC0-24h) corresponding to these 
NOAELs were 686 ng•h/mL in rats and 286 ng•h/mL in monkeys. This corresponds to projected 
exposure margins of approximately 0.05-fold to 0.1-fold based on mean exposure 
of 5231 ng•h/mL AUC0-24h in humans at a dose of 320 mg administered orally once-daily.  
Clinically significant changes in amylase, lipase, and glucose have not been noted in Study 
ONO-4059POE001, but these serum parameters will be monitored closely in clinical trials. 

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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 2 to 24 times 
the mean exposure in CLL patients receiving 80 or 600 mg tirabrutinib once daily. Tirabrutinib is 
not considered genotoxic and is considered not to have the potential to induce phototoxicity. In a 
TDAR assay in rats, tirabrutinib slightly decreased the anti-KLH IgM and/or IgG titers at doses 
of 10 mg/kg or higher. These changes were reversible and considered to be consistent with 
expected pharmacologic effects of BTK inhibition by tirabrutinib. 
In pre-clinical testing, tirabrutinib significantly suppressed adenosine 5’-diphosphate sodium salt 
(ADP) and collagen-induced platelet aggregation in vitro at concentrations of ≥ 10 μmol/L in 
platelet-rich plasma derived from healthy human volunteers. The NOEL of 6 μmol/L 
(2.73 μg/mL) corresponds to an estimated exposure multiple of approximately 2.2-fold above the 
observed Cmax of 1.26 μg/mL at 320 mg. In contrast, tirabrutinib did not induce platelet 
aggregation in platelet-rich plasma at concentrations up to the highest tested concentration of 
100 μmol/L (45.5 μg/mL) in the absence of aggregation inducers. This corresponds to an 
estimated exposure multiple of approximately 79-fold above the observed Cmax of 1.26 μg/mL at 
320 mg. 
The tirabrutinib clinical starting dose of 20 mg is ≥ 968- and 29- fold lower than the severely 
toxic dose in 10% of rats (STD10) and highest non-severely toxic dose (HNSTD) in the monkey 
when converted to a human equivalent dose (HED). Further, projected exposures at the proposed 
efficacious dose of 320 mg in the Phase 1 study are 2.8- to 8.6-fold (males/females) and 2.8-fold 
lower than exposures at the STD10 in the rat and HNSTD in the monkey. Overall, the 
nonclinical pharmacology and toxicology data support the potential clinical utility of tirabrutinib 
in the treatment of B-cell malignancies. 
A more detailed summary of findings from studies of tirabrutinib in rats and dogs is available in 
the IB. Investigators should refer to this document prior to initiating therapy with tirabrutinib. 
1.2.3. 
Clinical Trials of Tirabrutinib 
As of 1 March 2016, 7 clinical studies of tirabrutinib are ongoing. 
Ongoing Clinical Trials 
• Study ONO-4059POE001, An Open-Label, Multi-Center, Non-Randomized Phase 1 
Dose-Escalation Study to Investigate the Safety and Tolerability of tirabrutinib Given as 
Monotherapy in Patients with Relapsed/Refractory Non-Hodgkin’s Lymphoma (NHL) and 
relapsed/Refractory Chronic Lymphocytic Leukemia (CLL). This study has completed 
enrollment and all remaining subjects had transitioned to the long-term follow-up study, 
GS-US-401-1787, as of 31 December 2015. Data analysis and clinical study report are in 
progress. 
• Study ONO-4059-01: An open-label, multi-centre, non-randomised phase 1 dose-escalation 
study of tirabrutinib given as monotherapy in Japanese patients with relapsed/refractory 
B-NHL and CLL. No data are available to date. 

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• Study GS-US-401-1787, An Open-label Study to Assess the Long-term Safety and Efficacy 
of tirabrutinib in Subjects with Relapsed/Refractory B-cell malignancies: An open-label, 
multi-center, long term extension study comprised of subjects from ONO-4059POE001. No 
data are available to date. These subjects may transition to Study GS-US-401-1757 for 
long-term safety monitoring. Study GS-US-401-1787 will be closed once all subjects 
complete this transition. 
• Study GS-US-401-1767, a Phase 1, partially-blinded, single-dose, crossover, multiple-cohort 
study of capsule and tablet formulations of tirabrutinib to evaluate the relative bioavailability 
(rBA), food effect, and interaction with a proton pump inhibitor (PPI), omeprazole, in 
healthy subjects. The data indicates that there was no difference in plasma exposure 
(Cmax and AUC) of tirabrutinib between the capsule formulation and the 10% and 33% drug 
load formulation tablets when administered as a single 100-mg dose in the fasted state. This 
data supports switching from capsules to tablets without adjusting dosage. There was a slight 
increase in Cmax when the low drug load (10% w/w) tablet and high drug load (33% w/w) 
tablet was administered with a high-fat meal (19% and 38%, respectively) versus a fasted 
state, and minimal change in AUCinf (13% and 11% increase, respectively). There was a 
modest decrease in Cmax (37%) and minimal change in AUCinf (11% decrease) when the 
capsule was administered with a high-fat meal. Based on the wide dose/exposure range of 
tirabrutinib evaluated in subjects with B-cell malignancies that was shown to be well 
tolerated, the effect of food on tirabrutinib PK is not considered clinically relevant. As such, 
tirabrutinib may be administered without regard to food. Coadministration of omeprazole at 
20 mg (with a 5-day pretreatment at 20 mg once daily) with the tirabrutinib capsule 
formulation resulted in no change in AUC with a slight decrease in Cmax (20%) that was not 
considered clinically relevant. Coadministration of omeprazole 20 mg did not significantly 
alter the PK of the tirabrutinib low drug load (10% w/w) tablet. The 33% drug load 
formulation tablet was not evaluated in combination with omeprazole, but it is expected to 
perform similar to the low drug load (10% w/w) tablet formulation in combination with the 
gastric acid reducing agent omeprazole based on the comparable PK of the 2 formulations 
observed in the relative bioavailability and food effect cohorts. As such, tirabrutinib tablets 
may be co-administered with PPIs such as omeprazole.  
• Study GS-US-401-1765, an open-label, crossover, Phase 1 study to evaluate the effects of a 
single dose and multiple doses of rifampin on the PK of tirabrutinib in healthy subjects. A 
total of 15 subjects were enrolled; 14 subjects completed the study with 1 subject choosing to 
withdraw consent. There was a small increase in tirabrutinib exposure (~30% increase in 
Cmax and ~11% increase in AUC) when co-administered with a single dose of rifampin 
600 mg. The slight increase in tirabrutinib exposure observed in combination with single 
dose rifampin is not considered clinically relevant and does not preclude coadministration of 
OATP1B1/1B3 inhibitors. The half-life of tirabrutinib was unchanged and the exposure 
(Cmax and AUC) of tirabrutinib was significantly decreased (~70%) following multiple doses 
of the inducer rifampin. Exclusion of strong CYP3A4/P-gp inducers such as rifampin 
(i.e. PXR agonists) in combination with tirabrutinib in long-term clinical studies should be 
considered.  

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• Study GS-US-401-1768, a single-center, open-label, Phase 1, mass-balance study of 
tirabrutinib administered as a single, oral dose of radiolabeled [14C]- tirabrutinib in healthy 
subjects. tirabrutinib and its metabolites were eliminated in both urine and stool, with slightly 
more recovery in stool. Tirabrutinib was extensively metabolized and primarily eliminated as 
metabolites. Tirabrutinib metabolism involved oxidation, reduction, hydrolysis, 
N-acetylation, sulfation, glutathione conjugation, and glucuronidation. 
• Study GS-US-407-1833, an ongoing Phase 1, double-blinded, placebo-controlled, 
randomized study evaluating the safety and pharmacokinetics of tirabrutinib in two parts in 
healthy volunteers and subjects with rheumatoid arthritis (RA). The study consists of 
three planned cohorts: 10 healthy subjects randomized to receive 20 mg tirabrutinib 
(8 subjects) or tirabrutinib placebo-to-match-(2 subjects) orally once daily for 1 week; 
10 healthy subjects randomized to receive 10 mg tirabrutinib (8 subjects) or tirabrutinib 
placebo-to-match (2 subjects) orally twice daily for 1 week; and 20 subjects with RA 
randomized to receive 20 mg tirabrutinib (16 subjects) or tirabrutinib placebo-to-match 
(4 subjects) orally once daily for 4 weeks. The primary objectives are to assess the safety, 
tolerability and PK of tirabrutinib in healthy subjects and subjects with RA. This study is 
currently enrolling the RA cohort. 
For additional information, refer to the tirabrutinib IB. 
1.3. 
Idelalisib 
PI3Kδ is a central signaling enzyme that mediates the effects of multiple receptors and is critical 
for primary survival, proliferation, and homing signaling pathways active in malignant B-cells. 
Idelalisib (Zydelig®) is a PI3Kδ inhibitor which received accelerated approval in the US for the 
treatment of patients with relapsed FL and SLL who have received at least 2 prior systemic 
therapies and full approval in combination with rituximab for the treatment of patients with 
relapsed CLL for whom rituximab alone would be considered appropriate therapy due to other 
co-morbidities. Responses for SLL and FL were reported at 58% (0% CR) and 54% (8% CR) 
respectively with a duration of response of 11.9 months in SLL and not evaluable in FL. In CLL, 
the hazard ratio for PFS was 0.18 (95% CI; 0.10, 0.32) compared to rituximab alone.{Brown 
2014, Flinn 2014, Furman 2014}. Idelalisib as monotherapy or in combination with other agents 
(such as bendamustine, chlorambucil) and immunotherapy (rituximab, ofatumumab) has been 
shown to be tolerable and demonstrated clinical efficacy in clinical trials in patients with iNHL, 
CLL, and other hematological malignancies.  
The approved idelalisib dosing regimen is 150 mg twice daily (BID) administered as 
monotherapy or in combination with rituximab. Dose modification to 100 mg BID due to 
toxicity is included within prescribing guidelines.  
Idelalisib is metabolized primarily via aldehyde oxidase, and to a lesser extent via CYP3A and 
glucuronidation (UGT1A4). Its primary metabolite is GS-563117. Idelalisib is not an inhibitor of 
the metabolizing enzymes CYP1A2, CYP2B6, CYP2C, CYP2D6, CYP3A, or UGT1A1, or of 
the transporters P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Idelalisib’s 
primary metabolite, GS-563117, is also not an inhibitor of the metabolizing enzymes CYP1A2, 
CYP2B6, CYP2C, CYP2D6 or UGT1A1, or of the transporters P-gp, BCRP, OATP1B1, 
OATP1B3, OAT1, OAT3, or OCT2.  

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The metabolite, GS-563117, however, is a mechanism-based inhibitor of CYP3A (KI = 0.18 μM, 
kinact = 0.033 min-1) which may have implications for coadministration with tirabrutinib which 
has been identified as a CYP3A substrate. In a clinical study the coadministration of idelalisib 
with midazolam, a probe CYP3A substrate, resulted in a ~140% increase in Cmax and a 
~440% increase in AUCinf of midazolam due to the CYP3A inhibition by GS-563117. 
Accordingly, idelalisib is considered to be a strong CYP3A inhibitor.  
For current information about idelalisib (Zydelig®), refer to the idelalisib IB. 
1.4. 
Entospletinib  
Entospletinib is a potent and highly selective inhibitor of spleen tyrosine kinase (SYK) that is 
being developed by Gilead for oral administration in the treatment of hematologic malignancies 
and chronic graft versus host disease. 
Studies have suggested a role for the dysregulation of SYK in B-cell malignancies. SYK is 
expressed in B cells and is essentially involved in multiple signal transduction pathways 
downstream of the BCR. SYK trans-autophosphorylates and activates effector molecules such as 
phospholipase C gamma (PLCγ), PI3K, and mitogen-activated protein kinase (MAPK), and their 
associated signaling pathways, to induce an array of B-cell responses, including: proliferation, 
survival, differentiation, and apoptosis. In B-cell malignancies, including CLL, DLBCL, FL, 
MCL, MZL, and B-lineage acute lymphoblastic leukemia {Efremov 2011}, the BCR can deliver 
antigen-independent signals that have also been postulated to require SYK activity. Therefore, 
inhibition of BCR-mediated SYK activity is an attractive therapeutic target which could inhibit 
the proliferation and survival of malignant B cells. 
Preclinical evidence suggests that SYK inhibition may have independent benefit from BTK 
inhibition in B-cell malignancies. As a proof-of-concept in vitro, treating CLL B cells from an 
ibrutinib-resistant patient with a SYK inhibitor resulted in a potent anti-proliferative response. 
As of Amendment 9, Gilead has conducted an overall assessment of the entospletinib 
development program and has made a decision to discontinue entospletinib from further 
development. Therefore, supply of entospletinib to subjects on this study will be limited to 
31 December 2020. Subjects who are currently treated with entospletinib as part of a 
combination regimen with tirabrutinib will stop receiving entospletinib by 31 December 2020 
but may continue to be treated with tirabrutinib monotherapy. 
1.4.1. 
Nonclinical Pharmacology 
Entospletinib is an adenosine triphosphate (ATP) competitive inhibitor of SYK with an EC50 of 
8.5 ± 3.6 nM. Entospletinib binds in the ATP pocket of the SYK active site and disrupts the 
kinase activity of the enzyme. Kinase selectivity profiling showed a > 14-fold selectivity of 
entospletinib for SYK versus 359 non-mutant kinases and no significant binding (< 50%) to 
67 ion channels, transporters, and receptors screened at 1 µM entospletinib. No significant 
off- target or adverse pharmacological effects of clinical relevance were noted in preclinical 
evaluations. 

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Entospletinib was evaluated in a battery of safety pharmacology studies. The IC50 for the 
inhibitory effect of entospletinib on human ether-à-go-go-related gene (hERG) potassium current 
in vitro was estimated to be > 1 μM. In dogs, entospletinib caused small increases in heart rates 
at doses ≥ 15 mg/kg, but had no effects on electrocardiograms (ECGs) or blood pressure at up to 
150 mg/kg, the highest dose evaluated. Because entospletinib is 97.3% protein bound in human 
plasma and the total plasma concentration of entospletinib is in the 1 to 3 micromolar range, with 
a corresponding range of free entospletinib of 27 to 81 nM, it is unlikely that a clinically relevant 
effect on QT interval would occur.  
No entospletinib related effects were noted on neurological or respiratory function in rats at 
doses up to 1000 mg/kg. 
For further information on nonclinical pharmacology, refer to the entospletinib IB. 
1.4.2. 
Nonclinical ADME 
High bioavailability of entospletinib was observed in nonclinical species. Consistent with this 
finding, entospletinib showed high permeability across Caco-2 monolayers and low potential for 
efflux. Despite high plasma protein binding, entospletinib had a moderate volume of distribution, 
close to that of total body water. The systemic clearance was low in rats, moderate in dogs, and 
moderate to high in monkeys. 
Single-day dose escalation of entospletinib administered orally to rats, dogs, and monkeys 
showed a less than dose proportional increase in entospletinib systemic exposure in all species 
over the dose ranges tested.  
Entospletinib showed good metabolic stability with human hepatic material in vitro. Therefore, 
clearance through metabolism in humans is expected to be low. The primary routes of 
metabolism of entospletinib involved oxidative opening of the morpholine ring as well as further 
oxidation or conjugation. In vitro data indicates entospletinib is primarily metabolized by 
CYP2C9 and to a lesser extent by CYP3A and CYP1A2. Metabolism followed by biliary 
excretion is likely the major route of elimination of entospletinib and its metabolites, as < 5% of 
the radiolabeled dose administered orally to rats was recovered in urine. 
Entospletinib is an inhibitor of UGT1A1 and may transiently inhibit UGT1A1 activity in vivo at 
the expected clinical concentrations. Entospletinib is also an inhibitor of the uptake transporters 
OATP1B1 and OATP1B3 as well as the efflux transporters P-gp and BCRP with an IC50 value of 
approximately 2 μM for each of these transporters. Entospletinib may affect the activity of these 
transporters in vivo at the expected clinical concentrations and could transiently affect the 
disposition of other drugs, although high plasma protein binding (> 97%) may mitigate some of 
the potential drug-drug interactions at clinically relevant doses.  
Entospletinib is unlikely to cause clinically relevant drug interactions through inhibition of 
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 and is not a substrate 
for OATP1B1, OATP1B3, or OCT1.  

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For further information on nonclinical drug metabolism and pharmacokinetics, refer to the 
entospletinib IB. 
1.4.3. 
Nonclinical Toxicology 
Entospletinib was well tolerated in single-dose studies at doses of 1000 mg/kg in dogs, and 
cynomolgus monkeys. In repeat-dose studies in rats, entospletinib was well tolerated for 14 days 
at doses of 1000 mg/kg/day and for 4 weeks at 50 mg/kg/day. In dogs, entospletinib was well 
tolerated for 7 days at 50 mg/kg/day and for 4 weeks at 10 mg/kg/day. In cynomolgus monkeys, 
entospletinib was well tolerated for 13 weeks at 100 mg/kg/day which was the highest dose 
tested as dosing higher than that did not increase exposure. In rabbits, it was tolerated for 7 days 
at 300 mg/kg/day. 
The target organ(s) of toxicity identified in rats was the duodenum (enteropathy), and in rabbits 
and dogs were predominantly the gastrointestinal tract (hemorrhage and/or inflammation) and 
lymphoid organs. No target organs were identified in the cynomolgus monkeys.  
Additional organs potentially affected in individual dogs at higher doses included gallbladder, 
pancreas (rabbits and dogs), urinary bladder, and epididymis. Gastrointestinal tract toxicity in 
rats, rabbits, and dogs was associated with decreased food consumption and/or decreased body 
weight or body weight gain. However, decreased food consumption and body weight changes, in 
rabbits and dogs also occurred at doses lower than those which showed histological evidence of 
gastrointestinal toxicity. 
Increases in total and/or indirect bilirubin in rats, rabbits, and dogs were observed at 
≥ 30 mg/kg/day and may have been due to the inhibition of the enzyme UGT1A1. As no 
histological evidence of hepatobiliary toxicity was noted concurrently with bilirubin increases in 
entospletinib-treated rats or dogs, and entospletinib levels above the IC50 for UGT1A1 were 
achieved in serum, this seems a plausible mechanism for the noted increases in bilirubin. 
Hemorrhage and/or sinus erythrocytosis in lymph nodes with decreases in red cell mass in 
individual animals was noted in rabbits and dogs, but not in rats or cynomolgus monkeys. 
Although the mechanism for these changes is not clear, rodents with SYK deficiency or 
SYK-deficient bone marrow have been associated with hemorrhage, the latter in the presence of 
normal bleeding times, suggesting normal platelet function {Turner 2000}. No evidence of 
altered coagulation parameters were noted at any dose level in the entospletinib nonclinical 
studies and no biologically relevant effects were noted in an in vitro study of platelet 
aggregation. Other inhibitors of SYK have been found to have no effect on platelet function at 
efficacious dose levels in patients with rheumatoid arthritis (RA) as determined by ex vivo 
assays, and similarly, SYK inhibition has not been found to affect bleeding time in rodents 
{Braselmann 2006}.  
Adverse effects on lymphoid tissues including spleen, lymph nodes, and/or the thymus were 
noted in rabbits and dogs, but not in rats or cynomolgus monkeys despite higher exposures 
achieved in rats and monkeys. Recently, published data demonstrated that species-specific 
lymphoid changes can occur in dogs, but not in rats, cynomolgus monkeys, or humans treated 

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with small molecule kinase inhibitors that inhibit pathways that overlap with SYK signaling 
pathways; rabbits were not evaluated {Morris 2010}. Lymphoid toxicity also occurs in dogs 
treated with p38α MAPK inhibitors, but not in rats or cynomolgus monkeys despite higher 
exposure levels achieved in these species. There has been no evidence of significant 
immunotoxicity in clinical trials with p38α MAPK inhibitors. The relevance of the findings in 
rabbits and dogs to humans is unknown. 
Entospletinib was negative in bacterial mutation, in vitro chromosomal aberration, and rat 
micronucleus assays and is, therefore, considered non-genotoxic. Dose-range finding 
embryo-fetal developmental toxicity studies have been completed in rats and rabbits. Maternal 
toxicity was demonstrated by dose-dependent decreases in the body weight gains of the dams. 
Dose-dependent developmental findings included increased incidence of early and late fetal 
resorptions at 500 mg/kg/day (rat only) and reduced fetal weights (500 and ≥ 15 mg/kg/day; rats 
and rabbits, respectively) which correlated with the maternal toxicity. 
For further information on nonclinical toxicology, refer to the entospletinib IB. 
1.4.4. 
Clinical Trials 
Entospletinib has been administered to 540 subjects (328 healthy subjects, 7 subjects with RA, 
76 subjects with CLL, and 155 subjects with NHL) in 11 Phase 1 and Phase 2 clinical studies. 
Single agent efficacy has been demonstrated with entospletinib in subjects with relapsed or 
refractory hematologic malignancies (CLL, MCL, DLBCL, FL, LP, WM, SLL, or MZL). PFS 
rates are 70.1% (95% CI: 51.3%, 82.7%) at 24 weeks for subjects with CLL (n=41) and 
50.2% (95% CI: 29.3%, 67.9%) at 24 weeks in subjects with FL (n=41).  
The most common AEs (observed in ≥ 15% of subjects) in hematology patients receiving 
entospletinib alone (n = 186) include fatigue (52.5%), nausea (43.3%), diarrhea (40.8%), 
decreased appetite (27.1%), constipation (23.8%); cough (22.5.0%), dizziness (19.6%), pyrexia 
(18.8%), vomiting (18.3%), headache (17.9%), dyspnea (16.7%), insomnia (15.8%), dehydration 
(15.0%), and upper respiratory infection (15.0%). Thirty four subjects (14.2%) reported an AE of 
rash.  
Entospletinib is expected to produce asymptomatic and transient elevations of unconjugated 
(indirect) bilirubin due to inhibition of UGT1A1. In studies of subjects with hematologic 
malignancies, 9 of 252 subjects had elevations of direct bilirubin with the onset of elevation 
ranging from Day 8 to 85, except for 1 subject at Day 169. Bilirubin elevations were generally 
self-limited and did not result in discontinuation of entospletinib. 
In a phase 2, open label study evaluating the efficacy, safety, tolerability, and pharmacodynamics 
of the combination of entospletinib (MSA formulation) and idelalisib administered twice daily 
over multiple 28 day cycles to subjects with relapsed or refractory lymphoid malignancies, 
pneumonitis was reported in 12 of 66 subjects (18.2%), leading to the discontinuation of further 
evaluation of this combination. All subjects were to receive treatment with entospletinib and 
idelalisib twice daily under fasted conditions and the study allowed intra-subject dose escalations 
every 2 weeks. Of the 12 pneumonitis AEs, 11 (91.7%) were SAEs, 7 were Grade 3, 2 were 

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Grade 4, and 2 were Grade 5. The protocol was amended to allow a subset of subjects to receive 
monotherapy with entospletinib after a 14 to 28 day washout period with no subsequent cases of 
pneumonitis reported. Pneumonitis has not been identified as a risk with entospletinib 
monotherapy. 
Other AEs of interest included diarrhea (28.8%), rash (16.7%) and transaminase increase 
(21.2%). Increased transaminases were noted in some subjects approximately 2 weeks after 
completion of study drug.  
For current information about clinical studies, refer to the entospletinib IB. 
1.5. 
Obinutuzumab 
Obinutuzumab is a humanized and glycoengineered monoclonal antibody (mAb), derived by 
humanization of the parental B-Ly1 mouse antibody and subsequent glycol-engineering leading 
to the following characteristics {Mössner 2014}: 
• High affinity binding to CD20 type II epitope. 
• Increased antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) 
{Herter 2014}related to an improved binding of the antibody to the different allotypes of 
FcγRIIIa expressed by natural killer (NK) cells and monocytes. 
• Low complement-dependent cytotoxicity (CDC) activity related to the recognition of the 
CD20 type II epitope and the lack of CD20 localization into lipid rafts after binding of mAb 
to CD20. 
• Increased direct cell death induction related to an elbow hinge amino exchange of the 
Fragment antigen-binding (Fab) region and the recognition of CD20 type II epitope. 
Study CLL 11 compared the safety and efficacy of 3 regimens: chlorambucil vs. rituximab + 
chlorambucil vs. obinutuzumab + chlorambucil in previously untreated patients with CLL with 
either a cumulative illness rating scale score (CIRS) > 6 or creatinine clearance < 70 ml/min 
{Goede 2014}. The median age of subjects was 73 years old. The results show superiority of 
obinutuzumab + chlorambucil, with median PFS of 27 months compared to 16 months 
chlorambucil + rituximab and 11 months for chlorambucil alone. There was a statistically 
significant improvement in OS with obinutuzumab + chlorambucil vs chlorambucil (hazard ratio 
for death of 0.41; 95% CI, 0.23 to 0.74; P = 0.002). The CR rate was 21% with obinutuzumab + 
chlorambucil vs 7% with rituximab + chlorambucil. MRD negativity in the marrow was achieved 
in 19.5% of obinutuzumab + chlorambucil subjects vs only 2.6% of those receiving rituximab + 
chlorambucil. Infusion-related reactions and neutropenia were more common with obinutuzumab 
arm than with the rituximab arm, but the risk of infection was not increased. Most 
infusion-related reactions occurred with the first infusion of both CD20 antibodies, with overall 
frequency of 65% with obinutuzumab (20% Gr 3/4) and 27% with rituximab (3% Gr 3/4). Due to 
the high frequency of Day 1 infusion-related reactions, the study was amended to split the first 
dose of 1000 mg over 2 days (100 mg on Day 1 and 900 mg on Day 2), this leading to partial 
amelioration of the reactions. 

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The safety and efficacy of obinutuzumab combined with idelalisib 150 mg twice daily or 
chlorambucil has been evaluated in a randomized, open-label Phase 3 study (GS-US-312-0118). 
The safety run-in of 8 subjects treated with obinutuzumab and idelalisib with a follow-up 
duration ranging from 37 to 177 days underwent review in October 2015. Grade 3 or 4 treatment 
emergent AEs included neutropenia (n=4), thrombocytopenia (n = 2), anemia (n = 1), 
transaminase elevations (n = 3) and infusion reactions (n = 1) which were all manageable with 
conservative management or temporary treatment interruption and subsequent re-initiation of 
idelalisib.  
Obinutuzumab (Gazyva®/Gazyvaro®) is approved in the US and EU for use in combination with 
chlorambucil for the treatment of patients with previously untreated CLL. 
Obinutuzumab has also demonstrated an improvement in PFS (hazard ratio [HR], 0.48; 
95% confidence interval [CI], 0.34 - 0.68; P < .0001) in patients with relapsed FL when 
combined with bendamustine compared to bendamustine alone. Median progression-free 
survival was not reached in the obinutuzumab group, but was 13.8 months in the group receiving 
bendamustine alone. The most common Grade 3/4 hematologic adverse events included 
neutropenia (in 33.0% of the combination group and 26.3% of the monotherapy group), 
thrombocytopenia (10.8% vs 16.2%), anemia (7.7% vs 10.1%), febrile neutropenia 
(4.6% vs 3.5%), and leukopenia (1.0% vs 1.5%). The most common non-hematologic adverse 
events included vomiting, decreased appetite, and fatigue. 
For further information on obinutuzumab, refer to the approved local prescribing information. 
1.6. 
Rationale for This Study 
Despite an increase in the therapeutic options for B-cell lymphoma in the relapsed and refractory 
setting, complete responses are uncommon and treatment is usually administered chronically 
until toxicity or progression. An unmet need remains for novel targeted therapies that might 
improve complete response rates, improve progression free and overall survival, are associated 
with less toxicity, and/or require a shorter duration of therapy. 
Although more than half of patients have demonstrated improved PFS upon treatment with either 
ibrutinib (CLL, MCL, WM) or idelalisib (CLL, FL, SLL), as monotherapy, neither of these 
therapies alone are curative and complete responses are uncommon. Additionally, these and 
alternative agents are usually chronically administered until there is evidence of toxicity, 
intolerability, or disease progression, highlighting the need for more effective therapies across 
these diseases.  
Tirabrutinib, idelalisib and entospletinib each show significant single agent clinical activity in a 
variety of B-cell lymphoproliferative diseases. 
Pre-liminary in vitro data from ABC-DLBCL, MCL, and CLL cells have shown additive or 
synergistic growth inhibition when combining tirabrutinib and idelalisib or entospletinib, 
suggesting the potential for improved and more durable responses with combination treatment. 
While single mutations in drug targets have been shown to be sufficient for resistance to 

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single-agent therapy, combination therapy has the potential to improve duration of response by 
creating a higher threshold for the emergence of drug resistant malignant clones. Even with 
doses reduced from those used as single-agents, combining tirabrutinib and idelalisib in vitro 
demonstrated efficacy, supporting the possibility that low dose combinations of targeted agents 
may improve efficacy with less toxicity.  
The addition of an anti-CD20 antibody to CLL, iNHL, and DLBCL therapy has established 
benefit, with the potential superiority of obinutuzumab compared with rituximab demonstrated in 
CLL and iNHL (Genentech Inc 2016).  
1.6.1. 
Dose Rationale 
Tirabrutinib has been evaluated in a Phase 1 study conducted in the UK and France. As of the 
last formal data cutoff period of 30 April 2014, 69 subjects with CLL or NHL had received doses 
from 20 to 600 mg once daily. According to investigator reported IWCLL criteria (using a 
modified definition of partial response (PR) which includes PR with lymphocytosis), the CLL 
population demonstrated rapid reductions in lymphadenopathy between Cycle 1 and Cycle 3, 
accompanied by an increase in absolute lymphocyte count and durable responses over treatment 
up to 2 years. Subjects who demonstrated a very good clinical response during the first 6 months 
of treatment, but who started to exhibit signs of progression or who met the criteria for disease 
progression, but still showed evidence of clinical benefit in the opinion of the treating 
investigator prior to the end of the 6 months response assessment visit, had the option to increase 
their dose at, or after, their 6 month visit. The dose of tirabrutinib administered in these situations 
was limited to the highest dose that had been found to be safe and well tolerated in the dose 
escalation process up to that date. The ORR in CLL was 84% (21/25) and responses in NHL 
were also observed; 41% (7/17) in non-GCB-DLBCL, 60% (6/10) in MCL and WM 50% (1/2). 
No responses were observed in small subsets of FL (n =5), MZL (n = 1) and SLL (n = 1).  
In Study ONO-4059POE001, 480 mg once daily was identified as the MTD in the NHL cohort, 
based on DLT events of rash and non-immune reaction at the 600 mg once daily dose of 
tirabrutinib. No MTD was identified in the CLL cohort at dosing up to 600 mg once daily. There 
was no observed relationship (or trend) between the initial dose (20, 40, 80, 120, 240, 360, 400, 
and 480 mg) and the frequency of SAEs, overall AEs, drug-related AEs or Grade 3-5 AEs, in 
either disease cohort. 
Based on the promising early phase results, Gilead proposes to evaluate tirabrutinib both as a 
single agent in CLL and in combination with the PI3Kδ inhibitor, idelalisib, or the SYK 
inhibitor, entospletinib, in the following B-cell malignant lymphoproliferative diseases: CLL, 
SLL, MCL, WM, FL, MZL, and DLBCL. 
Subjects will be administered tirabrutinib once or twice daily and either idelalisib twice daily or 
entospletinib once or twice daily (based on the dose escalation level assigned), to evaluate the 
safety, tolerability, PK, and pharmacodynamics of tirabrutinib in combination with idelalisib or 
entospletinib. Obinutuzumab will be administered at the approved 1000 mg dose and schedule. 
The study will evaluate up to 376 subjects with relapsed or refractory FL, SLL, MCL, MZL or 

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WM who have received at least 2 prior therapies and for non-GCB-DLBCL (who are not 
transplant candidates) or CLL, at least 1 prior therapy. All subjects must have measurable disease 
at baseline by standard criteria. In addition, as of Amendment 9, up to 8 additional subjects from 
Study GS-US-401-1787 or previously enrolled in this study or Study GS-US-401-1787 who are 
currently receiving continued treatment via named patient use may be enrolled for long-term 
safety monitoring. 
In all arms of the study, antitumor activity will be evaluated at baseline and at appropriate 
intervals for specific malignancies using standard response criteria, with adjustment for 
redistribution lymphocytosis, consistent with the known effects of BTK and PI3Kδ inhibition. 
The results of this study will provide information on the safety profile of tirabrutinib alone and 
combined with idelalisib or entospletinib and obinutuzumab, and subjects will be monitored with 
regard to the incidence of AEs of interest, including diarrhea/colitis, transaminase elevation, 
rash, and pneumonitis, which have been reported with idelalisib and/or entospletinib 
administration and which may occur beyond the standard 28-day DLT window. Intra-subject 
dose escalation will not be permitted to evaluate the long-term safety of each dose level. 
Dose Rationale for tirabrutinib and idelalisib 
This study is a Phase 1b sequential dose-escalation study using a 3+3 design (maximum of 
6 subjects/cohort) to evaluate approximately 5 dose levels. The initial dose level tested will be 
20 mg tirabrutinib administered once daily combined with 50 mg of idelalisib administered 
twice daily. Tirabrutinib is a CYP3A4 substrate; co-administration with idelalisib, a CYP3A4 
inhibitor, may increase the exposure of tirabrutinib. Idelalisib is a strong CYP3A inhibitor at the 
registered dose of 150 mg twice daily, but is expected to be a moderate CYP3A inhibitor at the 
lower dose of 50 mg twice daily. A physiologically based pharmacokinetic model (PBPK) was 
used to simulate the drug-drug interaction of idelalisib 50 mg twice daily with the 
CYP3A4-sensitive substrate midazolam; plasma exposure (Cmax and AUC) of midazolam 
increased 1.8- and 2.6-fold, respectively. Thus, the exposure of 20 mg tirabrutinib once daily 
when administered with 50 mg idelalisib twice daily may be similar to the exposure of 
approximately 36 mg (estimate of Cmax) to 52 mg (estimate of AUC) tirabrutinib dosed as a 
single agent. Responses were observed in both CLL (1/3) and NHL (1/3) cohorts at 40 mg 
once daily in Study ONO-4059POE001and this dose is 1/12th of the MTD observed for the 
single agent in the NHL cohort. The initial idelalisib dose is proposed to be 50 mg BID, which is 
the lowest dose which demonstrated efficacy in a Phase 1 study of subjects with NHL or CLL. 
As preclinical data suggest synergistic effects in some cell lines, greater efficacy with less 
toxicity may be observed at doses which are lower than the dose used when either agent is given 
as monotherapy. Additional dosing regimens of idelalisib (up to 100 mg once daily) may also be 
considered based on emerging safety and efficacy data.  
The dose escalation for the combination of tirabrutinib and idelalisib will proceed with idelalisib 
remaining at 50 mg twice daily, while tirabrutinib will be increased by doses of ≤ 100% in each 
cohort. Once daily and twice daily dosing of tirabrutinib will be tested, as preclinical data 
suggests that twice daily dosing of tirabrutinib may provide greater efficacy than once daily 
dosing {Yoshizawa 2014}. The MTD for tirabrutinib once-daily will be determined separately 
from the MTD for tirabrutinib twice-daily.  

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Dose Rationale for tirabrutinib and entospletinib 
This study is a Phase 1b sequential dose-escalation study using a 3+3 design. The initial dose 
level tested in the tirabrutinib and entospletinib arm is proposed to be 40 mg tirabrutinib 
administered once daily combined with 200 mg of entospletinib administered once daily. This 
initial dose of tirabrutinib is chosen as a potentially minimally effective dose based on responses 
observed in both CLL (1/3) and NHL (1/3) cohorts at 40 mg of tirabrutinib once daily in Study 
ONO-4059POE001; this dose is 1/12th of the MTD observed for the single agent in the NHL 
cohort. Given that the entospletinib is not expected to lead to a clinically relevant change in 
tirabrutinib PK, the exposure of tirabrutinib at the 40 mg once daily in combination with 
entospletinib is expected to be similar to the exposure of tirabrutinib at the 20 mg once daily in 
combination with idelalisib. 
The initial dose of entospletinib in the combination arm will be 200 mg once daily. Entospletinib 
has been well tolerated at doses of up to 800 mg twice daily in patients with CLL. The dose and 
schedule used in the monotherapy setting resulted in consistent inhibition of a biomarker of SYK 
activity over the dosing interval. However, in vitro data indicates there may be additive or 
synergistic inhibition when entospletinib is combined with tirabrutinib. A 200 mg once daily 
dose of entospletinib is expected to provide plasma concentrations above EC50 for approximately 
12 hours a day and it is anticipated that target inhibition by entospletinib will be approximately 
24% at trough drug levels. Additionally, a starting dose of 200 mg of entospletinib once daily is 
1/8th the total daily dose that has been shown to be tolerated in patients. Additional dose 
levels/regimens of entospletinib (up to 400 mg once daily), may be studied based on emerging 
safety, efficacy, pharmacodynamic, and PK data. 
The dose escalation for the combination of tirabrutinib and entospletinib will proceed in 2 arms 
with entospletinib remaining at 200 mg once daily in Arm A, while tirabrutinib will be increased 
by ≤ 100% in each cohort. In Arm B, tirabrutinib will remain at 40 mg once daily, while total 
daily doses of entospletinib will be increased by ≤ 100% in each cohort. Additional dose level 
combinations may be evaluated based on emerging safety, efficacy, pharmacodynamic, and PK 
data. 
Dose Rationale for Single Agent tirabrutinib in Subjects with CLL 
The Phase 1 study, ONO-4059POE001 enrolled approximately 3 subjects with CLL at each dose 
level across a wide range of doses (20 mg to 600 mg once daily; total n = 28) and did not identify 
an MTD. No clear association between dose and toxicity was observed, but the small number of 
subjects at each dose level limited the ability to inform any firm conclusions. It is reassuring, 
however, that no SAE of a bleeding event in the CLL cohort occurred at a dose of < 400 mg.  
Evaluating an association of dose and efficacy was similarly limited by the small numbers of 
subjects in the ONO/GS-4059POE001 study; responses were observed in CLL at all dose levels 
but at doses ≥ 80 mg, all evaluable subjects reported a response, suggesting that 80 mg may be 
required in the single agent setting. In this ongoing study (GS-US-401-1757), early limited data 
suggests that full BTK occupancy of PBMCs requires once daily dosing of ≥ 40 mg. Taken 
together, this limited information suggests for subjects with CLL, single agent tirabrutinib at 
80 mg once daily may be an appropriate dose to maximize efficacy and minimize toxicity. The 

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addition of this single-agent arm with dose adjustments down to 40 mg once daily for toxicity 
and up to 160 mg once daily for lack of response (or progression) after at least 24 weeks of 
therapy will provide additional important data on the safety, tolerability and efficacy of the 
80 mg dose of tirabrutinib in the CLL patient population; which would be also important to 
demonstrate its contribution to the proposed combinations.  
1.6.2. 
Risk/Benefit Assessment for the Study 
Tirabrutinib 
In the completed Phase 1 study ONO-4059POE001, 90 patients with either NHL or CLL have 
received tirabrutinib at doses ranging from 20 to 600 mg per day for up to 3 years. Observed AEs 
were mainly Grades 1 and 2 in severity, and were most commonly infections, hematological 
abnormalities, skin disorders, gastrointestinal disorders, and general disorders. The majority of 
AEs were assessed by the investigator as not related to tirabrutinib. Hematological disorders and 
infections have been observed; irrespective of severity, the majority of these events did not 
preclude ongoing treatment. Grade 1 and 2 diarrhea has been observed in 20% and 4% of study 
participants, respectively. No Grade 3 or higher diarrhea attributed to tirabrutinib by the 
investigator has been reported. Bruising was observed frequently, although clinically-significant 
bleeding events (such as those requiring transfusions) were unusual and hemorrhage did not limit 
the ability to continue on therapy for the majority of subjects. 
In ongoing Study GS-US-401-1787 (rollover from Study ONO-4059POE001), AEs ≥ Grade 3 
assessed cumulatively from the beginning of Study ONO-4059POE001 (N = 90) were reported 
for 61 subjects (67.8%), most frequently neutropenia and thrombocytopenia (each 16 subjects, 
17.8%) followed by anemia (10 subjects, 11.1%) and lower respiratory tract infection 
(8 subjects, 8.9%). Overall, SAEs were reported for 44 subjects (48.9%). 
Please refer to the IB for more information. 
Idelalisib 
Idelalisib (Zydelig®) is a PI3Kδ inhibitor which is approved in 40 countries, including the US 
and EU, for the treatment of relapsed/refractory FL and CLL. Please refer to the SmPC for 
further information.  
Patients with lymphoid cancers receiving idelalisib have developed serious and fatal infections 
during therapy. Opportunistic infections, most notably PJP and CMV infection, have been 
reported with idelalisib, particularly in the context of concurrent myelosuppressive therapy such 
as rituximab and bendamustine. 
Based on data from the clinical development programs and post-marketing pharmacovigilance 
for idelalisib and other PI3K inhibitors {Flinn 2013} alone or in combination with chemotherapy 
or anti-CD20 antibodies, AEs including infection, diarrhea/colitis, transaminase elevation, rash, 
neutropenia, organizing pneumonia, and pneumonitis may be observed in subjects treated with 
idelalisib. Guidelines for managing these AEs have been incorporated into this protocol. The 
monitoring to be performed and the actions to be taken in response to toxicity are based on 
experience with interruption, dose modification, rechallenge, and re-escalation with idelalisib 
treatment.  

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In an embryo-fetal development study of idelalisib in rats, increased post-implantation loss, 
malformations (absence of caudal vertebrae and in some cases also of sacral vertebrae), skeletal 
variations, and lower fetal body weights were observed. Malformations were observed at 
exposures from 12 times the human exposure based on AUC. Effects on embryo-fetal 
development were not investigated in a second species. 
Entospletinib 
Entospletinib has been well tolerated across the 11 clinical studies in which it is being evaluated. 
Treatment emergent AEs commonly reported across the studies involving healthy volunteer 
subjects include headache, somnolence, and GI symptoms (nausea and abdominal pain), all of 
which were mild and reversible. 
Increased transaminases were noted in some subjects and were reversible.  
Entospletinib is an inhibitor of UGT1A1 and may transiently inhibit UGT1A1 activity in vivo at 
the expected clinical concentrations. Administration of drugs such as entospletinib that inhibit 
UGT1A1 are expected to increase total bilirubin due to decreased conjugation rather than liver 
dysfunction. The elevations in indirect bilirubin observed in clinical trials with entospletinib 
were generally self-limited and did not result in discontinuation of entospletinib.  
Spleen tyrosine kinase deficiency and SYK-deficient bone marrow in rodents have been 
associated with hemorrhage. In an ex vivo platelet function assay, entospletinib showed no 
biologically relevant inhibition or activation of platelets at concentrations up to 12.3 μM. No 
evidence of altered coagulation parameters was noted at any dose level in the entospletinib 
nonclinical studies.  
In rats the predominant organ affected was the duodenum, and in rabbits and dogs the 
gastrointestinal tract and lymphoid organs. No target organs were identified in the cynomolgus 
monkey. Oral administration of entospletinib to rats for up to 26 weeks or cynomolgus monkeys 
for up to 39 weeks showed no evidence of GI toxicity or lymphoid changes at exposures which 
overlapped with or exceeded those in dogs. Clinical assessments will monitor for signs and 
symptoms of infection, hemorrhage, GI distress, and changes in clinical pathology parameters 
(changes in hemoglobin, neutrophils, lymphocytes, liver enzymes, and total and indirect 
bilirubin) that could occur after entospletinib administration. Because evidence of lymphoid 
tissue depletion was noted in rabbits and dogs at high doses, clinical assessments will also 
include monitoring for signs and symptoms of infection.  
Obinutuzumab 
Obinutuzumab is an anti-CD20 monoclonal antibody approved in the US and EU for use in 
combination with chlorambucil for the treatment of patients with previously untreated CLL. It is 
also approved for use in the US and EU in combination with bendamustine for the treatment of 
patients with FL who are relapsed or refractory to rituximab-containing regimen. 

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The most common obinutuzumab-related adverse events are infusion related reactions and tumor 
lysis syndrome most commonly during the initial administration. Some patients receiving 
obinutuzumab have experienced cytopenias or infections. Obinutuzumab use has been associated 
with hepatitis B virus (HBV) reactivation and very rare cases of progressive multifocal 
leukoencephalopathy.  
Mitigation strategies are defined in the study design. To reduce the incidence and severity of 
obinutuzumab-related infusion reactions, established premedication regimens and infusion 
modification algorithms have been included (Section 5.3.1). To mitigate the risk of 
Pneumocystis jirovecii pneumonia, antibiotic prophylaxis is required (Section 7.5.1.6) 
To mitigate the risk of HBV reactivation, subjects will be excluded who screen positive for a 
prior history of or evidence of hepatitis B infection. 
Specific instructions for supportive care in response to myelosuppression are described. 
Investigators are instructed to institute prophylaxis and monitoring for tumor lysis syndrome for 
subjects with a high tumor burden, high circulating lymphocyte count (>25x109/L) or renal 
impairment (CrCl<70mL/min). 
Combination 
No potentially curative therapy exists for the patient population to be evaluated in this study. 
Dosing of each component in the dose escalation phase of this study starts at the lowest dose 
which may provide benefit to patients; the starting dose for tirabrutinib is < 1/12th of the MTD in 
monotherapy study, the starting dose of idelalisib is 1/3rd of the approved dose, and starting dose 
of entospletinib is 1/4th of the dose demonstrated to be tolerable in monotherapy study (no MTD 
identified).  
Assessments for AEs and monitoring for laboratory abnormalities will be conducted on Days 1, 
8, 15, and 22 of the first 28-day cycle. As toxicities related to study drug may manifest beyond 
the 28-day DLT window, no intra-subject dose escalation is allowed and frequent protocol 
mandated monitoring continues for all subjects beyond the first 28-day cycle: every 14 days until 
Week 24, then every 4 weeks, at the end of treatment, and at the 30-day safety follow-up visit. 
Physical examinations will be performed on Day 1 of each 28-day cycle until end of treatment 
followed by a 30-day safety follow-up visit. This monitoring frequency is considered to be 
sufficient to identify potential AEs as they emerge. 
In addition to initiating at low doses and disallowing intra-subject dose escalation, the expansion 
arms of up to approximately 30 subjects with a single disease type will provide the opportunity 
for close evaluation for potential long-term toxicities such as liver function test (LFT) elevations, 
rash, diarrhea, fatigue, or pneumonitis. Should they occur, these important safety events are 
expected to be relatively infrequent and therefore a sample size of up to approximately 
30 subjects will allow a larger degree of confidence in the safety and tolerability of these 
combinations prior to proceeding with future development. Additionally, guidelines for 
managing these AEs have been incorporated into this protocol including actions to be taken in 
response to toxicity including interruption, discontinuation, dose modification, and rechallenge. 

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In addition, the inclusion and exclusion criteria are designed to ensure subjects have acceptable 
organ function to be eligible for this study such that confounding significant co-morbidities are 
excluded. Subjects enrolling in the study are required to receive PJP prophylaxis per 
Section 5.3.2.1 and not have evidence of active CMV infection. Surveillance for active disease 
will occur approximately every 4 weeks throughout the course of treatment and if there is 
evidence of an active infection by clinical and laboratory assessments, the subject must 
permanently discontinue idelalisib and receive anti-CMV treatment according to local 
guidelines. Study medications will continue until disease progression, unacceptable toxicity, 
consent withdrawal, or subject’s refusal of treatment. 
1.6.3. 
Potential Benefits 
The potential benefits to a subject participating in this study include a higher likelihood of 
achieving a partial or complete response, and longer durability of the response compared to other 
available therapies. 
1.7. 
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 objectives of the study are: 
For the dose escalation phase:  
• To characterize the safety and tolerability of tirabrutinib combined with idelalisib or 
entospletinib in subjects with relapsed or refractory B-cell lymphoproliferative malignancies  
• To characterize the safety and tolerability of tirabrutinib combined with obinutuzumab and 
idelalisib or entospletinib in subjects with relapsed or refractory B-cell lymphoproliferative 
malignancies 
For the dose expansion phase: 
• To evaluate the preliminary efficacy of tirabrutinib combined with idelalisib or entospletinib 
in B-cell lymphoproliferative malignancies (subtype[s] to be determined based on the dose 
escalation phase) 
• To characterize the safety and tolerability and evaluate the preliminary efficacy of 
single-agent tirabrutinib in subjects with relapsed or refractory CLL. 
• To evaluate the preliminary efficacy of tirabrutinib combined with obinutuzumab and 
idelalisib or entospletinib in subjects with relapsed or refractory B-cell lymphoproliferative 
malignancies 
For long-term safety monitoring phase:  
• To evaluate the long-term safety of tirabrutinib as a monotherapy, and in combination with 
idelalisib or entospletinib, with or without obinutuzumab, in subjects with relapsed or 
refractory B-cell lymphoproliferative malignancies. 
The secondary objectives of the study are: 
For the dose escalation phase: 
• To evaluate the preliminary efficacy of tirabrutinib combined with idelalisib or entospletinib 
in subjects with relapsed or refractory B-cell lymphoproliferative malignancies 
• To evaluate the preliminary efficacy of tirabrutinib combined with obinutuzumab and 
idelalisib or entospletinib in subjects with relapsed or refractory B-cell lymphoproliferative 
malignancies 
• To evaluate the pharmacokinetics (PK) of tirabrutinib administered alone and in combination 
with idelalisib or entospletinib in subjects with relapsed or refractory B-cell 
lymphoproliferative malignancies 

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For the dose expansion phase: 
• To further characterize the safety and tolerability of tirabrutinib combined with idelalisib or 
entospletinib in subjects with a specific tumor subtype (to be determined)  
• To further characterize the safety and tolerability of tirabrutinib combined with 
obinutuzumab and idelalisib or entospletinib in subjects with a specific tumor subtype (to be 
determined) 
• To further characterize the safety and tolerability of tirabrutinib alone administered at 80 mg 
once daily in subjects with relapsed or refractory CLL. 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
I 
I 
I 

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3. 
STUDY DESIGN 
3.1. 
Endpoints 
The endpoints for this study are described in Section 8.1. 
3.2. 
Study Design 
This is a Phase 1b, open-label, multicenter, sequential dose-escalation study to evaluate the 
safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of tirabrutinib in 
combination with idelalisib or entospletinib in subjects with B-cell lymphoproliferative 
malignancies who have refractory or relapsed disease. The safety, tolerability, 
pharmacodynamics and efficacy of tirabrutinib in combination with obinutuzumab and idelalisib 
or entospletinib will also be evaluated in subjects with relapsed or refractory B-cell 
lymphoproliferative malignancies. 
3.2.1. 
Dose Escalation 
Subjects with B-cell malignancies who have refractory or relapsed disease will be sequentially 
enrolled at progressively higher dose levels in a standard 3 + 3 study design to receive oral 
tirabrutinib combined with idelalisib (Combination I) or entospletinib (Combination II).  
Once a dose level of the oral tirabrutinib combined with idelalisib or entospletinib has been 
deemed safe and tolerable, an additional cohort of subjects will be enrolled with the addition of 
obinutuzumab to the combination of oral targeted agents [tirabrutinib + idelalisib 
(Combination III) or tirabrutinib + entospletinib (Combination IV)]. Up to 2 dose levels for each 
triplet combination will be evaluated. 
The dose escalation rules are specified in Table 3-1, Table 3-2, Table 3-3, and Table 3-4. 
Combination I: Tirabrutinib and idelalisib: 
Initially, 3 subjects will enroll in Cohort 1A of Combination I; the starting dose will be 20 mg 
once daily of tirabrutinib and 50 mg twice daily of idelalisib. If a dose-limiting toxicity (DLT) 
occurs within 28 days from Cycle 1, Day 1 in Cohort 1A, this cohort will be expanded to enroll 
3 additional subjects. If ≥ 2 DLTs occur in Cohort 1A, (ie, ≥ 2 subjects experience DLTs) 
development of the combination of tirabrutinib and idelalisib will discontinue. 
If no DLT occurs in 3 subjects or < 2 DLTs occur in up to 6 subjects in Cohort 1A, then 
Cohort 2A will open. Cohort 2A will enroll 3 subjects with tirabrutinib dosed at 40 mg 
once daily and idelalisib 50 mg twice daily. Once enrollment is complete in Cohort 2A, 
Cohort 2B will enroll 3 subjects with tirabrutinib dosed at 20 mg twice daily and idelalisib 50 mg 
twice daily. Cohorts 2A and 2B will dose escalate independently and in parallel; if no DLT 
occurs in 3 subjects or < 2 DLTs occur in up to 6 subjects in Cohort 2A and Cohort 2B has 
completed enrollment, then the next 3 subjects will be enrolled in Cohort 3A with tirabrutinib 

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dosed at 80 mg once daily and idelalisib 50 mg twice daily. Similarly, if no DLT occurs in 
3 subjects or < 2 DLTs occur in up to 6 subjects at Cohort 2B, Cohort 3B will enroll 3 subjects 
with tirabrutinib dosed 40 mg twice daily and idelalisib 50 mg twice daily. Subsequent cohorts 
will enroll if no DLTs in 3 subjects or < 2 DLTs in up to 6 subjects are observed. If a second 
DLT is observed in any cohort, the maximum tolerated dose (MTD) of tirabrutinib combined 
with idelalisib will have been exceeded and the prior cohort will be the MTD. The MTD for 
tirabrutinib once-daily will be determined separately from the MTD for tirabrutinib twice-daily. 
A new cohort will not open for enrollment until the last subject has completed the 28-day safety 
period for the prior cohort. All available safety, tolerability, and PK data will be reviewed prior 
to proceeding to the next cohort. The design will be adaptive, with cohorts reduced or 
intermediate cohorts added based on emerging safety, PK, pharmacodynamics, and efficacy 
results. Additionally, either tirabrutinib once daily or tirabrutinib twice daily cohorts may be 
discontinued based on emerging safety and efficacy data. Subjects will return to the clinic for 
frequent evaluation and monitoring as per Appendix 2. If there is no evidence of clear benefit of 
twice daily dosing of tirabrutinib compared with once daily dosing based on available 
tolerability, efficacy, PK and pharmacodynamic data, dose escalation in the twice daily dosing 
arm may be terminated prior to identifying an MTD. Accordingly, as of 25 March 2016, 
enrollment in the cohorts evaluating twice daily dosing of tirabrutinib combined with idelalisib 
was discontinued due to 2 of 5 subjects reporting Grade 4 neutropenia (1 DLT with associated 
fever and infection and 1 DLT without) within the first 28 days of dosing in Cohort 2B. 
Subjects will return to the clinic for frequent evaluation and monitoring as per Appendix 2. 
The doses for each cohort are shown in the following table. 
Table 3-1. 
Dose Escalation for Combination I (of Tirabrutinib + Idelalisib) 
Dose Level 
Tirabrutinib 
idelalisib 
Tirabrutinib 
idelalisib 
 
A 
B 
1 
20 mg QD 
50 mg BID 
— 
— 
2 
40 mg QD 
50 mg BID 
20 mg BID 
50 mg BID 
3 
80 mg QD 
50 mg BID 
— 
— 
4 
80 mg QD 
100 mg QD 
— 
— 
5 
160 mg QD 
100 mg QD* 
— 
— 
QD= Once daily dosing, BID = Twice daily dosing, * Dose Level 5 (Combination I-A) will be limited to DLBCL only 
Once the MTD of the combination of tirabrutinib with 50 mg of idelalisib twice daily has been 
determined, based on safety and efficacy, additional cohorts may be enrolled at up to the MTD of 
tirabrutinib combined with 100 mg of idelalisib once daily.  

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Combination II: Tirabrutinib and Entospletinib  
Initially 3 subjects will enroll in Cohort 1A of Combination II; the starting dose will be 40 mg 
once daily of tirabrutinib and 200 mg once daily of entospletinib (Table 3-2). If a DLT occurs 
within 28 days from Cycle 1, Day 1 in Cohort 1A of Combination II, this cohort will be 
expanded to enroll 3 additional subjects. If ≥ 2 DLTs occur in Cohort 1A of Combination II, 
(ie, ≥ 2 subjects experience DLTs), development of the combination of tirabrutinib and 
entospletinib will discontinue. If no DLTs in 3 subjects or < 2 DLTs in up to 6 subjects are 
observed, then the dose will be escalated to Dose Level 2.  
Table 3-2. 
Dose Escalation for Combination II (Tirabrutinib + Entospletinib) 
Dose Level 
Tirabrutinib 
Entospletinib 
Tirabrutinib 
Entospletinib 
 
Combination II-A 
Combination II-B 
1 
40 mg QD 
200 mg QD 
— 
— 
2 
80 mg QD 
200 mg QD 
40 mg QD 
400 mg QD 
3 
150 mg QD 
200 mg QD 
80 mg QD 
400 mg QD 
4 
— 
— 
160 mg QD 
400 mg QD 
QD= Once daily dosing, BID = Twice daily dosing * Dose Level 4 (Combination II-B) will be limited to DLBCL only 
Dose Level 2 will consist of 2 cohorts: Cohort 2A with tirabrutinib 80 mg once daily and 
entospletinib 200 mg once daily and Cohort 2B with tirabrutinib 40 mg once daily and 
entospletinib 400 mg once daily. The first 3 subjects enrolled in Dose Level 2 will be assigned to 
Cohort 2A; the next 3 subjects will be assigned to Cohort 2B. 
Cohorts 2A and 2B will dose escalate independently; if 1 DLT occurs in Cohort 2A, then 
Cohort 2A will be expanded to enroll 3 additional subjects. Similarly, if 1 DLT occurs in 
Cohort 2B, then Cohort 2B will be expanded to enroll 3 additional subjects. If no DLT occurs in 
3 subjects or < 2 DLTs occur in up to 6 subjects in Cohort 2A then Cohort 3A may begin 
enrollment. Similarly, if no DLT occurs in 3 subjects or < 2 DLTs occur in up to 6 subjects in 
Cohort 2B then Cohort 3B may begin enrollment. 
If ≥ 2 DLTs are observed in Cohort 2A and < 2 DLTs occur in up to 6 subjects in Cohort 2B, 
then the MTD of tirabrutinib combined with entospletinib is 40 mg once daily. Cohort 3A will 
not be enrolled, however, Cohort 3B may continue with enrollment. 
Similarly if ≥ 2 DLTs are observed in Cohort 2B and < 2 DLTs occur in up to 6 subjects in 
Cohort 2A, then the MTD of entospletinib combined with tirabrutinib is 200 mg once daily. 
Cohort 3B will not be enrolled, however, Cohort 3A may continue with enrollment. 
A new cohort will not open for enrollment until the last subject has completed the 28 day safety 
period for the prior cohort. All available safety, tolerability, and PK data will be reviewed prior 
to proceeding to the next cohort. 

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The maximum dose to be tested will be 160 mg total daily dose of tirabrutinib and 400 mg total 
daily dose of entospletinib, however, the dose escalation will be adaptive, with cohorts for 
reduced dosing, intermediate dosing or different schedule (QD vs BID) added based on emerging 
safety, PK, pharmacodynamics, and efficacy results. Dose level 5 (Combination I-A) and Dose 
level 4 (Combination II-B) are limited to subjects with non-GCB DLBCL only. 
Combination III and Combination IV: The addition of obinutuzumab to Combination I 
or II 
Once a dose escalation cohort in Combination I or II has completed a 28 day safety review, an 
additional cohort of 3 (+3) subjects may be enrolled at this Dose Level with the addition of 
obinutuzumab. Up to 2 dose levels for each triplet combination may be evaluated. Initially 
3 subjects each will enroll at the chosen dose level(s) in Combination III and Combination IV in 
parallel (see Table 3-3). If 1 DLT occurs within 28 days from Cycle 1 in Combination III, the 
Combination III cohort will be expanded to enroll 3 additional subjects. Similarly if 1 DLT 
occurs within 28 days from Cycle 1 in Combination IV, the Combination IV cohort will be 
expanded to enroll 3 additional subjects. If ≥ 2 DLTs occur in Combination III or IV, 
(ie, ≥ 2 subjects experience DLTs), development of the specific Combination (III or IV) will be 
discontinued. 
Based on the results of Combination I and Combination II, the dose levels for each triplet 
combination (III and IV) will be determined. 
Table 3-3. 
Dose Evaluation for triplet combinations (Combination III and IV) 
Dose Level 
Combination III 
Combination IV 
Tirabrutinib + 
idelalisib 
Obinutuzumab 
Tirabrutinib + 
Entospletinib 
Obinutuzumab 
A 
Triplet Dose Level 1 
Dose determined by 
results of Combination I 
Dose Escalation 
(Table 3-1) 
1000 mg IV 
infusion 
x 
8 doses 
Dose determined by 
results of Combination II 
Dose Escalation 
(Table 3-2) 
1000 mg IV 
infusion 
x 
8 doses 
B 
Triplet Dose Level 2 
Dose determined by 
results of Combination I 
Dose Escalation 
(Table 3-1) 
1000 mg IV 
infusion 
x 
8 doses 
Dose determined by 
results of Combination II 
Dose Escalation 
(Table 3-2) 
1000 mg IV 
infusion 
x 
8 doses 
 
During the DLT assessment window, subjects who fail to complete at least 21 total days of 
tirabrutinib and idelalisib or entospletinib for reasons other than DLT will not be evaluable for 
DLT assessment and additional subjects may be enrolled to that cohort in order to provide 
adequate safety data for dose escalation decisions. In Combination III and Combination IV, 
subjects who only receive Study Day 1 obinutuzumab and do not receive any doses of 
tirabrutinib are not evaluable for DLT and will be replaced.  

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Decisions to open the next higher cohort to enrollment or expand the current cohort will be 
determined by the sponsor in consultation with study principal investigators (PIs). 
The MTD is defined as the highest tested dose associated with an observed DLT rate of 
<33% during the DLT window.  
A minimum of 6 subjects need to be treated in a cohort before this cohort can be determined as 
MTD. 
The recommended dosing regimen of the combination of tirabrutinib and idelalisib or 
entospletinib for use in future clinical trials in subjects with FL, MZL, CLL, SLL, MCL, WM, 
and non-GCB DLBCL will be chosen based on safety and efficacy data and supported by 
pharmacodynamics and PK data. 
Table 3-4. 
Dose escalation/ DLT Guidelines 
No. of Subjects with a 
DLT at a Given Cohort 
Escalation Decision Rule 
0 out of 3 
Enroll 3 subjects at the next higher cohort. 
If this cohort is the highest cohort, it will be declared the maximally administered 
dose, and enroll 3 additional subjects at this cohort. 
≥ 2 out of 3 
Dose escalation will be stopped. This cohort will be declared the maximally 
administered dose. Three additional subjects will be entered at the next lower cohort 
if only 3 subjects were treated previously at that dose. 
1 out of 3 
Enter 3 additional subjects in this cohort. 
• If 0 of these 3 subjects experience a DLT, proceed to the next higher cohort. 
• If 1 or more of these 3 subjects experience a DLT, then dose escalation is 
stopped, and this dose is declared the maximally administered dose. Three 
additional subjects will be entered at the next lower cohort if only 3 subjects 
were treated previously at that dose. 
≤ 1 out of 6 at highest 
dose level at or below the 
maximally administered 
dose 
This is the maximum tolerated dose (MTD) and generally the recommended Phase 2 
dose. At least 6 subjects must be enrolled at the MTD or the recommended Phase 2 
dose. The MTD for tirabrutinib once-daily will be determined separately from the 
MTD for tirabrutinib twice-daily. 
 
3.2.2. 
Dose Expansion 
Cohorts of up to approximately 30 subjects may be enrolled to explore safety and preliminary 
efficacy in a single B-cell lymphoproliferative malignancy disease type to further evaluate 
efficacy, safety, tolerability, PK, and pharmacodynamics of tirabrutinib combined with idelalisib 
or entospletinib in a specific B-cell malignancy subtype (eg, CLL, MCL, FL, 
non-GCB-DLBCL). Expansion cohorts of a triplet combination combined with obinutuzumab in 
specific B cell malignancies (CLL, iNHL, and non-GCB DLBCL) may also be evaluated. 

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The disease and dose chosen for expansion cohort(s) will be based on emerging safety, PK, 
pharmacodynamics, and efficacy result for the dose escalation. Dose expansion may occur after 
the next higher dose cohort has opened in the dose escalation. 
Group V: Tirabrutinib single agent 
Additionally, a cohort of up to approximately 30 subjects with relapsed or refractory CLL may 
be enrolled to receive tirabrutinib 80 mg once daily to provide preliminary safety and efficacy 
data at this dose as a single agent. 
The choice of enrolling a subject into a specific dose escalation arm (idelalisib or entospletinib or 
combination with obinutuzumab) or expansion arm (idelalisib or entospletinib or combination 
with obinutuzumab) will be based on the treatment slots open at the time of screening and at the 
discretion of the investigator. The tirabrutinib single agent arm will be limited to subjects with 
CLL. 
3.2.3. 
Long-Term Safety Monitoring 
As of Amendment 9, all subjects currently on the study will transition into long-term safety 
monitoring. Subjects from the ongoing Study GS-US-401-1787 and subjects who came off Study 
GS-US-401-1757 or Study GS-US-401-1787 but continued to receive treatment via named 
patient use (or individual expanded use) will be enrolled into Group VI to participate in 
long-term safety monitoring. Subjects enrolled in Group VI will continue the same treatment 
regimen in Study GS-US-401-1787 or named patient use starting from Long-Term Safety 
Monitoring Cycle 1 Day 1.  
Subjects from the ongoing Study GS-US-401-1787 who enroll into Group VI in this study should 
have their Study GS-US-401-1787 end of treatment (EOT) visit, Study GS-US-401-1757 
Screening, and Long-Term Safety Monitoring Cycle 1 Day 1 visit on the same day. Subjects on 
named patient use who enroll into Group VI should have their Study GS-US-401-1757 Screening 
and Long-Term Safety Monitoring Cycle 1 Day 1 visit on the same day.  
All active subjects who have no clinical evidence of disease progression will transition to 
long-term safety monitoring and will continue the same treatment regimen. Study visits will be 
completed every 12 weeks for the first 12 months, and then every 24 weeks during the long-term 
safety monitoring phase. 
3.3. 
Study Treatments 
For Combination I and II, subjects who meet eligibility criteria will receive a single dose of 
tirabrutinib on Cycle 1, Day 1 and then initiate idelalisib or entospletinib in combination with 
tirabrutinib on Cycle 1, Day 2. The first cycle will consist of 28 days (1 day single agent 
tirabrutinib and 27 days of combination treatment), and each subsequent cycle will be 28 days of 
combination treatment.  

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The Study Schemas for Combination I and II are presented in Figure 3-1 below: 
Figure 3-1. 
Dosing Schema for Dose Escalation (Combination I and II) 
 
For subjects enrolled in Combination III or IV, obinutuzumab will be initiated on Study Day 1 
with a test dose of 100 mg. If the dose is tolerated well, the remaining 900 mg may be 
administered. Alternatively, the remaining 900 mg may be given the next day, on Study Day 2. 
On Study Day 2 or 3 the combination of oral targeted agents (tirabrutinib + idelalisib or 
tirabrutinib + entospletinib) will be initiated. The day that tirabrutinib combination starts will be 
considered C1D1.  
Subsequent infusions of obinutuzumab will be administered on Week 2 Day 1, Week 3 Day 1, 
Week 5 Day 1 and then every 4 weeks through Week 21 for up to 8 intravenous infusions of 
1000 mg each. The combination of oral targeted agents will continue to be taken daily on a 
schedule (once daily or twice daily) as determined by the results of the previous cohorts. The 
28 day window for DLT evaluation will start with the initiation of the oral agent combination. 
Subjects who withdraw or discontinue study after only receiving obinutuzumab, will not be 
considered evaluable for the purposes of DLT determination and will be replaced.  
B-cell 
Lympho-
malignancies 
ONO/GS-4059 
Screening 
Enrollment Cl,01 
:,; 28 days 
!, 3 days 
ONO/GS-4059 
+ 
ldela 
or 
ONO/GS-4059 
+ 
ento 
Cl,D2 
Cl,028 
• 
Week 12/24 
CT scan 
Progression 
EQT 

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The Study Schemas for Combination III and IV are presented in Figure 3-2 below: 
Figure 3-2. 
Dosing Schema for Dose Expansion (Combination III and IV) 
 
For Group V subjects who meet eligibility criteria will initiate tirabrutinib alone on Cycle 1, 
Day 1. The first and subsequent cycles will be 28 days of combination treatment. 
A subject who does not show evidence of disease progression by clinical assessment or by CT 
(or MRI) as per disease subtype (Appendix 4, Appendix 5, and Appendix 6) may continue 
receiving study drugs daily until disease progression (clinical or radiographic), unacceptable 
toxicity, withdrawal of consent, or other reasons specified in Section 3.6. After discontinuation of 
treatment, subjects will be followed for safety for 30 days. 
Safety and efficacy assessments will occur on an outpatient basis including assessment of tumor 
response, physical exam, vitals, ECG, collection of blood samples (for routine safety labs, 
tirabrutinib and idelalisib or entospletinib PK, pharmacodynamics markers, and biomarkers at 
applicable visits), urine pregnancy (every 4 weeks while receiving tirabrutinib and idelalisib or 
entospletinib in females of childbearing potential), and assessment of AEs. In addition, subjects 
will undergo a CT (or MRI) scan every 12 weeks, except DLBCL and CLL. Subjects with 
DLBCL will have an additional scan at Week 6. Subjects with CLL will only undergo scans at 
baseline, 24 weeks, and at the time of progression. As of Amendment 7, CT/MRI scans will no 
longer be performed and will only be performed at the time of disease progression or at study 
discontinuation. 
Long-Term Safety Monitoring: 
As of Amendment 9, all subjects currently on the study will transition to long-term safety 
monitoring and will continue to receive the same treatment regimen starting from Long-Term 
Safety Monitoring Cycle 1 Day 1. Subjects from the ongoing Study GS-US-401-1787 and 
subjects who came off Study GS-US-401-1757 or Study GS-US-401-1787 but continued to 
8-cell 
Lympho-
malignancies 
Screening 
Enrollment Study 
Dayl 
Cl,01 
Cl,028 
,__ __ _,1..-___ _,'---.....---~ 
s 28 days 
3 days 
1- 3 days 
DLTwindow 
Scan 
Progression 
EOT 

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receive treatment via named patient use will be enrolled into Group VI to participate in 
long-term safety monitoring. Group VI subjects will receive the same treatment administered in 
Study GS-US-401-1787 or named patient use starting from Long-Term Safety Monitoring 
Cycle 1 Day 1.  
Subjects from the ongoing Study GS-US-401-1787 who enroll into Group VI in this study should 
have their Study GS-US-401-1787 EOT visit, Study GS-US-401-1757 Screening, and 
Long-Term Safety Monitoring Cycle 1 Day 1 visit on the same day. Subjects on named patient 
use who enroll into Group VI in this study should have their Study GS-US-401-1757 Screening 
and Long-Term Safety Monitoring Cycle 1 Day 1 visit on the same day. Study visits will be 
completed every 12 weeks for the first 12 months, and then every 24 weeks during the long-term 
safety monitoring phase per Appendix 3.  
3.4. 
Duration of Treatment  
Treatment will continue in the absence of disease progression, unacceptable toxicity, pregnancy, 
and substantial noncompliance with study procedures or study drug, initiation of another 
anti-cancer or experimental therapy, study discontinuation, or withdrawal from study. As of 
Protocol Amendment 8, the maximum participation in the treatment period for any subject is an 
additional 6 years from the date of that amendment (ie, until November 2025).  
As of Amendment 9, entospletinib will be provided until 31 December 2020 to subjects enrolled 
in Combination II and IV who are currently receiving entospletinib. Subjects treated with 
entospletinib as part of a combination regimen with tirabrutinib will stop receiving entospletinib 
by 31 December 2020 but may continue to be treated with tirabrutinib monotherapy.  
Tirabrutinib is supplied as 40 mg, 80 mg, and 100 mg until study completion. Idelalisib is 
supplied as 50 mg tablets until 31 December 2020 and 100 mg tablets until study completion. 
Subjects assigned to the 50 mg once daily idelalisib dose will be given the option, at the 
investigator’s discretion, to switch to 100 mg once daily idelalisib dose leading to an increase in 
total daily dose from 50 mg to 100 mg idelalisib, or to discontinue from the study by 
31 December 2020 and transition to standard of care treatment. Subjects receiving 50 mg 
once daily of idelalisib must not experience any ≥ Grade 3 AEs related to idelalisib to be eligible 
for this dose increase. Following the dose increase, if the subjects experience any drug-related 
≥ Grade 3 toxicity, they will discontinue idelalisib and be given the option to continue 
tirabrutinib monotherapy, at the investigator’s discretion.  
Subjects assigned to the 50 mg twice daily idelalisib dose will be given the option, at the 
investigator’s discretion, to switch to the 100 mg once daily idelalisib dose with no change to the 
total daily dose, or to discontinue from the study by 31 December 2020 and transition to standard 
of care treatment. 

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In subjects who have a tumor flare after the discontinuation of therapy or are at a high risk of 
such an event, the investigator and medical monitor should discuss and agree prior to the 
treatment being reinstituted or continued following progression until initiation of subsequent 
therapy and record this on the electronic case report form (eCRF).  
3.5. 
Dose Limiting Toxicities 
A DLT is a toxicity (defined below) which occurs during the DLT assessment window 
(Day 1 through Day 28) in each cohort: 
1) All Grade ≥ 4 hematological toxicities persisting for > 7 days 
2) All Grade ≥ 3 non-hematological toxicities (except for tumor lysis or alopecia, or Grade 3 
nausea, vomiting, diarrhea, or constipation that resolves within 72 hours with medical 
intervention) 
3) All Grade ≥ 4 non hematologic laboratory abnormalities 
4) Febrile Neutropenia (defined as ANC < 1.0 x 109/L with a single temperature > 38.3oC 
[101oF] or sustained temperature ≥ 38oC [100.4oF] for more than 1 hour) 
5) Grade ≥ 2 non-hematologic treatment-emergent adverse event (TEAE) that in the opinion of 
the investigator is of potential clinical significance such that further dose escalation would 
expose subjects to unacceptable risk 
All AEs should be considered relevant in determining DLTs and to reporting unless the event 
can clearly be determined to be unrelated to tirabrutinib and/or idelalisib or entospletinib. 
Lymphocytosis will not be considered a DLT. 
For certain toxicities, such as laboratory assessments without a clear clinical correlate, a 
discussion between the investigator and medical monitor, may take place to determine if this AE 
should be assessed as a DLT and necessitate dose interruption or dose reduction. 
3.6. 
Criteria for Discontinuation of Study Drug and Study 
Study medication may be discontinued in the following instances: 
• Documented progression of malignant disease 
• Pregnancy 
• Investigator discretion  
• Non-compliance with study drug 
• Protocol violation 
• Withdrawal of consent  
• Lost to follow-up 

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• Study termination by the sponsor 
• Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree 
• Death 
• Unacceptable toxicity, as defined in the toxicity management section of the protocol 
(Section 6.5), 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 
3.7. 
Criteria for Removal from Study 
Subjects may be removed from the study for the following reasons: 
• Documented progression of malignant disease 
• Death 
• Pregnancy 
• Investigator discretion 
• Non-compliance with study drug 
• Subject never dosed with study drug 
• Protocol violation 
• Withdrawal of consent 
• Lost to follow-up 
• Study termination by the sponsor 

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4. 
SUBJECT POPULATION 
4.1. 
Number of Subjects and Subject Selection 
Up to 98 subjects in the dose escalation phase and up to 270 subjects in the dose expansion phase 
will be enrolled.  
As of Amendment 9, all subjects currently on this study will transition into long-term safety 
monitoring. Up to 6 additional subjects in the UK from the ongoing Study GS-US-401-1787 and 
up to 2 subjects in total in the US and UK who came off Study GS-US-401-1757 or 
Study GS-US-401-1787 but continued to receive treatment via named patient use will be 
enrolled into Group VI to participate in long-term safety monitoring. 
4.2. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study. 
1) Male or female ≥ 18 years of age 
2) Diagnosis of FL, MZL, SLL, CLL, MCL, WM or non-GCB DLBCL as documented by 
medical records and with histology based on criteria established by the WHO. 
a) FL Grades 1, 2, or 3a 
b) SLL with absolute lymphocyte count of < 5 x 109 /L at initial diagnosis 
c) MZL (splenic, nodal, or extra-nodal) 
d) WM, measurable disease defined as serum monoclonal IgM > 0.5 g/dL or meeting at 
least 1 of the recommendations from the Second International Workshop on 
Waldenstrom’s Macroglobulinemia for requiring treatment (Appendix 4)  
3) Prior treatment for FL, MZL, SLL, MCL or WM with ≥ 2 or for CLL or non-GCB DLBCL 
with ≥1 chemotherapy-based or immunotherapy-based regimen who are not transplant 
eligible and have had either documented disease progression or no response (stable disease) 
to the most recent treatment regimen  
4) For diseases other than WM, presence of radiographically measurable lymphadenopathy or 
extra-nodal lymphoid malignancy (defined as the presence of ≥ 1 lesion that measures 
≥ 2.0 cm in the longest dimension [LD] and ≥ 1.0 cm in the longest perpendicular dimension 
[LPD] as assessed by CT or MRI) 
5) All acute toxic effects of any prior antitumor therapy resolved to Grade ≤ 1 before the start of 
study therapy (with the exception of alopecia [Grade 1 or 2 permitted], or bone marrow 
parameters [any of Grade 1 or 2 permitted]) 
6) ECOG PS ≤ 2 

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7) Adequate organ function defined as follows: 
a) Hematologic: Platelets ≥ 50 x 109/L; Hemoglobin ≥ 8.0 g/dL; ANC ≥ 1.0 x 109/L 
(without platelet transfusion or any growth factors within previous 7 days of the 
hematologic laboratory values obtained at screening visit) 
b) Hepatic: Aspartate transaminase (AST) / Alanine transaminase (ALT) ≤ 2.5 x upper limit 
of normal (ULN) Total or conjugated bilirubin ≤ 1.5 x ULN 
c) Renal: Serum Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 60 mL/min as 
calculated by the Cockcroft-Gault method 
8) For female subjects of childbearing potential, willingness to abstain from heterosexual 
intercourse or use a protocol-specified method of contraception as described in Appendix 8.  
9) Male subjects of reproductive potential who engage in heterosexual intercourse must agree to 
use protocol-specified method(s) of contraception as described in Appendix 8 
10) Able and willing to provide written informed consent to participate in the study 
11) Willingness and ability to comply with protocol-specified Pneumocystis jirovecii pneumonia 
PJP prophylaxis 
Group VI only (Numbers 12-18): 
12) Currently enrolled in Study GS-US-401-1787 or previously enrolled in Study 
GS-US-401-1757 or Study GS-US-401-1787 and currently receiving continued treatment via 
named patient use 
13) Continuing to benefit from the current treatment regimen in the opinion of the 
investigator/treating physician 
14) Negative urine pregnancy test is required for female subjects of childbearing potential as 
described in Appendix 8 
15) 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 
16) Lactating females must agree to discontinue nursing before the study drug is administered 
17) Ability and agreement to attend protocol-specified visits at the study site 
18) Able to comprehend and willing to sign the informed consent form 

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4.3. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. 
1) History of lymphoid malignancy other than those allowed per Inclusion Criteria  
2) Known active central nervous system or leptomeningeal lymphoma. Imaging documentation 
of the absence or presence of central disease is not required. 
3) History of myelodysplastic syndrome 
4) History of or current Richter’s transformation 
5) History of a non-lymphoid malignancy except for the following: adequately treated local 
basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial 
bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no 
requirement for therapy or requiring only hormonal therapy and with normal 
prostate-specific antigen for ≥ 1 year prior to start of study therapy, or any other cancer that 
has been in complete remission for ≥ 5 years.  
6) Less than 21 days since receiving treatment with biologic, small molecule, immunotherapy, 
chemotherapy, radiation, or other agent for lymphoid malignancy, including other 
investigational products. 
7) Ongoing liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary 
cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or 
portal hypertension 
8) Hepatitis B surface Antigen (HBsAG) positive or hepatitis B core antibody positive  
9) HCV antibody positive 
10) Known HIV infection 
11) Ongoing CMV infection, treatment, or prophylaxis within the past 28 days prior to the 
screening test for active CMV (subjects on study may receive CMV prophylaxis) 
12) Ongoing symptomatic pneumonitis 
13) Ongoing inflammatory bowel disease 
14) Pregnancy or breastfeeding 
15) History of prior therapy with any inhibitor of AKT, BTK, PI3K (including idelalisib, 
GS-9820, GS-9901), JAK, mTOR, or SYK except for group V (single-agent tirabrutinib), for 
which only prior BTK treatment is excluded 

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16) Ongoing immunosuppressive therapy, including systemic corticosteroids for treatment of 
lymphoid malignancy. Subjects may use topical, enteric, or inhaled corticosteroids as therapy 
for comorbid conditions and systemic steroids for autoimmune anemia and/or 
thrombocytopenia. Ongoing use of low-dose systemic corticosteroids (≤ 5 mg/day of 
methylprednisolone or equivalent) is permitted. During study participation, subjects may 
receive systemic or other corticosteroids as needed for treatment-emergent comorbid 
conditions.  
17) Life expectancy < 4 months as per investigator assessment 
18) Concurrent participation in another therapeutic clinical trial 
19) History of long QT syndrome or whose QTc interval measured (Fridericia method) at 
screening is prolonged (> 450 ms) 
20) History of stroke or intracranial hemorrhage within 12 months prior to enrollment 
21) Use of strong CYP3A4 and P-gp inducers within 2 weeks prior to the first dose of study drug 
for both arms of the study.  
22) For subjects enrolling in the entospletinib arm only: 
a) Use of strong CYP3A4 or CYP2C9 inducers or moderate CYP2C9 inducers within 
2 weeks prior to the first dose of study drug 
b) Use of a proton pump inhibitor during the screening window. H2 receptor antagonists are 
allowed. 
23) History of sensitivity or intolerance to any of the excipients of the drug to be administered 
based on the study arm (tirabrutinib, idelalisib, entospletinib, or obinutuzumab) 
24) For subjects enrolling in the idelalisib arm only: History of serious allergic reaction including 
anaphylaxis and toxic epidermal necrolysis 
25) For subjects enrolling in the obinutuzumab arms; prior treatment with obinutuzumab and/or 
any active infection 
Group VI only (Numbers 26-27):  
26) History of sensitivity or intolerance to any of the excipients of the drug to be administered 
based on the study arm (tirabrutinib, idelalisib, or entospletinib) 
27) Evidence of clinical or radiological disease progression 

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5. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
5.1. 
Randomization, Blinding and Treatment Codes 
5.1.1. 
Enrollment 
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, 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 from the IWRS. 
This is an open-label study. 
All baseline tests and procedures must be completed prior to the administration of the first dose 
of study drug on Cycle 1, 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 Study Drugs 
5.2.1. 
Tirabrutinib 
 
Formulation 
Tirabrutinib capsules are brown, opaque hard HPMC capsules. Each capsule contains the 
equivalent of 10 mg or 25 mg tirabrutinib as the hydrochloride salt (GS-4059-01). The 
tirabrutinib capsules contain the following inactive ingredients: microcrystalline cellulose, 
low-substituted hydroxypropyl 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, 40 mg, contain the equivalent of 40 mg tirabrutinib as the 
hydrochloride salt (GS-4059-01). The 33% drug load formulation tablet is an orange, 
plain-faced, round, film-coated tablet. The tirabrutinib film-coated tablets, 40 mg, contain the 
following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, 
colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene 
glycol, talc, FD&C yellow #6/sunset yellow FCF aluminium lake, and iron oxide yellow. 
5.2.1.1. 

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Tirabrutinib film-coated tablets, 75 mg, contain the equivalent of 75 mg tirabrutinib as the 
hydrochloride salt (GS-4059-01). The 33% drug load formulation tablet is an orange, 
plain-faced, round, film-coated tablet. The tirabrutinib film-coated tablets, 75 mg, contain the 
following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, 
colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene 
glycol, talc, FD&C yellow#6/sunset yellow FCF aluminum lake, and iron oxide yellow. 
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. 
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. 
As of Amendment 9, tirabrutinib is supplied as 40 mg, 80 mg, and 100 mg tablets until study 
completion. 
 
Packaging and Labeling 
Tirabrutinib capsules are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 30 capsules. Each bottle is enclosed with a white, continuous thread, 
child-resistant polypropylene screw cap with an induction sealed and aluminum-faced liner. 
Tirabrutinib tablets are 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), and/or other local regulations. 
 
Storage and Handling 
Study drug tirabrutinib should be stored at controlled room temperature of 25°C (77°F); 
excursions are permitted between 15°C and 30°C (59°F and 86°F). Storage conditions are 
specified on the label. Until dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel.  
5.2.1.2. 
5.2.1.3. 

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To ensure the stability and proper identification, study drug(s) should not be stored in a container 
other than the container in which they were 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 when handling. 
5.2.2. 
Idelalisib 
 
Formulation 
Idelalisib will be provided in tablets intended for oral administration. Each tablet contains 50 mg 
or 100 mg of active idelalisib. The 50 mg tablets are round, plain-faced and film-coated pink; the 
100 mg tablets are oval, debossed with “100” on one side and “GSI” on the other, and 
film-coated orange. The tablets include the following inactive excipients: microcrystalline 
cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, magnesium 
stearate, red iron oxide (50 mg tablets only), FD&C Yellow #6/Sunset Yellow FCF aluminum 
lake (100 mg tablets only), polyethylene glycol, talc, polyvinyl alcohol (PVA), and titanium 
dioxide. 
As of Amendment 9, idelalisib is supplied as 50 mg tablets until 31 December 2020 and as 
100 mg tablets until study completion. 
 
Packaging and Labeling 
Idelalisib tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 60 tablets 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), and/or other local regulations. 
 
Storage and Handling 
Idelalisib bottles should be stored at controlled room temperature of 25°C (77°F); excursions are 
permitted between 15°C and 30°C (59°F and 86°F). Storage conditions are specified on the label. 
Until dispensed to the subjects, all bottles of study drugs should be stored in a securely locked 
area, accessible only to authorized site personnel. 
To ensure the stability and proper identification, study drug(s) should not be stored in a container 
other than the container in which they were 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 idelalisib. 
5.2.2.1. 
5.2.2.2. 
5.2.2.3. 

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5.2.3. 
Entospletinib 
 
Formulation 
Entospletinib tablets, 200 mg strength, are available as blue, capsule-shaped film-coated tablets 
that are plain-faced. In addition to the active ingredient, entospletinib tablets contain the 
following inactive ingredients: methanesulfonic acid, hydroxypropyl methylcellulose 
(hypromellose), mannitol, microcrystalline cellulose, crospovidone, poloxamer 188, silicon 
dioxide, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and 
FD&C blue #2 aluminum lake.  
Entospletinib tablets, 200 mg strength, are also available as beige, capsule-shaped, film-coated 
tablets debossed with “GSI” on one side and “9973” on the other side. In addition to the active 
ingredient, entospletinib tablets contain the following inactive ingredients: methanesulfonic acid, 
hydroxypropyl methylcellulose (hypromellose), mannitol, microcrystalline cellulose, 
crospovidone, poloxamer 188, silicon dioxide, magnesium stearate, polyethylene glycol, 
polyvinyl alcohol, talc, titanium dioxide, ferrosoferric oxide/black iron oxide, iron oxide red, and 
iron oxide yellow.  
As of Amendment 9, entospletinib is supplied as 200 mg tablets until 31 December 2020. 
 
Packaging and Labeling 
Entospletinib tablets are packaged in white, high-density polyethylene bottles with silica gel 
desiccant, and polyester packing material in each bottle. Each bottle contains 60 tablets and is 
capped with a child-resistant polypropylene screw cap fitted with an induction-sealed, 
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), and/or other local regulations. 
 
Storage and Handling 
Entospletinib tablets should be stored at a controlled room temperature of 25 °C (77 °F); 
excursions are permitted between 15 °C and 30 °C (59 °F and 86 °F).  
To ensure stability of the tablets and proper product identification, the drug should not be stored 
in a container other than the container in which it is supplied. Measures that minimize drug 
contact with the body should always be considered during handling, preparation, and disposal 
procedures. 
5.2.3.1. 
5.2.3.2. 
5.2.3.3. 

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5.2.4. 
Obinutuzumab 
 
Formulation  
Obinutuzumab is a humanized anti-CD20 monoclonal antibody of the IgG1 subclass. It 
recognizes a specific epitope of the CD20 molecule found on B-cells. The molecular mass of the 
antibody is approximately 150 kDa. 
Obinutuzumab is produced by mammalian cell (CHO) suspension culture. It is a sterile, clear, 
colorless to slightly brown, preservative free liquid concentrate for intravenous administration. 
The product is formulated in 20 mM L-histidine/L-histidine hydrochloride, 240 mM trehalose, 
0.02% poloxamer 188. The pH is 6.0. 
 
Packaging and Labeling  
Obinutuzumab is supplied at a concentration of 25 mg/mL in 1000 mg/40 mL single use vials. 
 
Storage and Handling 
Obinutuzumab vials are stable at 2 °C to 8 °C (36 °F to 46 °F). Do not use beyond expiration 
date stamped on carton. Obinutuzumab vials should be protected from light. Do not freeze or 
shake obinutuzumab vials. 
For the diluted product, chemical and physical stability have been demonstrated in 0.9% NaCl at 
concentrations of 0.4 to 20 mg/mL for 24 hours at 2 °C to 8 °C (36 °F to 46 °F) followed by 
48 hours (including infusion time) at room temperature (≤ 30 °C/86 °F). Obinutuzumab does not 
contain antimicrobial preservatives. Therefore care must be taken to ensure that the solution for 
infusion is not microbiologically compromised during preparation. The solution for infusion 
should be used immediately. If not used immediately, the prepared solution may be stored up to 
24 hours at 2 °C to 8 °C. When splitting the first dose (1000 mg) into 2 infusions 
(Day 1 = 100 and Day 2 = 900 mg) the same vial may be used for the preparation of both 
infusions, but the second infusion must begin within 24 hours of the preparation. No 
incompatibilities between obinutuzumab and polyvinyl chloride or polyolefin infusion materials 
have been observed in concentration ranges from 0.4 to 20.0 mg/mL after dilution of 
obinutuzumab with 0.9% sodium chloride. 
5.3. 
Dosage and Administration of Study Drugs  
Tirabrutinib capsules or tablets, idelalisib or entospletinib tablets and obinutuzumab will be 
provided by Gilead Sciences, Inc. and will be taken orally. Initiation of treatment with the study 
drug will take place after enrollment and cohort assignment. Subjects will take only tirabrutinib 
on Cycle 1, Day 1 and then take tirabrutinib and idelalisib or entospletinib on Cycle 1, Day 2. 
Starting on Cycle 1, Day 2, subjects will continue to take both tirabrutinib and idelalisib or 
entospletinib at approximately the same time each day. To reduce variability, subjects will be 
instructed to take entospletinib approximately 1 hour before or 2 hours after a meal. Tirabrutinib 
and idelalisib may be taken without regard to food. 
5.2.4.1. 
5.2.4.2. 
5.2.4.3. 

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For patients assigned to the 150 mg tirabrutinib dose, 75 mg tirabrutinib capsules/tablets may be 
exchanged for 80 mg tirabrutinib tablets leading to an increase in total daily dose from 150 mg to 
160 mg. Based on the range of exposures of tirabrutinib observed in subjects with B-cell 
malignancies, the slight increase in daily dose is not considered clinically relevant. 
For patients assigned to the 20 mg tirabrutinib dose, 40 mg tirabrutinib tablets may be exchanged 
for 20 mg tirabrutinib tablets leading to an increase in total daily dose from 20 mg to 40 mg. 
Based on the range of exposures of tirabrutinib observed in subjects with B-cell malignancies, 
the slight increase in daily dose is not considered clinically relevant. 
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 12 hours has elapsed since the scheduled time of the missed dose 
for study drugs administered once daily or 6 hours has elapsed for study drug administered 
twice daily. In this case, the subject should be instructed to wait and take the next dose at the 
regularly scheduled time. 
Subjects who are enrolled in Combinations III or IV will receive obinutuzumab infusion on 
Study Day 1. Obinutuzumab will be administered as 8 intravenous infusions of 1000 mg each 
over approximately 21 weeks. A test dose of 100 mg will be administered on Study Day 1. If the 
dose is tolerated well, the remaining 900 mg will be administered. Alternatively, the remaining 
900 mg may be given the next day, on Study Day 2. Subsequent infusions of obinutuzumab will 
be administered on Cycle 1, Day 6 (+/- 2 days), Cycle 1, Day 13 (+/- 2 days), Cycle 2, Day 1 
(+/- 3 days) and then every 28 days(+/- 3 days) until Cycle 6, Day 1 (+/- 3 days). 
The combination of tirabrutinib with idelalisib or entospletinib will be initiated 1-3 days after 
Study Day 1. The first day of dosing these oral agents is considered Cycle 1, Day 1. The oral 
agents will be dosed daily (either once or twice daily) as determined by the results of the 
Combination I and II dose escalations. 28-day cycles will start with the first day of the oral 
combination.  
As of Amendment 9, tirabrutinib is supplied as 40 mg, 80 mg, and 100 mg tablets. Idelalisib is 
supplied as 50 mg tablets until 31 December 2020 and 100 mg tablets until study completion.  
Subjects assigned to the 50 mg once daily idelalisib dose will be given the option, at the 
investigator’s discretion, to switch to 100 mg once daily idelalisib dose leading to an increase in 
total daily dose from 50 mg to 100 mg idelalisib, or to discontinue from the study by 
31 December 2020 and transition to standard of care treatment. Subjects receiving 50 mg once 
daily of idelalisib must not experience any ≥ Grade 3 AEs related to idelalisib to be eligible for 
this dose increase. Following the dose increase, if the subjects experience any drug-related 
≥ Grade 3 toxicity, they will discontinue idelalisib and be given the option to continue 
tirabrutinib monotherapy, at the investigator’s discretion.  
Subjects assigned to the 50 mg twice daily idelalisib dose will be given the option, at the 
investigator’s discretion, to switch to the 100 mg once daily idelalisib dose with no change to the 
total daily dose, or to discontinue from the study by 31 December 2020 and transition to standard 
of care treatment.  

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Entospletinib supply will be provided until 31 December 2020 to subjects enrolled in 
Combination II and IV who are currently receiving entospletinib. Subjects treated with 
entospletinib as part of a combination regimen with tirabrutinib will stop receiving entospletinib 
by 31 December 2020 but may continue to be treated with tirabrutinib monotherapy. 
For the long-term safety monitoring phase, subjects currently on the study will continue the same 
treatment regimen. Subjects enrolled into Group VI will receive the same treatment administered 
in Study GS-US-401-1787 or named patient use starting from Long-Term Safety Monitoring 
Cycle 1 Day 1.  
5.3.1. 
Dosage and Administration of Obinutuzumab 
Liquid concentrate of obinutuzumab intended for IV. infusion is prepared by diluting the drug 
product to the final concentration into an infusion bag containing 0.9 % Sodium Chloride (NaCl). 
All patients should receive premedication before administration of obinutuzumab as 
follows: 
First infusion of obinutuzumab  
The following premedication should be administered (unless contraindicated) prior to the start of 
the first dosage of obinutuzumab (days 1 [and 2 in case of dose splitting] of the first cycle) to 
avoid infusion related reactions (IRRs): 
• Prednisolone or prednisone 100 mg IV ≥ 1 hrs before starting the obinutuzumab infusion 
(an equivalent dose of dexamethasone (20 mg) or methylprednisolone (80 mg) is permitted, 
but hydrocortisone should not be used) 
• Acetaminophen/paracetamol 1000 mg orally ≥ 30 min before starting the obinutuzumab 
infusion 
• Antihistamines including a H1-antagonist (e.g. diphenylhydramine IV) and a H2-antagonist 
(eg, ranitidine 50 mg IV) ≥ 30 min before starting the obinutuzumab infusion 
Please note that withholding of antihypertensive treatments should be considered for 12 hours 
prior to, throughout, and for the first hour after each obinutuzumab infusion as hypotension may 
occur as a result of an IRR. Antihypertensive treatment can still be used to treat IRR triggered 
hypertension, if required. 
Subsequent infusions of obinutuzumab 
All patients should receive oral acetaminophen/paracetamol (1000 mg) orally ≥ 30 min ahead of 
every obinutuzumab infusion (unless contraindicated). The antihistamine premedication may be 
omitted at the investigator’s discretion for the following obinutuzumab infusions if the 
previously administered obinutuzumab infusion did not result in an IRR CTCAE 
Grade > 1 (i.e., no medication was required to treat the IRR and there was no interruption of the 
infusion). A corticosteroid should be administered for premedication if the patient experienced a 
Grade 3 IRR during the previous infusion, the patient´s lymphocyte count is > 25,000/μl and at 

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the investigator‘s discretion. As during the first cycle, the investigator should consider 
withholding antihypertensive medication 12 hours prior and until 1 hour after the obinutuzumab 
infusion. 
Patients with a history of cardiac disease should be monitored closely. In addition these patients 
should be hydrated with caution in order to prevent a potential fluid overload. 
Patients with a high tumor burden (lymphocyte counts ≥ 25 x 109/L and/or bulky 
lymphadenopathy) and/or renal impairment (CrCL< 70 mL/min) are at risk for developing a 
tumor-lysis syndrome (TLS). These patients with a high tumor burden and also all other patients 
considered at risk for TLS by the investigator must receive prophylaxis for TLS prior to the 
initiation of treatment with obinutuzumab and ahead of all subsequent administrations of 
obinutuzumab until the tumor burden is reduced and risk for development of a TLS is 
minimized. Possible preventive measures include: 
• Adequate hydration (eg, intravenous administration of 1000 – 4000 mL NaCl 0.9% starting 
12 – 24 hours before treatment), 
• Prophylactic administration of an uric acid reducer (eg, allopurinol 300 mg once daily 
starting 72 hours prior to initiation of treatment) and/or 
• Rasburicase.  
In addition, a close monitoring of serum chemistry, particularly creatinine, potassium and uric 
acid levels should be performed. Patients with TLS should be treated per institutional practice 
(including correction of electrolyte abnormalities, monitoring of renal function and fluid balance, 
administration of supportive care, including dialysis as indicated). 
Infusion Rates 
First infusion: All subjects will receive an infusion of the fixed dose of 100mg obinutuzumab 
administered at a fixed rate of 25mg/h over 4 hours. If the first 100 mg obinutuzumab is tolerated 
well and completed without interruptions or adjustments of infusion rate and it is possible from 
an organizational point of view (enough time, medical supervision available throughout the 
infusion), patients are allowed to continue with the remaining 900 mg infusion on the same day. 
Otherwise this infusion should be started the next day. The infusion with 900 mg obinutuzumab 
shall be started at a rate of 50 mg/h in all patients and the infusion rate may be escalated in 
increments of 50 mg/h every 30 minutes to a maximum rate of 400 mg/h. 
Subsequent infusions: If the first infusion of obinutuzumab was well tolerated (defined by an 
absence of IRRs during a final infusion rate of ≥100 mg/h), subsequent infusions will be 
administered at an initial rate of 100 mg/h. The infusion rate may be increased by 100 mg/h 
increments at 30-minute intervals, as tolerated, to a maximum rate of 400 mg/h. Alternatively, if 
an IRR was present during the first infusion, the administration may be per the guidance from the 
first infusion with a maximum rate that which has been previously tolerated by the subject. At 
the investigator’s discretion, obinutuzumab infusions may be split and administered over 2 days. 

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Dose of Obinutuzumab 
Rate of Infusion (in the absence of infusion  
reactions/hypersensitivity during previous infusions) 
Day 1 
100 mg 
Administer at 25 mg/hr over 4 hours. 
Do not increase the infusion rate. 
Day 1 or 2 
900 mg 
Administer at 50 mg/hr. The rate of the infusion can be escalated in increments 
of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. 
Subsequent 
1000 mg 
Infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr 
increments every 30 minutes to a maximum of 400 mg/hr. 
 
Management of infusion-related reactions (IRRs)  
In case of IRR, the following measures should be considered depending on the severity of the 
IRR: 
• Acetaminophen/paracetamol 1000 mg if not administered during the last 4 hrs 
• antihistamines including a H1- (e.g. dimetindene 4 mg IV) and a H2-antagonist 
(eg, ranitidine 50 mg IV if not administered during the last 4 hours) 
• Prednisolone or prednisone 100 mg IV in case of urticarial, bronchospasm and dyspnea 
• Intravenous fluids 
• Bronchodilators and oxygen in case of bronchospasm and dyspnea 
• Vasopressors in case of hypotension  
Once symptoms have resolved completely, obinutuzumab may be resumed at 50% of the 
infusion-rate used prior to the interruption. If no infusion related symptoms occur, the rate of the 
infusion may be escalated stepwise with 50 mg/h every 30 minutes to a maximum rate of 
400 mg/h, except for the first administration of obinutuzumab. The first obinutuzumab 
administration (100mg) may be re-started at half initial rate (12.5 mg/h) upon complete 
resolution of symptoms; if this is tolerated well for an hour, the rate may be increased to a 
maximum of 25 mg/h. 
It needs to be stressed that in the event of a life-threatening (which may include pulmonary or 
cardiac events), prolonged or recurrent IRR, obinutuzumab should be discontinued immediately 
and no further obinutuzumab should be administered.  
Patients experiencing grade 3 or 4 IRRs twice should receive aggressive symptomatic treatment 
and will be discontinued from further study treatment with obinutuzumab. Treatment with oral 
agents should be continued with the subject remaining on study. 

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For guidance on the management of infusion-related reactions (IRRs) see the following table: 
Table 5-1. 
Guidance on the management of infusion-related reactions (IRRs)  
IRR Severity 
(NCI CTCAE 
v4.0) 
Recommendation 
Grade 1-2 
Reduce the infusion rate or hold infusion 
Administer supportive treatment 
Upon symptom resolution, restart infusion at no more than half the previous rate (the rate 
being used at the time that the IRR occurred) and, if patient does not experience any IRR 
symptoms, infusion rate escalation may resume at the increments and intervals as 
appropriate for the treatment dose 
Grade 3 
Discontinue infusion immediately 
Administer supportive treatment 
Upon symptom resolution, may resume infusion rate escalation, at the investigator’s 
discretion 
Treatment must be permanently discontinued, if same adverse event recurs with same 
severity. 
Grade 4 
Discontinue infusion immediately 
Treat symptoms aggressively 
Do not restart obinutuzumab 
 
Reductions in obinutuzumab dosing are not planned. Repeat obinutuzumab administrations may 
be delayed to allow subjects to recover from obinutuzumab-related adverse events or intercurrent 
illness. 
5.3.2. 
Prior and Concomitant Medications  
 
Pneumocystis (carinii) jirovecii Pneumonia Prophylaxis  
Antibiotic prophylaxis for PJP is mandatory for subjects on idelalisib therapy and should be 
continued for 2 to 6 months after idelalisib discontinuation. PJP prophylaxis should be instituted 
for patients with CLL irrespective of treatment arm unless medically contraindicated. PJP 
prophylaxis should be considered for up to 12 months following obinutuzumab treatment and 
throughout study drug therapy, particularly in subjects with multiple risk factors for 
Pneumocystis infection {Green 2007}. 
 
G-CSF 
Administration of G-CSF is permitted per institutional standard of care. 
 
IVIg 
Administration of IVIg is permitted per institutional standard of care. 
5.3.2.1. 
5.3.2.2. 
5.3.2.3. 

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5.3.3. 
Tirabrutinib  
In vitro data indicate tirabrutinib is a substrate of CYP3A4. Co-administration of CYP3A4 
inhibitors may increase tirabrutinib exposure. However, preliminary PK data from this study 
(GS-US-401-1757) indicates 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 on tirabrutinib and ≥ 2 weeks prior to study drug 
administration. Examples of strong CYP3A4 and P-gp inducers are provided in the table below.  
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.  
5.3.4. 
Idelalisib 
The metabolite of idelalisib, GS-563117, is a competitive and time dependent inhibitor of 
CYP3A; accordingly coadministration of idelalisib 150 mg twice daily with midazolam, a probe 
CYP3A substrate, resulted in an approximately 5-fold increase in midazolam systemic exposure 
(AUC). Coadministration of CYP3A substrates with idelalisib may result in an increase in their 
systemic exposures (eg, certain antiarrhythmics, calcium channel blockers, benzodiazepines, 
HMG-CoA reductase inhibitors, phosphodiesterase-5 [PDE5] inhibitors, and warfarin). 
Particular caution is recommended during coadministration of idelalisib with drugs that are 
highly dependent on CYP3A for clearance and for which elevated plasma concentrations are 
associated with serious and/or life-threatening events, including narrow therapeutic index 
CYP3A substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, 
fentanyl, quinidine, ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib. The 
investigator should review the prescribing information of the concomitant medication for 
guidance on coadministration with a CYP3A inhibitor. 
5.3.5. 
Entospletinib 
In vitro and in vivo data indicate that entospletinib is a substrate of CYP2C9 and to a lesser 
extent CYP3A. As such, coadministration of strong CYP3A and CYP2C9 inducers and moderate 
CYP2C9 inducers is prohibited in this study. Administration of these medicines is also 
prohibited for 2 weeks prior to study drug administration. Examples of these medicines are 
provided in Table 5-2. 
Caution should be exercised when coadministering drugs that are moderate or strong inhibitors 
of CYP2C9 (eg, fluconazole, voriconazole, and amiodarone) as they may increase entospletinib 
exposure. 

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In vitro data indicates that entospletinib has the potential to inhibit several transporters and the 
metabolizing enzyme UGT1A1, which may affect the plasma concentrations of substrates of 
these transporters and/or enzyme. Caution should be exercised when coadministering 
medications that are metabolized or transported by UGT1A1, OATP1B1, OATP1B3, MATE1, 
P-gp, and BCRP. The investigator should review the prescribing information of the concomitant 
medication for guidance on coadministration with an inhibitor of these transporters, such as 
additional monitoring, dose modifications or avoiding coadministration. In a study in healthy 
volunteers, entospletinib 400 mg twice daily increased rosuvastatin exposure by approximately 
4-fold; as such the following restrictions apply for subjects receiving entospletinib in this study: 
Table 5-2. 
Dosing restrictions for HMB-CoA reductase inhibitors for subjects 
receiving entospletinib 
Concomitant Medication 
Restriction 
Atorvastatin 
Maximum dose 20 mg QD 
Rosuvastatin 
Maximum dose 10 mg QD 
Pravastatin 
Maximum dose 40 mg QD 
Simvastatin 
Maximum dose 20 mg QD 
Lovastatin 
Maximum dose 20 mg QD 
Fluvastatin 
Maximum dose 20 mg BID or 40 mg QD 
Pitavastatin 
Maximum dose 1 mg QD 
 
Studies in healthy volunteers have demonstrated a significant reduction in entospletinib exposure 
when proton pump inhibitors are coadministered. Therefore, proton pump inhibitors 
(eg, omeprazole) are prohibited in combination with entospletinib. 
Table 5-3. 
Examples of Concomitant Medications Prohibited in this Study 
 
Strong 
Moderatea 
CYP3A4/P-gp Inducer 
carbamazepine, phenytoin, rifampin, 
St. John’s Wort, enzalutamide, rifabutin, 
phenobarbital, mitotane, avasimibe 
Not prohibited 
CYP2C9 Inducera 
 
carbamazepine, rifampin, ritonavir, 
enzalutamide 
Proton pump 
inhibitorsa 
omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, dexlansoprazole 
a 
Prohibited only in combination with entospletinib  

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5.3.6. 
Obinutuzumab  
In accordance with current obinutuzumab prescribing information, subjects should be 
premedicated with an antipyretic and an antihistamine to reduce the incidence and severity of 
infusion reactions. A recommended regimen is diphenhydramine, 25 to 50 mg orally, and 
acetaminophen (paracetamol) 650 to 1000 mg orally, both given approximately 30 minutes prior 
to each obinutuzumab infusion. In addition, an intravenous corticosteroid should also be 
administered as a premedication on Days 1, 2, 8, and 15 for all subjects, completed at least 
1 hour prior to administration of obinutuzumab, and then only as indicated per the prescribing 
information. Local practices and guidelines may be followed. 
 
Tumor Lysis Syndrome 
Subjects with a high tumor burden (lymphocyte count ≥ 25 × 109/L or bulky lymphadenopathy) 
must receive prophylaxis for tumor lysis syndrome prior to the initiation of treatment. 
Prophylaxis for subjects with renal impairment (CrCl < 70mL/min) should also be considered. 
Subjects must be well hydrated. It is desirable to maintain a fluid intake of approximately 3 liters 
per day, 1-2 days before the first dose of obinutuzumab. All subjects with high tumor burden 
must be treated with allopurinol (≥300 mg p.o./day) or a suitable alternative treatment 
(eg, rasburicase) starting 12-24 hours prior to the first infusion. Subjects should continue to 
receive repeated prophylaxis with allopurinol and adequate hydration prior to each subsequent 
infusion, if deemed appropriate by the investigator. Older and frail subjects will need special 
individualized care in fluid management, as 3 liters per day may not be tolerated. Rasburicase 
may be particularly indicated in such subjects. For all subjects, electrolytes should be monitored 
and corrected, fluid balance and renal function should be monitored, and supportive care should 
be administered, including dialysis as indicated. Hospitalization, particularly for older and frail 
subjects, should be considered. 
 
Antihypertensive Medication 
As infusion related reactions may include hypotension, the investigator should consider 
withholding antihypertensive treatments for 12 hours prior to and throughout each obinutuzumab 
infusion and for the first hour after completion of the infusion. 
5.4. 
Accountability for Study Drugs 
The investigator is responsible for ensuring adequate accountability of all used and unused Study 
Drug bottles. This includes acknowledgement of receipt of each shipment of Study Drug 
(quantity and condition). All used and unused Study Drug bottles dispensed to subjects must be 
returned to the site. 
5.3.6.1. 
5.3.6.2. 

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Tirabrutinib, idelalisib, entospletinib, and obinutuzumab accountability records will be provided 
to each study site to: 
• Record the date received and quantity of Study Drug bottles  
• Record the date, subject number, subject initials, the Study Drug bottles quantity dispensed 
• Record the date, quantity of used and unused Study Drug bottles returned, along with the 
initials of the person recording the information. 
5.4.1. 
Investigational Medicinal Product Return or Disposal 
Study drug should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. All study drug returned by the subject should be retained for review by 
the study site monitor prior to destruction. 
Please see Section 9.1.7 for more information. 

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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.  
As of Amendment 9, only study procedures for the long-term safety monitoring phase are to be 
conducted for each subject enrolled, as presented in Appendix 3. Screening procedures will only 
apply to Group VI. Subjects from the ongoing Study GS-US-401-1787 who enroll into Group VI 
in this study should have their Study GS-US-401-1787 EOT visit, Study GS-US-401-1757 
Screening, and Long-Term Safety Monitoring Cycle 1 Day 1 visit on the same day. Subjects on 
named patient use who enroll into Group VI in this study should have their 
Study GS-US-401-1757 Screening and Long-Term Safety Monitoring Cycle 1 Day 1 visit on the 
same day. Clinical evaluations and laboratory assessments will be performed every 12 weeks for 
the first 12 months, and then every 24 weeks during the long-term safety monitoring phase per 
institutional standard of care. 
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO). 
6.1. 
Subject Enrollment and Treatment Assignment 
It is the responsibility of the Investigator to ensure that each subject is eligible for the study 
before enrollment. Please refer to Section 5.1 for details about enrollment and treatment 
assignment. 
6.2. 
Study Procedure Descriptions 
During the treatment period, all visits may be performed within the specified window for that 
study visit (see Appendix 2). As of Amendment 9, only visits for the long-term safety monitoring 
phase are to be performed within the specified window for that study visit (see Appendix 3).  
6.2.1. 
Informed Consent 
All subjects must sign and date the most recent IRB/IEC-approved informed consent form before 
any study procedures are performed. 
 
 
Subjects who screen fail must re-sign the informed consent, if any screening procedures will be 
performed outside of the 28-day screening window from the time of the first informed consent.  
As of Amendment 9, all subjects currently on the study must be re-consented and assessed for 
clinical evidence of disease progression prior to transitioning to the long-term safety monitoring 
phase. If there is clinical evidence of disease progression, a confirmatory radiologic assessment 
should be performed per institutional standard of care. 
CCI
CCI

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6.2.2. 
Medical and Medication History 
A complete medical history will be obtained by the Investigator or designee. Medical history will 
include information on the subject’s significant past medical events (eg, prior hospitalizations or 
surgeries), a review of the disease under study, prior anti-cancer therapies, and any concurrent 
illnesses. Obtain smoking history at screening (for the past 60 Days) and at Day 1 of each Cycle 
(for the past 28 Days). 
As of Amendment 9, any ongoing AE at the time of enrollment will be considered medical 
history on this study and should be reported in the eCRFs and followed to resolution. 
6.2.3. 
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 (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 the first dose of study treatment baseline physical examination which 
represent a clinically significant deterioration will be documented on the AE page of the eCRF. 
Height (without shoes) should be measured at Screening only. 
As of Amendment 9, physical examinations will no longer be required. Clinical evaluations will 
be performed per institutional standard of care. 
6.2.4. 
Vital Signs 
Vital signs, including blood pressure, respiratory rate, pulse, and temperature will be measured at 
the time points listed in the Study Procedures Tables in Appendix 2. All measurements will be 
recorded on the appropriate eCRF page with appropriate source documentation. Any abnormal 
measurements may be repeated and reported as AEs if appropriate. All measures of blood 
pressure will be performed using standard sphygmomanometry. Measurements of blood pressure 
should be taken per institutional guidelines.  
As of Amendment 9, vital signs will no longer be required. Clinical evaluations will be 
performed per institutional standard of care. 
6.2.5. 
Electrocardiogram Assessment 
12-lead ECGs will be obtained in triplicate at the visits outlined in the Study Procedures Tables 
(Appendix 2) and transferred to a central vendor for storage. Subjects should be resting in supine 
position quietly for 5 minutes prior to ECG collection. 

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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. 
As of Amendment 7, ECGs will no longer be required. Clinical evaluations will be performed 
per institutional standard of care. 
6.2.6. 
ECOG Performance Status 
ECOG PS will be performed at the time points listed in the Study Procedures Tables 
(Appendix 2). ECOG will be scored using the scale index in Appendix 9. 
As of Amendment 9, ECOG PS will no longer be required. Clinical evaluations will be 
performed per institutional standard of care. 
6.2.7. 
Prior and Concomitant Medications 
At Screening, all medication taken up to 30 days prior to the screening visit will be recorded on 
the eCRF. At each study visit, the site will capture any and all medications taken by the subject 
since the last visit or during the visit (as applicable). Concomitant medications include 
prescription and non-prescription medications, pre-infusion medications (eg, anti-emetics), and 
vitamins and minerals. 
In addition, supportive therapies given during the course of the study (eg, blood transfusion, 
growth factor) should be collected and recorded on the eCRF. 
6.2.8. 
Adverse Events 
Subjects will be assessed for AEs per guidelines in the National Cancer Institute (NCI) CTCAE 
(version 4.03) at the time points outlined in the Study Procedures Tables (Appendix 2). After 
informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the electronic case report form eCRF: all SAEs and adverse events related 
to protocol-mandated procedures. 
Any AEs reported after informed consent is obtained and throughout the study will be recorded 
on the eCRF with appropriate source documentation. The site will contact the study subject by 
phone approximately 30 days after the last dose of study drug to assess AEs. Please refer to 
Appendix 7 for CTCAE grading criteria. 
Please refer to Section 7 for additional information on AE reporting. 
 
Evaluation for Gastrointestinal Events/Colitis  
For subjects who report diarrhea of colitis, obtain history of onset and duration, including 
description of the number of stools and stool composition (watery, bloody, nocturnal), travel 
history, diet changes and medication review to identify possible causes. Perform physical 
examination, including assessment for fever, dizziness, abdominal pain/cramping, and weakness 
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(ie, evaluate for sepsis, bowel obstruction, dehydration). Differentiation between small-bowel 
and large-bowel diarrhea: maybe possible on a clinical basis. If unclear, consider upper and 
lower tract endoscopy with biopsy. 
• Small bowel diarrhea is characterized by large volume diarrhea (more than one per day), 
possible associated dehydration weight loss and paraumbilical pain. Consider an endoscopic 
small-bowel biopsy and evaluate other etiologies such as celiac disease. 
• Large-bowel diarrhea may present with lower pelvic pain, tenesmus, generally smaller stool 
volume with gross blood frquently found in the stool; Condsider a colonoscopic evaluation 
and biopsy. 
• Ensure good hydration status 
For Grade ≥2 colitis and diarrhea (unless clinical diagnosis is established from medical history 
and physical examination), the following testing is required: 
• Stool culture for routine pathogens (Salmonella, Shigella, Campylobacter species, 
Clostridium difficile toxin, Rotavirus, Cytomegalovirus, Adenovirus) 
• Stool for Ova and Parasites (Cryptosporidium parvum, Isospora belli, Enterocytozoon 
bieneusi, Septata intestinalis, Strongyloides, Microsporidia, Entamoeba histolytica, 
Cyclospora), Giardia antigen 
For grade ≥ 3 or persistent grade 2 colitis or diarrhea, without clear etiology (eg, clostridium 
difficile enterocolitis),endoscopy with biopsy is required. All biopsy samples should include 
immunohistochemistry (IHC) and PCR for CMV and adenovirus. If an ileal biopsy is performed, 
consider Acid Fast Bacillus staining. 
6.2.9. 
Radiology Assessment  
CT (preferred) or MRI will be obtained to document disease and identify index lesions using the 
criteria in Appendix 4, Appendix 5, and Appendix 6 to assess response and disease progression. 
Imaging of the neck, chest, abdomen and pelvis by CT scan will be performed at the time points 
outlined in the Study Procedures Tables (Appendix 2). Scans taken as part of standard medical 
practice up to 28 days prior to first dose of tirabrutinib can be used for Screening. During the 
treatment phase, scans may be performed at time points other than specified in the Study 
Procedures Tables (Appendix 2) as clinically indicated to assess tumor progression. Scans should 
continue to be performed at time points outlined in the Study Procedures Tables (Appendix 2) 
for subjects who stop study treatment but did not have disease progression (eg. experienced 
unexpected toxicity) until radiographic progression is documented or until the subject starts a 
new systemic anti-cancer therapy other than the study treatment, whichever is earlier. Scans will 
be transferred to a central reader for collection and future analysis. The same imaging procedure 
and specifications (eg., contrast agent, scanner, slice thickness, etc.) used to define index and 
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All relevant clinical and radiographic information required to make each assessment must be 
made available for source verification. Investigators will assess the status of each subject’s 
disease status using the criteria in Appendix 4, Appendix 5, and Appendix 6. Scans will be 
transferred to a central reader for collection and future analysis. 
As of Amendment 7, CT/MRI scans will no longer be performed and will only be performed at 
the time of disease progression or at study discontinuation.  
As of Amendment 9, investigators will clinically assess each subject’s disease status every 
12 weeks for the first 12 months, and then every 24 weeks during the long-term safety 
monitoring phase per institutional standard of care (Appendix 3). If there is clinical evidence of 
disease progression, a confirmatory radiologic assessment should be performed per institutional 
standard of care. 
6.2.10. 
Tumor Status Assessments 
The determination of disease response and progression will be based on standardized criteria 
{Cheson 2007, Hallek 2008, Owen 2013} as specifically modified for this study to reflect 
current recommendations which consider the mechanism of action of idelalisib or entospletinib 
and similar drugs {Cheson 2012}. During the course of the study, investigators will clinically 
assess the status of each subject’s disease at 4 week intervals for the first 24 weeks. 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 and for potential submission to an Independent Review 
Committee (IRC). 
 
Bone Marrow 
Bone marrow assessments will be based on morphologic evaluation of bone marrow 
biopsies/aspirates (type of test at the investigator’s discretion). Immunohistochemistry may be 
used to assess response if the sample is indeterminate by morphology. 
In a subject who has a baseline bone marrow biopsy/aspirate showing bone marrow FL, MZL, 
CLL, or SLL or does not have a baseline bone marrow examination, declaration of an on-study 
CR requires bone marrow biopsy/aspirate documentation of the absence of bone marrow FL, 
MZL, or SLL. In a subject who has a baseline bone marrow biopsy/aspirate showing no evidence 
of FL, MZL, CLL, or SLL, declaration of an on-study CR does not require bone marrow 
examination as long as other criteria for CR are met. In a subjects with CLL, regardless of 
baseline findings, if a clinical CR is achieved a bone marrow analysis will be evaluated for 
minimal residual disease analysis (PCR or flow cytometry).  
 
Biopsy and Cytology 
Diagnosis of FL, MZL, SLL, CLL, MCL, WM, or non-GCB DLBCL will be documented by 
medical records and with histology based on criteria established by the WHO. Non-GCB 
DLBCL subtype may be determined by immunohistochemical testing (non-GCB) or gene 
expression profiling (ABC).  
Lymph node biopsy is not required in the determination of subject eligibility. However, subjects 
with evidence of transformed aggressive lymphoma on lymph node biopsy, other tissue biopsy or 
fluid cytology are ineligible for study participation. 
6.2.10.1. 
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During study participation, a subject who has a biopsy or cytology indicating transformation to 
an aggressive lymphoma will be considered to have progressive disease (PD) even in the absence 
of other evidence of PD. If the subject has no earlier objective documentation of PD, the date of 
the biopsy or cytology will be considered the date of disease progression. 
 
Definitions of Tumor Response and Progression 
Responses will be categorized as CR, PR, SD, or PD using the criteria in Appendix 4, 
Appendix 5, and Appendix 6. 
In addition, a response category of not evaluable (NE) is provided for situations in which there is 
inadequate information to otherwise categorize response status. A response category of no 
disease (ND) is included for situations in which there is absence of tumor both at baseline and on 
treatment. 
Every attempt should be made to keep the subject in the study and continue collecting CT or 
MRI scans for tumor assessment as per the schedule of assessments (Appendix 2) until disease 
progression or initiation of systemic anti-tumor therapy other than treatment per protocol. If this 
is not possible or acceptable to the subject or investigator, the subject may be withdrawn from 
the study. The subject will be asked to attend the post-treatment follow-up assessment visit when 
discontinuing from the study 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 counted in the denominators in calculations of tumor response rates. Where imaging 
data are available, these data will supersede physical examination data in determining tumor 
status. 
As of Amendment 7, CT/MRI scans will no longer be performed and will only be performed at 
the time of disease progression or at study discontinuation. 
As of Amendment 9, investigators will clinically assess each subject’s disease status every 
12 weeks for the first 12 months, and then every 24 weeks during the long-term safety 
monitoring phase per institutional standard of care (Appendix 3). If there is clinical evidence of 
disease progression, a confirmatory radiologic assessment should be performed per institutional 
standard of care. 
6.2.11. 
Blood and Urine Samples 
Blood and urine for laboratory safety tests will be collected according to the Study Procedures 
Tables (Appendix 2). The date and time of blood and urine collection will be recorded in the 
subject’s source documentation. The date and time of previous tirabrutinib and idelalisib or 
entospletinib dose will be recorded in the subject’s source documentation on days where PK is 
collected. The tests will be analyzed using standard procedures. White blood cell (WBC) 
differentials will be reported as absolute counts. All laboratory tests must be reviewed for 
clinical significance by the Investigator or qualified designee. Eligibility will be based on central 
laboratory assessments and will be collected within -28 days of Cycle 1, Day 1. 
Cycle 1, Day 1 pre-dose samples may be drawn up to 2 days prior to the Cycle 1, Day 1 visit. 
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As of Amendment 9, clinical evaluations and laboratory assessments will be performed every 
12 weeks for the first 12 months, and then every 24 weeks during the long-term safety 
monitoring phase per institutional standard of care (Appendix 3). The eligibility of subjects 
enrolling in Group VI will be based on local urine pregnancy testing as per local standard of 
care, if applicable. For Group VI, urine pregnancy testing performed up to 30 days and imaging 
performed up to 90 days prior to enrollment may be used to fulfill eligibility criteria. 
The analytes listed in Table 6-1 will be tested. 
6.2.12. 
Biomarker Samples to Address the Study Objectives  
As of Amendment 7, biomarker samples will no longer be collected. 
The biological specimens described herein will be collected in this study and will be used to 
evaluate the association of exploratory systemic and/or tissue specific biomarkers with study 
drug response including efficacy and/or adverse events, as well as to increase knowledge and 
understanding of the biology of these and related diseases and possible companion diagnostics 
development. The specific analyses will include, but not limited to, the biomarkers and assays 
described herein. Because biomarker science is a rapidly evolving area of investigation, it is not 
possible to specify prospectively all tests that will be done on the specimens provided. The 
testing outlined below is based upon the current state of scientific knowledge. It may be modified 
during or after the end of the study to remove tests no longer indicated and/or to add new tests 
based upon the growing state of the art knowledge. Biomarker samples may also be used for 
potential assay development of companion diagnostics.  
 
 
 
 
Blood Samples 
Pharmacodynamic activity of tirabrutinib alone or combined with idelalisib or entospletinib and 
obinutuzumab will be evaluated in blood samples using available assay such as BTK occupancy 
and signaling pathway biomarkers such as Syk, AKT, S6, NF-kB, PLCg2, ERK, NF-κB. Blood 
samples for pharmacodynamics will be collected at timepoints as outlined in the table of 
assessments. 
  
Circulating tumor DNA will also be explored in these plasma samples if technically feasible and 
where it may be informative for specific disease cohorts and to evaluate biomarkers such as 
MRD. 
Peripheral blood samples will be collected at CR from CLL and MCL subjects to assess MRD 
status using either flow cytometry or DNA analysis by PCR or sequencing.  
CLL, SLL, and MCL subjects: 
Exploratory biomarkers related to disease progression including mechanisms of resistance, 
response to treatment, and overall prognosis, will be assessed in peripheral blood samples. For 
these assessments, peripheral blood will be collected prior to therapy at Cycle 1, Day 1 and at 
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disease progression.
 
 
 
Tumor Tissue Samples 
If clinically feasible, lymph node biopsies will be performed on Cycle 1, Day 1 (- 7 days), 
Cycle 1 Day 8, and at disease progression and will be collected for tumor DNA, RNA, and 
protein expression analysis. These samples will be used to understand biomarkers associated 
with the disease, clinical responses, drug responses, and potential mechanisms of resistance. 
Signaling pathway activation such as signatures associated with BCR, NF-κB signaling, etc. will 
be assessed by gene expression analysis and protein biomarkers (phosphorylated AKT, S6, BTK, 
and SYK pathway markers) will be evaluated using immunohistochemistry based on available 
reagents in paired tumor specimens. Given the possibility that not all subjects will respond to 
therapy or subsets of patients will have greater magnitude of responses, tumor characteristics that 
may be associated with clinical responses will be investigated (MYD88, CD79b mutations) using 
samples collected at baseline.  
Bone marrow samples will be collected per Appendix 2 from WM subjects to determine DNA 
mutations such as MYD88 and CXCR4 and their association with responses. Bone marrow and 
blood samples will be collected at CR from CLL and MCL subjects to evaluate minimal residual 
disease (MRD) using either flow cytometry or molecular methods. 
Fifteen (15) recently prepared (not more than 2 weeks prior to submission) unstained slides from 
archival tumor tissue will be requested for all subjects who have tissue available and biopsy is 
not medically feasible.  
 
 
 
 
 
 
 
  
 
 
 
 
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6.2.15. 
Pregnancy Test for Females of Childbearing Potential 
All female subjects of childbearing potential (as defined in Appendix 7) will have a serum 
pregnancy test at Screening and a urine pregnancy test prior to Day 1 dosing, every 28 days 
thereafter, then every 12 weeks as of amendment 7 and at the EOT visit. The results must be 
confirmed as negative prior to continued administration of study drug.  
As of Amendment 9, female subjects of childbearing potential must have a negative urine 
pregnancy test at Screening to enroll into long-term safety monitoring. For Group VI, urine 
pregnancy testing performed up to 30 days may be used to fulfill eligibility criteria. 
6.2.16. 
Pharmacokinetic Samples 
Dose Escalation (Combination I and II): 
PK samples will be collected on Cycle 1, Day 1 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, and 
 
 post-dose of tirabrutinib and Cycle 1, Days 2 and 8 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 
 and 24 hours post-dose of tirabrutinib and idelalisib or entospletinib. 
 
 PK sample should be collected prior 
to evening dose when study drug is administered BID and 24 hour sample will be collected 
24 hours post-dose relative to morning dose. PK samples will be collected in all cohorts at 
pre-dose and 1-6 hours post-dose on Cycle 1 Day 15. A sparse PK sample will also be collected 
anytime on the first day of Cycles 2 to 6. 
Plasma concentrations of tirabrutinib, idelalisib, GS-563117, and entospletinib, as applicable, 
will be determined and PK evaluated. Plasma protein binding of each analyte may be evaluated. 
As of Amendment 7, PK samples will no longer be collected. 
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Dose expansion (Combination I and II): 
A PK sample will be collected on Cycle 1, Day 1 between 1.5 and 4 hours (inclusive) post-dose 
of tirabrutinib. On Cycle 1, Day 8 and Cycle 2, Day 1, a PK sample will be collected at pre-dose 
and between 1.5 and 4 hours (inclusive) post-dose of tirabrutinib and idelalisib or entospletinib. 
A sparse PK sample will also be collected anytime on the first day of Cycles 3 to 5 and at 
pre-dose on the first day of Cycle 6. 
Plasma concentrations of tirabrutinib, idelalisib, GS-563117, and entospletinib, as applicable, 
will be determined. Plasma protein binding of each analyte may be evaluated. 
The collection of some or all of these samples may not be feasible at the site due to shipment 
logistics depending on their geographic location. In addition, sampling time points may be 
eliminated or modified based upon emerging data. 
As of Amendment 7, PK samples will no longer be collected. 
Dose Escalation and Dose Expansion Combinations III and IV: 
A PK sample will be collected on Cycle 1, Day 1 between 1.5 and 4 hours post-dose of 
tirabrutinib. On Cycle 1, Day 8 and Cycle 2, Day 1, a PK sample will be collected at pre-dose 
and between 1.5 and 4 hours post-dose of tirabrutinib and idelalisib or entospletinib. A sparse PK 
sample will also be collected anytime on the first day of Cycles 3 to 5 and at pre-dose on the 
first day of Cycle 6. 
As of Amendment 7, PK samples will no longer be collected. 
Dose Expansion Group V:  
In all subjects, a PK sample will be collected on Cycle 1, Day 1 between 1.5 and 4 hours 
post dose of tirabrutinib. On Cycle 1, Day 8 and Cycle 2, Day 1, a PK sample will be collected at 
pre-dose and between 1.5 and 4 hours post-dose of tirabrutinib. A sparse PK sample will also be 
collected anytime on the first day of Cycles 3 to 5 and at pre-dose on the first day of Cycle 6. 
Up to 10 subjects will undergo more intensive PK sampling; Cycle 1, Day 8 at pre-dose and 2, 4, 
6, 8, 
 and 24 hours post-dose of tirabrutinib. Note: If a subject has intensive PK 
sampling on Cycle 1, Day 8, sparse PK samples do not need to be collected on Cycle 1, Day 8. 
As of Amendment 7, PK samples will no longer be collected. 
Long-Term Safety Monitoring:  
No PK samples will be collected. 
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6.2.17. 
Pharmacodynamic Samples 
Dose Escalation (Combination I and II): 
Blood samples for pharmacodynamics will be collected on Cycle 1, Day 1 at pre-dose, 2, and 
6 hours post-dose; on Cycle 1, Days 2 and 8 at pre-dose, 2, 6, and 24 hours post-dose; and at the 
EOT or disease progression. When study drug is administered twice daily, the 24 hour sample 
will be collected 24-hours post-dose relative to the morning dose. The collection of some or all 
of these samples may not be feasible at the site due to shipment logistics depending on their 
geographic location. In addition, sampling time points may be eliminated or modified based 
upon emerging data. 
As of Amendment 7, pharmacodynamics samples will no longer be collected.  
Dose Expansion (Combination I and II): 
Pharmacodynamic samples will be collected on Cycle 1, Day 1 at pre-dose and between 1.5 and 
4 hours post-dose of tirabrutinib. On Cycle 1, Day 8 and Cycle 2, Day 1, a pharmacodynamic 
sample will be collected at pre-dose and between 1.5 and 4 hours post-dose of tirabrutinib and 
idelalisib or entospletinib and at the EOT or disease progression.  
The collection of some or all of these samples may not be feasible at the site due to shipment 
logistics depending on their geographic location. In addition, sampling time points may be 
eliminated or modified based upon emerging data. 
As of Amendment 7, pharmacodynamics samples will no longer be collected. 
Dose Evaluation of Combinations III and IV:  
Pharmacodynamic samples will be collected on Cycle 1, Day 1 at pre-dose and between 1.5 and 
4 hours post-dose of tirabrutinib. On Cycle 1, Day 8 and Cycle 2, Day 1, a pharmacodynamic 
sample will be collected at pre-dose and between 1.5 and 4 hours post-dose of tirabrutinib and 
idelalisib or entospletinib and at the EOT or disease progression. 
As of Amendment 7, pharmacodynamics samples will no longer be collected. 
Dose Expansion Group V: 
Pharmacodynamic samples in these same subjects will be Cycle 1, Day 1 pre-dose and between 
1.5 and 4 hours post dose of tirabrutinib. Cycle 1, Day 8 and Cycle 2, Day 1 at pre-dose and 
between 1.5 and 4 hours and at the EOT or disease progression. 
As of Amendment 7, pharmacodynamics samples will no longer be collected. 
Long-Term Safety Monitoring:  
No pharmacodynamic samples will be collected. 

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Table 6-1. 
Blood and Urine Samples Collected During the Course of the Studyef  
Serum Chemistry 
Hematology 
Other 
Sodium 
Potassium 
Chloride 
Glucose 
Blood urea nitrogen 
Creatinineb 
ALT 
AST 
GGT 
Cholesterol 
Triglycerides 
Uric Acid 
Alkaline phosphatase 
Total bilirubina 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphate 
LDH 
Amylase 
Lipase 
Insulin 
C-peptide (subjects receiving exogenous 
insulin only) 
White Blood Cell (WBC) Count 
Hemoglobin 
Hematocrit 
Platelet Count 
Neutrophils (ANC) 
Lymphocytes 
Monocytes 
Basophils 
Eosinophils 
Tirabrutinib, idelalisib, GS-563117, 
and entospletinib, as applicable, plasma 
concentrations 
Other metabolites of tirabrutinib, 
idelalisib or entospletinib may be 
measured 
Blood and Tissue Biomarkers 
HBsAG 
Hepatitis B core antibody 
Hepatitis C antibody 
CMV serology 
CMV PCR or PP65 Agd 
Beta-2 microglobulin 
Serum quantitative immunoglobulins 
(IgG, IgM, IgA  
Lymphocyte Immunophenotyping by 
flow cytometry 
MRD 
Serum CH50 level 
Coagulation 
PT/INR 
aPTT 
Pregnancy Testing 
Urine 
Serum Qualitative β-HCG (females) 
Urine Pregnancy (females) 
Urinalysis 
Dipstick 
pH 
Occult blood 
Protein 
Glucose 
Ketones 
Bilirubin 
Urobilinogen 
Nitrite 
Leukocyte esterase 
Microscopicc 
WBC/High Power Field 
RBC/High Power Field 
Urine protein immunoelectropheresis  
a 
Includes direct bilirubin 
b 
Estimated creatinine clearance/glomerular filtration rate will be calculated based on the Cockcroft-Gault formula 
c 
To be performed only if the dipstick results are abnormal Note: Additional components, abnormal, and/or atypical cells will 
also be reported if present 
d 
Subjects on treatment with idelalisib only 
e 
As of Amendment 7, pharmacokinetics and pharmacodynamics samples will no longer be collected 
f 
As of Amendment 9, clinical evaluations and laboratory assessments will be performed every 12 weeks for the first 
12 months, and then every 24 weeks during the long-term safety monitoring phase per institutional standard of care. For 
subjects on treatment with idelalisib, CMV surveillance by PCR or PP65 Ag testing and clinical evaluation for CMV 
reactivation, to be done as per local standard of care at Long-Term Safety Monitoring Cycle 1 Day 1, every 12 weeks for the 
first 12 months, and then every 24 weeks during the long-term safety monitoring phase.  
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; CH50 = 50% hemolytic complement activity; CMV = cytomegalovirus; GGT = gamma-glutamyltransferase; 
INR = international normalized ratio; LDH = lactate dehydrogenase; MRD = minimal residual disease; PT = prothrombin time; 
RBC = red blood cell; WBC = white blood cell 

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6.2.18. 
Unscheduled Procedures 
Unscheduled procedures, including, but not limited to, vital signs, 12-lead ECG, and CT or MRI, 
will be recorded on the applicable eCRFs. 
6.3. 
Post-treatment Assessments 
6.3.1. 
Post-Study Phone Call 
Subjects will be contacted by phone 30 days (± 7 days) after the last dose of tirabrutinib and/or 
idelalisib or entospletinib to assess for AEs. For subjects who discontinue the study for reasons 
other than disease progression, the site should also obtain information post-study anti-cancer 
therapies, surgeries, and date of disease progression (if known). 
6.4. 
Criteria for Discontinuation of Study Treatment 
See Sections 3.4 and 3.5 for discontinuation criteria. 
6.5. 
Dose Interruption and Reduction 
The following are the guidelines for dose interruption and/or reduction. If an AE is attributed to 
study drug, the investigator’s discretion will be used to determine if the drug not attributed to the 
AE will be withheld based on the investigator’s assessment of risk-benefit of withholding the 
study drug. 
If a subject experiences a DLT prior to completion of dosing during Cycle 1 
(Day 1-29 inclusive), no further doses of either drug will be administered and the subject will be 
observed for resolution of the toxicity. The exception is if, in the Investigator’s opinion, the 
toxicity is solely due to idelalisib/entospletinib and the subject is deemed at risk for a withdrawal 
reaction from the sudden discontinuation of tirabrutinib, then tirabrutinib may be continued 
alone. 
Upon the initiation of Cycle 2, Day 1, an interruption of tirabrutinib and/or idelalisib or 
entospletinib administration of up to 2 weeks will be acceptable to allow for any reversal of 
toxicity between doses of tirabrutinib and/or idelalisib or entospletinib. If the toxicity does not 
resolve to CTC Grade ≤ 2 within 2 weeks, additional doses of the interrupted drug(s) will not be 
administered unless the toxicity is deemed related to the subject’s underlying disease in the 
opinion of the investigator. If the toxicity is deemed to be related to one agent (tirabrutinib or 
idelalisib or entospletinib), the subject may resume the other drug as a single agent, however, the 
discontinued drug may not be re-initiated on this study. 
Subjects experiencing a related or non-related AE at any point during the study that takes longer 
than 2 weeks to resolve will be reviewed on a case-by-case basis by the investigator and the 
sponsor. Upon resolution of the AE, or in the opinion of the Investigator if the AE is considered 
to be well controlled and if the subject is deemed to be gaining clinical benefit from treatment 
with tirabrutinib and/or idelalisib or entospletinib, a subject may continue to receive tirabrutinib 
and/or idelalisib or entospletinib at their assigned dose or at a lower dose (and consistent with 
Table 6-2). The dose may subsequently be increased back to the original dose level if considered 
safe to do so by the treating investigator and upon approval by the sponsor. 

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The dose modification instructions focus on the types of events most commonly attributed to 
each of the study agents. The recommendations provided in Table 6-2, Table 6-3, and Table 6-4 
comprise only guidelines; variations from these recommendations may be warranted based on an 
investigator’s individual judgment in considering potential risks, benefits, and therapeutic 
alternatives available to each subject. The exceptions are SJS, TEN, PJP infection, organizing 
pneumonia, bowel perforation, multiple recurrent episodes of ≥ Grade 2 diarrhea following 
idelalisib dose reduction, Grade 4 ALT/AST with bilirubin elevation, or ≥ Grade 2 
pneumonitis where idelalisib must be discontinued. 
Table 6-2. 
Dose Adjustments, Withholding and Discontinuation Related to 
Idelalisib and/or Tirabrutinib 
NCI CTCAE Grade 
Recommendation 
Idelalisib 
Tirabrutinib 
HEMATOLOGICAL ADVERSE EVENTS  
Neutropenia 
Grade ≤ 3 Neutropenia 
Maintain current dose level and 
schedule. Blood counts must be 
monitored at least weekly until Grade 
≤2. 
Maintain current dose level and 
schedule. 
Grade 4 neutropenia 
(or occurrence of 
neutropenic fever or 
infection 
Delay until Grade ≤2 (ANC ≥1 x 109/L 
and consider G-CSF support. Resume at 
same or reduced dose level at 
investigator discretion. Blood counts 
must be monitored at least weekly. 
Withhold tirabrutinib until resolved to 
Grade 2 or baseline (recovery). 
Tirabrutinib may be reinitiated at the 
previous dose or decrease one dose 
level. If the toxicity recurs, decrease 
by one dose level. If toxicity persists 
or recurs following 2 dose reductions 
discontinue tirabrutinib. 
Thrombocytopenia 
Grade ≤ 3 
Thrombocytopenia 
Withhold for clinically significant 
bleeding 
Withhold for clinically significant 
bleeding 
Grade 4 Thrombocytopenia 
Withhold tirabrutinib and idelalisib until resolved to Grade 1 or baseline 
(recovery). Tirabrutinib and idelalisib may be reinitiated at the previous dose. If 
the toxicity recurs, decrease by one dose level. A second reduction may be 
considered as needed. If toxicity persists or recurs following 2 dose reductions 
discontinue tirabrutinib and idelalisib. 
HEMATOLOGICAL ADVERSE EVENTS 
Hemorrhage 
 
 
Hold tirabrutinib for clinically 
significant bleeding. Reinitiate 
treatment at the prior dose after 
hemostasis is achieved. 

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NCI CTCAE Grade 
Recommendation 
Idelalisib 
Tirabrutinib 
NON-HEMATOLOGICAL ADVERSE EVENTS 
Dermatological/Rash 
Grade ≤ 2 
Maintain current dose level and 
schedule. 
Maintain current dose level and 
schedule. 
Grade 3 or 4 
Withhold tirabrutinib and idelalisib until resolved to Grade 1 or baseline 
(recovery). Tirabrutinib and idelalisib may be resumed at a lower dose. A second 
reduction may be considered as needed. If toxicity persists or recurs following 
2 dose reductions discontinue tirabrutinib and idelalisib. 
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis 
Any Grade 
Permanently discontinue idelalisib. Interrupt any co-administered medications 
potentially associated with SJS or TEN. 
Institute systemic immunosuppression per institutional standards. 
Bowel perforation 
Any grade 
Discontinue idelalisib  
 
Diarrhea 
Grade ≤ 1 
Provide anti-diarrheal (eg, loperamide) and maintain current tirabrutinib and 
idelalisib dose level and schedule 
Grade 2 
Withhold idelalisib until Grade ≤ 1. 
Provide anti-diarrheal (eg, loperamide). 
Resume idelalisib at previous dose level. 
If rechallenge results in recurrence, 
resume lower dose level. Consider 
addition of anti-inflammatory 
(eg, sulfasalazine, budesonide). If 
toxicity persists or recurs following a 
dose reduction discontinue idelalisib. 
Refer to Section 6.2.8.1 for required 
evaluation. 
Withhold tirabrutinib until resolved to 
Grade ≤1. If resolution occurs within 
7 days, tirabrutinib may be reinitiated 
at the previous dose. If the toxicity 
recurs, decrease by one dose level. A 
second reduction may be considered as 
needed. If toxicity persists or recurs 
following 2 dose reductions 
discontinue tirabrutinib. 
Grade 3 or 4 
Withhold study drug. Rule out infectious 
etiology including CMV (see 
Section 6.2.8.1). Consider anti-diarrheal 
(eg, loperamide) and/or addition of 
anti-inflammatory agent 
(eg, sulfasalazine, budesonide). At 
Grade ≤1, may resume at lower dose 
level or discontinue study drug at 
investigator discretion. 
If toxicity persists or recurs following a 
dose reduction permanently discontinue 
idelalisib. Refer to Section 6.2.8.1 for 
required evaluation. 
Withhold tirabrutinib until Grade ≤1. 
Provide anti-diarrheal 
(eg, loperamide). Resume at lower 
dose level. Consider addition of anti-
inflammatory (eg, sulfasalazine, 
budesonide). If toxicity persists or 
recurs following 2 dose reductions 
permanently discontinue tirabrutinib. 

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NCI CTCAE Grade 
Recommendation 
Idelalisib 
Tirabrutinib 
NON-HEMATOLOGICAL ADVERSE EVENTS 
Hepatic Adverse Events (elevations in ALT, AST or bilirubin) 
Grade 1 
(ALT/AST ≤ 3xULN) 
(Bilirubin ≤ 1.5xULN) 
Maintain current dose level and 
schedule. 
Maintain current dose level and 
schedule. 
Grade 2 
(ALT/AST > 3-5xULN) 
(Bilirubin>1.5 -≤ 3xULN) 
Monitor ALT, AST, ALP, and bilirubin 
at least 1x per week. 
Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week. 
Grade 3 
(ALT/AST > 5-20xULN) 
(Bilirubin > 3-10xULN) 
Withhold tirabrutinib and idelalisib. Monitor ALT, AST, ALP, and bilirubin at 
least 1x per week until all abnormalities are Grade ≤ 1 or baseline. If bilirubin 
abnormality was Grade < 3, resume tirabrutinib and idelalisib at previous dose 
level. If bilirubin abnormality was Grade ≥ 3, resume tirabrutinib and idelalisib at 
lower dose level. 
Grade 4 
(ALT/AST > 20xULN) 
(Bilirubin > 10xULN) 
Withhold tirabrutinib and idelalisib. Monitor ALT, AST, ALP, and bilirubin at 
least 1x per week until all abnormalities are Grade ≤ 1 or baseline. If bilirubin 
abnormality was Grade ≤ 3, resume tirabrutinib and idelalisib at lower dose level. 
If bilirubin was Grade 4, discontinue tirabrutinib and idelalisib. In case of Grade 4 
ALT/AST with bilirubin elevation idelalisib must be discontinued  
Organizing Pneumonia 
Any Grade 
Required Action: Discontinue idelalisib 
permanently. 
Institute supportive care as appropriate. 
May resume tirabrutinib only at 
investigator discretion. 
Pneumonitis  
Grade 1 (asymptomatic) 
Required Action: Withhold idelalisib 
until resolution to baseline.  
Maintain current dose level and 
schedule. 
Grade 2 
Required Action: Discontinue idelalisib 
permanently in subjects with any 
severity of symptomatic pneumonitis 
and institute therapy as clinically 
appropriate. 
Withhold tirabrutinib until Grade ≤ 1, 
consider systemic corticosteroids and 
Pneumocystis treatment. Upon 
resolution may resume at initial or 
lower dose level at investigator 
discretion. 
Grade 3 
 Required Action: Discontinue 
idelalisib permanently in subjects with 
any severity of symptomatic 
pneumonitis and institute therapy as 
clinically appropriate. 
Withhold tirabrutinib until Grade ≤ 1. 
Consider systemic corticosteroids and 
Pneumocystis treatment. Upon 
resolution, may resume at lower dose 
level (after discussion with the sponsor) 
or discontinue tirabrutinib at 
investigator discretion. 
Grade 4 
Required Action: Discontinue idelalisib and tirabrutinib permanently and institute 
therapy as clinically appropriate. 
Pneumocystis pneumonia (PJP Infection) 
Any Grade 
Discontinue idelalisib 
 

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NCI CTCAE Grade 
Recommendation 
Idelalisib 
Tirabrutinib 
NON-HEMATOLOGICAL ADVERSE EVENTS 
Unequivocal CMV infection 
Any Grade 
Discontinue idelalisib and undergo 
effective antiviral treatment according 
to established clinical guidelines. 
 
Hypersensitivity 
Any Grade 
Consider interrupting or discontinuing tirabrutinib treatment  
OTHER NON-HEMATOLOGICAL ADVERSE EVENTS 
Grade 1 
Maintain current dose level and schedule 
Grade 2 
Withhold tirabrutinib and idelalisib until Grade ≤1 or baseline. May resume 
tirabrutinib and idelalisib at initial or lower dose level or discontinue tirabrutinib 
and idelalisib at investigator discretion. 
Grade 3 
Withhold tirabrutinib and idelalisib until Grade ≤1 or baseline. May resume 
tirabrutinib and idelalisib at lower dose level or discontinue tirabrutinib and 
idelalisib at investigator discretion. 
Grade 4 
Discontinue tirabrutinib and idelalisib. 
 
Table 6-3. 
Restarting Doses of Tirabrutinib after Treatment Interruption for 
Drug-related Grade 3 or 4 Toxicity*  
Tirabrutinib Dose at the time of the first toxicity 
1st dose reduction 
2nd dose reduction 
40 mg QD 
Discontinue 
- 
80 mg QD 
40 mg QD 
Discontinue 
100 mg QD 
80 mg QD 
40 mg QD 
150 mg QD or 160 mg QD 
80 mg QD 
40 mg QD 
400 mg QD 
240 mg QD 
140 mg QD 
480 mg QD 
300 mg QD 
140 mg QD 
* 
Toxicity may be a new event or recurrence of a prior Grade 3 or 4 toxicity 
Use Table 6-2 to guide Grade 4 hematologic drug related toxicity dose reductions 
Table 6-4. 
Restarting Doses of Idelalisib after Treatment Interruption for 
Drug-related Grade 3 or 4 Toxicity*† 
Idelalisib Dose at the time of the toxicity 
1st dose reduction 
2nd dose reduction 
50 mg BID or 100 mg QD 
50 mg QD† 
Discontinue 
* 
Toxicity may be a new event or recurrence of a prior Grade 3 or 4 toxicity. 
† 
After 31 December 2020, subjects receiving 100 mg QD who experience any drug-related ≥ Grade 3 toxicity will 
discontinue idelalisib and be given the option to continue tirabrutinib monotherapy, at the investigator’s discretion.  
Use Table 6-2 to guide Grade 4 hematologic drug related toxicity dose reductions 

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Table 6-5. 
Dose Adjustments, Withholding and Discontinuation Related to 
Entospletinib and/or Tirabrutinib 
NCI CTCAE Grade 
Recommendation 
Entospletinib 
Tirabrutinib 
HEMATOLOGICAL ADVERSE EVENTS  
Neutropenia 
Grade ≤ 3 Neutropenia 
Maintain current dose level and schedule. 
Maintain current dose level and schedule. 
Grade 4 neutropenia 
(or occurrence of neutropenic 
fever or infection 
Withhold tirabrutinib and entospletinib until resolved to Grade 1 or baseline (recovery). 
Tirabrutinib and entospletinib may be reinitiated at the previous dose or decrease one dose. 
If the toxicity recurs, decrease by one dose level. If toxicity persists or recurs following 
2 dose reductions discontinue tirabrutinib and entospletinib. 
Thrombocytopenia 
Grade ≤ 3 Thrombocytopenia 
Maintain current dose level and schedule. 
Maintain current dose level and schedule. 
Grade 4 Thrombocytopenia 
Withhold tirabrutinib and entospletinib until resolved to Grade 1 or baseline (recovery). 
Tirabrutinib and entospletinib may be reinitiated at the previous dose. If the toxicity recurs, 
decrease by one dose level. A second reduction may be considered as needed. If toxicity 
persists or recurs following 2 dose reductions discontinue tirabrutinib and entospletinib. 
Hemorrhage 
 
Consider holding entospletinib for clinically 
significant bleeding. Reinitiate treatment at 
the prior dose after hemostasis is achieved. 
Hold tirabrutinib for clinically significant 
bleeding. Reinitiate treatment at the prior 
dose after hemostasis is achieved. 
NON-HEMATOLOGICAL ADVERSE EVENTS 
Dermatological 
Grade ≤ 2 
Maintain current dose level and schedule. 
Maintain current dose level and schedule. 
Grade 3 or 4 
Withhold tirabrutinib and entospletinib until resolved to Grade 1 or baseline (recovery). 
Tirabrutinib and entospletinib may be resumed at a lower dose. A second reduction may be 
considered as needed. If toxicity persists or recurs following 2 dose reductions discontinue 
tirabrutinib and entospletinib. 
Diarrhea 
Grade ≤ 1 
Provide anti-diarrheal (eg, loperamide) and maintain current tirabrutinib and entospletinib 
dose level and schedule 
Grade 2 
Withhold entospletinib until Grade ≤ 1. 
Provide anti-diarrheal (eg, loperamide). 
Resume entospletinib at previous dose 
level. If rechallenge results in recurrence, 
resume lower dose level. Consider addition 
of anti-inflammatory (eg, sulfasalazine, 
budesonide). If toxicity persists or recurs 
following 2 dose reductions discontinue 
entospletinib. 
Withhold tirabrutinib until resolved to 
Grade ≤1. If resolution occurs within 7 days, 
tirabrutinib may be reinitiated at the previous 
dose. If the toxicity recurs, decrease by one 
dose level. A second reduction may be 
considered as needed. If toxicity persists or 
recurs following 2 dose reductions 
discontinue tirabrutinib. 
Grade 3 or 4 
Withhold tirabrutinib and entospletinib until Grade ≤1. Provide anti-diarrheal 
(eg, loperamide). Resume at lower dose level. Consider addition of anti-inflammatory 
(eg, sulfasalazine, budesonide). If toxicity persists or recurs following 2 dose reductions 
discontinue tirabrutinib and entospletinib. 

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NCI CTCAE Grade 
Recommendation 
Entospletinib 
Tirabrutinib 
NON-HEMATOLOGICAL ADVERSE EVENTS 
Hepatic Adverse Events (elevations in ALT, AST or bilirubin) 
Grade 1 
(ALT/AST ≤ 3xULN) 
(Bilirubin ≤ 1.5xULN) 
Maintain current dose level and schedule. 
Maintain current dose level and schedule. 
Grade 2 
(ALT/AST > 3-5xULN) 
(Bilirubin>1.5 -≤ 3xULN) 
Maintain current dose level and schedule. 
Monitor ALT, AST, ALP, and bilirubin at 
least 1x per week. 
Maintain current dose level and schedule. 
Monitor ALT, AST, ALP, and bilirubin at 
least 1x per week. 
Grade 3 
(ALT/AST > 5-20xULN) 
(Bilirubin > 3-10xULN) 
Withhold tirabrutinib and entospletinib. Monitor ALT, AST, ALP, and bilirubin at least 
1x per week until all abnormalities are Grade ≤ 1 or baseline. If bilirubin abnormality was 
Grade < 3, resume tirabrutinib and entospletinib at previous dose level. If bilirubin 
abnormality was Grade ≥ 3, resume tirabrutinib and entospletinib at lower dose level. 
Grade 4 
(ALT/AST > 20xULN) 
(Bilirubin > 10xULN) 
Withhold tirabrutinib and entospletinib. Monitor ALT, AST, ALP, and bilirubin at least 
1x per week until all abnormalities are Grade ≤ 1 or baseline. If bilirubin abnormality was 
Grade ≤ 3, resume tirabrutinib and idelalisib at lower dose level. If bilirubin was Grade 4, 
discontinue tirabrutinib and entospletinib. 
Pneumonitis  
Grade 1 
Maintain current dose level and schedule. Consider Pneumocystis therapy 
Grade 2 
Withhold tirabrutinib and entospletinib until Grade ≤ 1, consider systemic corticosteroids 
and Pneumocystis treatment. Upon resolution may resume at initial or lower dose level at 
investigator discretion. 
Grade 3 
Withhold tirabrutinib and entospletinib until Grade ≤ 1, consider systemic corticosteroids 
and consider Pneumocystis treatment. Upon resolution may resume at lower dose 
(after discussion with the sponsor) level or discontinue tirabrutinib and entospletinib at 
investigator discretion.  
Grade 4 
Discontinue tirabrutinib and entospletinib. 
Hypersensitivity 
Any Grade 
Consider interrupting or discontinuing tirabrutinib treatment  
OTHER NON-HEMATOLOGICAL ADVERSE EVENTS 
Grade 1 
Maintain current dose level and schedule 
Grade 2 
Withhold tirabrutinib and entospletinib until Grade ≤1 or baseline. May resume tirabrutinib 
and entospletinib at initial or lower dose level or discontinue tirabrutinib and entospletinib 
at investigator discretion. 
Grade 3 
Withhold tirabrutinib and entospletinib until Grade ≤1 or baseline. May resume tirabrutinib 
and entospletinib at lower dose level or discontinue tirabrutinib and entospletinib at 
investigator discretion. 
Grade 4 
Discontinue tirabrutinib and entospletinib. 
 

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Table 6-6. 
Restarting Doses of Entospletinib after Treatment Interruption for 
Drug-related Grade 3 or 4 Toxicity* 
Entospletinib dose at the time of the first toxicity 
1st dose reduction 
2nd dose reduction 
200 QD 
Discontinue 
- 
200 BID or 400 QD 
200 QD 
Discontinue 
* 
Toxicity may be a new event or recurrence of a prior Grade 3 or 4 toxicity. 
Use Table 6-2 to guide Grade 4 hematologic drug related toxicity dose reductions 
Table 6-7. 
Dose Adjustment Guidelines for Subjects Receiving Obinutuzumab 
NCI CTCAE Grade 
Recommendation 
Toxicity attributable to obinutuzumab 
HEMATOLOGICAL ADVERSE EVENTS  
Neutropenia 
Grade ≤ 2 Neutropenia 
Maintain current dose level and schedule. 
Grade ≤ 3 Neutropenia 
Maintain current dose level and schedule. Consider G-CSF support 
Grade 4 neutropenia 
(or occurrence of neutropenic 
fever or infection 
Delay obinutuzumab until Grade ≤ 2 (ANC ≥ 1 × 109/L) and/or neutropenic 
fever or infection is resolved; thereafter, resume at full dose. Consider 
G-CSF support to avoid delays. If delay is > 4 weeks, discontinue 
obinutuzumab. 
Thrombocytopenia 
Grade ≤ 3 Thrombocytopenia 
Maintain current dose level and schedule. 
Grade 4 Thrombocytopenia 
Delay obinutuzumab until Grade ≤ 3 (platelets ≥ 25 × 109/L); thereafter, 
resume at full dose. If delay is > 4 weeks, discontinue obinutuzumab, unless 
the Grade 4 thrombocytopenia occurred after the first 3 weekly doses. 
Hemorrhage 
 
Hold obinutuzumab in case of platelets < 20,000/μL. If Day 8 is delayed then 
skip Day 8 and administer Day 15 as previously scheduled (if symptomatic 
bleeding has resolved). If Day 15 is delayed then skip Day 15 dosing and 
administer Day 29 of obinutuzumab as scheduled (if symptomatic bleeding 
has resolved). 
At the discretion of the study investigator, for subjects who are on low 
molecular weight heparin (LMWH), when thrombocytopenia with platelets 
<20,000/μL develops, reduce the dose of LMWH or new oral anticoagulants 
(NOAC) used. 
 
At the discretion of the study investigator, for subjects who are on platelet 
inhibitors, when thrombocytopenia with platelets <20,000/μL develops, 
consideration should be given to temporarily pause obinutuzumab. 
Hold tirabrutinib and obinutuzumab for clinically significant bleeding 
(irrespective of platelet count) until it resolves. 

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NCI CTCAE Grade 
Recommendation 
Toxicity attributable to obinutuzumab 
NON-HEMATOLOGICAL ADVERSE EVENTS 
Cutaneous 
Grade ≤ 2 
Maintain current dose level and schedule. 
Grade 3 or 4 
Delay obinutuzumab until Grade ≤ 1; thereafter, may resume at full dose or 
discontinue obinutuzumab at investigator discretion. 
Gastrointestinal Inflammation/Diarrhea 
Grade ≤ 2 
Maintain current dose level and schedule. 
Grade 3 and 4 
Delay obinutuzumab as necessary to ensure subject is sufficiently stable to 
receive further treatment; thereafter maintain full dose and schedule. 
Hepatic Adverse Events (elevations in ALT, AST or bilirubin) 
Grade ≤ 2 (ALT/AST ≤ 3xULN) 
(Bilirubin ≤ 1.5xULN) 
Maintain current dose level and schedule. 
Grade 3  
(ALT/AST > 5-20xULN) 
(Bilirubin > 3-10xULN) 
Delay obinutuzumab as necessary to ensure subject is sufficiently stable to 
receive further treatment; thereafter maintain full dose and schedule. If 
bilirubin abnormality was Grade ≥ 3, resume tirabrutinib and entospletinib at 
lower dose level. 
Grade 4 
(ALT/AST > 20xULN) 
(Bilirubin > 10xULN) 
Delay obinutuzumab as necessary to ensure subject is sufficiently stable to 
receive further treatment; thereafter maintain full dose and schedule. If 
bilirubin abnormality was Grade ≥ 3, resume tirabrutinib and entospletinib at 
lower dose level. 
Pneumonitis  
Grade 1 
Maintain current dose level and schedule. Consider Pneumocystis therapy 
Grade 2 
Delay obinutuzumab as necessary to ensure subject is sufficiently stable to 
receive further treatment; thereafter maintain full dose and schedule. 
Grade ≥ 3 
Delay obinutuzumab as necessary to ensure subject is sufficiently stable to 
receive further treatment; thereafter maintain full dose and schedule or 
discontinue obinutuzumab at investigator discretion. 
OTHER NON-HEMATOLOGICAL ADVERSE EVENTS 
Grade ≤ 2 
Maintain current dose level and schedule 
Grade ≥ 3 
If felt to be related to obinutuzumab, delay obinutuzumab as necessary to 
ensure subject is sufficiently stable to receive further treatment; thereafter 
maintain full dose and schedule or discontinue obinutuzumab at investigator 
discretion. 
 
6.6. 
End of Study 
End of study will be defined when the last subject reaches the last scheduled follow-up 
timepoint, is lost to follow-up, withdraws from the study, dies, or the time at which the Sponsor 
closes the study. At the end of the study, subjects will transition onto standard of care treatment. 
6.7. 
Post Study Care 
There is no plan to provide post study care to subjects that have participated in this study. 

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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 or conditions that increase in severity or change in 
nature after the consent form is signed or as a consequence of participation in the clinical study 
will 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 adverse event and must be reported. 
• Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions) 
• Overdose without clinical sequelae (see Section 7.6.1) 
• 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) or serious adverse drug reactions (SADR) 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. 
Disease Progression and Death Related to Disease Progression: 
Given the endpoints of the study, in order to maintain the integrity of the study, the following 
events that are assessed as unrelated to study drugs will not be considered 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 (i.e., by a means other than lack of effect). Unrelated disease progression 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). 

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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 adverse event 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 adverse event 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 adverse event has an etiology other than the study procedure. 
• Yes: The adverse event 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 (Appendix 7). For each 
episode, the highest severity grade attained should be reported.  
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the AE. For purposes of consistency with 
the CTCAE, these intensity grades are defined in Table 7-1. 

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Table 7-1. 
Grading of Adverse Event Severity 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not expected to 
have a clinically significant effect on the subject’s overall health and 
well-being, does not interfere with the subject’s usual function, and is 
not likely to require medical attention. 
Grade 2 
Moderate 
Sign or symptom causes interference with usual activity or affect 
clinical status, and may require medical intervention. 
Grade 3 
Severe 
Sign or symptom is incapacitating or significantly affects clinical status 
and likely requires medical intervention and/or close follow-up. 
Grade 4 
Life-threatening 
Sign or symptom results in a potential threat to life. 
Grade 5 
Fatal 
Sign or symptom results in death. 
 
The distinction between the seriousness and the severity of an AE should be noted. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met 1 of the 
criteria for serious events listed in Section 7.1.2.  
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 the electronic case report form eCRF: all SAEs and adverse events 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 adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period. 
Serious Adverse Events 
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Pharmacovigilance and Epidemiology (PVE) as instructed. This 
also includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed. 

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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 document 
and report the event to Gilead PVE 
• All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
CRF/eCRF completion guideline.  
Electronic Serious Adverse Event (eSAE) Reporting Process  
• Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead PVE 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 information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to: 
Gilead PVE: 
Fax: 1-650-522-5477 
Email: Safety_FC@Gilead.com 
 
• 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 form 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 document to the subject identifiers. 
• Additional information 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 form. 

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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 investigator’s brochure or relevant local label as applicable.  
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. 
Toxicity Management 
Treatment-emergent toxicities will be noted by the Investigator and brought to the attention of 
the Gilead Sciences Medical Monitor or designee. Whether or not considered treatment-related, 
all subjects experiencing AEs must be monitored periodically until symptoms subside, any 
abnormal laboratory values have resolved or returned to baseline levels or they are considered 
irreversible, or until there is a satisfactory explanation for the changes observed. 
Grade 3 or 4 clinically significant laboratory abnormalities should be confirmed by repeat testing 
as soon as practical to do so, and preferably within 3 calendar days after receipt of the original 
test results. Any questions regarding toxicity management should be directed to the 
Gilead Sciences Medical Monitor or designee. 
7.5.1. 
Warnings and Precautions  
 
Hemorrhage 
Tirabrutinib: 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, and petechiae, and major hemorrhagic events 
such as small intestinal hemorrhage and subdural hematoma.  
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. 
Subjects should be monitored for signs of bleeding and treated appropriately. 
7.5.1.1. 

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Dermatological and Hypersensitivity Events 
Idelalisib: Subjects receiving idelalisib with ≥ Grade 3 rash have generally presented with a 
maculopapular rash on the trunk and extremities that is occasionally associated with fever and/or 
pruritus and responded to treatment with diphenhydramine and/or topical or oral corticosteroids.  
For subjects who develop a severe rash for which an underlying etiology cannot be identified 
(e.g., infection, co-suspect drug), study drug should be interrupted. Resumption of study drug 
should be considered once rash resolves. 
Severe cutaneous reactions, including fatal events of Stevens-Johnson syndrome (SJS) and 
toxic epidermal necrolysis (TEN), have been reported in subjects receiving idelalisib. 
Assessment of potential causal association between idelalisib and the occurrence of SJS or TEN 
has been confounded by the coadministration of antineoplastic agents (e.g., bendamustine, 
rituximab) and/or other concomitant medications known to be associated with SJS or TEN 
(e.g., allopurinol). If SJS or TEN is suspected, idelalisib and all coadministered medications 
associated with SJS or TEN should be interrupted and the subject treated accordingly.  
Subjects should be monitored for the development of SJS, TEN, or other severe cutaneous 
reactions and idelalisib treatment must be permanently discontinued if such events occur. 
Tirabrutinib: If patients experience a hypersensitivity reaction whilst on tirabrutinib, 
consideration should be given to interruption or discontinuation. 
 
Gastrointestinal Events 
Idelalisib: Isolated cases of gastrointestinal inflammation (eg, stomatitis, colitis, cecitis) have 
been noted in subjects receiving idelalisib. Rare cases of gastrointestinal perforation have 
occurred, generally in the setting of occult carcinoma, mesenteric embolus or diverticular 
disease. Study treatment (idelalisib/placebo) should be discontinued in subjects who experience 
bowel perforation 
Cholangitis manifest as hyperbilirubinemia out of proportion to serum transaminase elevations 
has been observed. While disease-related factors, neutropenia, toxicity from prior therapies, 
effects of ongoing supportive care, or pre-existing cholelithiasis may have initiated such events, 
it is possible that idelalisib played a contributory role. In such subjects, rechallenge with 
idelalisib has been possible and has not been associated with other severe adverse events. 
Subjects who have developed evidence of enteritis during idelalisib therapy have been 
successfully treated with antidiarrheals (eg, loperamide) and with enteric steroidal 
(eg, budesonide) or non-steroidal (eg, sulfasalazine [Azulfidine®]) anti-inflammatory agents and 
have been able to continue or resume idelalisib. 
For study subjects who develop severe abdominal pain the possibility of a bowel obstruction or 
perforation should be considered. Appropriate clinical and radiographic examination should be 
performed and supportive care or surgical intervention should be considered. Among 
idelalisib-treated patients who reported diarrhea or colitis, the median time to onset of any grade 
diarrhea or colitis was 1.9 months (range, 0.0–29.8), of grade 1 or 2 was 1.5 months 
(range, 0.0-15.2) and of grade 3 or 4 was 7.1 months (range, 0.5–29.8). Kaplan–Meier curves of 
time to onset of diarrhea or colitis are shown for all idelalisib- treated patients in Figure 7-1 
{Coutre 2015}.  
7.5.1.2. 
7.5.1.3. 

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Figure 7-1. 
Kaplan-Meier Time to Diarrhea or Colitis  
 
Idelalisib-associated severe diarrhea responds poorly to antimotility agents however, 
median time to resolution ranged between 1 week and 1 month across trials following 
interruption of idelalisib treatment and, in some instances, initiation of corticosteroid treatment 
{Gilead Sciences Inc 2014}. 
For subjects who develop persistent diarrhea, causes related to concomitant medications or 
gastrointestinal infections such as Clostridium difficile (particularly for patients recently treated 
with broad spectrum antibiotics), Shigella, Campylobacter, Yersinia and CMV should be 
considered and treated if appropriate. Depending upon the clinical circumstances, endoscopy and 
biopsy, with bacterial and viral IHC staining should be considered. In the event that an infectious 
cause is not identified, an antimotility agent (eg, loperamide) may lessen symptoms and 
intervention with enteric steroidal (eg, budesonide) or non-steroidal (eg, sulfasalazine) 
anti-inflammatory agents should be considered. In such subjects, rechallenge with idelalisib at a 
lower dose level has resulted in recurrence of symptoms in some but not all subjects and has not 
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Hepatic Events 
Idelalisib: Transaminase Elevations: Consistent with observations in a dog toxicology study, 
reversible asymptomatic ALT/AST increases were also observed early in the idelalisib program 
in phase 1 studies (101-02 and 101-07) in subjects with hematologic malignancies. Transaminase 
elevations generally occurred within 4 to 12 weeks of drug initiation, and resolved spontaneously 
over a period of 2 to 4 weeks with drug being continued for Grade 1 and 2 elevations and drug 
withheld for Grade 3 or 4 elevations until resolution. These early observations have been 
consistent with the ongoing experience with idelalisib treatment and transaminase elevations are 
now well characterized as most frequently asymptomatic, transient and occurring within the 
first 3 months of treatment. 
Grade 1 or 2 elevations commonly resolve despite continued idelalisib treatment and Grade 3 or 
4 elevations can be managed by temporarily withholding idelalisib. Successful rechallenge after 
resolution at either the same or lower dose level of idelalisib has been achieved in the majority of 
subjects. There has been no evidence of impaired synthetic function. Close monitoring of hepatic 
laboratory tests during therapy is important to allow for appropriate idelalisib interruption and 
reinstitution so that subjects may continue with study drug treatment. 
Entospletinib: Entospletinib is expected to produce asymptomatic and transient elevations of 
unconjugated (indirect) bilirubin due to inhibition of UGT1A1. In studies of subjects with 
hematologic malignancies, 3.6% (9/252) subjects had elevations of direct bilirubin with the onset 
of elevation ranging from Day 8 to 85, except for 1 subject at Day 169. Bilirubin elevations were 
generally self-limited and did not result in discontinuation of entospletinib. Transaminase 
increase was reported as an AE in approximately 45% of subjects. Increased transaminases were 
noted in some subjects approximately 2 weeks after completion of study drug. 
 
Hematological and Immunological Events 
Tirabrutinib: Neutropenia and anemia have also occurred in subjects treated with tirabrutinib. 
The anemia seen in subjects treated with tirabrutinib has generally been self-limiting, without the 
requirement for intervention and with improvement on continued therapy.  
Idelalisib: In the Phase 1 experience with idelalisib in patients with NHL and CLL, subjects with 
Grade ≥3 neutropenia, anemia, and/or thrombocytopenia were enrolled to clinical trials. 
Decreased levels of neutrophil counts, hemoglobin, or platelet counts during idelalisib 
administration were largely due to minor fluctuations in these parameters among subjects with 
pre-existing hematological abnormalities due to disease or prior therapy. Thus, idelalisib did not 
appear to induce overt myelosuppression. Obvious patterns of drug-mediated reductions in 
circulating CD4+ lymphocyte counts or suppression of serum IgG levels were also not observed. 
7.5.1.4. 
7.5.1.5. 

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Treatment-emergent Grade 3 or 4 neutropenia events including those accompanied by fever or 
infection have occurred in subjects treated with idelalisib, most commonly in the context of 
myelosuppressive agents such as bendamustine. All subjects will have their absolute neutrophil 
count monitored at least every two weeks for the first 24 weeks of idelalisib treatment. 
Management of neutropenia, including administration of G-CSF should be per established 
clinical guidelines and institutional standard of care. 
No modification of any drug for changes in circulating CD4+ counts or Ig levels is planned. 
 
Infectious Events 
Tirabrutinib: 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. 
Idelalisib: Patients with lymphoid cancers receiving idelalisib have developed serious and fatal 
infections during therapy. Opportunistic infections, most notably PJP and CMV infection, have 
most frequently occurred within the first 6 months of treatment with idelalisib and are increased 
in the context of concurrent myelosuppressive therapy such as bendamustine. 
Subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP 
throughout the course of treatment. Prophylaxis will continue for a period of 2 to 6 months after 
idelalisib discontinuation. The duration of prophylaxis should be based on clinical judgment and 
may take into account risk factors such as concomitant corticosteroid treatment and prolonged 
neutropenia after idelalisib treatment ends. Subjects must permanently discontinue idelalisib 
upon diagnosis of PJP. 
CMV surveillance for active disease (quantitative PCR or PP65 antigen) must be conducted 
throughout the course of treatment. CMV viral load testing should be performed from the same 
specimen type whenever possible and caution should be exercised when comparing CMV viral 
load results across different testing centers. If unequivocal clinical or laboratory evidence of 
CMV infection is present, the subject must permanently discontinue idelalisib treatment and 
undergo effective antiviral treatment according to established clinical guidelines. 
In high-risk subjects (history of recurrent infection, allogeneic transplant, treatment with 
alemtuzumab, hypogammaglobulinemia) other infection prophylaxis should be considered per 
consensus guidelines. Administration of intravenous immunoglobulin is permitted per standard 
institutional practice {Raanani 2009}. For subjects who develop an infection, appropriate 
medical therapy should be instituted in a timely manner. 
7.5.1.6. 

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Pulmonary Events 
Idelalisib: Documented bacterial, fungal, viral, and PJP infections have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some study subjects receiving 
idelalisib alone or in combination have developed evidence of pneumonitis or organizing 
pneumonia, respectively without documented pulmonary infection. Some of these events have 
required mechanical ventilation or have been fatal. Nonclinical evaluations of pulmonary 
function and pathology do not indicate a direct toxic effect of idelalisib on the lungs, and 
disease-related factors or toxicity from prior or concomitant therapies may have contributed to 
these clinical events. In subjects presenting with serious lung events, idelalisib should be 
interrupted and the subject assessed for an explanatory etiology. If organizing pneumonia is 
diagnosed, treatment with idelalisib should be permanently discontinued and the subject treated 
accordingly.  
Entospletinib: Documented pneumonia has been identified in patients receiving single agent 
entospletinib. Pneumonitis has not been identified as a risk with entospletinib monotherapy. 
Tirabrutinib: Documented pneumonia has been identified in patients receiving single agent 
tirabrutinib. In an ongoing Phase 1 single agent study in Japanese subjects, an SAE of 
pneumonitis has been reported in 1 subject who had pre-existing organizing pneumonia. The 
pneumonitis resolved with interruption of tirabrutinib and treatment with corticosteroids. 
Given the potential for infectious or drug-related pulmonary adverse events, clinicians should be 
particularly observant for evidence of respiratory events in subjects participating in this trial. 
Subjects who describe pulmonary symptoms (eg, dyspnea on exertion, cough, 
shortness of breath); manifest a decline from baseline of ≥5% in oxygen saturation, or 
demonstrate evidence of pulmonary inflammation (eg, focal or diffuse interstitial pattern or 
ground-glass opacities on chest CT) should be evaluated. Potential bacterial, fungal, or viral 
etiologies should be assessed. Noninfectious etiologies such as pulmonary edema or 
thromboembolism should also be considered. 
As appropriate for the clinical situation and culture results, subjects should be treated empirically 
or given specific antibiotics, antifungals, or antiviral agents for a cultured organism. Supportive 
care, including oxygen or mechanical ventilation, should be provided as necessary. 
For subjects with suspected Grade 1 pneumonitis, withhold idelalisib until resolution to baseline. 
For subjects with suspected Grade > 2 pneumonitis (eg, new onset or worsening of baseline of 
cough, dyspnea, hypoxia and/or a diffuse interstitial pattern or ground-glass opacities on chest 
imaging without obvious infectious etiology), idelalisib must be discontinued permanently and 
therapy initiated as clinically appropriate. Entospletinib and/or tirabrutinib should be interrupted 
and therapy with systemic corticosteroids (eg, prednisone, 60mg/day) should be instituted 
rapidly {Liote 2010}. Supportive care, including oxygen or mechanical ventilation, should be 
provided as necessary. 
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Secondary Malignancies 
Idelalisib: Subjects receiving idelalisib for CLL or iNHL have developed pre-malignant and 
secondary malignant diseases, such as basal cell carcinoma, myelodysplastic syndrome, 
myeloproliferative disorders, and more aggressive lymphoid malignancies (eg, have had Richter 
transformation). Generally this has occurred in subjects who have received multiple previous 
lines of therapy and when idelalisib is combined with other therapies such as rituximab or 
bendamustine. The specific association of the therapeutic agents with these types of events has 
not been determined. 
7.6. 
Special Situations Reports 
7.6.1. 
Definitions of Special Situations 
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events 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.  
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. 
7.6.2. 
Instructions for Reporting Special Situations 
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. 
7.5.1.8. 
7.6.2.1. 

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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.  
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 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: 
Gilead PVE: Fax: 1-650-522-5477 
 
 
Email: Safety_FC@Gilead.com  
Refer to Appendix 8 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements. 
 
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 situation 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. 
7.6.2.2. 

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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Endpoints 
8.1.1. 
Primary Endpoint 
Dose Escalation Phase: The primary endpoint is safety. Safety will be evaluated by: 
• Occurrence of AEs and laboratory abnormalities defined as DLTs 
Dose Expansion Phase: The primary endpoint is efficacy. Efficacy will be evaluated by:  
• ORR at Week 12 for non-CLL subjects and Week 24 for CLL subjects, defined as the 
proportion of subjects who achieve a CR or PR as assessed by disease type (Appendix 4, 
Appendix 5, and Appendix 6). In subjects with CLL, the proportion of subjects achieving CR 
and negative minimal residual disease (MRD) will also be evaluated.  
Long-Term Safety Monitoring Phase: The primary endpoint is safety. Safety will be evaluated 
by: 
• The incidence and severity of AEs as defined by CTCAE v4.03. 
8.1.2. 
Secondary Endpoints 
• ORR defined as the proportion of subjects who achieve a CR or PR as assessed by disease 
type. 
• PFS defined as the interval from the start of the study therapy to the earlier of the 
first documentation of definite disease progression or death from any cause 
• Duration of response (DOR) defined as the interval from the first documentation of CR or PR 
to the earlier of the first documentation of definite disease progression or death from any 
cause. 
• Time to response (TTR) defined as the interval from start of treatment to the 
first documentation of CR or PR 
• In subjects with CLL only: proportion of subjects who achieve minimal residual negative 
disease (< 1 leukemia cell/10,000 leukocytes) 
• Pharmacokinetic parameters (Cmax, and AUCtau) for tirabrutinib, idelalisib and idelalisib 
metabolite GS-563117, and entospletinib, as applicable 

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8.2. 
Analysis Sets 
8.2.1. 
All Enrolled Analysis Set 
The All Enrolled Analysis Set includes all subjects who are enrolled in the study. This analysis 
set will be used in the analyses of subject characteristics, disposition, and efficacy. Subjects will 
be grouped by dose level assigned, and overall where appropriate.  
 
Safety Analysis Set 
Safety Analysis Set includes subjects who receive at least 1 dose of study treatment. Subjects 
will be grouped by dose level received, and overall where appropriate. 
CCI
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Pharmacokinetics Analysis Set 
The Pharmacokinetic Analysis Set includes subjects who receive at least one dose of study 
treatment and have the necessary baseline and on-study measurements to provide interpretable 
results for the specific parameters of interest. This analysis set will be used in the analysis of 
tirabrutinib, idelalisib, GS-563117 and entospletinib plasma pharmacokinetics, as applicable. 
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 (number in population), 
n (number with data), mean, standard deviation, 90% confidence intervals (CIs) on the mean, 
median, minimum, and maximum. Summary tables for categorical variables will include: N, n, 
percentage, and 90% CIs on the percentage. Unless otherwise indicated, 90% CIs for binary 
variables will be calculated using the binomial distribution (exact method) and will be 2 sided. 
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 informative. 
The baseline value used in each analysis will be the last (most recent) pre-treatment value. 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 performed on log-transformed data or nonparametric tests may 
be applied, as appropriate.  
Unless otherwise specified, all analyses will be 2-sided at the 0.05 level of significance.  
8.4. 
Demographic Data and Baseline Characteristics 
A listing of all enrolled subjects will be generated to describe site, subject number, 
first screening date, first treatment date, dose level, duration of study drug treatment, and the 
reason for discontinuing study treatment. Available information on subjects who were screened 
but not treated may be listed separately. 
Subject demographic and baseline characteristics will be listed and summarized by dose level 
using the all enrolled analysis set. 
8.5. 
Efficacy Analysis 
Response criteria for each disease are included in Appendix 4, Appendix 5, and Appendix 6.  
8.5.1. 
Primary Analysis 
Overall response rate along with the 95% CI will be estimated. Subjects who do not have 
sufficient baseline or on study tumor assessment to characterize response will be counted as 
non-responders. 
8.2.1.2. 

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Duration of response and progression free survival will be analyzed using Kaplan-Meier (KM) 
methods. The KM estimate of the survival function will be computed and the results will be 
presented using KM curves. The median will be provided along with the corresponding 95% CI. 
Additionally, the 25% and 75% percentiles for these endpoints will also be provided. In addition, 
the estimated rate at 12, 18 and 24 months will be reported. 
The following censoring rules will be applied: 
• For a subject who is not known to have relapsed or died by the end of the study follow-up or 
data cutoff, PFS and DOR are censored on the date of the last available disease assessment of 
the subject. 
8.6. 
Safety Analysis 
All safety data collected on or after the date of first dose of study treatment up to 30 days after 
the date of last dose of treatment will be summarized by dose level and overall.  
8.6.1. 
Extent of Exposure 
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 and idelalisib or entospletinib 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). 
8.6.2. 
Adverse Events 
The focus of AE summarization will be on TEAE. A TEAE is defined as an AE that onset in the 
period from the first dose of study treatment to 30 days after the last dose of study treatment. All 
adverse events, if reported, will be included in data listings. 
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High Level Term, 
Preferred Term, and Lower-Level Term. The severity of adverse events will be 
graded by the investigator according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, the 
grade corresponding to the appropriate adjective will be used by the investigator to describe the 
maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the adverse event to the study 
treatment will be assessed by the investigator and categorized as related or unrelated. 

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Treatment-emergent adverse events will be summarized. Summary tables will be presented to 
show the number of subjects reporting treatment-emergent adverse events by severity grade and 
corresponding percentages. A subject who reports multiple treatment-emergent adverse events 
within the same Preferred Term (or System Organ Class) is counted only once for that Preferred 
Term (or System Organ Class) using the worst severity grade. Adverse event 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 
adverse events: 
• Study-drug-related adverse events 
• Adverse events that are Grade ≥ 3 in severity 
• Adverse events leading to study treatment interruption and/or dose modification 
• Adverse events leading to study treatment discontinuation 
• Serious adverse events  
• DLT will be listed and summarized; DLT rate will be presented by phase and dose level and 
the corresponding 90% CIs will be presented 
8.6.3. 
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 to 30 days after the last dose of study treatment. If baseline data 
are missing, then any graded abnormality (ie, an abnormality that is Grade >=1 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 central 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 
baseline to a particular visit). 

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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 
(normal, low and high [or abnormal] to each visit (normal, low and high [or abnormal]). 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. 
Separate listings and summaries will be prepared for laboratory abnormalities that are Grade ≥ 3 
in severity. 
8.7. 
Pharmacokinetic Analysis 
Concentrations of tirabrutinib, idelalisib, GS-563117, and entospletinib (as applicable) in plasma 
will be determined using a validated bioanalytical assay. Plasma concentrations will be displayed 
as individual concentration vs. time using scheduled sampling times. Concentrations and PK 
parameters (Cmax, Ctau, AUClast, AUCtau, Tmax, and t½, as applicable) will be listed by subject and 
summarized using descriptive statistics (eg, n, arithmetic mean, geometric mean, % coefficient of 
variation [CV], StD, median, Q1, Q3, min, and max). Mean (±StD) plasma concentration-time 
curves will be plotted in both semi-logarithmic and linear formats. 
8.8. 
Biomarker Analysis 
Changes in biomarkers will be evaluated descriptively. Data explorations may be performed to 
evaluate potential associations between subject characteristics and outcome measures. 
Explorations may also be performed to assess the potential associations between different 
outcomes measures (eg, relationships between biomarkers and clinical endpoints of response). 
8.9. 
Sample Size 
The trial employs the standard National Cancer Institute (NCI) definition of MTD (starting dose 
associated with DLT in < 33.3% of subjects during the DLT assessment window) to determine 
dose escalation. The cohort size and dose-escalation rules establish a low probability of 
increasing the dose if the true rate of DLT is high while there is a high likelihood of escalating or 
proceeding to the next cohort of the study if the true underlying probability of DLT is low. For 
example, if the true underlying proportion of DLT is low (eg, ≤ 10%) at the current dose level, 
there is a high probability (≥ 0.91) of dose escalation to the next dose level. Conversely, if the 
true underlying proportion of DLT is high (eg, ≥ 60%) at the current dose level, there is a low 
probability (≤ 0.08) of escalation to the next dose level (see Table 8-1). 
Table 8-1. 
Probability of Dose Escalation (N=3+3) 
True Incidence of DLT 
Probability of Escalating 
10% 
0.91 
20% 
0.71 
30% 
0.49 
40% 
0.31 
50% 
0.17 
60% 
0.08 
 

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It is estimated that approximately 90 evaluable subjects will be needed for the planned dose 
escalation phase of the study. Under the assumption that ~10% of enrolled subjects may not be 
evaluable for DLT, approximately 98 subjects will be enrolled during the dose escalation phase.  
During the dose expansion phase, up to 270 subjects will be enrolled under the assumption that 
up to 9 dose levels and/or disease types will be selected and up to approximately 30 subjects are 
to be enrolled in each expansion cohort. The sample size of the expansion cohort is determined 
based on Simon’s 2-stage optimal design. If 3 or less out of the first 11 subjects achieve 
response, then the expansion of the cohort will be stopped; else the enrollment will continue to 
30 subjects. The design will have about 83% power to rule out that ORR is below 25% based on 
a 1-sided binomial test at 0.05 significance level with assumed response rate of 50%. 
In addition, as of Amendment 9, up to 8 additional subjects from Study GS-US-401-1787 or 
previously enrolled in Study GS-US-401-1757 or Study GS-US-401-1787 who are currently 
receiving continued treatment via named patient use may be enrolled for long-term safety 
monitoring.  
Therefore, up to 376 subjects may be enrolled in the study. 
8.10. 
Timing of Analyses 
8.10.1. 
Interim Analysis 
After the subjects enrolled under Protocol Amendment 8 (or earlier versions) complete their 
efficacy assessments, interim analysis will be performed on these subjects. 
8.10.2. 
Final Analysis 
Final study reporting is expected to occur after all subjects have discontinued from the 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 Harmonization (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 sub investigator’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/IEC 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/IEC 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. 

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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/IEC -approved consent form for documenting 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 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/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, 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence. 

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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 
• 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 adverse events 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. 

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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. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. 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 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 (e.g. 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 IRB/IEC or to regulatory authority or health authority 
inspectors. 

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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/IEC in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented. 
9.2.2. 
Study Report and Publications 
A clinical study report (CSR) will be prepared and provided to the regulatory agenc(ies). 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, e.g. 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. 

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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. 
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. 
REFERENCES 
Aoki Y, Isselbacher KJ, Pillai S. Bruton tyrosine kinase is tyrosine phosphorylated and activated 
in pre-B lymphocytes and receptor-ligated B cells. Proc Natl Acad Sci U S A 
1994;91 (22):10606-9. 
Asghar A, Naaz S, Agrawal D, Sharma PK. Morphometric Study of Spleen in North Indian 
Adult Population: CT Scan Image Based Study. Journal of Clinical and 
Diagnostic Research 2011;5 (5):974-77. 
Bezerra AS, D'Ippolito G, Faintuch S, Szejnfeld J, Ahmed M. Determination of splenomegaly by 
CT: is there a place for a single measurement? AJR Am J Roentgenol 2005;184 
(5):1510-3. 
Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom M, et al. R406, an orally available 
spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune 
complex-mediated inflammation. J Pharmacol Exp Ther 2006;319 (3):998-1008. 
Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, et al. Idelalisib, 
an inhibitor of phosphatidylinositol 3 kinase p110d, for relapsed/refractory 
chronic lymphocytic leukemia [Prepublished Manuscript]. Blood 2014:1-28. 
Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus 
Ofatumumab in Previously Treated Chronic Lymphoid Leukemia. N Engl J Med 
2014. 
Cheson BD, Byrd JC, Rai KR, Kay NE, O'Brien SM, Flinn IW, et al. Novel targeted agents and 
the need to refine clinical end points in chronic lymphocytic leukemia. J Clin 
Oncol 2012;30 (23):2820-2. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007;25 (5):579-86. 
Colomer D, Campo E. Unlocking new therapeutic targets and resistance mechanisms in mantle 
cell lymphoma. Cancer cell 2014;25 (1):7-9. 
Coutre SE, Barrientos JC, Brown JR, de Vos S, Furman RR, Keating MJ, et al. Management of 
adverse events associated with idelalisib treatment - expert panel opinion. Leuk 
Lymphoma 2015:1-20. 
Davis RE, Ngo VN, Lenz G, Tolar P, Young R, Romesser PB, et al. Chronic Active B Cell 
Receptor Signaling in Diffuse Large B Cell Lymphoma. Nature 2010;463 
(7277):88-92. 

Tirabrutinib 
 
Protocol GS-US-401-1757 
Final 
Gilead Sciences, Inc.  
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de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, et al. The clinically active 
BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled 
adhesion and migration in chronic lymphocytic leukemia. Blood 2012;119 
(11):2590-4. 
de Weers M, Verschuren MC, Kraakman ME, Mensink RG, Schuurman RK, van Dongen JJ, et 
al. The Bruton's tyrosine kinase gene is expressed throughout B cell 
differentiation, from early precursor B cell stages preceding immunoglobulin gene 
rearrangement up to mature B cell stages. European journal of immunology 
1993;23 (12):3109-14. 
Di Bella N, Taetle R, Kolibaba K, Boyd T, Raju R, Barrera D, et al. Results of a phase 2 study of 
bortezomib in patients with relapsed or refractory indolent lymphoma. Blood 
2010;115 (3):475-80. 
Diehl V, Thomas RK, Re D. Part II: Hodgkin's lymphoma--diagnosis and treatment. Lancet 
Oncol 2004;5 (1):19-26. 
Dighiero G, Hamblin TJ. Chronic lymphocytic leukaemia. Lancet 2008;371 (9617):1017-29. 
Dreyling M, Williams M. Mantle cell lymphoma: Pathology, diagnosis and treatment. Chapter 
11, Pages 154-167, Cambridge Medicine.  2007:  
Efremov DG, Laurenti L. The Syk kinase as a therapeutic target in leukemia and lymphoma. 
Expert opinion on investigational drugs 2011;20 (5):623-36. 
Eichhorst B, Hallek M, Dreyling M. Chronic lymphocytic leukaemia: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21 Suppl 
5:v162-4. 
Erturk SM, Mortele KJ, Binkert CA, Glickman JN, Oliva MR, Ros PR, et al. CT features of 
hepatic venoocclusive disease and hepatic graft-versus-host disease in patients 
after hematopoietic stem cell transplantation. AJR Am J Roentgenol 2006;186 
(6):1497-501. 
Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008. Cancer incidence and mortality worldwide: 
IARC CancerBase No. 10. Lyon: International agency for research on cancer 
2010. 
Flinn IW, Kahl BS, Leonard JP, Furman RR, Brown JR, Byrd JC, et al. Idelalisib, a selective 
inhibitor of phosphatidylinositol 3-kinase-d, as therapy for previously treated 
indolent non-Hodgkin lymphoma. Blood 2014:1-35. 

Tirabrutinib 
 
Protocol GS-US-401-1757 
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Gilead Sciences, Inc.  
Amendment 10 
CONFIDENTIAL 
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Flinn IW, Patel M, Horwitz S, Younes A, Foss FM, Oki Y, et al. Preliminary Safety and Efficacy 
Of IPI-145, a Potent Inhibitor Of Phosphoinositide-3-Kinase-δ,γ, In Patients With 
Chronic Lymphocytic Leukemia [Oral Presentation]. 12th International 
Conference on Malignant Lymphoma; 2013 June 19-22; Lugano, Switzerland.  
Friedberg JW. New strategies in diffuse large B-cell lymphoma: translating findings from gene 
expression analyses into clinical practice. Clin Cancer Res 2011;17 (19):6112-7. 
Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and 
rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370 
(11):997-1007. 
Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, et al. Long-term 
progression-free survival of mantle cell lymphoma after intensive front-line 
immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized 
phase 2 multicenter study by the Nordic Lymphoma Group. Blood 2008;112 
(7):2687-93. 
Genevier HC, Hinshelwood S, Gaspar HB, Rigley KP, Brown D, Saeland S, et al. Expression of 
Bruton's tyrosine kinase protein within the B cell lineage. European journal of 
immunology 1994;24 (12):3100-5. 
Gilead Sciences Inc. ZYDELIG® (idelalisib) tablets, for oral use. U.S. Prescribing Information. 
Foster City, CA. July 2014: 
Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obinutuzumab plus 
chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 
2014;370 (12):1101-10. 
Goy A, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, et al. Bortezomib in 
patients with relapsed or refractory mantle cell lymphoma: updated time-to-event 
analyses of the multicenter phase 2 PINNACLE study. Ann Oncol 2009;20 
(3):520-5. 
Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in non-
HIV immunocompromised patients. Cochrane Database Syst Rev 2007 (3):1-49. 
Gribben JG, O'Brien S. Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 
2011;29 (5):544-50. 
Hadzidimitriou A, Agathangelidis A, Darzentas N, Murray F, Delfau-Larue MH, Pedersen LB, et 
al. Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic 
support from a series of 807 cases. Blood 2011;118 (11):3088-95. 

Tirabrutinib 
 
Protocol GS-US-401-1757 
Final 
Gilead Sciences, Inc.  
Amendment 10 
CONFIDENTIAL 
Page 138 
01 May 2020 
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines 
for the diagnosis and treatment of chronic lymphocytic leukemia: a report from 
the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 
updating the National Cancer Institute-Working Group (NCI-WG) 1996 
guidelines. Blood 2008;111 (12):5446-56. 
Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of 
rituximab to fludarabine and cyclophosphamide in patients with chronic 
lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376 
(9747):1164-74. 
Hendriks RW, Yuvaraj S, Kil LP. Targeting Bruton's tyrosine kinase in B cell malignancies. 
Nature reviews. Cancer 2014;14 (4):219-32. 
Herman SE, Mustafa RZ, Gyamfi JA, Pittaluga S, Chang S, Chang B, et al. Ibrutinib inhibits 
BCR and NF-kappaB signaling and reduces tumor proliferation in tissue-resident 
cells of patients with CLL. Blood 2014;123 (21):3286-95. 
Herrera AF, Jacobsen ED. Ibrutinib for the treatment of mantle cell lymphoma. Clin Cancer Res 
2014;20 (21):5365-71. 
Herter S, Birk MC, Klein C, Gerdes C, Umana P, Bacac M. Glycoengineering of therapeutic 
antibodies enhances monocyte/macrophage-mediated phagocytosis and 
cytotoxicity. J Immunol 2014;192 (5):2252-60. 
Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, et al. Phase III study 
to evaluate temsirolimus compared with investigator's choice therapy for the 
treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 2009;27 
(23):3822-9. 
Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, et al. The Bruton 
Tyrosine Kinase Inhibitor PCI-32765 Blocks B-cell Activation and is Efficacious 
in Models of Autoimmune Disease and B-Cell Malignancy. PNAS 2010;107 
(29):13075-80. 
Hoppe RT, Advani RH, Ambinder RF, Bierman PJ, Bloomfield CD, Blum K, et al. Hodgkin 
disease/lymphoma. J Natl Compr Canc Netw 2008;6 (6):594-622. 
Jares P, Colomer D, Campo E. Molecular pathogenesis of mantle cell lymphoma. J Clin Invest 
2012;122 (10):3416-23. 
Jefferies CA, Doyle S, Brunner C, Dunne A, Brint E, Wietek C, et al. Bruton's tyrosine kinase is 
a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear 
factor kappaB activation by Toll-like receptor 4. J Biol Chem 2003;278 
(28):26258-64. 

Tirabrutinib 
 
Protocol GS-US-401-1757 
Final 
Gilead Sciences, Inc.  
Amendment 10 
CONFIDENTIAL 
Page 139 
01 May 2020 
Jost L. Hodgkin's disease: ESMO clinical recommendations for diagnosis, treatment and follow-
up. Ann Oncol 2007;18 (Suppl 2):ii53-4. 
Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, et al. Therapeutic role of alemtuzumab 
(Campath-1H) in patients who have failed fludarabine: results of a large 
international study. Blood 2002;99 (10):3554-61. 
Kristinsson SY, Dickman PW, Wilson WH, Caporaso N, Bjorkholm M, Landgren O. Improved 
survival in chronic lymphocytic leukemia in the past decade: a population-based 
study including 11,179 patients diagnosed between 1973-2003 in Sweden. 
Haematologica 2009;94 (9):1259-65. 
Lenz G, Dreyling M, Hoster E, Wormann B, Duhrsen U, Metzner B, et al. Immunochemotherapy 
with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone 
significantly improves response and time to treatment failure, but not long-term 
outcome in patients with previously untreated mantle cell lymphoma: results of a 
prospective randomized trial of the German Low Grade Lymphoma Study Group 
(GLSG). J Clin Oncol 2005;23 (9):1984-92. 
Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, et al. Stromal gene signatures in large-
B-cell lymphomas. N Engl J Med 2008;359 (22):2313-23. 
Liote H, Liote F, Seroussi B, Mayaud C, Cadranel J. Rituximab-induced lung disease: A 
systematic literature review. Eur Respir J 2010;35 (3):681-7. 
Morris DL, O'Neil SP, Devraj RV, Portanova JP, Gilles RW, Gross CJ, et al. Acute lymphoid 
and gastrointestinal toxicity induced by selective p38alpha map kinase and map 
kinase-activated protein kinase-2 (MK2) inhibitors in the dog. Toxicol Pathol 
2010;38 (4):606-18. 
Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma 
incidence patterns by WHO subtype in the United States, 1992-2001. Blood 
2006;107 (1):265-76. 
Moskowitz AJ, Perales MA, Kewalramani T, Yahalom J, Castro-Malaspina H, Zhang Z, et al. 
Outcomes for patients who fail high dose chemoradiotherapy and autologous stem 
cell rescue for relapsed and primary refractory Hodgkin lymphoma. Br J 
Haematol 2009;146 (2):158-63. 
Mössner E, Brünker P, Moser S, Püntener U, Schmidt C, Herter S, et al. Increasing the efficacy 
of CD20 antibody therapy through the engineering of a new type II anti-CD20 
antibody with enhanced direct- and immune effector cell-mediated B-cell 
cytotoxicity. Blood 2014:1-26. 
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in 
Oncology: Non-Hodgkin's Lymphomas. Version 2.2015.  2015. 

Tirabrutinib 
 
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Final 
Gilead Sciences, Inc.  
Amendment 10 
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01 May 2020 
Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, et al. Response assessment 
in Waldenstrom macroglobulinaemia: update from the VIth International 
Workshop. Br J Haematol 2013;160 (2):171-6. 
Pharmacyclics LLC. IMBRUVICA® (ibrutinib) capsules, for oral use. US Prescribing 
Information. Sunnyvale, CA. Revised May.  2016: 
Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin 
prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic 
review and meta-analysis. Leuk Lymphoma 2009;50 (5):764-72. 
Recher C, Coiffier B, Haioun C, Molina TJ, Ferme C, Casasnovas O, et al. Intensified 
chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab 
for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label 
randomised phase 3 trial. Lancet 2011;378 (9806):1858-67. 
Rickert RC. New insights into pre-BCR and BCR signalling with relevance to B cell 
malignancies. Nature reviews 2013;13 (8):578-91. 
Roschewski M, Staudt LM, Wilson WH. Diffuse large B-cell lymphoma-treatment approaches in 
the molecular era. Nature reviews. Clinical oncology 2014;11 (1):12-23. 
Salles GA. Clinical features, prognosis and treatment of follicular lymphoma. Hematology / the 
Education Program of the American Society of Hematology. American Society of 
Hematology 2007:216-25. 
Santoro A, Bonadonna G, Valagussa P, Zucali R, Viviani S, Villani F, et al. Long-term results of 
combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority 
of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol 1987;5 
(1):27-37. 
Schulz H, Bohlius JF, Trelle S, Skoetz N, Reiser M, Kober T, et al. Immunochemotherapy with 
rituximab and overall survival in patients with indolent or mantle cell lymphoma: 
a systematic review and meta-analysis. J Natl Cancer Inst 2007;99 (9):706-14. 
Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, et al. Expression of 
Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-
regulated in T lymphocytes and plasma cells. J Immunol 1994;152 (2):557-65. 
Sweetenham J. Diffuse large B cell lymphoma: Lymphoma – Pathology, diagnosis and 
treatment. Chapter 12, Pages 168-181, Cambridge Medicine.  2007:  
Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. MYD88 L265P somatic mutation in 
Waldenstrom's macroglobulinemia. N Engl J Med 2012;367 (9):826-33. 

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Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, et al. Deficient expression 
of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. 
Cell 1993;72 (2):279-90. 
Turner M, Schweighoffer E, Colucci F, Di Santo JP, Tybulewicz VL. Tyrosine kinase SYK: 
essential functions for immunoreceptor signalling. Immunology today 2000;21 
(3):148-54. 
Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, et al. The gene involved in 
X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine 
kinases. Nature 1993;361 (6409):226-33. 
Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with ibrutinib in 
relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369 (6):507-16. 
Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, et al. Ofatumumab 
as single-agent CD20 immunotherapy in fludarabine-refractory chronic 
lymphocytic leukemia. J Clin Oncol 2010;28 (10):1749-55. 
Williams ME, Dreyling M, Winter J, Muneer S, Leonard JP. Management of mantle cell 
lymphoma: key challenges and next steps. Clinical lymphoma, myeloma & 
leukemia 2010;10 (5):336-46. 
Wilson WH, Gerecitano JF, Goy A, de Vos S, Kenkre VP, Barr PM, et al. The Bruton's Tyrosine 
Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), Has Preferential Activity in the 
ABC Subtype of Relapsed/Refractory De Novo Diffuse Large B-Cell Lymphoma 
(DLBCL): Interim Results of a Multicenter, Open-Label, Phase 2 Study [Abstract 
686]. American Society of Hematology (ASH) Annual Meeting; 2012 December 
08-11; Atlanta, GA.  
Yang G, Zhou Y, Liu X, Xu L, Cao Y, Manning RJ, et al. A mutation in MYD88 (L265P) 
supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine 
kinase in Waldenstrom macroglobulinemia. Blood 2013;122 (7):1222-32. 
Yoshizawa T, Yasuhiro T, Honda H, Kawabata K. ONO-4059 - a Potent and Selective 
Reversible Bruton’s Tyrosine Kinase (Btk) Inhibitor: Single Agent, Twice Daily 
(BD) Dosing and Dosing with Food Results in Sustained, High Trough Levels of 
ONO-4059, Translating into 100% Tumour Remission in a TMD-8 Xenograft 
Model [Abstract 4502]. 56th American Society of Hematology (ASH) Annual 
Meeting and Exposition; 2014 December 06-09; San Francisco, CA.  
Zelenetz AD, Abramson JS, Advani RH, Andreadis CB, Bartlett N, Bellam N, et al. Non-
Hodgkin's lymphomas. J Natl Compr Canc Netw 2011;9 (5):484-560. 
 
 

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11. 
APPENDICES 
Appendix 1. 
Investigator Signature Page 
Appendix 2. 
Study Procedures Table (Dose Escalation and Dose Expansion) 
Appendix 3. 
Study Procedures Table (Long-Term Safety Monitoring) 
Appendix 4. 
Waldenstrom’s Macroglobulinemia Assessment 
Appendix 5. 
Modified International Workshop on Chronic Lymphocytic Lymphoma Leukemia 
(IWCLL) Criteria for Response Assessment 
Appendix 6. 
Follicular Lymphoma, Marginal Zone Lymphoma, Small Lymphocytic Lymphoma, 
Diffuse Large Cell Lymphoma and Mantle Cell Lymphoma Response Assessment 
Appendix 7. 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 
Appendix 8. 
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements 
Appendix 9. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 

Tira br uti ni b  
 
Pr ot oc ol G S -U S -4 0 1 -1 7 5 7  
Fi nal  
Gilea d Scie nces, I nc.  
A me n d me nt 1 0  
C O N FI D E N TI A L  
P a ge  1 4 3  
0 1 Ma y 2 0 2 0  
A p pe n di x  1 . 
I n vesti g at or Si g n at ure P a ge 
GI L E A D S CI E N C E S, I N C . 
3 3 3 L A K E SI D E D RI V E  
F O S T E R CI T Y, C A 9 4 4 0 4  
 
S T U D Y A C K N O W L E D G E M E N T  
A P h ase 1 b D ose Esc al ati o n a n d D ose E x p a nsi o n St u d y of Tir a br uti ni b (O N O/ G S -4 0 5 9 )  
i n C o m bi n ati o n wit h ot her T ar gete d A nti -c a ncer T her a p ies  
i n S u bjects wit h B -cell M ali g n a ncies   
G S -U S -4 0 1 -1 7 5 7 , Pr ot oc ol  A me n d me nt 1 0 , 0 1 M a y  2 0 2 0  
T his pr ot oc ol has bee n a p pr o ve d b y Gilea d Scie nces, I nc. T h e f oll o wi n g si g nat ur e d oc u me nts 
 
Na me ( Pri nte d)  
A ut h or  
 
S
 
 
 
Date  
 
 
 
I N V E S TI G A T O R S T A T E M EN T  
I h a ve rea d t he pr ot oc ol, i ncl u di n g all a p p e n dices, a n d I a gree t hat it c o ntai ns all necessar y 
details f or me a n d m y staff t o c o n d uct t his st u d y as descri be d. I will c o n d uct t his st u d y as 
o utli ne d herei n a n d will ma ke a reas o na bl e eff ort t o c o m plete t he st u d y wit hi n t he ti me 
desi g nat e d.  
I will pr o vi de all st u d y p ers o n nel u n der m y s u p er visi o n c o pies of t he pr ot o c ol a n d access t o all 
i nf ormati o n pr o vi de d b y Gilea d Scie nces, I nc. I will disc uss t his material wit h t he m t o e ns ure 
t hat t he y are f ull y i nf or me d a b o ut t he dr u gs a n d t h e st u d y. 
 
 
 
Pri nci pal I n v esti gat or Na me ( Pri nte d)  
 
Si g nat ure  
 
 
 
 
Date  
 
Site N u m ber  
 
P P D
P P D
Ma y 1 2 0 2 0
\ 
.... 

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Appendix 2. 
Study Procedures Table (Dose Escalation and Dose Expansion) 
Study Phase 
Screening 
 
First 29 Days 
Cycle 2 and 
3 Day 1 and 
every 
2 weeks, 
Cycle 4 +, 
Day 1 and 
every 
4 weeksee 
Cycle 2 
and 3 
Day 8 
Every 
12 weeks 
(6 weeks for 
DLBCL)a,ee 
Every 
12 weeks as 
of 
amendment 7 
ff 
EOT 
30-day 
Safety 
Follow-upb 
Cycle Day 
Day -28 
Study 
Day 1 
Cycle 1 
Day 1 
Cycle 1 
Day 2 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 1 
Day 22 
Window (day) 
-28 
 
0 
±1 
±1 
±2 
±2 
±7 
±7 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
Medication Historyc  
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Physical Examinationd 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
Vital Signse 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
ECOG Performance 
Status 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
Single 12-lead ECG 
dose escalationf 
X 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
Single 12-lead ECG 
dose expansionf 
X 
 
X 
 
 
 
 
Xg 
 
 
 
 
 
Adverse 
events/Concomitant 
medicationsh 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
X 
X 
IP Accountability 
and/or Dispensingi 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
Obinutuzumabdd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pneumocystis jirovecii 
pneumonia (PJP) 
prophylaxis  
 
 
Xcc 
 
 
 
 
 
 
 
Xcc 
 
 
CBC with differential 
X 
 
X 
 
X 
X 
X 
Xbb 
 
 
X 
X 
 
Chemistry 
X 
 
X 
 
X 
X 
X 
X 
Xj 
 
X 
X 
 

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Study Phase 
Screening 
 
First 29 Days 
Cycle 2 and 
3 Day 1 and 
every 
2 weeks, 
Cycle 4 +, 
Day 1 and 
every 
4 weeksee 
Cycle 2 
and 3 
Day 8 
Every 
12 weeks 
(6 weeks for 
DLBCL)a,ee 
Every 
12 weeks as 
of 
amendment 7 
ff 
EOT 
30-day 
Safety 
Follow-upb 
Cycle Day 
Day -28 
Study 
Day 1 
Cycle 1 
Day 1 
Cycle 1 
Day 2 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 1 
Day 22 
Window (day) 
-28 
 
0 
±1 
±1 
±2 
±2 
±7 
±7 
±7 
 
±7 
±7 
Coagulation 
(INR, aPTT) 
X 
 
X 
 
X 
 
 
Xk 
 
 
X 
X 
 
Lymphocyte 
Immunophenotyping 
and Immunoglobulinsl  
X 
 
 
 
 
 
 
Xl 
 
X 
 
 
  
Hepatitis Serologym 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CMV Serology n 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Evaluation for CMV 
reactivation 
X 
 
X 
 
 
 
 
Xaa 
 
 
Xaa 
 
 
Urinalysis and Urine 
Chemistry 
 
 
X 
 
X 
 
 
Xk 
 
 
 
 
 
Pregnancy Testingo 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
PK sampling in dose 
escalationp 
 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
PK sampling in dose 
expansionq 
 
 
X 
 
X 
 
 
Xk 
 
 
 
 
 
Pharmacodynamic 
sampling in dose 
escalationr 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Pharmacodynamic 
sampling in dose 
expansions 
 
 
X 
 
X 
 
 
Xs 
 
 
 
 
 
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Study Phase 
Screening 
 
First 29 Days 
Cycle 2 and 
3 Day 1 and 
every 
2 weeks, 
Cycle 4 +, 
Day 1 and 
every 
4 weeksee 
Cycle 2 
and 3 
Day 8 
Every 
12 weeks 
(6 weeks for 
DLBCL)a,ee 
Every 
12 weeks as 
of 
amendment 7 
ff 
EOT 
30-day 
Safety 
Follow-upb 
Cycle Day 
Day -28 
Study 
Day 1 
Cycle 1 
Day 1 
Cycle 1 
Day 2 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 1 
Day 22 
Window (day) 
-28 
 
0 
±1 
±1 
±2 
±2 
±7 
±7 
±7 
 
±7 
±7 
Disease biomarkers 
(CLL, MCL, SLL 
only)u 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Archival Tumor 
Tissuev  
 
 
X 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
evaluationx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Radiographic Tumor 
evaluationa 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Treatment Response 
Assessmentz 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
+ 
Day 1 of subsequent cycles. 
a 
Tumor evaluation by neck, chest abdomen and pelvis will be performed during screening (within 28 days of Cycle 1, Day 1) and every 12 weeks (in DLBCL every 6 weeks 
for the first 12 weeks). Subjects with CLL will only undergo scans at baseline, 24 weeks and at the time of progression. The same radiographic procedure used to define 
measurable lesions must be used throughout the study for each subject. CT or MRI should be conducted at the EOS visit if not conducted within the previous 4 weeks. Scan at 
EOT visit is not necessary if restaging scan is performed within 4 weeks of the EOT. Scans will be transferred to a central reader for collection and future analysis. Tumor 
evaluation for WM will include serum IgM. If Complete Response, bone marrow evaluation may be required for some diseases and/or to evaluate MRD (as per Appendix 4, 
Appendix 5, and Appendix 6). As of Amendment 7, CT/MRI scans will no longer be performed and will only be performed at the time of disease progression or at study 
discontinuation. 
b 
Subjects who miss the 30 day Safety Follow-up visit will be contacted by phone 30 days (± 7 days) after the last dose of tirabrutinib and idelalisib or entospletinib to assess 
AEs.  
c 
Medical history includes significant past medical events (eg, prior hospitalizations or surgeries), a review of the disease under study, prior anti-cancer therapies, and any 
concurrent medical illnesses. Obtain smoking history at screening (for the past 60 days) and at Day 1 of each Cycle (for the past 28 Days).  
d 
Screening and End of Treatment will be complete physical examinations. 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). Weight (without shoes) should be measured at each PE. 
Height (without shoes) should be measured at screening only. 
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e 
Cycle 1, Day 1 vital signs will be taken within 15 min pre-tirabrutinib dose and 2 and 4 hours post dose (+/- 15 min); vital signs will be taken pre-dose only at all subsequent 
visits. For subjects in Group V the 2 and 4 hour post-dose vital signs are not required. 
f 
ECG: ECGs should be performed in triplicate. Subjects should be resting quietly in supine position 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 and 
transferred to a central vendor for storage. As of Amendment 7, this will no longer be performed. 
g 
In dose expansion ECGs will occur at screening, baseline and then C1D1 up to C6. As of Amendment 7, ECGs will no longer be performed. 
h 
Adverse events will be assessed at pre- and post-tirabrutinib and idelalisib or entospletinib dosing during applicable clinic visits. Subjects will also return to clinic at 30-day 
post last IP dose, to assess AEs and SAEs. If an AE of diarrhea is reported see Section 6.2.8.1 for full evaluation details.,  
i 
Tirabrutinib will be dispensed on Cycle 1, Day 1. Idelalisib or entospletinib will be dispensed on Cycle 1, Day 2. Tirabrutinib and idelalisib or entospletinib will be dispensed 
on Day 1 of all subsequent cycles. 
j 
Liver Function Tests only on Day 8 of Cycle 2 and 3; AST, ALT, Alkaline phosphatase, GGT, total bilirubin, direct bilirubin 
k 
Discontinue after Cycle 6, Day 1 
l 
Lymphocyte Immunophenotyping by flow cytometry serum quantitative immunoglobulins (IgG, IgM, IgA) , serum CH50 at screening, C2D1, C4D1, then every 12 weeks, 
end of treatment (EOT) and 30 day safety follow-up visits. As of Amendment 7, this will no longer be performed. 
m 
Hepatitis Serology includes: HBsAG, Hepatitis B core antibody and Hepatitis C antibody.  
n 
CMV Serology testing includes: CMV serology. 
o 
Serum pregnancy test will be performed at screening for all women of childbearing potential (defined in Appendix 8). Urine pregnancy test will be conducted prior to Cycle 1, 
Day 1, every 28 days thereafter, then every 12 weeks as of amendment 7 and at EOT visit. The results must be confirmed as negative prior to continued administration of 
  
 
 
 
 
 
 
 
 
q 
A plasma sample will be collected on Cycle 1, Day 1 between 1.5-4 hours inclusive post-dose of tirabrutinib. On Cycle 1, Day 8 and Cycle 2, Day 1, a PK sample will be 
collected at pre-dose and one between 1.5 and 4 hours inclusive post-dose of tirabrutinib and idelalisib or entospletinib. A sparse PK sample will also be collected anytime on 
the first day of Cycles 3 to 5 and at pre-dose on the first day of Cycle 6.  
r 
Blood samples for pharmacodynamics will be collected on Cycle 1, Day 1 at pre-dose, 2 and 6 hours post-dose, Cycle 1, Days 2 and 8 at pre-dose, 2, 6 and 24 hours post-dose 
and end of treatment or disease progression. When study drug is administered BID, the 24 hour sample will be collected 24 hours post-dose relative to morning dose. The 
collection of some or all of these samples may not be feasible at the site due to shipment logistics depending on their geographic location. In addition, sampling time points 
may be eliminated or modified based upon emerging data. As of Amendment 7, Pharmacodynamics samples will no longer be collected. 
s 
Pharmacodynamic samples will be collected on Cycle 1, Day 1 at predose and between 1.5 and 4 hours inclusive post-dose of tirabrutinib. On Cycle 1, Day 8 and Cycle 2, 
Day 1, a pharmacodynamic sample will be collected at pre-dose and between 1.5 and 4 hours inclusive post dose of tirabrutinib and idelalisib or 
entospletinib. Pharmacodynamic samples should be collected at approximately the same time as PK samples, where applicable. As of Amendment 7, Pharmacodynamics 
samples will no longer be collected. 
t 
 
 
  
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u 
Disease specific biomarkers (e.g. prognostic) for CLL, SLL, MCL subjects: peripheral blood will be collected prior to therapy at Cycle 1, Day 1 and at disease progression. 
For CLL and MCL patients, a blood sample will be collected at CR for MRD testing. As of Amendment 7, Pharmacodynamics samples will no longer be collected. 
v 
If available, paraffin embedded archival tumor tissue block for shipment to Gilead or its designee will be requested after Cycle 1, Day 1 only if biopsy is not medically 
feasible. 
w 
 
 
 
x 
For Waldenstrom’s macroglobulinemia subjects, bone marrow aspirates will be collected prior to the first dose if MYD88 and CXCR4 mutation status is not known and at 
disease progression. For CLL and MCL subjects, bone marrow aspirates will be collected at CR for MRD testing. As of Amendment 7, these will no longer be collected. 
y 
 
z 
Clinical Assessment of response based on available data every 4 weeks starting with Cycle 2, Day 1 until Cycle 6, Day 1, and then every 12 weeks. As of Amendment 7, these 
will no longer be performed. 
aa 
For subjects on treatment with idelalisib, CMV surveillance by PCR or PP65 Ag testing and clinical evaluation for CMV reactivation, to be done as per local standard of care 
at screening, C1D1, approximately every 28 days and every 12 weeks as of amendment 7.  
bb CBC with differential every 2 weeks for the first 24 weeks of Idelalisib treatment 
cc 
Antibiotic prophylaxis for PJP is mandatory for subjects on idelalisib therapy and should be continued for 2-6 months after idelalisib discontinuation. PJP prophylaxis should 
be instituted for patients with CLL irrespective of treatment arm unless medically contraindicated. PJP prophylaxis should be considered for up to 12 months following 
obinutuzumab treatment and throughout study drug therapy, particularly in subjects with multiple risk factors for Pneumocystis infection.  
dd Obinutuzumab will be initiated on Study Day 1 with a test dose of 100 mg. If this dose is tolerated well, the remainder of the full dose will be subsequently administered on 
Study Day 1. Alternatively, the remaining 900 mg will be administered on Study Day 2. Subsequent infusions of obinutuzumab will be administered on Cycle 1, Day 6 (+/- 2 
days), Cycle 1, Day 13 (+/- 2 days), Cycle 2, Day 1 (+/- 3 days) and then every 28 days(+/- 3 days) until Cycle 6, Day 1 (+/- 3 days) for up to 8 intravenous infusions of 
1000 mg each.  
ee 
As of amendment 7, these assessments will no longer be completed after subjects have completed at least 1 year on treatment. 
ff 
As of amendment 7, study visits will occur every 12 weeks after subjects have completed at least 1 year on treatment. 
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Appendix 3. 
Study Procedures Table (Long-Term Safety Monitoring) 
Study Phase 
Screeninga,b 
Long-Term Safety 
Monitoring 
Cycle 1 Day 1b 
Every 12 Weeks 
(First 12 Months) 
Every 24 Weeks 
(After First 
12 Months) 
EOT 
30-day Safety 
Follow-up 
Cycle Day 
Day -28 
Window (day) 
-28 
0 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
Verification of 
Eligibilitya 
X 
 
 
 
 
 
Clinical Assessment 
Xf,g 
Xf,g 
Xg 
Xg 
 
 
Medical and 
Medication Historye 
X 
X 
 
 
 
 
Adverse Events/ 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
IP Accountability 
and/or Dispensing 
 
X 
X 
X 
X 
 
Pneumocystis jirovecii 
Pneumonia (PJP) 
Prophylaxisc 
 
X 
X 
X 
X 
 
Evaluation for CMV 
Reactivationd 
 
X 
X 
X 
 
 
Urine Pregnancy 
Testing 
Xa 
X 
X 
X 
X 
 
AE = adverse event; CLL = chronic lymphocytic leukemia; CMV = cytomegalovirus; EOT = end of treatment; IP = investigational product; PJP = Pneumocystis jirovecii 
pneumonia 
a 
Screening will only apply to Group VI. Urine pregnancy testing performed up to 30 days prior to enrollment and imaging performed up to 90 days prior to enrollment may be 
used to determine eligibility.  
b 
Subjects from the ongoing Study GS-US-401-1787 who enroll into Group VI in this study should have their Study GS-US-401-1787 EOT visit, Study GS-US-401-1757 
Screening, and Long-Term Safety Monitoring Cycle 1 Day 1 visit on the same day. Subjects on named patient use who enroll into Group VI in this study should have their 
Study GS-US-401-1757 Screening and Long-Term Safety Monitoring Cycle 1 Day 1 visit on the same day. 
c 
Antibiotic prophylaxis for PJP is mandatory for subjects on idelalisib therapy and should be continued for 2 to 6 months after idelalisib discontinuation. PJP prophylaxis 
should be instituted for patients with CLL irrespective of treatment arm unless medically contraindicated. PJP prophylaxis should be considered for up to 12 months following 
obinutuzumab treatment and throughout study drug therapy, particularly in subjects with multiple risk factors for Pneumocystis infection.  

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d 
For subjects on treatment with idelalisib, CMV surveillance by PCR or PP65 Ag testing and clinical evaluation for CMV reactivation, to be done as per local standard of care 
at Long-Term Safety Monitoring Cycle 1 Day 1, every 12 weeks for the first 12 months, and then every 24 weeks during the long-term safety monitoring phase. 
e 
Medical and medication history will only apply to Group VI. Medical history should include AE that are ongoing at the time of enrollment in this study. 
f 
Subjects in screening and subjects currently on the study who have no clinical evidence of disease progression may enroll or transition into long-term safety monitoring. If 
there is clinical evidence of disease progression, a confirmatory radiologic assessment should be performed per institutional standard of care. 
g 
Clinical assessment should include assessment for disease progression and laboratory assessments per institutional standard of care. 

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Appendix 4. 
Waldenstrom’s Macroglobulinemia Assessment 
Category 
Finding 
Laboratory 
Serum monoclonal IgM > 0.5 g/dL  
Hemoglobin level < 10 g/dL  
Platelet count < 100 x 109 /L 
Laboratory + symptoms 
Cryoglobulinemia with symptoms 
Hyperviscosity with symptoms 
Physical Findings 
Bulky adenopathy 
Organomegaly  
Symptoms 
Recurrent fevers 
Night sweats 
Weight loss  
Fatigue 
Symptomatic neuropathies 
Organ Disease 
Nephropathy 
Amyloidosis 
Pathology 
Disease Transformation 
 
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, ie, 
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, ie, 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, ie, 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, ie, 
lymphadenopathy/splenomegaly if present at baseline; 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 5. 
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, 
idelalisib, entospletinib and similar drugs. 
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 LD × the 
LPD will be recorded (in cm) for each index lesion. The product of the perpendicular diameters 
(PPD) for each index lesion and the 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). 
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD will be considered PD. 

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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 s 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, PR with Lymphocytosis, 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 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. Minimal Residual Disease (MRD) 
• Achieving MRD is defined as < 1 leukemia cell/10,000 leukocytes (10-4) in patients who 
have also achieved a CR 
1.4.3. 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 Appendix 4, Section 1.2 
― In a subject with enlargement of the liver at baseline, a hepatomegaly response as defined 
in Appendix 4, 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) 

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1.4.4. 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 
1.4.5. 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 or aspirate 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  
1.4.6. 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. 
1.4.7. PR with Lymphocytosis  
• Tirabrutinib, idelalisib, 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. 
• 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 and idelalisib or 
entospletinib 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 
Sections 3.6 and 3.7. 

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Appendix 6. 
Follicular Lymphoma, Marginal Zone Lymphoma, Small 
Lymphocytic Lymphoma, Diffuse Large Cell Lymphoma and Mantle 
Cell Lymphoma Response Assessment 
The determination of FL, MZL, SLL, DLBCL and MCL 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 
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. 
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). 

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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. 
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.  

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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.  
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 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 Appendix 5, 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 
• 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 

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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 
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) 

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― 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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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 to be 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 
Tirabrutinib is contraindicated in pregnancy as non-clinical studies in rats and rabbits have 
demonstrated embryo-fetal toxicity and reproductive failure. Both idelalisib and entospletinib are 
contraindicated in pregnancy due to a strong suspicion of human teratogenicity/fetotoxicity in 
early pregnancy based on non-clinical studies in rats and rabbits that have demonstrated 
teratogenic effects. 
Currently, insufficient data exists for any of the 3 Gilead study drugs to exclude the possibility of 
a clinically relevant interaction 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 in this study. 
For additional information on any of these study investigational products, please refer to the 
latest version of the relevant IB. 
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. Also, subjects must 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 urine pregnancy test on the Cycle 1, Day 1 visit prior to dosing. Urine 
pregnancy tests will be performed at 28-day intervals thereafter, then every 12 weeks as of 
Amendment 7 and at the EOT visit. 

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As of Amendment 9, female subjects of childbearing potential must have a negative urine 
pregnancy test at Screening to enroll into long-term safety monitoring. Urine pregnancy tests will 
be performed at Long-Term Safety Monitoring Cycle 1 Day 1, every 12 weeks for the first 
12 months, and then every 24 weeks during the long-term safety monitoring phase, and at the 
EOT visit. 
Female subjects of childbearing potential must agree to one of the following from Screening 
until 30 days following the final dose of either tirabrutinib, idelalisib, or entospletinib, or until 
18 months following the final dose of obinutuzumab (whichever is later).  
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. 
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 following the final dose of either tirabrutinib, idelalisib, or ENTO, or 
until 18 months following the final dose of obinutuzumab (whichever is later).  
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 who can 
father a child must limit intercourse to female partners who are surgically sterile, post-
menopausal, or use effective contraception; or agree to use a recommended method of 
contraception during heterosexual intercourse throughout the study treatment period and until 
90 days following the final dose of either tirabrutinib, idelalisib, or entospletinib, or until 
18 months following the final dose of obinutuzumab (whichever is later). Additional 
contraception recommendations should also be considered if the female partner is not pregnant. 
For this study, a man is considered able to father a child unless he has had a vasectomy on both 
sides, had had removal of both testicles, or is undergoing testicular suppression with a depot 
luteinizing hormone-releasing hormone (LH-RH) drug such as goserelin acetate (Zoladex®), 
leuprolide acetate (Lupron®), or triptorelin pamoate (Trelstar®). 

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Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
following the final dose either tirabrutinib, idelalisib, or entospletinib, or until 18 months 
following the final dose of obinutuzumab (whichever is later). 
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
Female 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 the final dose of either 
tirabrutinib, idelalisib, or entospletinib, or until 18 months following the final dose of 
obinutuzumab (whichever is later). 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. Male subjects whose female 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 7.6.2.1. 

Tirabrutinib 
 
Protocol GS-US-401-1757 
Final 
Gilead Sciences, Inc.  
Amendment 10 
CONFIDENTIAL 
Page 167 
01 May 2020 
Appendix 9. 
Eastern Cooperative Oncology Group (ECOG) Performance 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 self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead