A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (GS-4059) and Entospletinib With and Without Obinutuzumab in Subjects With Chronic Lymphocytic Leukemia
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia
Sponsor: Gilead Sciences

                   
CLINICAL STUDY PROTOCOL
Study Title:
A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate 
the Safety and Efficacy of the Combination of Tirabrutinib 
(GS-4059) and Entospletinib with and without Obinutuzumab in 
Subjects with Chronic Lymphocytic Leukemia
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
This is a non-IND study
2016-002768-15
NCT02983617
Indication:
Chronic Lymphocytic Leukemia
Protocol ID:
GS-US-401-2076
GCLLSG Protocol ID:
CLLRUmbrella2
Gilead Clinical Program 
Manager:
Name:
Telephone:
+
Gilead Medical Monitor:
Name:
Telephone:
GCLLSG Global Principal 
Investigator:
Name:
Telephone:
+
GCLLSG Coordinating 
Physician:
Name:
 
Telephone:
+
Protocol Version/Date:
Original:
25 August 2016
Amendment 1: 
16 November 2016
Amendment 2:
02 February 2017
Amendment 3:     24 August 2017
Amendment 4:     15 January 2019
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The information contained in this document, particularly unpublished data, is the property or under 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.
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................18
1.
INTRODUCTION ..............................................................................................................................................21
1.1.
Background ............................................................................................................................................21
1.1.1.
Chronic Lymphocytic Leukemia..........................................................................................21
1.2.
Entospletinib ..........................................................................................................................................22
1.2.1.
General Information .............................................................................................................22
1.2.2.
Spleen Tyrosine Kinase in Hematologic Malignancies........................................................22
1.2.3.
Nonclinical Pharmacology and Toxicology of Entospletinib...............................................22
1.2.4.
Clinical Trials of Entospletinib ............................................................................................22
1.3.
Tirabrutinib ............................................................................................................................................23
1.3.1.
General Information .............................................................................................................23
1.3.2.
BTK in B-cell Malignancies.................................................................................................23
1.3.3.
Nonclinical Pharmacology and Toxicology of Tirabrutinib.................................................25
1.3.4.
Clinical Trials of Tirabrutinib ..............................................................................................25
1.4.
Obinutuzumab........................................................................................................................................27
1.5.
Rationale for This Study ........................................................................................................................28
1.5.1.
Rationale for Dose Selection................................................................................................28
1.6.
Risk/Benefit Assessment for the Study..................................................................................................30
1.7.
Compliance ............................................................................................................................................32
2.
OBJECTIVES.....................................................................................................................................................33
3.
STUDY DESIGN................................................................................................................................................34
3.1.
Study Design..........................................................................................................................................34
3.2.
Study Treatments ...................................................................................................................................34
3.3.
Duration of Treatment............................................................................................................................36
3.4.
Criteria for Discontinuation of Study Treatment....................................................................................37
3.5.
Duration of Study...................................................................................................................................37
3.6.
Criteria for Discontinuation from Study ................................................................................................37
3.7.
GCLLSG CLL Registry .........................................................................................................................38
3.8.
Post Study Care......................................................................................................................................38
4.
SUBJECT POPULATION..................................................................................................................................39
4.1.
Number of Subjects................................................................................................................................39
4.2.
Inclusion Criteria....................................................................................................................................39
4.3.
Exclusion Criteria...................................................................................................................................40
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................42
5.1.
Randomization .......................................................................................................................................42
5.2.
Description and Handling of Tirabrutinib, Entospletinib, and Obinutuzumab.......................................42
5.2.1.
Tirabrutinib ..........................................................................................................................42
5.2.2.
Entospletinib.........................................................................................................................43
5.2.3.
Obinutuzumab ......................................................................................................................44
5.3.
Dosage and Administration of Tirabrutinib, Entospletinib, and Obinutuzumab....................................45
5.3.1.
Tirabrutinib and Entospletinib..............................................................................................45
5.3.2.
Obinutuzumab ......................................................................................................................45
5.4.
Prior and Concomitant Medications.......................................................................................................48

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5.4.1.
IVIg and G-CSF ...................................................................................................................49
5.4.2.
Prior and Concomitant Medications with Tirabrutinib.........................................................49
5.4.3.
Prior and Concomitant Medications with Entospletinib.......................................................49
5.4.4.
Prior and Concomitant Medications with Obinutuzumab ....................................................51
5.5.
Accountability for Tirabrutinib, Entospletinib, and Obinutuzumab.......................................................51
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................52
6.
STUDY PROCEDURES ....................................................................................................................................53
6.1.
Subject Enrollment, Randomization and Treatment Assignment...........................................................53
6.2.
Study Procedure Descriptions ................................................................................................................53
6.2.1.
Informed Consent.................................................................................................................53
6.2.2.
Medical and Medication History..........................................................................................53
6.2.3.
Physical Examination...........................................................................................................54
6.2.4.
Vital Signs............................................................................................................................54
6.2.5.
ECOG Performance Status/B-Symptoms.............................................................................54
6.2.6.
12-lead ECG.........................................................................................................................54
6.2.7.
Binet and Rai Staging...........................................................................................................54
6.2.8.
Geriatric assessment.............................................................................................................54
6.2.9.
Prior and Concomitant Medications.....................................................................................55
6.2.10.
Adverse Events.....................................................................................................................55
6.2.11.
Radiology Assessment .........................................................................................................55
6.2.12.
Blood and Urine Samples.....................................................................................................55
6.2.13.
Bone Marrow Assessment....................................................................................................56
6.2.14.
Laboratory Samples to Address the Study Objectives .........................................................56
6.2.15.
Samples for Optional Future Research.................................................................................57
6.2.16.
Pregnancy Test for Females of Childbearing Potential ........................................................57
6.2.17.
Pharmacokinetic Samples.....................................................................................................57
6.3.
Assessments for Premature Discontinuation from Study.......................................................................59
6.4.
Criteria for Discontinuation of Study Treatment....................................................................................59
6.5.
Dose Interruption and Reduction ...........................................................................................................59
6.6.
Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific 
Adverse Events or Conditions................................................................................................................64
6.6.1.
Hemorrhage..........................................................................................................................64
6.6.2.
Infectious Events..................................................................................................................64
6.6.3.
Dermatological and Hypersensitivity Events .......................................................................64
6.6.4.
Hepatic Events......................................................................................................................65
6.6.5.
Hematological Events...........................................................................................................65
6.6.6.
Progressive Multifocal Leukoencephalopathy (PML)..........................................................65
6.6.7.
Further Safety Information...................................................................................................65
6.7.
End of Treatment....................................................................................................................................66
6.8.
Unscheduled Procedures ........................................................................................................................66
6.9.
Post Study Care......................................................................................................................................66
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................67
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................67
7.1.1.
Adverse Events.....................................................................................................................67
7.1.2.
Serious Adverse Events........................................................................................................67
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................68
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................68
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................68
7.2.2.
Assessment of Severity ........................................................................................................69
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................69

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7.4.
Gilead Reporting Requirements.............................................................................................................71
7.5.
Toxicity Management ............................................................................................................................71
7.6.
Special Situations Reports......................................................................................................................72
7.6.1.
Definitions of Special Situations..........................................................................................72
7.6.2.
Instructions for Reporting Special Situations.......................................................................72
8.
STATISTICAL CONSIDERATIONS................................................................................................................74
8.1.
Analysis Objectives and Endpoints........................................................................................................74
8.1.1.
Analysis Objectives..............................................................................................................74
8.1.2.
Primary Endpoint .................................................................................................................74
8.1.3.
Secondary Endpoints............................................................................................................74
8.1.4.
Exploratory Endpoints..........................................................................................................74
8.2.
Analysis Conventions.............................................................................................................................75
8.2.1.
Analysis Sets ........................................................................................................................75
8.3.
Data Handling Conventions ...................................................................................................................76
8.4.
Demographic Data and Baseline Characteristics ...................................................................................76
8.5.
Efficacy Analysis ...................................................................................................................................77
8.5.1.
Primary Endpoint .................................................................................................................77
8.5.2.
Secondary Endpoints............................................................................................................77
8.6.
Safety Analysis.......................................................................................................................................77
8.6.1.
Extent of Exposure...............................................................................................................77
8.6.2.
Adverse Events.....................................................................................................................77
8.6.3.
Laboratory Evaluations ........................................................................................................78
8.7.
Pharmacokinetic Analysis......................................................................................................................79
8.8.
Biomarker Analysis................................................................................................................................79
8.9.
Sample Size............................................................................................................................................79
8.10.
External Data Monitoring Committee....................................................................................................79
8.11.
Endpoint Adjudication Committee.........................................................................................................80
9.
RESPONSIBILITIES..........................................................................................................................................81
9.1.
Investigator Responsibilities ..................................................................................................................81
9.1.1.
Good Clinical Practice..........................................................................................................81
9.1.2.
Independent Ethics Committee Review and Approval.........................................................81
9.1.3.
Informed Consent.................................................................................................................81
9.1.4.
Confidentiality......................................................................................................................82
9.1.5.
Study Files and Retention of Records ..................................................................................82
9.1.6.
Case Report Forms...............................................................................................................83
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................84
9.1.8.
Inspections............................................................................................................................84
9.1.9.
Protocol Compliance............................................................................................................84
9.2.
Sponsor Responsibilities ........................................................................................................................84
9.2.1.
Protocol Modifications.........................................................................................................84
9.2.2.
Study Report and Publications .............................................................................................85
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................85
9.3.1.
Payment Reporting...............................................................................................................85
9.3.2.
Access to Information for Monitoring..................................................................................85
9.3.3.
Access to Information for Auditing or Inspections ..............................................................86
9.3.4.
Study Discontinuation..........................................................................................................86
10.
REFERENCES ...................................................................................................................................................87
11.
APPENDICES ....................................................................................................................................................91

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Appendix 1.
       Investigator Signature Page.............................................................................................92
Appendix 2.
Study Procedures Table..........................................................................................................93
Appendix 3.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03....................................96
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................97
Appendix 5.
Eastern Cooperative Oncology Group (ECOG) Performance Status ...................................100
Appendix 6.
Modified IWCLL 2008 Response Criteria ...........................................................................101
Appendix 7.
Cumulative Illness Rating Scale (CIRS) ..............................................................................103
Appendix 8.
Cockcroft-Gault Method for Estimating Creatinine Clearance ............................................104
Appendix 9.
Binet and Rai Staging Systems for the Classification of CLL..............................................105
Appendix 10.
The G8 Screening Questionnaire..........................................................................................106
LIST OF IN-TEXT TABLES
Table 5-1.
Examples of Concomitant Medications Prohibited in this Study ...........................................50
Table 5-2.
Recommended dose limits for HMG-CoA reductase inhibitors.............................................50
Table 6-1.
Blood and Urine Samples Collected During the Course of the Study....................................58
Table 6-2.
Dose Adjustments, Withholding and Discontinuation Related to Entospletinib 
and/or Tirabrutinib..................................................................................................................60
Table 6-3.
Dose Adjustment Guidelines for Subjects Receiving Obinutuzumab ....................................62
Table 7-1.
Grading of Adverse Event Severity........................................................................................69
Table 8-1.
90% Confidence Intervals at Different CR Rates...................................................................79
LIST OF IN-TEXT FIGURES
Figure 1-1.
Inhibition of the BCR Pathway ..............................................................................................25

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate 
the Safety and Efficacy of the Combination of Tirabrutinib
(GS-4059) and Entospletinib with and without Obinutuzumab in 
Subjects with Chronic Lymphocytic Leukemia
IND Number:
EudraCT Number:
Clinical Trials.gov
Identifier:
This is a non-IND study
2016-002768-15
NCT02983617
Study Centers Planned:
Approximately 25 centers in Germany
Objectives:
Primary Objective:

To determine the preliminary efficacy of finite therapy with the 
combination of tirabrutinib, entospletinib with obinutuzumab in 
subjects with relapsed or refractory chronic lymphocytic 
leukemia (CLL)
Secondary Objective:

To evaluate the safety and tolerability of the combination of 
tirabrutinib and entospletinib with and without obinutuzumab
Exploratory Objectives:
 
Endpoints:
Primary Endpoint:
The primary endpoint is the rate of complete remission (CR) per 
modified International Workshop on CLL (IWCLL 2008) criteria
{Hallek 2008} at Week 25
Secondary Endpoints:

Rate of complete response (CR) with bone marrow minimal 
residual disease (MRD) negativity (CR/BM MRD-) at Week 25

Rate of CR with MRD negativity (<10-4) in peripheral blood 
(CR/PB MRD-) at Week 25
CCII 
I 

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
Overall response rate (ORR) at Week 25 including CR, CR with 
incomplete bone marrow recovery (CRi), partial remission 
(PR), and PR with lymphocytosis

Type, frequency, and severity of adverse events (AEs) and 
serious adverse events (SAEs)
Exploratory Endpoints:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCII 
I 
I 
I 
I 
I 
I 
I 
I 

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Study Design:
This is a Phase 2, prospective, open-label, multicenter trial to 
evaluate the safety and efficacy of the combination of tirabrutinib 
(GS-4059) and entospletinib with and without obinutuzumab in 
subjects with relapsed or refractory CLL.
Eligible subjects will be treated with the combination of tirabrutinib
and entospletinib and stratified by the presence of 17p 
deletion/TP53 mutation (del17p/TP53mut) in CLL cells. Following 
stratification, subjects will be randomized 1:1 to treatment with the 
combination of tirabrutinib and entospletinib with or without 
obinutuzumab.

Arm A: tirabrutinib + entospletinib

Arm B: tirabrutinib + entospletinib + obinutuzumab

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Study Design Schema
With Amendment 3, randomization was discontinued. All 
subsequently enrolled subjects will enter Arm B (tirabrutinib + 
entospletinib + obinutuzumab).
With Amendment 4, the Post Treatment period will no longer be 
applicable.
Screening 
Arm A 
N =30 
/ 
ArmB 
N =30 
GS-4059 
Entospletinib 
1:1 Randomizat:ion 
GS-4059 
Entospletinib 
Obinutuzurnab 
Week 25 
~
-
........................................................ ......, 
Obinut uzumab: 21 weeks 
Gs.-4059 + Entosplet inib: Up to 104 weeks 
Total Duration: 5 years 
'Wttk:25 
. . 
----- ·~--------------
Tirt bn!tti'llb 
11:ntospletlnlb 
Ol)lnut11tumab 
oblnulllrurnab: 21 weelci 
Total 1Duradon: 5, yurs 
EOT 
EOT 
Post-Treatment 
On-Study 
Scheduled Assessments 
Polit-1r-Htm4t.llt 
On-Study_ 
EOS 
OS 

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Sueenllilg 
GS-4059 
Entos;p1etf n'lb 
1.1 R:andomlzatlo:n, 
GS-4059 
Entosple lnlb 
Oblnutuzumab 
O:b nlltuZiumab: 21 weeks 
w,eekzs 
GS-4059 + [ntosp' :ti'n b: Up to 104 w 
il!cs 
EOT 

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Enrollment will be paused following enrollment of the first 6 subjects
into Arm B, who will be observed for safety for 28 days following the 
first dose of study treatment including weekly evaluation through that 
period. Additional subjects may be enrolled into the safety cohort if any 
of the first 6 subjects in Arm B discontinue therapy during the initial 
28 days for reasons unrelated to toxicity. A Safety Review Team (SRT) 
will review 28-day safety data from the first 6 subjects in Arm B and 
determine whether enrollment may resume and if weekly clinical 
evaluation through the first 28 days should continue or may be reduced 
in frequency for the remainder of subjects enrolled in the study. The 
safety review will include assessment of the following:

Grade ≥ 4 hematological toxicities persisting for > 7 days

Grade ≥ 4 non-hematologic laboratory abnormalities except for 
asymptomatic AST/ALT elevation, LDH, or uric acid

Grade ≥ 3 non-hematological toxicities (except alopecia or the 
following that resolve within 72 hours with medical intervention: 
tumor lysis, nausea, vomiting, diarrhea, or constipation)

Grade ≥ 2 non-hematologic treatment-emergent adverse events 
(TEAE) that in the opinion of the investigator are of potential 
clinical significance such that further dosing would expose subjects 
to unacceptable risk
A decision to prematurely terminate the study will be made by the 
sponsor in consultation with the investigators in accordance with 
regulatory and ethical principles.
Criteria for termination of the study are:
1) An unacceptable safety profile or incidence of AEs or SAEs revealed 
in this or any other study in which the combination of agents is 
administered
2) Any other factor that in the view of the sponsor constitutes an 
adequate reason for terminating the study 
As agreed with the German Federal Institute for Drugs and Medical 
Devices Agency (BfArM), a safety report including the cumulative 
safety results and summary of the conclusion of the SRT following 
assessment of the safety cohort was submitted to BfArM shortly after 
the assessment.
The study steering committee, including representatives from the 
German CLL Study Group (GCLLSG) and Gilead, will review ongoing 
safety data at least quarterly throughout the treatment period and 
regularly for the complete duration of the study.

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Number of 
Subjects Planned:
Approximately 36 evaluable in total; 30 evaluable in Arm B and 
approximately 6 in Arm A
Target 
Population:
Adults with relapsed or refractory CLL
Duration of 
Treatment:
Obinutuzumab will be administered for up to 8 doses over 21 weeks to 
subjects randomized or enrolled to treatment with tirabrutinib + 
entospletinib + obinutuzumab (Arm B). Combination treatment with the 
oral agents will continue for all subjects for up to 104 weeks in the 
absence of disease progression, unacceptable toxicity or documentation 
of CR/BM MRD-. If CR/BM MRD- is documented on study, treatment 
will stop after the earlier of:
1) an additional 3 months of therapy or
2) 104 weeks of total treatment. 
Long-Term 
Follow-up After 
End of Study:
Consenting subjects for inclusion in the German CLL Study Group 
(GCLLSG) registry is requested at screening or as soon as possible 
thereafter.
Diagnosis and 
Main Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all the following criteria to be eligible for 
participation in this study:
1) Documentation of relapsed or refractory CLL
2) Have an indication for treatment per modified IWCLL 2008 criteria; 
subjects without radiographically measureable disease (defined as ≥
1 lesion > 1.5cm in diameter as assessed by computer tomography 
(CT) or magnetic resonance imaging [MRI]) must have bone 
marrow evaluation at screening
3) Adequate hematologic function as indicated by a platelet count 
≥50 x 109/L, a neutrophil count ≥ 1 x 109/L and a hemoglobin 
≥8g/dL unless lower values are directly attributable to documented 
bone marrow burden of CLL
4) Adequate renal function as indicated by a CrCl ≥50 mL/min 
calculated by the modified Cockroft-Gault formula or from a 24h 
urine collection

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5) Adequate liver function as indicated by total bilirubin 
≤1.5x institutional upper limit of normal (ULN) unless attributed to 
Gilbert’s syndrome and AST/ALT ≤ 2.5×ULN
6) Male or female ≥ 18 years of age
7) Eastern Cooperative Oncology Group (ECOG) Performance Status 
(PS) ≤ 2
8) Absence of active HBV infection (serological testing within 6 weeks 
prior to randomization or enrollment with the following results: 
HBsAg negative AND anti-HBcAb negative, or if anti-HBcAb 
positive, HBV DNA PCR negative)
9) HCV Ab negative or if Ab positive, negative HCV RNA PCR within 
6 weeks prior to randomization or enrollment
10) Negative testing for HIV within 6 weeks prior to randomization or 
enrollment
11) Satisfies the following criteria:
a) For female subjects of childbearing potential, willingness to 
abstain from sexual intercourse or use a protocol-specified 
method of contraception as described in Appendix 4
b) Male subjects of reproductive potential who engage in sexual 
intercourse must agree to use protocol-specified method(s) of 
contraception as described in Appendix 4
12) Ability and willingness to provide written informed consent and 
adhere to protocol requirements including study visit schedule, drug 
administration plan, imaging studies, laboratory testing, other study 
procedures and restrictions
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not 
eligible for participation in this study:
1) Known transformation of CLL (ie, Richter’s transformation, 
prolymphocytic leukemia)
2) Known CNS involvement
3) Progression on treatment with any inhibitor of BTK, SYK, PI3K, 
BCL-2, or obinutuzumab. The treatment and disease response 
history of subjects with prior treatment with agents in these classes 
should be reviewed by the sponsor or the GCLLSG study office
prior to enrollment to clarify sensitivity to these treatments.
4) Any treatment for CLL other than corticosteroids for symptomatic 
management within 28 days of the start of study treatment
5) Participation in a concurrent therapeutic clinical trial unless all 
treatment is complete with only ongoing surveillance

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6) Diagnosis of or concern for progressive multifocal 
leukoencephalopathy
7) History of myelodysplastic syndrome or another malignancy other 
than CLL, except for the following: any malignancy that has been in 
complete remission for 3 years, 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.
8) Active infection requiring systemic therapy
9) Pregnant or nursing women (a negative pregnancy test is required 
for all women of childbearing potential within 7 days before start of 
treatment and monthly during therapy)
10) Active autoimmune disease including autoimmune hemolytic 
anemia or idiopathic thrombocytopenic purpura requiring a higher 
corticosteroid equivalent than prednisone 10 mg daily. Higher doses 
of corticosteroids prescribed for any indication must be stopped 
> 14 days prior to randomization or enrollment; exceptions may be 
made for corticosteroids prescribed specifically for management of 
CLL symptoms after discussion with the study medical monitor.
11) Diagnosis of inflammatory bowel disease or ongoing symptomatic 
pneumonitis
12) History of stroke or intracranial hemorrhage within 12 months of 
randomization or enrollment; subjects requiring therapeutic 
anticoagulation for any indication should be discussed with the 
GCLLSG coordinating physician and/or medical monitor prior to 
screening.
13) Legal incapacity, prisoners or subjects institutionalized by regulatory 
or court order, or any individual in dependence to study sponsor or 
any investigator
14) Anticipated chronic use of strong CYP3A4/CYP2C9 inducers, 
moderate CYP2C9 inducers, or strong P-gp inducers while on study; 
use within 2 weeks of first dose of study treatment should be 
avoided.
15) Requirement for proton pump inhibitor (PPI) therapy
16) Demonstration of QTc interval >450 milliseconds or requirement for 
ongoing treatment with concomitant medications that prolong the 
QT interval
17) Known hypersensitivity to obinutuzumab, entospletinib, tirabrutinib,
or any of the excipients

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Test Product, Dose, 
and Mode of 
Administration:
Tirabrutinib and Entospletinib:
Tirabrutinib 80 mg will be self-administered orally once daily and 
entospletinib 400 mg will be self-administered orally once daily. Dosing 
of both agents will begin on Week 1 Day 1 of the study and thereafter 
continue at approximately the same time each day until the earlier of 
i) 3 months after documentation of CR/MRD- or ii) completion of 
104 weeks of treatment. Tirabrutinib is supplied as 20 mg (4 x 20 mg)
tablets, 40 mg (2 x 40 mg) tablets, or as 80 mg tablets. Entospletinib is 
supplied as 200 mg (2 x 200 mg) tablets.
Obinutuzumab:
Obinutuzumab will be administered as 8 intravenous infusions of 
1000 mg each over 21 weeks. A test dose of 100 mg will be 
administered on Week 1 Day 1. If this dose is tolerated, the remainder of 
the full dose may be subsequently administered on Day 1. Alternatively, 
the remaining 900 mg will be administered on Day 2.
Subsequent infusions will be administered on Week 2 Day 1, Week 3 
Day 1, Week 5 Day 1 and then every 4 weeks through Week 21.
Reference Therapy, 
Dose, and Mode of 
Administration:
Not applicable
Criteria for 
Evaluation:
Safety:
Safety will be evaluated by the documentation of AEs and monitoring of 
clinical laboratory tests.
Efficacy:
Efficacy will be assessed per modified IWCLL 2008 criteria
{Hallek 2008}:

Lymph node, spleen and liver measurements by physical 
examination

Complete blood count

Lymph node, spleen and liver measurements by CT or MRI

Peripheral blood MRD assessment

Bone marrow assessment including standard histopathology and 
MRD assessment
Pharmacokinetics:
Plasma drug concentrations of tirabrutinib and entospletinib as assessed 
by validated bioanalytical methods

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Sample Size 
Determination
The primary goal of this study is to evaluate the efficacy of the 
combination of tirabrutinib and entospletinib with obinutuzumab in 
relapsed and refractory CLL. The primary endpoint for this study is the 
rate of CR at Week 25. The corresponding single-agent CR rate with 
BTK and SYK inhibitors in subjects with relapsed or refractory CLL is 
≤5%. The 90% CI corresponding to different CR rates ranging from 
20% to 60% for a sample size of 30 is provided in the table below. With 
a sample size of 30, the lower bound of the 90% CI of an observed CR 
rate of 20% or above will exclude 5%.
90% Confidence Intervals at Different CR Rates
Sample Size
Observed 
CR Rate
90% Confidence Interval
using Clopper-Pearson Method
30
20%
(9.1%, 35.7%)
30
30%
(16.6%, 46.5%)
30
40%
(25.0%, 56.6%)
30
50%
(33.9%, 66.1%)
30
60%
(43.4%, 75.1%)
With Amendment 3, randomization was discontinued. All subsequently 
enrolled subjects will enter Arm B. A total of approximately 6 subjects 
in Arm A and 30 subjects in Arm B will be enrolled, thus the total 
sample size for the study will be approximately 36 subjects.
Statistical Methods:
The Full Analysis Set (FAS) consists of all subjects randomized or 
enrolled to each study arm who received at least 1 dose of any study 
treatment. The per-protocol (PP) analysis set consists of all randomized
or enrolled subjects who received at least 1 dose of any study treatment 
and have a baseline disease assessment and at least 1 post-baseline 
response measurement. The safety analysis set consists of all 
randomized or enrolled subjects who received at least 1 dose of any 
study treatment.
All efficacy analyses will be based on the FAS and the analyses of 
response endpoints will be repeated using the PP analysis set.
Tumor response will be based on investigator’s assessment according to 
modified IWCLL 2008 criteria (see Appendix 6). CR rate, ORR, rate of 
CR/BM MRD-, and rate of CR/PB MRD- will be estimated for each arm 
and their associated 90% confidence intervals will be calculated using 
the Clopper-Pearson method.
Time-to-event endpoints (DOR, PFS, TTNT, and OS) will be analyzed 
using the Kaplan-Meier method. The median and quartiles and their 
associated 90% confidence intervals for these endpoints will be 
provided if estimable.

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Adverse events will be coded using the current version of MedDRA and 
graded using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) criteria and will be summarized 
by system organ class and preferred term and by severity and 
relationship to study treatment. Clinical laboratory tests and their 
changes from baseline will be summarized descriptively.
Subject enrollment and disposition will be summarized descriptively by 
treatment arms. Reasons for premature discontinuation from study 
treatment will be provided.
Subject demographics and baseline characteristics as well as baseline 
disease characteristics will be summarized descriptively by treatment 
arms using the FAS. Medical history and concomitant medication use 
will be summarized using the safety analysis set. In general, continuous 
variables will be summarized by sample size, mean, standard deviation, 
median, quartiles, minimum and maximum and categorical variables 
will be summarized by counts and percentages.
Treatment exposure and compliance will be summarized descriptively 
using treatment duration, number of doses, average dose, dose 
modifications, and treatment adherence rate based on the safety analysis 
set.
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
ADME
absorption, distribution, metabolism, and excretion 
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transaminase
aPTT
activated partial thromboplastin time
ANC
absolute neutrophil count
AST
aspartate transaminase 
AUC0-24h
mean exposure
BCL-2
B-cell lymphoma 2
BCR
B-cell receptor
BHCG
Beta-human chorionic gonadotropin
BID
twice daily
BTK
Bruton’s tyrosine kinase
BUN
blood urea nitrogen
CBC
complete blood count
CIRS
cumulative illness rating scale
CI
confidence interval
CLL
chronic lymphocytic leukemia
Cmax
maximum observed plasma/serum concentration of drug
CMV
Cytomegalovirus
CNS
central nervous system
CR
complete response/complete remission
CR/BM MRD-
complete response with bone marrow minimal residual disease negativity (<10-4 CLL cells 
present)
CR/PB MRD-
complete response with peripheral minimal residual disease negativity (<10-4 CLL cells present)
CrCl
creatinine clearance
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 Terminology Criteria for Adverse Events
CYP
cytochrome P450 enzyme
DDI
drug-drug interaction
del17p
deletion of short arm of chromosome 17
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of response

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ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
end of treatment
EU
European Union
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
GCLLSG
German CLL Study Group
GCP
good clinical practice
GGT
gamma-glutamyltransferase
HBcAb
anti-hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDPE
high density polyethylene 
HIV
human immunodeficiency virus
HNSTD
highest toxic dose
IB
Investigator’s Brochure
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
IEC
independent ethics committee
IMP
investigational medicinal product
iNHL
indolent non-Hodgkin lymphoma
INR 
international normalized ratio
IP
investigational product
IRC
independent review committee
IWCLL
International Workshop on CLL
LDH
lactate dehydrogenase
MAPK
mitogen-activated protein kinase
MCL
mantle cell lymphoma
MRD
minimal residual disease, with positivity defined as >1/104 CLL cells present in a sample
MRI
magnetic resonance imaging
MTD
maximum tolerated dose

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MZL
marginal zone lymphoma
NA
not applicable
NCI
National Cancer Institute
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease
PFS
progression-free survival
PI3K
phosphatidylinositol 3-kinase
PK
Pharmacokinetics
PP
per protocol
PPI
proton pump inhibitor
PS
performance status
PR
partial response/partial remission
PT
prothrombin time
PVE
(Gilead) 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
SUSAR
suspected unexpected serious adverse reaction
SYK
spleen tyrosine kinase
TEAE
treatment-emergent adverse event
TLR
Toll-like receptor
TP53mut
mutation within TP53 genomic locus
TTNT
time to next therapy
ULN
upper limit of normal
US
United States
WBC
white blood cell
WM
Waldenstrom's macroglobulinemia

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1.
INTRODUCTION
1.1.
Background
1.1.1.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is the most commonly occurring leukemia in Europe and 
the United States (US) with an estimated lifetime risk of 1:167 in the US (NIH SEER database)
{Sant 2010, Surveillance Epidemiology and End Results (SEER) Program 2011}. CLL is 
marked by the progressive accumulation of functionally impaired monoclonal B lymphocytes in 
blood, bone marrow, lymph nodes, spleen, and liver {Dighiero 2008}. Symptoms include fever, 
night sweats, and weight loss, and disease progression is often accompanied by 
lymphadenopathy, splenomegaly, or hepatomegaly. The course of CLL is highly variable, with a 
median survival of more than 10 years in low-risk patients compared with 2 years in high-risk 
subjects. CLL is largely a disease of the elderly; at diagnosis, 70% of subjects are ≥65 years of 
age and the median age is 71 years {National Cancer Institute (NIH) 2016}. Subjects with CLL 
harboring a deletion of the short arm of chromosome 17 (del17p) or an inactivating mutation in
the TP53 gene (TP53mut) are a particularly high risk CLL population and have shorter intervals 
prior to disease progression and shorter overall survival (OS) {Stephens 2015}.
For the majority of patients, chemoimmunotherapy remains the current standard of care for 
initial treatment {Gribben 2011}. The CLL8 study of the German CLL Study Group (GCLLSG)
comparing FC (fludarabine and cyclophosphamide) vs FCR (FC and CD20) {Hallek 2010}
established the benefit of addition of an anti-CD20 monoclonal antibody to a combination of a 
purine analog and alkylating agent in achieving a durable remission and prolonging survival
{Byrd 2005, Catovsky 2007, Hallek 2010, Robak 2010}. The subsequent CLL-10 study of FCR 
vs. BR (bendamustine and CD20) {Eichhorst 2016} clarified the role of both regimens in the 
initial treatment of CLL. However, for the overwhelming majority of subjects, these treatments 
are not curative; the disease will usually relapse and further intervention is required to obtain and 
maintain tumor control. While repeat treatment with chemoimmunotherapy can be pursued at the 
time of disease relapse, it has toxicity, including myelosuppression and fatigue. These toxicities
limit the suitability of FCR and BR in subjects with significant comorbidities or limited 
functional status. Similarly, subjects with a limited response to initial therapy (refractory) and 
those who have recurrent disease within 3 years are poorly served by repeated treatment with 
chemoimmunotherapy.
The approval and ongoing development of new, effective, oral small molecule targeted agents 
for the treatment of relapsed and refractory CLL has changed the treatment landscape. For 
subjects with del17p or TP53mut who respond poorly to chemoimmunotherapy in the frontline 
setting, these agents have yielded meaningful improvements in response rate and duration of 
response.
How best to combine targeted agents remains an area of interest due to the potential to achieve 
deeper and more durable responses in the treatment of CLL.

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1.2.
Entospletinib
1.2.1.
General Information
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.
1.2.2.
Spleen Tyrosine Kinase in Hematologic Malignancies
Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily 
expressed in cells of hematopoietic lineage. It is an important mediator of immunoreceptor 
signaling in macrophages, neutrophils, mast cells, and B cells. SYK contains 2 adjacent SH2 
domains that bind to immunoreceptor tyrosine-based activation motifs (ITAMs) to 
autophosphorylate and activate the enzyme. This allows SYK to phosphorylate its specific 
substrates including other enzymes and adaptor proteins, orchestrating a complex series of 
cellular responses such as cell proliferation, differentiation, survival, and phagocytosis.
Recent studies have suggested a role for the dysregulation of the tyrosine kinase SYK in B-cell 
malignancies. SYK is expressed in B cells and is essentially involved in multiple signal 
transduction pathways downstream of the B-cell receptor (BCR). In this process, SYK 
trans-autophosphorylates, and activates effector molecules such as PLC, PI3K, and 
mitogen-activated protein kinase (MAPK) and their associated signaling pathways, to induce a 
variety of responses including: proliferation, survival, differentiation, anergy, and apoptosis 
(Figure 1-1). In B cells, entospletinib effectively blocks BCR-mediated activation and 
proliferation (data on file). Additionally, the BCR can deliver antigen-independent signals that 
have also been postulated to require SYK activity. Both antigen-dependent and independent 
signals have been implicated in the pathogenesis of several common B-cell malignancies, 
including CLL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell 
lymphoma (MCL), marginal zone lymphoma (MZL), and B-lineage acute lymphoblastic 
leukemia (B-ALL) {Efremov 2011}. As a result, inhibitors of SYK activity are an attractive 
therapeutic option for hematopoietic B-cell lymphomas and other NHL varieties where SYK 
inhibition would prevent B-cell receptor-mediated signaling and therefore the uncontrolled 
growth of lymphoma cells.
1.2.3.
Nonclinical Pharmacology and Toxicology of Entospletinib
Please refer to the entospletinib IB for information regarding the nonclinical pharmacology, 
absorption, distribution, metabolism, and elimination (ADME) and nonclinical toxicity of 
entospletinib.
1.2.4.
Clinical Trials of Entospletinib
To date, 16 clinical studies have been initiated with entospletinib including treatment of over 
300 healthy subjects, 75 subjects with CLL and 150 with NHL. For complete details on the 
completed and ongoing studies with entospletinib, please refer to the entospletinib IB.

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The spray-dried dispersion formulation of the entospletinib tablet will be used in the current 
study and its superiority to prior tablet formulations in bioavailability and drug-drug interactions 
was established by Study GS-US-339-0111: A Phase 1 Open-Label, Adaptive Study of Novel 
Entospletinib Tablets Formulations to Evaluate the Effect of Acid Reducing Agents and Food on 
Entospletinib PK and Relative Bioavailability of the Novel Entospletinib Tablet Formulations.
The PK and PD of this formulation were further evaluated in healthy volunteers in Study 
GS-US-245-1222. A less-than-proportional increase in exposure was seen with repeated dosing 
of 400 mg entospletinib in comparison with 200 mg entospletinib. While there was no clinically 
meaningful effect of coadministration of a PPI (omeprazole) on entospletinib PK with 
entospletinib 200 mg once daily, entospletinib exposure (AUCtau) was significantly reduced
(59%) at a dose of entospletinib 400 mg twice daily.
The single agent entospletinib treatment experience in the ongoing Phase 2 GS-US-339-0102 
study showed a benefit in relapsed and refractory CLL. The primary efficacy endpoint for a CLL 
specific cohort with 41 subjects was PFS rate at 24 weeks and was assessed by the independent 
review committee (IRC) to be 69% (95% CI: 51.3, 82.7). With a median exposure of 36 weeks 
(range of 1 to 131 weeks), the safety data for the 41 subjects in the CLL cohort showed 
entospletinib treatment to be generally well tolerated. Treatment emergent AEs with an incidence 
over 15% in the study overall were as follows: fatigue, nausea, diarrhea, decreased appetite, 
constipation, cough, headache, dizziness, pyrexia, anemia, vomiting, dyspnea, and insomnia. The 
most frequently reported SAEs included dyspnea (4%), pneumonia (4%), febrile neutropenia 
(3%), dehydration (3%), and pyrexia (2%).
The ongoing Phase 1b GS-US-401-1757 study is evaluating the safety and tolerability of the 
combination of entospletinib with tirabrutinib and provides the primary supportive data for this 
Phase 2 study. The preliminary safety results from this study are summarized in the dose 
rationale Section 1.5.1.
1.3.
Tirabrutinib
1.3.1.
General Information
Tirabrutinib (also known as 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.
1.3.2.
BTK in 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 

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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 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, diffuse large B-cell lymphoma [DLBCL], mantle cell 
lymphoma [MCL], and lymphocytic lymphoma/Waldenstrom’s macroglobulinemia [WM]). A 
first-in-class BTK inhibitor, ibrutinib (Imbruvica®), has demonstrated clinical benefit to subjects
with CLL, MCL, and WM {Pharmacyclics Inc. 2015}. Additionally, transient clinical responses 
were observed in a pilot study of relapsed DLBCL, primarily in the non-GCB subtype {Wilson 
2012}.

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Figure 1-1.
Inhibition of the BCR Pathway
Adapted from {Herrera 2014}
1.3.3.
Nonclinical Pharmacology and Toxicology of Tirabrutinib
Please refer to the tirabrutinib IB for information regarding the nonclinical pharmacology, 
absorption, distribution, metabolism, and elimination (ADME) and nonclinical toxicity of 
tirabrutinib.
1.3.4.
Clinical Trials of Tirabrutinib
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 {Walter 2015}. This study 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 
GS-40$9 
,entosphttinib 
act~ loo 

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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. For CLL patients, the most common AEs were contusion, neutropenia, anemia, and 
nasopharyngitis and the most frequent AEs attributed to tirabrutinib were hematoma, macule, dry 
skin, neutropenia, pruritus, diarrhea and contusion. The most frequent ≥ Grade 3 AEs were 
neutropenia, anemia, thrombocytopenia, and lower respiratory tract infection.
All subjects continuing on tirabrutinib treatment have been transitioned to the GS-US-401-1787 
continuation study; as of 01 June 2016, 27 subjects (18 with CLL) are continuing on treatment 
with tirabrutinib doses ranging from 80 to 600 mg once daily.
Study ONO-4059-01 is an ongoing open-label, multi-center, non-randomized Phase 1 
dose-escalation study of tirabrutinib monotherapy in Japanese subjects with relapsed/refractory 
B-NHL and CLL. This study utilizes a 3+3 design with dose levels ranging from 160 to 600 mg
daily. As of 05 May 2016, 17 subjects had enrolled. The only AEs attributable to study drug 
were Mallory-Weiss syndrome (1), HBV reactivation (1), and pneumonitis (1; subject had 
pre-existing organizing pneumonia). All subjects resumed treatment with lower doses of study 
drug. Rash, anemia, lymphopenia, hypophosphatemia, hypokalemia and emesis were the only 
AEs reported in more than 1 subject (n=2 for all except n=5 for rash).
Study GS-US-401-1767 is 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 PPI, omeprazole, in healthy subjects. PK data from this 
study show no difference in plasma exposure (Cmax and AUC) of tirabrutinib between the capsule 
formulation and the low and high drug load (10% and 33% w/w, respectively) 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 no clinically relevant 
effect of food (high-fat meal) on the PK of a single 100-mg dose of tirabrutinib administered as 
the low and high drug load formulation tablets; as such, tirabrutinib tablets may be administered 
without regard to food. There was no clinically relevant effect of multiple doses of omeprazole 
on the PK of a single 100-mg dose of tirabrutinib administered as the low drug load formulation 
tablet and tirabrutinib tablets may be co-administered with PPIs such as omeprazole.
Study GS-US-401-1765 is an open-label, crossover, Phase 1 study to evaluate the effects of an 
OATP1B1/1B3 inhibitor, single dose rifampin, and a strong CYP3A4/p-gp inducer, multiple 
doses of rifampin, on the PK of tirabrutinib in healthy subjects. 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. Strong CYP3A4/P-gp inducers such as
rifampin have the potential to decrease efficacy by reducing exposure.

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Study GS-US-401-1768 is 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
with preliminary results showing extensive metabolism after oral administration by oxidation, 
reduction, hydrolysis, N-acetylation, sulfation, glutathione conjugation and glucuronidation.
Study GS-US-401-1757, an ongoing Phase 1b dose-escalation study of tirabrutinib in 
combination with other anti-cancer therapy, provides the primary supportive data for this Phase 2 
trial. This study used a 3+3 dose-escalation and dose-expansion design to establish a safe and 
well-tolerated dose of tirabrutinib in combination with entospletinib. Tirabrutinib administered at 
doses up to 160 mg once daily combined with entospletinib administered at doses up to 400 mg 
once daily has been well tolerated with no DLTs. Further safety results are discussed in the dose 
rationale Section 1.5.1.
For additional information, refer to the tirabrutinib IB.
1.4.
Obinutuzumab
Obinutuzumab (GA-101) 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.
The CLL11 study, led by Roche and the GCLLSG, compared the safety and efficacy of 
3 regimens: Chlorambucil vs. Rituximab + Chlorambucil (R/Chl) vs. Obinutuzumab (GA-101) + 
Chlorambucil (G/Chl) in previously untreated patients with CLL with either cumulative illness 
rating scale (CIRS) score >6 or CrCl <70 mL/min {Goede 2014}. The median age of subjects 
was 73 years. The results show superiority of G/Chl, with median PFS of 11, 16, and 27 months 
in Chl, R/Chl and G/Chl respectively. There was a statistically significant improvement in OS 
with G/Chl vs. Chl (hazard ratio for death of 0.41; 95% CI, 0.23 to 0.74; P = 0.002). The CR rate 
was 21% with G/Chl vs. 7% with R/Chl. MRD negativity in the marrow was achieved in 19.5% 
of G/Chl subjects vs. only 2.6% of those receiving R/Chl. Infusion-related reactions and 
neutropenia were more common with G/Chl than with R/Chl, 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 

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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.
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.
For further information on obinutuzumab, refer to the local prescribing information (PI).
1.5.
Rationale for This Study
Despite an increase in therapeutic options for CLL, few subjects are cured with current therapy. 
Small molecule targeted therapy for CLL avoids many of the toxicities of chemoimmunotherapy 
but requires chronic administration due to generally low CR rates. Novel regimens combining 
targeted therapy have the potential to improve CR rates, PFS and OS while limiting toxicity.
Tirabrutinib and entospletinib each show significant single-agent clinical activity in CLL. The 
addition of an anti-CD20 antibody to CLL therapy has an established benefit {Hallek 2010} with 
the potential superiority of obinutuzumab in comparison with rituximab {Goede 2014}.
Preliminary in vitro data from primary CLL samples have shown additive or synergistic growth 
inhibition when combining tirabrutinib and entospletinib, suggesting the possibility of improved 
depth of response with combination treatment. While single mutations in drug targets have been 
shown to be sufficient for resistance to 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 entospletinib in vitro had striking efficacy, supporting the possibility 
of improving efficacy with low toxicity.
As of June 7, 2017 10 subjects with CLL have been treated on Phase 1b Study GS-US-401-1757 
with the combination of tirabrutinib and entospletinib with a median exposure of 43 weeks 
(range: 18-55). All 10 subjects continue on study and treatment at this time; however no CLL 
subjects have achieved a CR. Given the lack of CRs in the ongoing treatment experience with the 
combination of tirabrutinib and entospletinib, enrollment into the doublet combination of 
tirabrutinib and entospletinib was discontinued with Amendment 3. Arm B continued enrollment 
as the safety and preliminary efficacy of the combination with the addition of obinutuzumab 
retains the potential to be safe and achieve a high rate of deep response.
1.5.1.
Rationale for Dose Selection
This Phase 2 study will evaluate the efficacy and safety of the combination of tirabrutinib and 
entospletinib with and without obinutuzumab in subjects with relapsed or refractory CLL.
In the combination proposed for this study, the doses of both tirabrutinib and entospletinib have 
been reduced from the maximal safe doses previously used as single agent therapy. Prior 
single-agent dose-ranging with tirabrutinib in the ONO-4059POE001/GS-US-401-1787 study

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did not identify a MTD in subjects with CLL at doses up to tirabrutinib 600 mg daily. Similarly, 
there was no MTD identified for entospletinib as monotherapy in subjects with CLL at doses up 
to 400 mg twice daily. The tirabrutinib dose of 80 mg once daily used in this study is 
approximately 13% of highest safe single-agent dose in ONO-4059POE001; the entospletinib 
dose of 400 mg once daily represents a 50% reduction from that used in Phase 2 monotherapy 
treatment for CLL in the GS-US-339-0102 study. The combination of tirabrutinib 80 mg once 
daily and entospletinib 400 mg once daily was shown to be safe and tolerable in the Phase 1b 
GS-US-401-1757 study.
Based on data as of 22 July 2016, the median time on treatment with tirabrutinib and 
entospletinib in the GS-US-401-1757 study was 114 days (range: 29-239) in 17 subjects with 
lymphoid malignancies, of whom 3 had CLL. Two subjects reported a Grade 3 or 4 AE that was 
attributed by the investigator to be related to treatment. One subject with DLBCL at the 
tirabrutinib 150 mg/entospletinib 200 mg dose level experienced Grade 4 hyperglycemia; the 
subject remained on therapy throughout with standard-of-care management. One subject with 
WM at the tirabrutinib 40 mg/entospletinib 400 mg dose level developed Grade 3 neutropenia 
that resolved with conservative management within 2 weeks while remaining on treatment.
Three subjects reported an SAE on study. One subject with WM at the tirabrutinib
40 mg/entospletinib 200 mg dose level reported an SAE of pneumonia that did not necessitate
interruption of treatment. One subject with FL at the tirabrutinib 80 mg/entospletinib 200 mg 
dose level had pyrexia and atrial fibrillation in the context of a pneumonia requiring 
hospitalization for management. One subject with DLBCL at the tirabrutinib 80 mg/entospletinib 
400 mg dose level reported hematemesis in the 30-day window following treatment 
discontinuation due to progressive disease.
Data from both the single-agent treatment experience and the combination Phase 1b 
GS-US-401-1757 study support the potential efficacy of the combination of tirabrutinib 80 mg
once daily and entospletinib 400 mg once daily.
Preliminary BTK occupancy data in peripheral blood mononuclear cells demonstrates no 
detectable free BTK at tirabrutinib doses of 40 mg once daily and higher. At doses of tirabrutinib
≥80 mg daily in the ONO-4059POE001 single-agent dose escalation study with tirabrutinib, 20 
of 21 evaluable subjects with CLL had at least a PR; at a tirabrutinib dose of 20 mg or 40 mg, 2/3 
subjects at each dose level had a PR or better. Entospletinib demonstrates 40% inhibition of 
B-cell receptor pathway activation with a dose of 400 mg daily. In the combination Phase 1b 
GS-US-401-1757 study, 8 subjects treated with tirabrutinib and entospletinib are evaluable for 
response across dose levels, of whom, 4 have had a best response of a PR.
Obinutuzumab will be used at the approved 1000 mg dose and schedule. The safety of the 
addition of obinutuzumab to the combination of tirabrutinib 80 mg daily and entospletinib 
400 mg once daily will be initially evaluated in the safety run-in before additional subjects are 
enrolled.

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1.6.
Risk/Benefit Assessment for the Study
Tirabrutinib
In the completed single-agent Phase 1 study ONO-4059POE001, 28 subjects with 
relapsed/refractory CLL were treated with 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, 
respectively, was observed in 20% and 4% of study participants. No Grade 3 or higher diarrhea 
attributed to tirabrutinib by the investigator has been reported as of October 2015. Bruising was 
observed frequently; however, 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%).
Entospletinib
Entospletinib has been well tolerated across the 16 clinical studies in which it has been
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. The safety profile for subjects with CLL treated with entospletinib 
is described in Section 1.2.4.
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.
Obinutuzumab
Obinutuzumab (Gazyva®/Gazyvaro®) is an anti-CD20 mAb which is approved in the US and EU 
for use in combination with chlorambucil for the treatment of patients with previously untreated 
CLL. The safety reference documents for obinutuzumab will be the Summary of Product 
Characteristics (SmPC). Please refer to the SmPC for further information.

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In a Phase 3 trial, patients were treated with chlorambucil alone, GAZYVARO in combination 
with chlorambucil, or rituximab product in combination with chlorambucil. The Stage 1 analysis 
compared GAZYVARO in combination with chlorambucil vs. chlorambucil alone, and Stage 2 
compared GAZYVARO in combination with chlorambucil vs. rituximab product in combination 
with chlorambucil.
The most common Grade 3 to 4 adverse reactions (incidence ≥10%) observed in patients with 
CLL in the GAZYVARO containing arm of clinical trials were neutropenia, infusion reactions, 
and thrombocytopenia.
The most common adverse reactions (incidence ≥10%) observed in patients with CLL in the 
GAZYVARO containing arm were infusion reactions, neutropenia, thrombocytopenia, anemia, 
pyrexia, cough, nausea, and diarrhea.
The most common adverse reactions (incidence ≥10%) observed in patients with CLL in the 
GAZYVARO containing arm were infusion related reactions, neutropenia, thrombocytopenia, 
anemia, pyrexia, cough, nausea, and diarrhea.
The most common obinutuzumab-related events are infusion-related reactions and tumor lysis 
syndrome, most commonly during the initial administration, hypersensitivity (immediate or 
delayed onset), and worsening of pre-existing cardiac conditions. 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 this protocol. To reduce the incidence 
and severity of obinutuzumab-related infusion reactions, established premedication regimens and 
infusion modification algorithms have been included (Section 5.3.2). To mitigate the risk of 
Pneumocystis jirovecii pneumonia, antibiotic prophylaxis is mandated unless medically 
contraindicated.
To mitigate the risk of HBV reactivation in subjects treated with an anti-CD20 antibody, 
hepatitis B virus screening will be performed. Subjects who are hepatitis B core antibody 
positive at screening may be enrolled only if the plasma DNA PCR test is negative, and will be 
monitored for potential HBV reactivation (manifested as detectable HBV DNA by quantitative 
PCR). Subjects will be tested monthly for the duration of CD20 therapy and every 3 months 
thereafter for 1 year from the last dose of CD20 during study participation. 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 therapy
Although new toxicities due to the combination of agents remains a possibility, the safety and 
tolerability of tirabrutinib combined with entospletinib has been previously evaluated in Study
GS-US-401-1757. Entospletinib 400 mg once daily does not increase the exposure of tirabrutinib
significantly based on preliminary PK data from this study.

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The safety of the combination of tirabrutinib 80 mg once daily and entospletinib 400 mg once
daily will be further evaluated in this Phase 2 study through a review of the safety data for the 
initial 6 subjects treated with the combination through 28 days of therapy prior to the enrollment 
of additional subjects. Similarly, the safety of the addition of obinutuzumab to the combination 
of tirabrutinib and entospletinib will be evaluated through a review of the safety data for the 
initial 6 subjects treated through 28 days of therapy prior to the enrollment of additional subjects 
on this treatment arm. Study visits including laboratory monitoring will occur weekly for the first 
28 days of treatment for close monitoring. Following evaluation of the safety data for the first 
6 subjects in each treatment arm, the SRT will determine if weekly visits for the first 28 days 
should continue or may be reduced in frequency for the remainder of subjects enrolled in the 
study.
Benefits from combination therapy include the potential to achieve higher rates of response and 
improve DOR and the potential for reduced toxicity with increased efficacy by the use of lower 
individual study drug doses in combination.
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 objective of this study is:

To determine the preliminary efficacy of the combination of tirabrutinib and entospletinib
with obinutuzumab in subjects with relapsed or refractory CLL
The secondary objective of this study is:

To evaluate the safety and tolerability of the combination of tirabrutinib and entospletinib
with and without obinutuzumab
The exploratory objectives of this study are:
 
 
CCII 
I 

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3.
STUDY DESIGN
3.1.
Study Design
This is a Phase 2, prospective, open-label, multicenter trial to evaluate the safety and efficacy of 
the combination of tirabrutinib (GS-4059) and entospletinib with and without obinutuzumab in 
subjects with relapsed or refractory CLL.
3.2.
Study Treatments
Combination therapy of tirabrutinib (BTK inhibitor) 80 mg once daily and entospletinib 
(SYK inhibitor) 400 mg once daily with and without obinutuzumab will be evaluated for 
efficacy, safety, and tolerability.
Eligible subjects will be treated with the combination of tirabrutinib and entospletinib and
stratified by the presence of del17p/TP53mut in CLL cells. Following stratification, subjects will 
be randomized 1:1 to treatment with the combination of tirabrutinib and entospletinib with or 
without obinutuzumab.
Study Design Schema
Screening 
ArmA 
N = 30 
Arm8 
N =30 
<»-4059 
Ent ospletrnib 
1:1 Randomization 
<»-4059 
Entospletinib 
Obinutuzurnab 
Obinut uzumab: 21 w eeks 
Week25 
G.s--4059 + Ent osplet inib: Up t o 104 w eeks 
Total Du rat ion: 5 years 
EOT 
Post-Treatment 
On-Study 
Scheduled Assessments 
EOS 

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With Amendment 3, randomization was discontinued. All subsequently enrolled subjects entered 
Arm B (tirabrutinib + entospletinib + obinutuzumab).
With Amendment 4, the Post Treatment period will no longer be applicable.
Enrollment will be temporarily paused following enrollment of the first 6 subjects into Arm B, 
who will be observed for safety for 28 days following the first dose of study treatment including 
weekly evaluation through that period. Additional subjects may be enrolled into the safety cohort 
if any of the first 6 subjects in Arm B discontinue therapy during the initial 28 days for reasons 
unrelated to toxicity. A Safety Review Team (SRT) will review 28-day safety data from the first 
6 subjects in Arm B and determine whether enrollment may resume and if weekly clinical 
evaluation through the first 28 days should continue or may be reduced in frequency for the 
remainder of subjects enrolled in the study.
Oblnucuzumab 
oblrwbii11mab: ;n w• 
GS-4059 
Entospletlnlb 
Gs-4059 
IEnto1pletlnlb, 
Oblnutuzumab 
WHU'S 
Oblnutuwm 'b: 21 weaks 
Weakl:5 
GS ,059 + Ent05pletlrr1lb/ lcil 'lallsib: Up t,o 104 weeks 
EOT 
Post-Trotme11t 
0 ~ 
E-0S, 
SCMdultdAs-
EOT 

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The SRT will consist of at least one investigator from the GCLLSG and Gilead Sciences, Inc. 
(Gilead) study team members including but not limited to: the medical monitor, representatives 
from Pharmacovigilance and Epidemiology (PVE), and Biostatistics.
The safety review will include the assessment of the following:

Grade ≥ 4 hematological toxicities persisting for > 7 days

Grade ≥ 4 non-hematologic laboratory abnormalities except for asymptomatic AST/ALT 
elevation, LDH, or uric acid

Grade ≥ 3 non-hematological toxicities (except for alopecia or the following that resolve 
within 72 hours with medical intervention: tumor lysis, nausea, vomiting, diarrhea, or 
constipation)

Grade ≥ 2 non-hematologic treatment-emergent adverse events (TEAE) that in the opinion of 
the investigator are of potential clinical significance such that further dosing would expose 
subjects to unacceptable risk
Criteria for termination of the study are:
1) An unacceptable safety profile or incidence of AEs or SAEs revealed in this or any other 
study in which the combination of agents is administered
2) Any other factor that in the view of the sponsor constitutes an adequate reason for 
terminating the study 
As agreed with the German Federal Institute for Drugs and Medical Devices Agency (BfArM), a
safety report including the cumulative safety results and summary of the conclusion of the SRT 
following assessment of the safety cohort was submitted to BfArM shortly after the assessment.
The study steering committee, including representatives from the GCLLSG and Gilead, will 
review ongoing safety data at least quarterly throughout the treatment period and regularly for 
the complete duration of the study.
3.3.
Duration of Treatment
Obinutuzumab will be administered for up to 8 doses over 21 weeks to subjects randomized or 
enrolled to Arm B (tirabrutinib + entospletinib + obinutuzumab). Combination treatment with the 
oral agents (tirabrutinib and entospletinib) will continue for all subjects for up to 104 weeks in 
the absence of disease progression, unacceptable toxicity, or documentation of CR/BM MRD-. If 
CR/BM MRD- is documented on study, treatment will stop after the earlier of:
1) an additional 3 months of therapy or
2) 104 weeks of total treatment

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3.4.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Documented progression of CLL

Non-study treatment for CLL

Development of malignant disease requiring systemic therapy

Pregnancy

Investigator discretion

Non-compliance with study treatment

Severe protocol violation

Subject request to discontinue for any reason

Lost to follow-up

Death

Study termination by the sponsor

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Unacceptable toxicity, as defined in the toxicity management section of the protocol 
(Section 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
3.5.
Duration of Study
This study will continue to monitor subjects for up to 30 days post end of treatment, or up to 
Week 25 should a subject discontinue treatment prior to Week 25 for reasons other than disease 
progression.
3.6.
Criteria for Discontinuation from Study
Subjects may be removed from the study for the following reasons:

Death

Investigator discretion

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
Withdrawal of consent

Study termination by the sponsor
3.7.
GCLLSG CLL Registry
Consenting subjects for inclusion in the GCLLSG registry is requested at screening or as close 
thereafter as possible.
3.8.
Post Study Care
At this time, there is no plan to provide post-study care to subjects who have participated in this 
study.

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4.
SUBJECT POPULATION
4.1.
Number of Subjects
The study will enroll approximately 36 subjects in total; 30 subjects in Arm B and approximately 
6 subjects in Arm A.
4.2.
Inclusion Criteria
Subjects must meet all the following criteria to be eligible for participation in this study:
1) Documentation of relapsed or refractory CLL
2) Have an indication for treatment per modified IWCLL 2008 criteria; subjects without
radiographically measureable disease (defined as ≥ 1 lesion > 1.5cm in diameter as assessed 
by CT or MRI) must have bone marrow evaluation at screening
3) Adequate hematologic function as indicated by a platelet count ≥50 x 109/L, a neutrophil 
count ≥ 1 x 109/L and a hemoglobin ≥8g/dL unless lower values are directly attributable to 
documented bone marrow burden of CLL
4) Adequate renal function as indicated by a CrCL ≥50 mL/min calculated by the modified 
Cockroft-Gault formula or from a 24h urine collection
5) Adequate liver function as indicated by total bilirubin ≤1.5x institutional upper limit of 
normal (ULN) unless attributed to Gilbert’s syndrome and AST/ALT ≤ 2.5xULN
6) Male or female ≥ 18 years of age
7) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
8) Absence of active HBV infection (serological testing within 6 weeks prior to randomization 
or enrollment with the following results: HBsAg negative AND anti-HBcAb negative, or if 
anti-HBcAb positive, HBV DNA PCR negative)
9) HCV Ab negative or if Ab positive, negative HCV RNA PCR within 6 weeks prior to 
randomization or enrollment
10) Negative testing for HIV within 6 weeks prior to randomization or enrollment
11) Satisfies the following criteria:
a) For female subjects of childbearing potential, willingness to abstain from sexual 
intercourse or use a protocol-specified method of contraception as described in 
Appendix 4
b) Male subjects of reproductive potential who engage in sexual intercourse must agree to 
use protocol-specified method(s) of contraception as described in Appendix 4

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12) Ability and willingness to provide written informed consent and adhere to protocol
requirements including study visit schedule, drug administration plan, imaging studies, 
laboratory testing, other study procedures and restrictions
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not eligible for participation in this 
study:
1) Known transformation of CLL (ie, Richter’s transformation, prolymphocytic leukemia)
2) Known CNS involvement
3) Progression on treatment with any inhibitor of BTK, SYK, PI3K, BCL-2, or obinutuzumab.
The treatment and disease response history of subjects with prior treatment with agents in 
these classes should be reviewed by the sponsor or the GCLLSG study office prior to 
enrollment to clarify sensitivity to these treatments.
4) Any treatment for CLL other than corticosteroids for symptomatic management within 
28 days of the start of study treatment
5) Participation in a concurrent therapeutic clinical trial unless all treatment is complete with 
only ongoing surveillance
6) Diagnosis of or concern for progressive multifocal leukoencephalopathy
7) History of myelodysplastic syndrome or another malignancy other than CLL, except for the 
following: any malignancy that has been in complete remission for 3 years, 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.
8) Active infection requiring systemic therapy
9) Pregnant or nursing women (a negative pregnancy test is required for all women of 
childbearing potential within 7 days before start of treatment and monthly during therapy)
10) Active autoimmune disease including autoimmune hemolytic anemia or idiopathic 
thrombocytopenic purpura requiring a higher corticosteroid equivalent than prednisone 
10 mg daily. Higher doses of corticosteroids prescribed for any indication must be stopped 
> 14 days prior to randomization or enrollment; exceptions may be made for corticosteroids 
prescribed specifically for management of CLL symptoms after discussion with the study 
medical monitor.
11) Diagnosis of inflammatory bowel disease or ongoing symptomatic pneumonitis

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12) History of stroke or intracranial hemorrhage within 12 months of randomization or 
enrollment; subjects requiring therapeutic anticoagulation for any indication should be 
discussed with the GCLLSG coordinating physician and/or medical monitor prior to
screening
13) Legal incapacity, prisoners or subjects institutionalized by regulatory or court order, or any 
individual in dependence to study sponsor or any investigator
14) Anticipated chronic use of strong CYP3A4/CYP2C9 inducers, moderate CYP2C9 inducers,
or a strong P-gp inducers while on study; use within 2 weeks of first dose of study treatment
should be avoided.
15) Requirement for PPI therapy
16) Demonstration of QTc interval > 450 milliseconds or requirement for ongoing treatment with 
concomitant medications that prolong the QT interval
17) Known hypersensitivity to obinutuzumab, entospletinib, tirabrutinib, or any of the excipients

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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization
It is the responsibility of the Investigator to ensure that subjects are eligible for the study prior to 
randomization or enrollment. Subjects will be assigned a unique screening number at the time of 
consent. A medical review of selected screening data will be performed by members of the 
GCLLSG to confirm eligibility and must be completed prior to randomization or enrollment.
Once eligibility is confirmed, subjects will be assigned a unique subject number from the 
interactive web response system (IWRS), randomized in a 1:1 ratio to treatment with the 
combination of tirabrutinib and entospletinib with and without obinutuzumab. The 
randomization will be stratified by the presence of del17p/TP53mut in CLL cells. Once a subject 
number is assigned to a subject, it will not be reassigned to another subject. This is an open-label 
study.
With Amendment 3, randomization of subjects will no longer be performed as only Arm B of the 
study will continue to enroll.
All Day 1 tests and procedures must be completed prior to the dispensation and administration of 
the first dose of study treatment on Week 1 Day 1.
5.2.
Description and Handling of Tirabrutinib, Entospletinib, and Obinutuzumab
5.2.1.
Tirabrutinib
5.2.1.1.
Formulation
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.

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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.
5.2.1.2.
Packaging and Labeling
Tirabrutinib tablets, 20 mg, 40 mg, and 80 mg, 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. Tirabrutinib shall be labeled to 
meet applicable requirements of the EU Guideline to Good Manufacturing Practice - Annex 13 
(Investigational Medicinal Products) and/or other local regulations.
5.2.1.3.
Storage and Handling
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. 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. Keep the bottle tightly closed to protect from moisture.
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.
Entospletinib
5.2.2.1.
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.

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5.2.2.2.
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.
Entospletinib to be distributed to centers in the EU shall be labeled to meet applicable 
requirements of the EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational 
Medicinal Products), and/or other local regulations.
5.2.2.3.
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). 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. Keep the bottle tightly closed to protect from moisture.
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.
5.2.3.
Obinutuzumab
5.2.3.1.
Formulation
Please refer to the Gazyvaro (obinutuzumab) SmPC.
5.2.3.2.
Packaging and Labeling
Commercially available product of obinutuzumab will be used for this study.
Obinutuzumab to be distributed to centers in the EU shall be labeled to meet applicable 
requirements of the EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational 
Medicinal Products), and/or other local regulations.
5.2.3.3.
Storage and Handling
Commercially available obinutuzumab will be used for this study. Further information regarding 
storage and handling are available in the Gazyvaro (obinutuzumab) SmPC.

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5.3.
Dosage and Administration of Tirabrutinib, Entospletinib, and 
Obinutuzumab
5.3.1.
Tirabrutinib and Entospletinib
Tirabrutinib and entospletinib will be provided by Gilead Sciences, Inc. Tirabrutinib tablets 
(4 x 20 mg, 2 x 40 mg, or 1 x 80 mg) and entospletinib tablets (2 x 200 mg) will be self-
administered orally once daily. Dosing with both agents will begin on Week 1 Day 1 of the study 
and thereafter at approximately the same time each day until end of treatment. Study drugs 
should be swallowed whole with water. Tirabrutinib may be administered without regard to food.
Subjects will be instructed to take entospletinib at least 1 hour before and at least 2 hours after a 
meal.
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. In this case, the subject should be instructed to wait and 
take the next dose at the regularly scheduled time.
5.3.2.
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]) 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 p.o. ≥ 30 min before starting the obinutuzumab 
infusion

Antihistamines including a H1-antagonist (eg, dimentindene 4 mg IV) and a H2-antagonist
(eg, ranitidine 50 mg IV) ≥ 30 min before starting the obinutuzumab infusion

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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) p.o. ≥ 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 
(ie, 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 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 (leukocyte 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 12 – 24 hours prior to initiation of treatment) and/or

rasburicase (Fasturtec®).
In addition, a close monitoring of serum chemistry, particularly creatinine, potassium and uric 
acid levels must 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 100 mg obinutuzumab 
administered at a fixed rate of 25 mg/hr over 4 hours. If the first 100 mg obinutuzumab is 
tolerated well and completed without interruptions or adjustments of infusion rate and it is 

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possible from an organizational and medical 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 should be started at a rate of 50 mg/hr in all patients and the infusion 
rate may be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 
400 mg/hr.
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/hr), subsequent infusions will be 
administered at an initial rate of 100 mg/hr. The infusion rate may be increased by 100 mg/hr
increments at 30-minute intervals, as tolerated, to a maximum rate of 400 mg/hr. 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.
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- (eg, dimetindene 4 mg IV) and a H2-antagonist (eg. rantidine 
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

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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/hr every 30 minutes to a maximum rate of 
400 mg/hr, except for the first administration of obinutuzumab. The first obinutuzumab 
administration (100 mg) may be re-started at half initial rate (12.5 mg/hr) upon complete 
resolution of symptoms; if this is tolerated well for an hour, the rate may be increased to a 
maximum of 25 mg/hr.
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.
For guidance on the management of infusion-related reactions (IRRs) see the following table:
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 (as described in Section 8.5.1)
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 AEs or intercurrent illness.
5.4.
Prior and Concomitant Medications
Subjects must not have previously progressed on treatment with inhibitors of BTK, SYK, PI3K, 
BCL-2 or obinutuzumab.

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Pneumocystis jirovecii pneumonia (PJP) prophylaxis is mandated unless medically 
contraindicated throughout the course of active treatment.
Strong CYP3A4/CYP2C9/P-gp inducers or moderate CYP2C9 inducers should be avoided 
within 2 weeks of study treatment initiation; if administration of such an agent is medically
needed after study initiation, this situation should be immediately discussed with the study 
medical monitor.
Subjects should not receive PPI therapy within 2 weeks of study treatment initiation; if 
administration of such an agent is required after study initiation, this situation should be 
immediately discussed with the study medical monitor.
Immunization with live or attenuated viral vaccines is not recommended while on treatment 
during this study.
5.4.1.
IVIg and G-CSF
Administration of IVIg or G-CSF is permitted per institutional standard of care.
5.4.2.
Prior and Concomitant Medications with Tirabrutinib
In vitro data indicate tirabrutinib is a substrate of CYP3A4 and P-gp. Co-administration of 
CYP3A4 inhibitors may increase tirabrutinib exposure. Preliminary PK data from study 
GS-US-401-1757 indicates tirabrutinib is not a sensitive CYP3A4 substrate. As such, 
co-administration of strong CYP3A4 inhibitors with study drug is allowed in this study, but 
caution should be exercised. Co-administration of the strong CYP3A4/P-gp inducer, rifampin, 
resulted in a significant decrease in tirabrutinib exposure (~70%). As such, potent CYP3A4/P-gp
inducers are prohibited while subjects are on study drug and should be avoided within 2 weeks 
prior to study drug administration. Examples of strong CYP3A4/P-gp inducers are provided in 
Table 5-1.
In vitro data indicate tirabrutinib has the potential to inhibit several CYPs and transporters. 
Therefore, tirabrutinib may affect the plasma concentrations of their substrates. Caution should 
be exercised when co-administering concomitant medications that are metabolized by CYP3A4/5 
and transported by OAT3, OATP1B1, MATE1, OCT1, OCT2, or P-gp.
5.4.3.
Prior and Concomitant Medications with Entospletinib
In vitro and in vivo data indicates that entospletinib is a substrate of CYP2C9 and CYP3A. In a 
study in healthy subjects, co-administration of the strong CYP3A4 / CYP2C9 inducer rifampin 
resulted in a significant decrease in entospletinib exposure (~70%). As such, co-administration of 
strong CYP3A and CYP2C9 inducers, and moderate CYP2C9 inducers are prohibited in this 
study. In addition, administration of strong CYP3A and CYP2C9 inducers and moderate 
CYP2C9 inducers should be avoided for 2 weeks prior to study drug administration. Caution 
should be exercised when co-administering drugs that are moderate/strong inhibitors of CYP2C9 
(eg. fluconazole, voriconazole or amiodarone) as they may increase entospletinib exposure.

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Studies in healthy volunteers have demonstrated a significant reduction in entospletinib exposure 
when proton pump inhibitors are co-administered. Therefore, proton pump inhibitors are 
prohibited in combination with entospletinib. Use of a proton pump inhibitor should be avoided 
for 1 week prior to study drug administration. H2 blockers and antacids will be allowed for use 
during the protocol.
Table 5-1.
Examples of Concomitant Medications Prohibited in this Study
Strong
Moderate
CYP3A/P-gp Inducer
carbamazepine, phenytoin, rifampin, St. 
John’s Wort, enzalutamide, rifabutin, 
phenobarbital, mitotane, avasimibe
Not prohibited
CYP2C9 Inducer
carbamazepine, rifampin, ritonavir, 
enzalutamide
Proton Pump Inhibitors
omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole
In vitro data indicates that entospletinib has the potential to inhibit several drug 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 co-administering 
medications that are transported by OATP1B1, OATP1B3, MATE1, P-gp and BCRP or 
metabolized by UGT1A1; dose adjustment or switching to an alternative medication may be 
necessary if clinically indicated.
In a study in healthy subjects, entospletinib 400 mg twice daily increased rosuvastatin exposure 
by approximately 3.8-fold. In reviewing the safety of subjects whom have received a statin with 
entospletinib there have been no reports of rhabdomyolysis or a different adverse event profile, 
but in the interest of caution, restrictions apply to the use of HMG-CoA reductase inhibitors with 
entospletinib in this study (Table 5-2).
Table 5-2.
Recommended dose limits for HMG-CoA reductase inhibitors
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

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5.4.4.
Prior and Concomitant Medications with 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 administration. 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.
5.4.4.1.
Tumor Lysis Syndrome
Subjects with a high tumor burden (WBC ≥ 25 x 109/L or bulky lymphadenopathy) must receive 
prophylaxis for tumor lysis syndrome (TLS) 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.
5.4.4.2.
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.
5.5.
Accountability for Tirabrutinib, Entospletinib, and Obinutuzumab
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug bottles and vials. This includes acknowledgement of receipt of each shipment of IMP 
(quantity and condition). All used and unused IMP bottles dispensed to subjects must be returned 
to the site.
Tirabrutinib, entospletinib, and obinutuzumab accountability records will be provided to each 
study site to:

Record the date received and quantity of IMP bottles and vials

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
Record the date, subject number, subject initials, and the quantity of IMP bottles and vials
dispensed

Record the date, quantity of used and unused IMP bottles returned, along with the initials of 
the person recording the information.
5.5.1.
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.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
The study steering committee, including representatives from the GCLLSG and Gilead, will 
meet at least monthly throughout the treatment period and regularly for the complete duration of 
the study to review ongoing safety data.
6.1.
Subject Enrollment, Randomization and Treatment Assignment
It is the responsibility of the Investigator to ensure that each subject is eligible for the study 
before randomization or enrollment. Please refer to Section 5.1 for details about randomization
and treatment assignment. With Amendment 3, all subsequent subjects will be enrolled in Arm 
B.
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).
6.2.1.
Informed Consent
All subjects must sign and date the most recent IEC approved informed consent form before any 
study procedures are performed. Optional procedures may require separate subject consent, 
either within the main informed consent form or on a separate informed consent form, per IEC 
requirements.
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.
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. History of smoking in the past 30 days and CIRS score should be determined at 
screening.

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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 
(EOT) will be a complete physical examination. Beginning at Week 1 Day 1, a modified 
physical examination will be performed to monitor for any changes (lymph nodes, size of liver 
and spleen, lung, cardiac, abdomen, skin, neurologic, and any other systems, as clinically 
indicated). Physical examination findings will either be reported as medical history or AEs based 
on the requirements in Section 7.
Weight should be measured with each physical examination.
Height will be measured at Screening only.
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. Only the screening 
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.
6.2.5.
ECOG Performance Status/B-Symptoms
ECOG PS and B-Symptoms 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 5.
6.2.6.
12-lead ECG
A 12-lead ECG will be obtained at the time points listed in the Study Procedures Table 
(Appendix 2).
6.2.7.
Binet and Rai Staging
Binet and Rai staging will be assessed at the time points listed in the Study Procedures Table 
(Appendix 2). CLL staging will be evaluated using the table in Appendix 9.
6.2.8.
Geriatric assessment
The G8 geriatric screening tool (Appendix 10) will be used for assessment for subjects aged 
> 70 years as outlined in the Study Procedures Table (Appendix 2).

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6.2.9.
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.
6.2.10.
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: AEs related to protocol-mandated 
procedures, and all SAEs.
Any AEs reported after informed consent is obtained and throughout the study will be recorded 
on the eCRF with appropriate source documentation. Please refer to Appendix 3 for CTCAE 
grading criteria.
Please refer to Section 7 for additional information on AE reporting.
6.2.11.
Radiology Assessment
The radiology assessment in this study is consistent with the European Society for Medical 
Oncology (ESMO) clinical practice guidelines for CLL {Eichhorst 2015}. Imaging of the neck, 
chest, abdomen and pelvis by CT scan (preferred) or MRI will be performed at screening. Scans
already completed up to 42 days prior to the first dose of treatment may be used for the screening 
assessment. One additional radiologic evaluation is specified per protocol, at the Week 25 visit, 
with evaluation of areas affected by CLL during the screening evaluation. During the treatment 
phase, if an improvement in clinical response is noted following the Week 25 assessment or if 
disease progression is suspected, additional scans may be performed as clinically indicated. 
Scans should continue to be performed at Week 25 for subjects who stop study treatment but did 
not have disease progression (e.g. experienced unexpected toxicity) unless radiographic 
progression is previously documented or unless the subject starts on subsequent therapy for CLL.
6.2.12.
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 volume of blood phlebotomized will be roughly 100 mL at 
Screening and subsequently is not to exceed 200 mL every 3 months. The date and time of 
previous tirabrutinib and entospletinib administration, and whether the dose was taken with or 

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without food, will be recorded in the subject’s source documentation on days when blood for PK 
analysis is collected. The tests will be analyzed using standard procedures. All laboratory tests 
must be reviewed for clinical significance by the Investigator or qualified designee.
The analytes listed in Table 6-1 will be tested.
6.2.13.
Bone Marrow Assessment
For subjects without radiographic evidence of disease at screening, a bone marrow biopsy 
including aspirate is required within the screening window.
A bone marrow biopsy including aspirate is required at Week 25 for subjects who otherwise 
would meet criteria for a CR or complete remission with incomplete bone marrow recovery 
(CRi).
An additional bone marrow biopsy, including aspirate, may be obtained on protocol per 
investigator discretion following evidence of an improvement in clinical response.
Any bone marrow aspirate obtained should be sent for central MRD assessment, 
immunophenotyping, bio-banking, and follow-up research.
6.2.14.
Laboratory Samples to Address the Study Objectives
The biological specimens described herein will be collected in this study and will be used to 
evaluate the association of systemic and/or tissue specific biomarkers with study drug response 
including efficacy and/or AEs, as well as to increase knowledge and understanding of the 
biology of these and related diseases and possible companion diagnostics development. 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.
Specimens will be collected from all subjects. These samples will be destroyed and tested no 
later than the end of study, unless a subject consents to the optional future storage samples.
Biomarker testing will include but not limited to the following:
6.2.14.1.
Laboratory Samples

Assessment by fluorescence in situ hybridization (FISH) and mutation analysis of TP53 and 
IGHV will be performed from peripheral blood at Screening at the GCLLSG molecular 
cytogenetics reference laboratory in Ulm.

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
Immunophenotyping for confirmation of diagnosis as well as assessment of CD38 and 
ZAP70 and karyotyping will be performed from peripheral blood at Screening at the 
GCLLSG reference laboratory in Cologne.

MRD assessments of peripheral blood and bone marrow are to be performed at Week 1 
Day 1 and at intervals specified in Study Procedures Table (Appendix 2) on samples sent to 
the Durchflußzytometrisches Labor at the Hämatologielabor Kiel.

Pharmacodynamic activity of tirabrutinib and entospletinib may be assessed through 
proteomic analysis and rare cell analysis may be performed to detect resistant CLL clones.
 
 
 

Immune cell phenotyping may be performed to monitor changes in immune cell subsets over 
time.
6.2.15.
Samples for Optional Future Research
 
 
 
 
6.2.16.
Pregnancy Test for Females of Childbearing Potential
All female subjects of childbearing potential (as defined in Appendix 4) will have a serum 
pregnancy test at Screening and a urine pregnancy test prior to Week 1 Day 1 dosing and 
throughout the study as indicated in the Study Procedures Table (Appendix 2). The results must 
be confirmed as negative prior to continued administration of study drug.
6.2.17.
Pharmacokinetic Samples
A PK sample will be collected on Week 1 Day 1 at 2 (1) hours (inclusive) post-dose of
tirabrutinib and entospletinib. At the visits on Week 5, 13, and 21, a PK sample will be collected 
at pre-dose (within 2 hours prior to dosing) and 1 sample will be collected at 2 (1) hours 
(inclusive) post-dose of tirabrutinib and entospletinib. Subjects should be instructed to hold their 
dose of tirabrutinib and entospletinib on the morning of the visit at Weeks 5, 13, and 21 until 
after collection of the pre-dose PK sample.
CCI
CCI
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Plasma concentrations of tirabrutinib and entospletinib will be determined. Plasma 
concentrations of metabolites may be determined. Plasma protein binding of each analyte may be 
evaluated.
Table 6-1.
Blood and Urine Samples Collected During the Course of the Study
Serum Chemistry
Hematology
Other
Sodium
Potassium
Chloride
Glucose
Blood urea nitrogen or urea
Creatininea
ALT
AST
GGT
Cholesterol
Triglycerides
Uric Acid
Alkaline phosphatase
Total and direct bilirubin
Total protein
Albumin
Calcium
Magnesium
Phosphate
LDH
Amylase
Lipase
WBC
RBC
Hemoglobin
Hematocrit
Platelet Count
Neutrophils (ANC)
Lymphocytes
Monocytes
Basophils
Eosinophils
Reticulocytes
Tirabrutinib, entospletinib, plasma 
concentrations
Other metabolites of tirabrutinib and 
entospletinib may be measured
FISH/Karyotyping
TP53 Status
IGHV status
MRD
Immunophenotyping
Serum Beta2- Microglobulin
Serum Thymidine kinase
Blood Pharmacodynamic Biomarkers
CLL mutational and phenotypic 
analysis HBsAG
Hepatitis B core antibody
HBV DNA if HBVcAb+
Hepatitis C antibody
HCV PCR if HCVAb+
CMV IgG, IgM
HIV serology
Serum quantitative immunoglobulins
Coagulation
PT/INR
aPTT
Pregnancy Testing
Urinalysisb
Serum Qualitative -HCG (females)
Urine Pregnancy (females)
pH
Occult blood
Protein
Glucose
Ketones
Bilirubin
Urobilinogen
Nitrite
Leukocyte esterase
Microscopicb
WBC/High Power Field
RBC/High Power Field
a
Estimated creatinine clearance/glomerular filtration rate will be calculated based on the Cockroft-Gault formula
(see Appendix 8 for formula)
b
Dipstick will be used for Screening urinalysis: Microscopic evaluation to be performed only if the dipstick results are 
abnormal Note: Additional components, abnormal, and/or atypical cells should also be reported if present
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = 
blood urea nitrogen; CMV = cytomegalovirus; GGT = gamma-glutamyltransferase; INR = international normalized ratio; 
LDH = lactate dehydrogenase; PT = prothrombin time; RBC = red blood cell; WBC = white blood cell

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6.3.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 6.4 Criteria for Discontinuation of Study Treatment). If 
this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study. Long-term follow-up within the GCLLSG registry is recommended.
6.4.
Criteria for Discontinuation of Study Treatment
See Sections 3.4 and 3.6 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.
An interruption of tirabrutinib and/or entospletinib administration will be acceptable to allow for 
any reversal of toxicity of tirabrutinib and/or entospletinib. Unless the toxicity is deemed related 
to the subject’s underlying disease in the opinion of the investigator, subsequent treatment with 
the suspected offending agent should only be undertaken after reevaluation of the potential risk. 
If the toxicity is deemed to be related to one agent, resuming single-agent therapy with the other 
drug should be considered.
A subject who discontinues obinutuzumab for any reason other than progression should remain 
on study and may continue receiving the combination of tirabrutinib and entospletinib in 
accordance with the guidelines in Table 6-2 and Table 6-3.
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 entospletinib, a subject may continue to receive tirabrutinib and/or 
entospletinib at their assigned dose or at a lower dose (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.
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, and Table 6-3 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.

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Table 6-2.
Dose Adjustments, Withholding and Discontinuation Related to 
Entospletinib and/or Tirabrutinib
Entospletinib
Tirabrutinib
Starting dose
400 mg
80 mg
Dose level -1
200 mg
40 mg
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 ≤ 3 or baseline; 
consider G-CSF. Tirabrutinib and entospletinib may be reinitiated at the previous 
dose. If the toxicity recurs, decrease tirabrutinib or entospletinib by one dose level. If 
toxicity recurs and persists following a dose reduction in both tirabrutinib and 
entospletinib, discontinue tirabrutinib and/or entospletinib.
Thrombocytopenia
Grade 3 Thrombocytopenia
In the absence of symptomatic 
bleeding, maintain current dose level
and schedule. With bleeding, withhold 
entospletinib until Grade ≤ 2.
In the absence of symptomatic bleeding,
maintain current dose level and schedule.
With bleeding, withhold tirabrutinib until 
Grade ≤ 2.
Grade 4 Thrombocytopenia
Withhold tirabrutinib and entospletinib until resolved to Grade ≤ 2 or baseline. 
Tirabrutinib and entospletinib may be reinitiated at the previous dose. If the toxicity 
recurs, decrease tirabrutinib or entospletinib by one dose level. If toxicity persists or 
recurs following a dose reduction in both tirabrutinib and entospletinib, discontinue 
tirabrutinib and/or entospletinib.
NON-HEMATOLOGICAL ADVERSE EVENTS
Dermatological
Grade ≤ 2
Maintain current dose level and 
schedule.
Maintain current dose level and schedule.
Grade 3 or 4
Withhold study treatment until resolved to Grade 1 or baseline. Tirabrutinib and 
entospletinib may be reinitiated at the previous dose. If the toxicity recurs, decrease 
tirabrutinib or entospletinib by one dose level. If toxicity persists or recurs following 
a dose reduction in both tirabrutinib and entospletinib, discontinue tirabrutinib
and/or entospletinib.
Diarrhea
Grade ≤ 1
Provide anti-diarrheal (eg, loperamide) and maintain current tirabrutinib and 
entospletinib dose level and schedule
Grade 2
Withhold tirabrutinib and entospletinib until resolved to Grade 1 or baseline. 
Tirabrutinib and entospletinib may be reinitiated at the previous dose. If the toxicity 
recurs, decrease tirabrutinib or entospletinib by one dose level. If toxicity persists or 
recurs following a dose reduction in both tirabrutinib and entospletinib, discontinue 
tirabrutinib and/or entospletinib.

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NCI CTCAE Grade
Recommendation
Entospletinib
Tirabrutinib
Grade 3 or 4
Withhold all study treatment until Grade ≤1. Consider anti-diarrheal (eg, 
loperamide) and/or anti-inflammatory (eg budesonide). Consider resuming with 
lower dose level of both tirabrutinib and/or entospletinib. If toxicity persists or 
recurs following dose reduction of both tirabrutinib and entospletinib, discontinue 
tirabrutinib and/or entospletinib.
Hepatic Adverse Events (elevations in ALT, AST or bilirubin)
Grade 1
(ALT/AST ≤3xULN)
(Bilirubin ≤1.5xULN)
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.
Grade 3
(ALT/AST > 5-20xULN)
(Bilirubin > 3-10xULN)
Withhold all study treatment. 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 or at lower 
dose level per investigator discretion. If bilirubin abnormality was Grade ≥ 3, discuss 
with medical monitor prior to resuming tirabrutinib or entospletinib.
Grade 4
(ALT/AST > 20xULN)
(Bilirubin > 10xULN)
Withhold all study treatment. 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 at previous or lower dose level and entospletinib at 
lower dose level. If bilirubin was Grade 4, discontinue tirabrutinib and entospletinib.
Pneumonitis 
Grade 1
Maintain current dose level and schedule. Consider Pneumocystis treatment.
Grade 2
Withhold all study treatment until Grade ≤ 1, consider systemic corticosteroids and
Pneumocystis treatment. Upon resolution discuss with medical monitor prior to 
study drug reinitiation.
Grade 3 or 4
Discontinue all study treatment, consider systemic corticosteroids. 
Progressive Multifocal Leukoencephalopathy (PML)
Any Grade
Discontinue all study treatment; refer subject to a neurologist for further evaluation 
(see Section 6.6.6).
Hypersensitivity
Any Grade
Consider interrupting or discontinuing tirabrutinib treatment (see Section 6.6.3).
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/or entospletinib at initial or lower dose level or discontinue
tirabrutinib and/or entospletinib at investigator discretion.
Grade 3
Withhold tirabrutinib and entospletinib until Grade ≤1 or baseline. May resume
tirabrutinib and/or entospletinib at lower dose level or discontinue tirabrutinib and/or 
entospletinib at investigator discretion.
Grade 4
Discontinue all study treatment. Discuss with medical monitor prior to reinitiation of 
any treatment.
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Table 6-3.
Dose Adjustment Guidelines for Subjects Receiving Obinutuzumab
NCI CTCAE Grade
Recommendation
Toxicity attributable to obinutuzumab
HEMATOLOGICAL ADVERSE EVENTS*
Neutropeniaa
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 all study treatment 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
Maintain current dose level and schedule.
Grade 4
Delay all study treatment until Grade 2 or baseline; 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
N/A
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.
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.
Hold all study medication for clinically significant bleeding (irrespective of platelet 
count) until it resolves.
NON-HEMATOLOGICAL ADVERSE EVENTS
Cutaneous
Grade 2
Maintain current dose level and schedule.
Grade 3 or 4
Delay all study treatment until Grade 1; thereafter, may resume at full dose or 
discontinue obinutuzumab at investigator discretion.
Gastrointestinal Inflammation/Diarrhea
Grade 1
Maintain current dose level and schedule.
Grade 2
Maintain current dose level and schedule.
Grade 3
Delay all study treatment until subject is sufficiently stable to receive further treatment; 
thereafter maintain full dose and schedule.
Grade 4
Delay all study treatment until subject is sufficiently stable to receive further treatment; 
thereafter maintain full dose and schedule or discontinue at investigator discretion.
Hepatic Adverse Events (elevations in ALT, AST, or bilirubin)
Grade 1
(ALT/AST3×ULN)
(Bilirubin1.5×ULN)
Maintain current dose level and schedule.

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NCI CTCAE Grade
Recommendation
Toxicity attributable to obinutuzumab
Grade 2
(ALT/AST>3-5×ULN)
(Bilirubin>1.5-3×ULN)
Maintain current dose level and schedule.
Grade 3
(ALT/AST>5-20×ULN)
(Bilirubin>3-10×ULN)
Delay all study treatment until subject is sufficiently stable to receive further treatment; 
thereafter maintain full dose and schedule.
Grade 4
(ALT/AST>20×ULN)
(Bilirubin>10×ULN)
Delay all study treatment until subject is sufficiently stable to receive further treatment; 
thereafter maintain full dose and schedule or discontinue at investigator discretion.
Pneumonitis
Grade 1
Maintain current dose level and schedule.
Grade 2
Delay obinutuzumab as necessary to ensure subject is sufficiently stable to receive 
further treatment; thereafter maintain full dose and schedule.
Grade 3
Discontinue all study treatment, consider systemic corticosteroids.
Progressive Multifocal Leukoencephalopathy (PML)
Any Grade
Discontinue all study treatment; refer subject to a neurologist for further evaluation (see 
Section 6.6.6).
Hypersensitivity
Any Grade
Stop the infusion and discontinue obinutuzumab treatment (see section 6.6.3)
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.
Grade 4
Delay all study treatment until subject is sufficiently stable to receive further treatment. 
Discuss with medical monitor prior to reinitiation of treatment or discontinue treatment 
at investigator discretion.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST= aspartate aminotransferase, 
ANC=absolute neutrophil count, CTCAE=Common Terminology Criteria for Adverse Events, G-CSF=granulocyte
colony-stimulating factor, NCI=National Cancer Institute, ULN=upper limit of normal
a
Neutropenia and thrombocytopenia should not necessarily lead to delay in dosing of study treatment if it is believed that the 
cytopenia is due to CLL, and not to the treatment(s).

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6.6.
Recommendations for Evaluation, Intervention, and Drug Discontinuation 
for Specific Adverse Events or Conditions
6.6.1.
Hemorrhage
Bleeding events have occurred in subjects with relapsed/refractory chronic lymphocytic 
leukemia (CLL) and relapsed/refractory non-Hodgkin’s lymphoma (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.
6.6.2.
Infectious Events
Subjects with lymphoid cancers receiving tirabrutinib or obinutuzumab have developed serious 
and fatal infections during therapy. Monitor subjects for fever and infections and treat 
appropriately. Therapy should not be initiated in the context of an active infection.
6.6.3.
Dermatological and Hypersensitivity Events
Subjects receiving entospletinib or tirabrutinib 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 treatment should be interrupted. Resumption of study 
treatment should be considered once rash resolves.
Hypersensitivity symptoms can occur after previous exposure and very rarely with the first 
infusion of obinutuzumab. If a hypersensitivity reaction is suspected during or after an infusion, 
the infusion must be stopped and treatment permanently discontinued. Patients with known 
hypersensitivity to obinutuzumab must not be treated. Subjects receiving obinutuzumab may also 
experience hypersensitivity reactions with immediate (e.g. anaphylaxis) and delayed onset (e.g. 
serum sickness); these may be difficult to distinguish from infusion related reactions. 
If a hypersensitivity reaction is suspected during or after an obinutuzumab infusion, the infusion 
must be stopped and treatment permanently discontinued. If patients experience a 
hypersensitivity reaction whilst on tirabrutinib, consideration should be given to interruption or 
discontinuation.

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6.6.4.
Hepatic Events
Transaminase Elevations: Reversible asymptomatic ALT/AST increases have been observed 
with entospletinib in subjects with hematologic malignancies. Successful rechallenge after 
resolution at either the same or lower dose level of entospletinib has been achieved in the 
majority of subjects. Close monitoring of hepatic laboratory tests during therapy is important to 
allow for appropriate treatment interruption and reinstitution.
HBV Reactivation: HBV reactivation can occur with treatment, most commonly in patients 
treated with obinutuzumab. The risk is very low among patients with negative anti-HBc serology
and/or undetectable HBV DNA as assessed by quantitative PCR. Although some subjects who 
are HBc antibody positive with negative PCR may have had passive transfer of antibody from 
intravenous IgG, it cannot be known for certain that any such subject did not have natural HBV 
infection. Therefore, all subjects who are HBc antibody positive at screening will be monitored 
for potential HBV reactivation (manifest as detectable HBV DNA by quantitative PCR).
Surveillance of subjects who test positive for HBc antibody for HBV reaction will be performed 
according to the Study Procedures Table (Appendix 2). If there is evidence of HBV reactivation 
immediately stop study treatment and start appropriate treatment for HBV. In the event of HBV 
reactivation, please contact the Medical Monitor prior to re-initiation of study treatment.
6.6.5.
Hematological Events
Treatment-emergent Grade 3 or 4 neutropenia events including those accompanied by fever or 
infection have occurred in subjects treated with entospletinib.Neutropenia and anemia have also 
occurred in subjects treated with tirabrutinib. The anemia in subjects treated with tirabrutinib has 
generally been self-limiting, without the requirement for intervention and with improvement on 
continued therapy.
Management of neutropenia, including administration of G-CSF should be per established 
clinical guidelines and institutional standard of care.
6.6.6.
Progressive Multifocal Leukoencephalopathy (PML)
PML has been reported in patients treated with obinutuzumab and should be considered in any 
patient presenting with new-onset or changes to pre-existing neurologic manifestations. Therapy 
with all medications should be withheld during investigation of potential PML and permanently 
discontinued in case of confirmed PML. The subject should be referred to a neurologist for the 
evaluation and treatment of PML with evaluation including, but not limited to, brain MRI and 
lumbar puncture with cerebrospinal fluid testing (include testing for John Cunningham viral 
DNA).
6.6.7.
Further Safety Information
Further safety information regarding the study drug may be found in the Investigator’s Brochures
for entospletinib and tirabrutinib and the current product labeling for obinutuzumab.

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6.7.
End of Treatment
The EOT visit should be scheduled for 30 days following discontinuation of all study treatment 
to satisfy the requirement for a 30-day post-treatment safety assessment. Please consider 
enrollment of subjects at EOT in the non-interventional GCLLSG CLL registry for subjects that 
did not enroll at screening.
For subjects that permanently discontinue all study treatments prior to the Week 25 visit without 
experiencing disease progression, the Week 25 Day 1 visit should be performed on schedule per 
the Study Procedures Table (Appendix 2).
6.8.
Unscheduled Procedures
Unscheduled procedures will be recorded on the applicable eCRFs.
6.9.
Post Study Care
At this time there is no plan to provide post-study care to subjects who have participated on 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, overdose, drug abuse/misuse reports, or occupational 
exposure. Preexisting events that increase in severity or change in nature during or as a 
consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an 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 (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae

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 
eCRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
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 (e.g., 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 (e.g., 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).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator 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 sub-investigator 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 (e.g., 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.

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The relationship to study procedures (e.g., 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, (e.g.., venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be recorded and graded according to the NCI CTCAE, Version 4.03, 
published 14 June 2010.
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 intensity of the AE. For purposes of consistency with the CTCAE, 
these intensity grades are defined in Table 7-1.
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 eCRF: adverse events related to protocol-mandated procedures, and all 
SAEs.

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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 occur after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required 30 day post treatment follow-up period, which concludes 
at the EOT visit, must be reported to the 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.
Investigators are not obligated to actively seek beyond the end of study; 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 
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:
Email: 

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.
PPD
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
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.
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 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.
Please refer to the current tirabrutinib or entospletinib IB and local obinutuzumab prescribing
information for information related to toxicity management. See Section 6.6 for more
information related to recommended dose modifications associated with toxicities.

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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
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead PVE using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to the eCRF completion guidelines for full instructions on the mechanism of pregnancy 
reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.

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A spontaneous abortion is always considered to be an SAE and will be reported as such.
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 or Gilead PVE using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead PVE.
Gilead PVE:
Fax:
Email: 
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications.
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form.
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to the eCRF completion guidelines for full instructions on the mechanism of special 
situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
PPD
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is:

To determine the preliminary efficacy of the combination of tirabrutinib and entospletinib
with obinutuzumab in subjects with relapsed or refractory CLL
The secondary objective of this study is:

To evaluate the safety and tolerability of the combination of tirabrutinib and entospletinib
with and without obinutuzumab
The exploratory objectives of this study are:
 
 
8.1.2.
Primary Endpoint
The primary endpoint is the rate of CR per modified IWCLL 2008 {Hallek 2008} criteria at 
Week 25
8.1.3.
Secondary Endpoints
The secondary endpoints of this study are:

Rate of CR/BM MRD- at Week 25

Rate of CR/PB MRD- at Week 25

ORR at Week 25 including CR, CRi, PR, and PR with lymphocytosis

Type, frequency, and severity of AEs and SAEs
8.1.4.
Exploratory Endpoints
CCI
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8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis is the Full Analysis Set (FAS), which is defined as 
all subjects randomized or enrolled into each study arm who received at least 1 dose of any study 
treatment. Following the ITT principle, subjects are analyzed according to the study treatment 
they are assigned to at randomization or enrollment.
The PP analysis set is defined as all randomized or enrolled subjects who received at least 1 dose 
of any study treatment and had disease assessment at baseline and at least 1 evaluable response 
assessment post baseline. This analysis set will be used in the supplementary analysis of 
response endpoints.
8.2.1.2.
Safety
The primary analysis set for safety analyses is the safety analysis set, which is defined as all 
randomized or enrolled subjects who received at least 1 dose of any study treatment, with study 
treatment assignment designated according to the actual treatment received.
CCII 
I 
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8.2.1.3.
Pharmacokinetics
The pharmacokinetic (PK) analysis set includes all subjects who received at least 1 dose of study 
treatment and had at least 1 non-missing post-dose concentration value for the corresponding 
analyte in plasma.
8.2.1.4.
Biomarkers
The biomarker analysis set consists of randomized or enrolled subjects who have at least 
1 evaluable biomarker sample in this study.
8.3.
Data Handling Conventions
By-subject listings will be presented for all randomized or enrolled subjects in the FAS and 
sorted by subject ID number, visit date, and time if applicable. Data collected on log forms, such 
as AEs, will be presented in chronological order within subject. Summary tables for continuous 
variables will contain the following statistics: N (number in population), n (number with data), 
mean, standard deviation, median, minimum, and maximum. Summary tables for categorical 
variables will include: N, n, and percentage.
The baseline value is generally defined as the last (most recent) pre-treatment value in safety 
analyses and the last (most recent) pre-randomization value for efficacy analyses. Data from all 
sites will be pooled for all analyses. If there is a significant degree of non-normality, analyses 
may be performed on log-transformed data, as appropriate.
In general, missing data will not be imputed. For response endpoints, if a subject is missing 
baseline or post baseline assessments, the subject will be treated as non-responders. For duration 
of response, PFS, OS and TTNT, if the outcome event is not observed, the data will be 
right-censored at the date of last adequate assessment. Methods for imputing partially missing 
dates and laboratory results beyond limit of quantification will be provided in the SAP.
8.4.
Demographic Data and Baseline Characteristics
Subject demographic variables (age, sex, race and ethnicity), baseline characteristics (including 
body weight, height, body mass index, and ECOG Performance Status) as well as baseline 
disease characteristics (including time since initial diagnosis, disease staging at study entry, 
cytogenetic risk group, refractory and relapse status) will be summarized descriptively by 
treatment arms and overall based on the FAS. Medical history and concomitant medication use 
will be summarized using safety analysis set.
In general, continuous variables will be summarized by sample size, mean, standard deviation, 
median, quartiles, minimum and maximum and categorical variables will be summarized by 
counts and percentages.

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8.5.
Efficacy Analysis
8.5.1.
Primary Endpoint
Tumor response will be based on investigator’s assessment according to the modified IWCLL 
2008 criteria (see Appendix 6).
Rate of CR will be calculated by treatment arms using the FAS. The 2-sided 90% exact 
confidence interval (CI) of CR will be estimated using the Clopper-Pearson method.
No inferential test will be performed. The goal of this analysis is to obtain preliminary estimates
of the CR rate.
In addition, the analysis of the primary endpoint will be performed using the PP analysis set.
8.5.2.
Secondary Endpoints
ORR and rate of CR/MRD- will be estimated for each arm and their associated 90% confidence 
intervals will be calculated using the exact method.
 
 
For subjects who have not experienced disease progression or death, their data for DOR and PFS 
will be censored on the date of the last available valid disease assessment. Detailed censoring 
rules will be described in the SAP.
8.6.
Safety Analysis
8.6.1.
Extent of Exposure
Treatment exposure and compliance will be summarized descriptively by treatment group based 
on safety analysis set. Summaries will include treatment duration, number of doses, average 
dose, dose modifications, and treatment adherence rate.
8.6.2.
Adverse Events
Clinical and laboratory adverse events (AEs) will be coded using the current version of Medical 
Dictionary for Regulatory Activities (MedDRA). The severity of AEs will be graded according 
to the NCI-CTCAE, Version 4.03. The relationship of the AE to the study treatment will be 
assessed by the investigator as related or unrelated.
All AEs will be listed. The focus of AE summarization will be on treatment-emergent AEs 
(TEAEs). A TEAE is defined as an AE that occurs or worsens in severity on or after the date of 
the first dose of study treatment but no later than 30 days after the last dose of study treatment.
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Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC
and PT) will be provided by treatment group:

All TEAEs

TEAEs of Grade 3 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

All treatment-emergent SAEs

All treatment-related SAEs

All AEs leading to premature discontinuation of study drug

All AEs leading to dose modification or temporary interruption of study drug

All SAEs leading to death (ie, outcome of death)
8.6.3.
Laboratory Evaluations
Safety laboratory results will be graded according to NCI-CTCAE Version 4.03. Summaries of 
laboratory data will be provided for the safety analysis set and will include data collected up to 
the last dose of study drug plus 30 days. The analysis will be based on values reported in 
conventional units.
Descriptive statistics will be provided by treatment groups for each safety laboratory test as 
follows:

Baseline values (defined as the last measurement obtained on or prior to the date/time of 
first dose of study drug)

Post baseline maximum value

Change from baseline to post baseline maximum value

Post baseline minimum value

Change from baseline to post baseline minimum value
In addition, treatment-emergent laboratory abnormalities will be summarized descriptively using 
number and percentages of subjects by treatment group for the following:

Grade 3 or 4 laboratory abnormalities

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
Shift from baseline in laboratory toxicity grade
Subjects will be categorized according to the most severe post baseline abnormality grade for a 
given lab test.
8.7.
Pharmacokinetic Analysis
Plasma concentrations will be listed and summarized using descriptive statistics (eg, sample size, 
arithmetic mean, geometric mean, % coefficient of variation, standard deviation, median, 
minimum, and maximum).
8.8.
Biomarker Analysis
Changes from baseline in biomarkers will be summarized descriptively. Data explorations may 
be performed to evaluate potential associations between biomarkers and subject characteristics or 
outcome measures.
8.9.
Sample Size
The primary goal of this study is to evaluate the efficacy of the combination of tirabrutinib and 
entospletinib with obinutuzumab in relapsed and refractory CLL. The primary endpoint for this 
study is the rate of CR at Week 25. The corresponding single-agent CR rate with BTK and SYK 
inhibitors in subjects with relapsed or refractory CLL is ≤5%. The 90% CI corresponding to 
different CR rates ranging from 20% to 60% for a sample size of 30 is provided in the table 
below. With a sample size of 30, the lower bound of the 90% CI of an observed CR rate of 20% 
or above will exclude 5%.
Table 8-1.
90% Confidence Intervals at Different CR Rates
Sample Size
CR Rate
90% Confidence Interval
using Clopper-Pearson Method
30
20%
(9.1%, 35.7%)
30
30%
(16.6%, 46.5%)
30
40%
(25.0%, 56.6%)
30
50%
(33.9%, 66.1%)
30
60%
(43.4%, 75.1%)
With Amendment 3, randomization was discontinued. All subsequently enrolled subjects will 
enter Arm B. A total of approximately 6 subjects in Arm A and 30 subjects in Arm B will be 
enrolled, thus the total sample size for the study will be approximately 36 subjects.
8.10.
External Data Monitoring Committee
No external independent Data Monitoring Committee is used in this study.

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8.11.
Endpoint Adjudication Committee
No independent endpoint adjudication committee is used in this study.

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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the EU 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 sub-investigators 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 
sub-investigator 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.
Independent Ethics Committee 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 IEC. The investigator will not begin any study subject activities until 
approval from the 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 IEC any modifications made to the protocol or any accompanying material to be provided to 
the subject after initial IEC approval, with the exception of those necessary to reduce immediate 
risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IEC-approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 

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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 IEC local 
requirements. The consent form will inform subjects about pharmacogenomic testing and sample 
retention, and their right to receive clinically relevant pharmacogenomic 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, 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, eCRF and query forms, IEC
and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

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
Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all 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.
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. eCRFs 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 

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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 (eg, data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files.
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors or to regulatory authority or health authority inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IEC in 
accordance with local requirements and receive documented IEC approval before modifications 
can be implemented.

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

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9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies) 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
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in pre-B lymphocytes and receptor-ligated B cells. Proc Natl Acad Sci U S A 
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Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE, et al. Addition of 
rituximab to fludarabine may prolong progression-free survival and overall 
survival in patients with previously untreated chronic lymphocytic leukemia: an 
updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. 
Blood 2005;105 (1):49-53.
Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF, et al. Assessment of 
fludarabine plus cyclophosphamide for patients with chronic lymphocytic 
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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.
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 
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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 
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1993;23 (12):3109-14.
Dighiero G, Hamblin TJ. Chronic lymphocytic leukaemia. Lancet 2008;371 (9617):1017-29.
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, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, et al. First-line 
chemoimmunotherapy with bendamustine and rituximab versus fludarabine, 
cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic 
leukaemia (CLL10): an international, open-label, randomised, phase 3, non-
inferiority trial. Lancet Oncol 2016;17 (7):928-42.

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Eichhorst B, Robak T, Montserrat E, Ghia P, Hillmen P, Hallek M, et al. Chronic lymphocytic 
leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol 2015;26 Suppl 5:v78-84.
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.
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.
Gribben JG, O'Brien S. Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 
2011;29 (5):544-50.
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.
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.
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. Proc Natl Acad Sci U S A 
2010;107 (29):13075-80.
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.

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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 Cancer Institute (NIH). SEER*Stat Databases: November 2015 Submission.  Available 
at: http://seer.cancer.gov/data/seerstat/nov2015/. Accessed on 23 August.  2016:
Pharmacyclics Inc., Janssen Biotech Inc. IMBRUVICA® (ibrutinib) capsules, for oral use. US 
Prescribing Information. Revised January 2015:
Rickert RC. New insights into pre-BCR and BCR signalling with relevance to B cell 
malignancies. Nature reviews 2013;13 (8):578-91.
Robak T, Dmoszynska A, Solal-Celigny P, Warzocha K, Loscertales J, Catalano J, et al. 
Rituximab plus fludarabine and cyclophosphamide prolongs progression-free 
survival compared with fludarabine and cyclophosphamide alone in previously 
treated chronic lymphocytic leukemia. J Clin Oncol 2010;28 (10):1756-65.
Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O, et al. Incidence of 
hematologic malignancies in Europe by morphologic subtype: results of the 
HAEMACARE project. Blood 2010;116 (19):3724-34.
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.
Stephens DM, Ruppert AS, Weirda WG, Jones JA, Woyach JA, Maddocks K, et al. Externally 
validated predictive clinical model for untreated del(17p13.1) chronic 
lymphocytic leukemia patients [Accepted Article]. Am J Hematol 2015.
Surveillance Epidemiology and End Results (SEER) Program. SEER Stat Fact Sheets: Chronic 
Lymphocytic Leukemia. Available at: 
http://seer.cancer.gov/statfacts/html/clyl.html. Accessed 12 May 2011.
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.
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.
Walter HS, Rule SA, Dyer MJ, Karlin L, Jones C, Cazin B, et al. A phase 1 clinical trial of the 
selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell 
malignancies. Blood 2015.

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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. 

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11.
APPENDICES
Appendix 1.
       Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 5.
Eastern Cooperative Oncology Group (ECOG) Performance Status
Appendix 6.
Modified IWCLL 2008 Response Criteria
Appendix 7.
Cumulative Illness Rating Scale (CIRS)
Appendix 8.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Appendix 9.
Binet and Rai Staging Systems for the Classification of CLL
Appendix 10.
The G8 Screening Questionnaire

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Appendix 2.
Study Procedures Table
Screening
24 Weeks
Week 
25 Day 
119
Week 
29 Day 
1
Every 
12 weeks 
starting 
Week 33 
until Week 
105
EOT17
Day 
-28
Week 
1
Day 1
Week 
2
Day 1
Week 
3 Day 
1
Week 
4 
Day 
116
Week 
5
Day 1
Week 
9
Day 1
Week 
13 Day 
1
Week 
17 Day 
1
Week 
21 Day 
1
Visit Window (days)
0
2
2
2
2
2
2
2
2
7
7
7
7
Informed Consent
X
Medical and Medication 
History1
X
Physical Examination2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance 
Status / B-symptoms
X
X
X
X
X
X
X
X
X
X
X
Binet/Rai Staging
X
G8 Geriatric Screening 
Tool3
X
X
X
X
12-lead ECG4
X
X
X
X
X
X
X
X
X
Adverse events/ 
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tirabrutinib + 
entospletinib 
Dispensing5
X
X
X
X
X
X
X
X
X
Tirabrutinib + 
entospletinib 
Accountability
X
X
X
X
X
X
X
X
X
Obinutuzumab 
Administration6
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Screening
24 Weeks
Week 
25 Day 
119
Week 
29 Day 
1
Every 
12 weeks 
starting 
Week 33 
until Week 
105
EOT17
Day 
-28
Week 
1
Day 1
Week 
2
Day 1
Week 
3 Day 
1
Week 
4 
Day 
116
Week 
5
Day 1
Week 
9
Day 1
Week 
13 Day 
1
Week 
17 Day 
1
Week 
21 Day 
1
Chemistry18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation (PT/INR, 
aPTT)
X
X
Peripheral Blood MRD7
X
X
X
X
X
Urinalysis and Urine 
Chemistry
X
Pregnancy Testing8
X
X
X
X
X
X
X
X
X
X
X
Viral Serologies9
X
PK sampling10
X
X
X
X
CLL phenotyping12
X
X
Radiographic Tumor 
evaluation13
X
X
Bone marrow 
evaluation14
X
X
Response Assessment15
X
X
X
X
X
X
X
X
X
1
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. History of smoking in the past 30 days and CIRS score should be determined at screening.
2
Screening and End of Treatment will be complete physical examinations. Beginning at Week 1 Day 1, a modified physical examination will be a performed to monitor for any 
changes (eg, lymph nodes, size of the liver and spleen, lung, cardiac, abdomen, skin, neurologic, and any system clinically indicated). Weight should be measured at each PE. 
Height should be measured at screening only.
3
The G8 screening questionnaire will be used for assessment of subjects aged > 70 years at Week 1 Day 1 and every 6 months until EOT.
4
Subjects should be resting quietly in supine position for 5 minutes prior to ECG collection. The Investigator or qualified designee will review all ECGs.
5
Study drug is not dispensed at the Week 105 visit.
CCI

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6
Obinutuzumab: 100 mg will be administered intravenously on Day 1 and 900 mg on either Day 1 or 2 (Week 1); then 1000 mg on Day 8 (Week 2), Day 15 (Week 3), and on 
Weeks 5, 9, 13, 17 and 21 for a total of 8 doses of 1000 mg over 21 weeks. If the 100 mg infusion on Day 1 is well tolerated, the remaining 900 mg (scheduled for Day 2) 
may be given on Day 1.
7
Peripheral blood MRD will be assessed on Day 1 of Weeks 1, 13, 25, 33, 45, 105, and EOT. EOT collection is not needed for subjects who complete the Week 105 visit.
8
Serum pregnancy test will be performed at screening for all women of childbearing potential (defined in Appendix 4). Urine pregnancy tests will be conducted prior to 
Week 1 Day 1 and then every 4 weeks until the EOT visit. Pregnancy kits may be provided for home testing. The results must be confirmed as negative prior to continued 
administration of study drug.
9
Hepatitis serology includes HBsAg, HBcAb, HCV Ab; patients with positive HBcAb and negative HBsAg should have HBV DNA PCR performed prior to treatment start to 
rule out occult infection, then monthly through 6 months and then at subsequent clinic visits for at least 1 year following the EOT visit. HIV testing and CMV IgG and IgM 
testing should be performed at screening.
10
A PK sample will be collected approximately 2 hours (± 1 hour) post-dose on Week 1, Day 1. On Day 1 of Weeks 5, 13, and 21 a PK sample will be drawn at pre-dose 
(within 2 hours prior to AM dosing) and at 2 hours (± 1 hour) post-dose.
 
12
CLL immunophenotyping, karyotyping and FISH, TP53 and IgHV mutation status, CD38 and ZAP70 expression will be evaluated from peripheral blood at screening. In the 
event of disease progression, only FISH and TP53 will be evaluated.
13
Tumor evaluation by CT scan (preferred) or MRI of neck, chest abdomen and pelvis will be performed at screening (unless scan was already completed up to 42 days prior to 
first dose). At the Week 25 visit, the same type of evaluation should be performed on those body regions which showed involvement by CLL at screening. An additional CT 
may be obtained on protocol per investigator discretion following evidence of an improvement in clinical response if the response assessment at the Week 25 visit is less than 
a complete response or in the event of suspected disease progression.
14
A bone marrow evaluation is required in the screening window for subjects without radiographic evidence of disease. Bone marrow aspirate and biopsy should be performed 
at Week 25 for subjects fulfilling clinical response criteria for complete remission (CR) or complete remission with incomplete bone marrow recovery (CRi) per the modified 
IWCLL 2008 criteria. MRD should be assessed from bone marrow aspirate at the reference laboratory in Kiel; 
 
 The analysis of the biopsy should be performed at the site´s local laboratory. An 
additional bone marrow biopsy may be obtained on protocol per investigator discretion following evidence of an improvement in clinical response if the response assessment 
at the Week 25 visit is less than a complete response.
15
Qualitative treatment response assessment based on physical exam, laboratory parameters and presence of B-symptoms should be performed every 4 weeks until Week 33 
Day 1 and then at all scheduled visits thereafter following the modified IWCLL 2008 criteria, with the exception of lymphadenopathy, hepatomegaly, splenomegaly, and bone 
marrow. Assessment of response per modified IWCLL 2008 criteria should also be recorded at the completion of 24 weeks on treatment and subsequent to any CT and/or 
bone marrow biopsy that is repeated while on study.
16
Following evaluation of the safety data for the first 6 subjects enrolled in each treatment arm, the Safety Review Team (SRT) will determine if weekly clinical evaluation 
should continue for the duration of the study.
17
The EOT visit should be scheduled for approximately 30 days following discontinuation of all study treatment. For subjects that permanently discontinue all treatment prior to
Week 25 Day 1, the Week 25 Day 1 visit should also be performed and may satisfy the requirement for the EOT visit if falling into the +30 days ± 7 day window from all 
study drug discontinuation.
18
Screening results should include creatinine clearance, and serum thymidine kinase, serum beta2-microglobulin and serum quantitative immunoglobulins.
19
The window for bone marrow assessments is -7 days or +14 days as calculated from Week 1 Day 1.
CCI
CCI

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Appendix 3.
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 4.
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 the risks of treatment during pregnancy have not 
been evaluated. Entospletinib is 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 study investigational products 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. There are no data with 
obinutuzumab use in pregnant women to inform a drug-associated risk. For further information 
on obinutuzumab, refer to the SmPC.
For additional information on any of these study investigational products, please refer to the 
latest version of the relevant IB or label in the applicable country.

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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 Week 1, Day 1 visit prior to dosing. 
Pregnancy tests will be performed at the timepoints specified in the Study Procedures Table 
(Appendix 2). Female subjects of childbearing potential must agree to one of the following from 
Screening until 30 days following the final dose of either tirabrutinib or entospletinib or 
18 months from the last 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
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 or entospletinib or 
18 months from the last 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 with female 
partners of childbearing potential must use condoms during treatment and until 90 days 
following the final dose of either tirabrutinib or entospletinib or 18 months from the last dose of 
obinutuzumab (whichever is later). Additional contraception recommendations should also be 
considered if the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
following the final dose of either tirabrutinib or entospletinib or 18 months from the last dose of 
obinutuzumab (whichever is later).

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4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, 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
or entospletinib or 18 months from the last 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.

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Appendix 5.
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

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Appendix 6.
Modified IWCLL 2008 Response Criteria
The determination of CLL response and progression will be based on standardized International 
Workshop on CLL (IWCLL) 2008 criteria {Hallek 2008}, as specifically modified for this study 
to reflect current recommendations which consider the mechanism of action of small molecule 
targeted therapy {Cheson 2012}.
Complete remission (CR):
All below listed criteria must be fulfilled and no disease related symptoms should be present.
Complete remission with incomplete recovery of the bone marrow (CRi):
All below listed criteria must be fulfilled, except for an incomplete recovery of the bone marrow 
with persisting anemia, thrombocytopenia and/or neutropenia (related to toxicity of treatment 
and not due to CLL) and no disease related symptoms should be present.
Partial response (PR):
Among the below listed criteria at least 2 from group A and 1 from group B must be fulfilled.
Partial response with lymphocytosis (PR-L):
Among the below listed criteria at least 2 from group A and 1 from group B must be fulfilled, 
however, a lymphocytosis related to treatment may be present.
Nodular partial response (nPR):
All criteria for a CR/CRi are fulfilled, but the bone marrow shows lymphoid nodules. As in a lot 
of cases these nodules are related to bone marrow proliferation during recovery, efforts should be 
made to prove that these lymphocytes are no CLL cells by 4-colour-flow cytometry to be able to 
define these patients as CR/CRi. If this cannot be proved by either FACS or MRD from the bone 
marrow patients will be considered PR and therefore this category will not appear on the eCRF.
Stable disease (SD):
Failure to achieve a PR and absence of PD.
Progressive disease (PD):
Presence of at least 1 of the below enlisted criteria or appearance of new lymph nodes > 1.5 cm,
hepato- or splenomegaly or organ infiltration by CLL.

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Response criteria
Parameter
CR
CRi
PR
PR-L
PD
Group A (indicating tumor load)
Lymphadenopathy1
none > 1.5 cm
decrease ≥50 %
increase by ≥50 %
or new lymph nodes
≥1.5 cm
Hepatomegaly
none
decrease ≥50 %
Increase by ≥50 %
Splenomegaly
none
decrease ≥50 %
Increase by ≥50 %
Blood lymphocytes
< 4000/µL
decrease of
≥50 % from
baseline
increase
Increase by ≥50% 
over baseline2 to 
≥5000/µL
Bone marrow
Normocellular
hypocellular
50% reduction in BM 
infiltrates3
irrelevant
30 % lymphocytes, no 
B-lymphoid nodules
Group B (indicating function of the hematopoietic system)
Platelet count
≥100000/µL
Irrelevant
≥100000/µL or increase by
≥50 % from baseline
Decrease by ≥50 %
due to CLL
Hemoglobin
> 11 g/dL
irrelevant
> 11 g/dL or increase by
≥50 % from baseline
Decrease by 
> 2 g/dL
Neutrophil count
> 1500/µL
Irrelevant
> 1500/µL or increase by
≥50% from baseline
irrelevant
1
Assessed as sum of the products of multiple lymph nodes, if available an indicator lymph node (the largest palpable) from
every region should be compared in every staging.
2
Patients with treatment-related lymphocytosis should not be rated PD and remain on study treatment if other criteria for
progressive disease are absent.
3
In case of B-lymphoid nodules a 4-colour-flow cytometry is recommended to clarify if this is related to CLL, if FACS is 
negative these patients can be rated as CR/CRi, if all other criteria are fulfilled.
MRD response rate
The MRD response is assessed with four-color-flow cytometry (FACS) and MRD negativity is
defined as one CLL cell per 10,000 leukocytes [0.01 %], ie, <10-4 and patients are defined as 
MRD negative if their disease burden is below this threshold MRD in the bone marrow will be 
assessed after the completion of 24 weeks of treatment and MRD in the peripheral blood will be 
assessed in the schedule outlined in Appendix 2 in the event that peripheral blood ALC<4K/µL.
I 

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Amendment 4
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Appendix 7.
Cumulative Illness Rating Scale (CIRS)
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions. For each condition selected from the CIRS List of Comorbid 
Conditions, please rate the severity of that condition. For the severity rating, please use the 
scoring guidelines shown in the table below, considering the magnitude of symptoms, how 
manageable the condition is, and the extent of intervention required.
Please take into account that CLL induced illness or organ damage are not included in this rating 
scale. The goal of this rating scale is to assess comorbidity other than CLL in the patient. If there 
are two or more illnesses/impairments of one organ system, the illness/impairment with the 
highest severity should be evaluated.
CIRS Rating Strategy of Comorbidity
Score
Severity
Findings
0
No problem
Organ system not compromised
1
Mild
Illness/impairment with/without requirement of therapy, excellent prognosis, 
patient with normal activity
2
Moderate
Illness/impairment requiring therapy, good prognosis, compromised activity of 
patient
3
Severe
Illness/impairment with urgent requirement of therapy, prognosis unclear, marked 
restriction in activity
4
Extremely severe
Life threatening illness/impairment, emergency case of therapy, adverse prognosis
CIRS List of Comorbid Conditions
Organ System
If illness/impairment present, please specify
Score
Heart
Blood Pressure
Vascular
Respiratory
Eye/ear/nose/throat/larynx
Upper gastrointestinal
Lower gastrointestinal
Liver
Renal
Genitourinary
Musculoskeletal
Endocrine/metabolic
Neurological
Psychiatric
Total Score

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Appendix 8.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used.
Serum
Creatinine Units
Gender
Formula
mg/dL
Males
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1
72 subject serum creatinine [mg/dL]
Females eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 0.85
72 subject serum creatinine [mg/dL]
mol/L
Males
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.23
Subject serum creatinine [mol /L]
Females eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.04
Subject serum creatinine [mol /L]
Abbreviation: eCcr=estimated creatinine clearance

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Appendix 9.
Binet and Rai Staging Systems for the Classification of CLL
Binet
Stage
Lymph Node Areas
Hemoglobin
< 10 g/dL
Platelet
< 100 x 109/L
A
< 3
No
No
B
≥3
No
No
C

Either present
Rai
Stage
Lymphocytosis
Lymph Node 
Enlargement
Spleen/Liver 
Enlargement
Hemoglobin 
< 11 g/dL
Platelet
< 100 x 109/L
0
Yes
No
No
No
No
I
Yes
Yes
No
No
No
II
Yes

Yes
No
No
III
Yes


Yes
No
IV
Yes



Yes

Tirabrutinib & Entospletinib 
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Appendix 10. 
The GS Screening Questionnaire 
• 8 questions 
• Nurse administered 
• Takes 5-10 minutes to 
perform 
-
Appetite, weight loss, 
BMI 
-
Mobility 
-Mood and cognition 
-
Nwnberof 
medications 
-
Patient-related health 
-
Age categories 
• Abnormal if score:::; 14 
-
Preliminary analysis 
-
Sensitivity: 89.6% 
-
Specificity: 60.4% 
CONFIDENTIAL 
A 
B 
C 
E 
F 
-
H 
p 
,-
II 
Items 
II 
Has food intake declined over the 
past 3 months due to loss of 
appetite, digestive problems, or 
chewing 01· swallowing difficulties? 
Weight loss during the last 
3 months 
II 
Mobility 
II 
Neuropsychological problems 
II 
Body mass index 
(BMI weight in kg) / (height in m)2 
Takes more than 3 prescription 
dmgs per day 
In comparison with other people 
of the same age how do they 
consider their health status? 
Age 
Total Score 
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Amendment4 
Possible answers (score) 
O: severe decrease in food intake 
1: moderate decrease in food intake 
2: no decrease in food intake 
0: weight loss > 3 kg 
1: does not know 
2: weight loss between 1 and 3 kg 
3: no weight loss 
0: bed or chair bound 
1: able to get out of bed/chair but does not go out 
2: goes out 
O: severe dementia or depression 
1: mild dementia or depression 
2: no psychological problems 
0: BMI < 18.5 
1: BMl = 18.5 to BMI < 21 
2: BMI= 21 toBM1 < 23 
3: BMI = 23 and > 23 
0: yes 
1: no 
0: not as good 
0.5: does not know 
1: as good 
2: better 
0: > 85 yr 
1: 80-85 yr 
2: <80yr 
0-17 
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