Clinical trial NCT02701634
Conditions: Chronic Graft Versus Host Disease
Keywords: Chronic Graft Versus Host Disease (cGVHD) newly diagnosed cGVHD immune reconstitution Immune System Diseases allogeneic stem cell transplantation SYK inhibitor
Sponsor: Gilead Sciences
Start date: 2016-05-27; Completion date: 2018-03-06
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the effect of entospletinib (ENTO) on the best overall response rate in adults with chronic graft versus host disease (cGVHD) who are currently receiving systemic corticosteroids as part of first-line therapy for cGVHD.

Detailed description:

Arms: arm 1: ENTO 400 mg or 200 mg tablet twice daily for 48 weeks arm 2: Placebo to match tablet twice daily for 48 weeks
Interventions: intervention 1: ENTO intervention 2: Placebo
Intervention descriptions: intervention 1: Tablets administered orally intervention 2: Tablets administered orally

Protocol documents:
Prot_003.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Clinical Program 
Manager: 
Gilead Medical 
Monitor: 
(!') GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Efficacy and Tolerability ofEntospletinib, a Selective 
SYK Inhibitor, in Combination with Systemic Cmiicosteroids as 
First-Line Therapy in Subjects with Chronic Graft Versus Host 
Disease ( cGVHD) 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
129907 
2015-004572-30 
NCT02701634 
Chronic Graft Versus Host Disease (cGVHD) 
GS-US-406-1840 
Name: 
Telephone: 
Name: 
Telephone: 
Fax: 
Mobile: 
PPD 
PPD 
Mario Marcondes, MD, PhD 
PPD 
PPD 
PPD 
Protocol Version/Date: 
Original 
11 November 2015 
14 March 2016 
Amendment 1.0 (UK only) 
Amendment 1.0 (Global) 
Amendment 2.0 (Global) 
02 May2016 
31 August 2016 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, prui icularly unpublished data, is the prope11y or 
lmder 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 infmm ation 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 infmm ation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infmm ed consent from those 
persons to whom the dmg 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
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................13
1.
INTRODUCTION ..............................................................................................................................................17
1.1.
Background ............................................................................................................................................17
1.1.1.
Background on Chronic Graft Versus Host Disease ............................................................17
1.2.
Entospletinib (ENTO)............................................................................................................................20
1.2.1.
Preclinical Pharmacology and Toxicology...........................................................................21
1.2.2.
Clinical Trials of Entospletinib (ENTO) ..............................................................................22
1.2.3.
Interaction with Proton Pump Inhibitors ..............................................................................23
1.3.
Rationale for This Study ........................................................................................................................24
1.4.
Rationale for Dose Selection..................................................................................................................24
1.5.
Risk/Benefit Assessment for the Study..................................................................................................24
1.6.
Compliance ............................................................................................................................................25
2.
OBJECTIVES.....................................................................................................................................................26
3.
STUDY DESIGN................................................................................................................................................27
3.1.
Endpoints ...............................................................................................................................................27
3.2.
Study Design..........................................................................................................................................28
3.3.
Study Treatments ...................................................................................................................................28
3.4.
Discontinuation Criteria.........................................................................................................................30
3.5.
Biomarker Testing..................................................................................................................................30
3.5.1.
Biomarker Samples to Address the Study Objectives:.........................................................30
3.5.2.
Optional Future Research.....................................................................................................31
3.5.3.
Optional Sub-study to study cellular turnover {Emson et al 2013, Ladell 
et al 2008, Messmer et al 2005}...........................................................................................31
4.
SUBJECT POPULATION..................................................................................................................................32
4.1.
Number of Subjects and Subject Selection ............................................................................................32
4.2.
Inclusion Criteria....................................................................................................................................32
4.3.
Exclusion Criteria...................................................................................................................................33
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................35
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................35
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................35
5.2.
Description and Handling of Study Drug...............................................................................................36
5.2.1.
Formulation..........................................................................................................................36
5.2.2.
Packaging and Labeling .......................................................................................................36
5.2.3.
Storage and Handling...........................................................................................................36
5.3.
Dosage and Administration....................................................................................................................37
5.4.
Prior and Concomitant Medications.......................................................................................................37
5.5.
Opportunistic Infections and Prophylactic Regimens ............................................................................41
5.6.
Accountability for Investigational Medicinal Product ...........................................................................41
5.6.1.
Investigational Medicinal Product Return or Disposal.........................................................41
6.
STUDY PROCEDURES ....................................................................................................................................42


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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................42
6.2.
Study Assessments.................................................................................................................................42
6.2.1.
Screening Visit .....................................................................................................................47
6.3.
Baseline/Day 1 Visit ..............................................................................................................................47
6.4.
Treatment Assessments (Weeks 2-48 and OLE)....................................................................................48
6.5.
Post-treatment Assessments ...................................................................................................................49
6.5.1.
Unscheduled Visit ................................................................................................................49
6.5.2.
Early Study Drug Discontinuation (ESDD) .........................................................................50
6.6.
30 Day Follow-Up Visit.........................................................................................................................50
6.7.
End of Study...........................................................................................................................................50
6.8.
Vital Signs..............................................................................................................................................51
6.9.
Biomarker Sample Collection ................................................................................................................51
6.10.
Clinical Laboratory Tests/Assessments..................................................................................................51
6.11.
Criteria for Discontinuation of Study Treatment....................................................................................51
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................54
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................54
7.1.1.
Adverse Events.....................................................................................................................54
7.1.2.
Serious Adverse Events........................................................................................................54
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................55
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................55
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................55
7.2.2.
Assessment of Severity ........................................................................................................56
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................57
7.4.
Gilead Reporting Requirements.............................................................................................................59
7.4.1.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events Toxicity Management .....................................59
7.4.2.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................59
7.4.3.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................60
7.4.4.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................60
7.5.
Toxicity Management ............................................................................................................................60
7.6.
Special Situations Reports......................................................................................................................61
7.6.1.
Definitions of Special Situations..........................................................................................61
7.6.2.
Instructions for Reporting Special Situations.......................................................................61
8.
STATISTICAL CONSIDERATIONS................................................................................................................63
8.1.
Analysis Objectives and Endpoints........................................................................................................63
8.1.1.
Analysis Objectives..............................................................................................................63
8.1.2.
Primary Endpoint .................................................................................................................64
8.1.3.
Secondary Endpoint .............................................................................................................64
8.1.4.
Other Endpoints of Interest ..................................................................................................65
8.2.
Analysis Conventions.............................................................................................................................65
8.2.1.
Analysis Sets ........................................................................................................................66
8.3.
Data Handling Conventions ...................................................................................................................66
8.4.
Demographic Data and Baseline Characteristics ...................................................................................68
8.5.
Efficacy Analysis ...................................................................................................................................68
8.5.1.
Primary Analysis..................................................................................................................68
8.5.2.
Secondary Analyses .............................................................................................................68
8.5.3.
Exploratory Analyses ...........................................................................................................69
8.5.4.
Interim Analysis ...................................................................................................................69
8.5.5.
Final Analysis.......................................................................................................................69
8.6.
Safety Analysis.......................................................................................................................................69


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8.6.1.
Extent of Exposure...............................................................................................................70
8.6.2.
Adverse Events.....................................................................................................................70
8.6.3.
Laboratory Evaluations ........................................................................................................70
8.6.4.
Other Safety Evaluations......................................................................................................70
8.7.
Pharmacokinetic Analysis......................................................................................................................70
8.8.
Biomarker Analysis................................................................................................................................71
8.9.
Sample Size............................................................................................................................................71
8.10.
Data Monitoring Committee ..................................................................................................................71
9.
RESPONSIBILITIES..........................................................................................................................................72
9.1.
Investigator Responsibilities ..................................................................................................................72
9.1.1.
Good Clinical Practice..........................................................................................................72
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................72
9.1.3.
Informed Consent.................................................................................................................72
9.1.4.
Confidentiality......................................................................................................................73
9.1.5.
Study Files and Retention of Records ..................................................................................73
9.1.6.
Case Report Forms...............................................................................................................74
9.1.7.
IMP Destruction ...................................................................................................................75
9.1.8.
Inspections............................................................................................................................75
9.1.9.
Protocol Compliance............................................................................................................75
9.2.
Sponsor Responsibilities ........................................................................................................................75
9.2.1.
Protocol Modifications.........................................................................................................75
9.2.2.
Study Report and Publications .............................................................................................76
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................76
9.3.1.
Payment Reporting...............................................................................................................76
9.3.2.
Access to Information for Monitoring..................................................................................76
9.3.3.
Access to Information for Auditing or Inspections ..............................................................77
9.3.4.
Study Discontinuation..........................................................................................................77
10.
REFERENCES ...................................................................................................................................................78
11.
APPENDICES ....................................................................................................................................................81
Appendix 1.
Investigator Signature Page....................................................................................................82
Appendix 2.
For Screening: NIH cGVHD Diagnosis and Staging Criteria, Global Severity Score 
{Jagasia et al 2015}................................................................................................................83
Appendix 3.
For Screening: NIH cGVHD Diagnosis and Staging Criteria (NCDSC) Form 
{Jagasia et al 2015}................................................................................................................84
Appendix 4.
For Baseline + Subsequent Visits:  Response Determination for the NIH cGVHD
Activity Assessment (NCAA) {Lee et al 2015}.....................................................................88
Appendix 5.
For Baseline + Subsequent Visits: Chronic GVHD Activity Assessment- Clinician.............89
Appendix 6.
For Baseline + Subsequent Visits: Lee Symptom Scale {Lee et al 2002} .............................96
Appendix 7.
Grading of Adverse Event Severity........................................................................................99
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................100
Appendix 9.
Schedule of Assessments for the Optional Cellular Turnover Sub-study*..........................103


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LIST OF IN-TEXT TABLES
Table 5-1.
Tapering of Prednisone after reaching PR/CR .......................................................................38
Table 5-2.
Examples of Prohibited Agents ..............................................................................................40
Table 5-3.
List of Sensitive Substrates of UGT1A1, OATP1B1, OATP1B3, P-gp and BCRP...............40
Table 6-1.
Schedule of Assessments........................................................................................................43
Table 7-1.
Grading of Adverse Event Severity........................................................................................56
Table 7-2.
Grading of Adverse Event Severity: Upper Respiratory ........................................................57
Table 8-1.
Criteria for time point response determination.......................................................................64
LIST OF IN-TEXT FIGURES
Figure 1-1.
cGVHD prophylaxis with rituximab.  (A) Cumulative incidence of cGVHD. 
(B) Non-relapse mortality & GVHD recurrence. (C) Overall survival ..................................18
Figure 1-2.
Entospletinib Induces Apoptosis in B Cells from cGVHD Patients.......................................20
Figure 3-1.
Study Schema.........................................................................................................................29


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Efficacy and Tolerability of Entospletinib, a Selective 
SYK Inhibitor, in Combination with Systemic Corticosteroids as 
First-Line Therapy in Subjects with Chronic Graft Versus Host 
Disease (cGVHD)
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
129907
2015-004572-30
NCT02701634
Study Centers 
Planned:
Approximately 30 centers in the North America, Europe, Asia and 
Australia 
Objectives:
The primary objective is:
To evaluate the effect of ENTO on the best overall response rate 
(BORR) as assessed by the NIH cGVHD Activity Assessment 
(NCAA) by 24 weeks in the setting of add-on to systemic 
corticosteroids as part of first-line therapy for cGVHD
The key secondary objectives are:

To evaluate the effect of ENTO on the skin domain of the Lee 
Symptom Scale (LSS)  (Appendix 6) at 24 weeks

To evaluate the effect of ENTO on the mouth domain of the LSS 
at 24 weeks

To evaluate the effect of ENTO on the eyes domain of the LSS at 
24 weeks

To evaluate the effect of ENTO on the total score of the LSS at 
24 weeks
Additional secondary objectives include:

To evaluate the effect of ENTO on duration of response (DOR)

To evaluate the effect of ENTO on dose reduction of 
corticosteroids


Entospletinib 
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Study Design: 
Number of Subjects 
Planned: 
Target Population: 
CONFIDENTIAL 
• 
To evaluate the effect ofENTO on initiation of second-line 
therapy for cGVHD 
• 
To evaluate the effect ofENTO on progression of cGVHD 
• 
To evaluate the safety and tolerability ofENTO 
Exploratmy objectives include: 
~ 
I 
I 
Randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the efficacy and safety ofENTO (Treatment Alm 1) 
vs. placebo (Treatment Alm 2) in combination with systemic 
cmticosteroids for subjects with cGVHD. 
An interim analysis for futility is planned when approximately 50% of 
subjects have been on study for 24 weeks. The primary endpoint will 
be evaluated when all subjects complete 24 weeks of treatment. 
Duration and quality of response will be evaluated up to 48 weeks of 
blinded treatment. 
After 48 weeks, subjects who are still on investigational treatment 
(ENTO or PTM) and ar·e eligible to remain on study will have the 
option to receive open-label extension (OLE) with ENTO and attend 
visits per the schedule of assessments (Table 6-1) for an additional 
96 weeks. 
Subjects who complete the study through Week 48 and do not wish to 
patiicipate in the OLE will be required to retum to the clinic after 
completion of study dmg for a 30-Day Follow-up Visit. 
Approximately 100 subjects. Randomization will be stratified 
by 1) calcineurin inhibitor or mycophenolate mofetil (MMF) use 
(no vs. yes) and 2) moderate vs. severe cGVHD as detetmined by the 
NIH cGVHD Diagnosis and Staging Criteria (NCDSC) at the 
Screening visit. 
Adult males or non-pregnant, non-lactating, female subjects with 
cGVHD 
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Duration of 
Treatment:
48 weeks in the double-blind, placebo-controlled period.  After 
48 weeks subjects who are still on investigational treatment (ENTO or 
PTM) and are eligible to remain on study will have the option to 
receive OLE with ENTO and attend visits per the schedule of 
assessments (Table 6-1) for an additional 96 weeks.
Diagnosis and Main 
Eligibility Criteria:
The following are a summary of the key criteria: 
Key Inclusion Criteria: 

Male or non-pregnant, non-lactating, female subjects 

18-75 years of age, inclusive at Screening

Newly diagnosed cGVHD defined by:
a) At least 100 days after receiving any allogeneic hematopoietic 
stem cell transplant 
AND 
b) Receiving a new course of systemic corticosteroids 
(1.0 mg/kg/day or prednisone equivalent) as first-line cGVHD 
therapy for at least 1 day and no more than 21 days  prior to 
first dose of ENTO/Placebo 
AND
c) Moderate to severe cGVHD as assessed by NCDSC with at 
least three organ systems involved OR one organ system with 
a score of 2 OR lung organ score = 1 (Appendix 2) 

Subjects who have undergone transplant for hematologic 
malignancy are required to be in complete remission. 

Have either a normal ECG or one with abnormalities that are 
considered clinically insignificant by the investigator in 
consultation with the Sponsor 
Key Exclusion Criteria:

Uncontrolled infection within 4 weeks prior to Randomization

History of the following therapies in the post-transplant period:
B cell depleting biologic agents 
CD19 CAR-T cells based therapies 
BTK/SYK/JAK/PI3K inhibitors
Phototherapy-unless administered for acute GVHD 


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
Treatment of cGVHD with anti-thymocyte globulins (ATG), or 
campath within 60 days of Screening visit  unless used for  
treatment of acute GVHD

Severe organ dysfunction manifested during Screening period: 
Requiring supplemental oxygen at more than 2 L/min
Uncontrolled arrhythmia or heart failure
Study Procedures/
Frequency:
Eligible subjects will be randomized 1:1 to Treatment Arm 1 or 
Treatment Arm 2 to receive study drug for 48 weeks.  Following 
Screening and Baseline/Day 1 Visits, subjects will return for study 
visits at Weeks: 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48.  Subjects 
that participate in the OLE will return for visits at Weeks: 50, 52, 56, 
60, 64, 72 and visits every 12 weeks thereafter. During the OLE, the 
maximum period of co-administration of ENTO with Cyclosporine, 
Tacrolimus or MMF should not exceed 3 months. Subjects who do 
not wish to participate in the OLE will have a 30-day Follow-Up visit 
after their week 48 visit. 
NOTE for subjects receiving tacrolimus, cyclosporine or MMF: 
For subjects receiving these medicines at enrolment and are
continuing on these medicines, the blood levels of tacrolimus, 
cyclosporine or the active metabolite of MMF (MPA) will be 
monitored at Baseline/Day 1 (prior to starting ENTO or 
placebo-to-match [PTM]), on Day 2 or Day 3 and Day 6 or Day 7 
after initiating ENTO or PTM, and at the end of Week 2 and Week 50
study visit. Beyond these time points, concentration monitoring for 
tacrolimus, and cyclosporine should follow the treating institution’s 
protocol and therapeutic range for monitoring these medicines. For 
subjects who initiate these medicines while already receiving ENTO, 
concentration monitoring for tacrolimus, cyclosporine and MPA 
should follow the treating institution’s protocol and therapeutic range 
for monitoring these medicines. When a concentration sample is taken
at a local lab in accordance with the treating institution’s protocol for 
monitoring these medications, a sample may also be requested for 
central lab analysis.
At Screening the NIH cGVHD Diagnosis and Staging Criteria 
(NCDSC) (Appendix 3) will be administered. At Baseline/Day1 and 
Weeks 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, 56, 60, 64, 72, every 12 
weeks thereafter and Early Study Drug Discontinuation (ESDD) the 
NCAA (Appendix 5), and the LSS (Appendix 6) will be administered.
Serological screening for HIV antibody (Ab), hepatitis B antigen, 
hepatitis C Antibody will be collected at the Screening visit. For 
subjects with hematologic malignancy, assessments of residual 
disease will be followed per the institutional guidelines.  


Entospletinib 
Protocol GS-US-406-1840 
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Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
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Final 
Amendment 2.0 Global 
Blood and urine will be collected at all study visits per the schedule of 
assessments (Table 6-1). 
Blood for selected biomarkers will be collected at all study visits per 
the Schedule of Assessments (Table 6-1). 
PPD 
I 
I 
Treatment Alm 1: ENTO 400 mg twice daily: 2 X 200 mg tablets 
twice daily, for subjects cunently on proton pump inhibitors (PPI)* 
Treatment Alm 2: Placebo-to-match (PTM) twice daily 
Both treatment atms will be administered orally without food (in a 
fasted state) for 48 weeks. 
*For subjects NOT cmTently taking a PPI, the dose will be adjusted to 
ENTO 200 mg twice daily: 1 X 200 mg tablet orally twice daily 
without food (in a fasted state) for 48 weeks. 
Systemic c01ticosteroids at a dose and route consistent with first-line 
therapy for newly diagnosed cGVHD. 
Systemic c01ticosteroids will be administered per provided treatment 
schema. 
Safety evaluations include documentation of AEs, physical 
examination, vital signs, ECGs, and clinical laboratory evaluations. 
The primru.y endpoint is BORR by 24 weeks, as assessed by the 
NCAA, in the setting of add-on therapy to systemic cmticosteroids as 
pa11 of first-line therapy for cGVHD. 
The key secondru.y endpoints are: 
• 
Change from Baseline in the skin domain of the LSS at 24 weeks 
• 
Change from Baseline in the mouth domain of the LSS at 
24 weeks 
• 
Change from Baseline in the eyes domain ofLSS at 24 weeks 
• 
Change from Baseline in the total score of the LSS at 24 weeks 
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Entospletinib 
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Phmmacokinetics: 
Statistical Methods: 
CONFIDENTIAL 
Other secondary endpoints include: 
• 
DOR 
Final 
Amendment 2.0 Global 
• 
Prop011ion of subjects who achieve at least 50% reduction in 
systemic c01ticosteroid dose relative to baseline 
• 
Prop011ion of subjects who initiate second-line therapy for 
cGVHD 
• 
Failme-free-smvival (FFS) 
• 
Safety and tolerability ofENTO 
Explorat01y endpoints of this study include: 
~ 
D 
I 
I 
I 
PK blood sampling will occm at Weeks 2 through Week 48 and then 
eve1y 12 weeks thereafter. 
The primmy endpoint ofBORR by 24 weeks is defmed as the 
proportion of subjects who achieve a complete or pmtial response 
(CR or PR) within 24 weeks, as assessed by the NCAA. A CR is 
achieved when all signs and symptoms of cGVHD have resolved. A 
PR is achieved when an objective response is observed in any organ 
system without progression in another organ system, and no 
additional systemic therapy is needed. 
The primmy analysis for BORR will be perf01med in the 
intent-to-treat (ITT) Analysis Set, which includes all subjects who 
were randomized. Response rate will be Slli'lllnarized by cmmt and 
percent of subjects with each ordinal response (CR, PR, and 
CR + PR). A stratified Cochran-Mantel-Haenszel (CMH) Chi-square 
test will be perf01med to compm·e BORR between ENTO and PTM by 
24 weeks. The difference in response rates between treatment groups 
and the conesponding 95% Cis will be presented. 
Change from Baseline in the LSS scores will be analyzed using a 
mixed model repeated measmes (MMRM) model. Dmation of 
response (DOR) will be analyzed using the Kaplan-Meier method. 
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A sequential testing strategy will be implemented to preserve the 
overall type I error rate across the primary and key secondary 
endpoints of the study at a 2-sided significance level of 0.05. If the 
primary hypothesis is rejected, the key secondary endpoints will be 
sequentially tested at the 2-sided 0.05 significance level in the
following order: (1) change from Baseline in the skin domain of the 
LSS, (2) change from Baseline in the mouth domain of the LSS, 
(3) change from Baseline in the eyes domain of the LSS, and 
(4) change from Baseline in the total score of the LSS. If a null 
hypothesis is not rejected, formal sequential testing will stop and only 
nominal significance will be cited for the remaining endpoints.
With 40 subjects per treatment group, there is 75% power to detect a 
30% improvement in response rate at the 2-sided 0.05 significance 
level using a Fisher’s exact test, assuming a placebo response rate of 
50%. A total of 100 subjects (50 per treatment group) will be enrolled 
assuming a 20% dropout rate.  
Safety data will be listed by subject and summarized by treatment and 
frequency of event/abnormality or descriptive statistical summaries, 
as appropriate. The endpoints to be evaluated will include AEs, 
physical examination, clinical laboratory test findings, ECG 
abnormalities and interval measurements, and vital signs 
measurements.
An external multidisciplinary data monitoring committee (DMC) will 
review the progress of the study, perform interim reviews of safety 
data at regular intervals approximately every 3 months, and perform 
an interim review of efficacy data for futility when approximately 
50% of subjects have been on study for 24 weeks, as described in the 
DMC Charter.  The DMC will provide recommendations to Gilead as 
to whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the 
study in the best interests of the participants, whether the study should 
continue as planned, or the study should continue with modifications.
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
aGVHD
Acute Graph Versus Host Disease 
ADL
Activities of daily living 
AKT
Protein kinase B
ALT
alanine aminotransferase
AML
acute myeloid leukemia 
APC
antigen presenting cell 
AST
aspartate aminotransferase
ATG
anti-thymocyte globulins
AUC
area under curve versus time
BAFF
B cell Activating Factor
BCMA
B cell maturation antigen
BCR
B cell receptor
BCRP
breast cancer resistance protein
BLNK
B cell linker protein
BLQ
below limit of quantitation
BTK
Bruton’s tyrosine kinase
BORR
best overall response rate
cGMP
Current Good Manufacturing Practice
CI
confidence interval
cGVHD
Chronic Graft Versus Host Disease
Clast
last observed quantifiable concentration
CL
systemic clearance following IV administration
CLL 
chronic lymphocytic leukemia
Cmax
maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
concentration at the end of the dosing interval
CONMED
concomitant medication
CPK
creatine phosphokinase
CR
complete response
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
DSPH
Drug Safety and Public Health
DMC
Data Monitoring Committee
DOR
duration of response
E2
Estradiol
ECG
Electrocardiogram


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eCRF
electronic case report form(s)
ENTO
Entospletinib 
ENTO BIS-MSA
Entospletinib bismesylate monohydrate
ENTO MSA
Entospletinib methanesulfonate
ENTO SSD
Entospletinib spray-dried dispersion tablet
ERK
Extracellular signal regulated kinase
ESR
erythrocyte sedimentation rate
ET
early termination
FDA
(United States) Food and Drug Administration
FFS
failure-free survival
FSH
follicle-stimulating hormone
cGVHD
Chronic Graph Versus Host Disease 
GCP
Good Clinical Practice (Guidelines)
GGT
Gamma-glutamyl transferase
GVHD
Graph Versus Host Disease 
GSI
Gilead Sciences, Inc.
Hb
Hemoglobin
HBV
Hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDPE
high-density polyethylene
hERG
human-ether-a-go-go related gene
HIV
Human immunodeficiency virus
HSCT
hematopoietic stem cell transplant
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IgG
immunoglobulin G
IgM
immunoglobulin M
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
IRB
institutional review board
ITT
intent-to-treat 
IUD
intrauterine device
IV
Intravenous
IxRS
interactive voice/web response system
JAK
janus kinase
LDL
low-density lipoprotein


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LLN
lower limit of the normal range
LLOQ
lower limit of quantitation
LOCF
last observation carried forward
LOEL
lowest observed effect level
LOQ
limit of quantitation
LSS
Lee Symptom Scale 
MAD
multiple ascending dose
MAP
mitogen-activated protein
MedDRA
Medical Dictionary for Regulatory Activities
MK2
MAP kinase activated protein kinase-2
MMF
mycophenolate mofetil
MMP9
Matrix metallopeptidase-9
MMRM
mixed model repeated measures
µm
Micro millimeter
NDA
New Drug Application
NCAA
NIH cGVHD Activity Assessment
NCDSA
NIH cGVHD Diagnosis and Staging Criteria
NIH
National Institute of Health
NOAEL
no observable adverse effect level
NRI
non-responder imputation
PE
physical examination
PFT 
pulmonary function tests 
PI3K
phosphatidylinositol-4,5-bisphosphate 3-kinase
PK
Pharmacokinetic
PP
per-protocol
PR
pulse rate
PPI
proton pump inhibitor
PTM
placebo-to-match
Q1
first quartile
Q3
third quartile
QTcF
Quantum Tunnelling Composite Fridericia
RA
rheumatoid arthritis
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SEM
standard error of measure
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction


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SYK
Spleen tyrosine kinase
TACI
Transmembrane activator and CAML interactor
TLC
total lung capacity
tmax
the time (observed time point) of Cmax
t½
an estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant 
(λz)
UGT1A1
uridine disphosphate glucuronosyltransferase 1A1
ULN
upper limit of the normal range
US
United States
Vz
apparent volume of distribution following IV administration
WBC
White blood cell
WHO
World Health Organization
λz 
terminal phase rate constant


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1.
INTRODUCTION
1.1.
Background
1.1.1.
Background on Chronic Graft Versus Host Disease
Chronic Graft Versus Host Disease (cGVHD) is a disease observed in recipients of allogeneic 
hematopoietic stem cells, where the new immune system is reconstituted without complete 
tolerance to the host and begins to attack multiple organ systems including eyes, skin, mucosa, 
lungs, gut, and liver. Classic acute GVHD (aGVHD) occurs in episodes with donor cell 
engraftment before 100 days post-transplant and is thought to be mediated by donor T cells. 
Acute GVHD is observed in 35-50% of patients receiving hematopoietic stem cell transplant 
(HCT) {Jacobsohn et al 2007}. Acute GVHD is a risk factor for developing cGVHD, but 
cGVHD can develop without history of aGVHD. Chronic GVHD occurs in 35-70% of patients 
receiving allogeneic transplants. In the U.S., the incidence of cGVHD is estimated at 
~3000-5000 patients per year, with prevalence at approximately 10,000 {Vigorito et al 2009}. 
Initial therapy for cGVHD consists of high dose systemic corticosteroids, however 50 to 60% of 
patients fail to have a complete response to this line of therapy. 
No agents are currently approved for cGVHD. A combination of calcineurin inhibitors, mTOR 
inhibitors and mycophenolate mofetil (MMF) are frequently added as second-line therapy with 
an initial response rate of 20-70% {Flowers et al 2015}. The majority of responses are not 
durable, and cGVHD is associated with a 5-year mortality of 30-50% {Blazar et al 2012}. 
Current immunosuppressive treatments also increase the rate of life-threatening infections and 
cancer relapse due to presumably the loss of graft versus tumor effect. The absence of effective 
therapies is attributed to the limited understanding of disease pathophysiology and limited 
directed development by industry.  
1.1.1.1.
Role of SYK in cGVHD
Unlike aGVHD which is believed to be mediated by allo-reactive T cells; the current biological 
and clinical evidence implicates that dysregulated B cell homeostasis is involved in 
establishment of the chronic phase of GVHD.  B cell depletion in the peri-HSCT period is 
correlated with a reduction in the incidence of cGVHD. In addition, antibodies against minor 
histocompatibility antigens have been associated with the occurrence of cGVHD.  In murine 
models of cGVHD, donor B cell alloantibodies have been shown to be responsible for the 
pathogenesis of the disease.  A single open label study with the CD20 B cell depleting 
agent -rituximab- evaluated the potential of prophylactic therapy for development of cGVHD 
post-transplant period {Cutler et al 2013}. This study demonstrated clinically relevant 
differences in the cumulative incidence of cGVHD and overall survival (Figure 1-1).


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Figure 1-1.
cGVHD prophylaxis with rituximab. 
(A) Cumulative incidence of cGVHD.
(B) Non-relapse mortality & GVHD recurrence.
(C) Overall survival
In a subsequent study, subjects with steroid-refractory cGVHD received open-label rituximab 
{Cutler et al 2006} and an overall response rate of 70% was observed. This is in comparison to 
an expected response rate of ~50% for those receiving standard of care alone {Cutler et al 2013, 
Inamoto et al 2014}. These efficacy data with rituximab in cGVHD represent clinical validation
that therapy targeting B cells in this disease indication is effective. However, treatment of 
cGVHD with rituximab is suboptimal. The treatment effect is not durable as altered B cell 
populations recover {Sarantopoulos et al 2011}, and non-selective depletion of B cells results in 
complications such as hypogammaglobulinemia {Cutler et al 2013}. Targeting the pathogenic
B cell subpopulation that drives cGVHD may therefore yield enhanced efficacy and safety.
Emerging data also indicates that alterations in B cell homeostasis play a pathogenic role in 
cGVHD {Sarantopoulos et al 2015}. In healthy individuals, newly generated B cells emerge 
from the bone marrow as transitional B cells and must complete maturation and selection in the 
periphery {Wardemann et al 2003}. About 40% of these newly emerged B cells are auto 
reactive. Transitional B cells are dependent upon both BAFF (B cell Activating Factor) and BCR 
signaling for their differentiation/maturation and survival.  Low BAFF levels facilitate deletion 


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of autoreactive B cells.  Following HSCT, donor B cell reconstitution occurs in the presence of a
high foreign antigen load and high BAFF levels. This unique setting promotes the survival of 
activated, potentially allo- and auto-reactive B cells that would normally undergo negative 
selection. These donor-derived B cells can react with recipient tissue, facilitate tissue damage, 
produce inflammatory cytokines and serve as antigen presenting cell (APCs). Importantly, 
patients with cGVHD treated with anti-CD20 who have persistent B cell lymphopenia after 
treatment experience worsening symptoms, suggesting that both high BAFF levels and limited 
capacity to generate sufficient native and transitional B cells contribute to the abnormal B cell 
homeostasis that underlies the disease pathology.  High numbers of native and transitional 
B cells protect from cGVHD development, possibly by binding and decreasing BAFF levels.  
These results further support the hypothesis that normal B cell homeostasis is required for 
protection from cGVHD.  
As described, BAFF and B cell receptor (BCR) signaling play critical roles in the establishment 
of B cell homeostasis by regulating the auto-reactive B cell population.  Patients with cGVHD 
have significantly increased BAFF levels versus B cell numbers {Sarantopoulos et al 2011}.  
Circulating CD27+ B cell subsets are increased and have high expression levels of the BAFF 
receptors.  These cells are present in patients with autoimmune disease, but are absent in healthy 
individuals.  These CD27+ cells are able to constitutively produce IgG and potentially mediate 
anti-recipient tissue responses.  In the cGVHD murine model, elevated BAFF was shown to 
maintain B cells in a state of heightened sensitivity to antigen stimulation following BCR 
stimulation. This observation led to the hypothesis that B cells of cGVHD patients become more 
sensitive to antigen stimulation via BCR stimulation, resulting in loss of peripheral tolerance and 
survival of autoreactive B cell clones.  In vitro studies in human B cells from cGVHD patients
vs. those without cGVHD, revealed that cGVHD B cells have increased proliferative responses 
to BCR stimulation and reduced apoptosis {Allen et al 2012}.   
A mechanistic understanding of BAFF and BCR signaling in cGVHD is currently being 
investigated and highlights that therapeutic kinase inhibition may benefit cGVHD patients with 
altered B cell homeostasis.  The aberrant B cell survival in cGVHD patients is postulated to 
involve BAFF signaling via a SYK-AKT-ERK axis {Allen et al 2012}.  Following HSCT, 
peripheral B cells isolated from cGVHD patients signal through protein kinase B and ERK and 
have decreased expression of the proapoptotic molecule, BIM, resulting in heightened 
metabolism and resistance to apoptosis {Allen et al 2012}.  Importantly, B cells from cGVHD 
patients also have increased proliferative responses to BCR stimulation, with concomitant 
elevations in B cell linker protein (BLNK) and SYK phosphorylation compared to patients 
without cGVHD {Allen et al 2014}.  Pharmacologically blocking SYK kinase activity with 
fostamatinib in vitro in cGVHD donor B cells, prevented BCR hyper-responsiveness of B cells 
to BCR stimulation with anti-IgM {Allen et al 2014}.  Inhibition of Burton’s tyrosine kinase 
(BTK) activity by ibrutinib blocked PLC- gamma 2 activation in cGVHD patient B cells; 
impacting survival of cGVHD B cells in a BTK dependent manner {Dubovsky et al 2014, 
Miklos et al 2015}. These data suggest that BAFF and BCR cooperate to prime cGVHD B cells 
for survival and antigen responsiveness by lowering the threshold for BCR activation in cGVHD.  
Blockade of BCR signaling, therefore, could be of therapeutic benefit by reestablishing normal 
B cell homeostasis. Therefore, both SYK and BTK inhibition have potential to modulate aberrant 


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B cell function in cGVHD. In contrast to SYK, there are no published data to indicate that BTK 
is activated in cGVHD patient samples. Preliminary unpublished data from the 
Sarantopoulos Lab at Duke University with ENTO in the same assay with active cGVHD patient 
samples demonstrates a dose-dependent effect of ENTO to induce apoptosis of B cells vs. in 
samples from patients without active cGVHD (Figure 1-2).
Figure 1-2.
Entospletinib Induces Apoptosis in B Cells from cGVHD Patients
In summary, failed induction of B cell tolerance after HSCT is postulated to underlie the 
pathophysiology of human cGVHD.  Factors contributing to impaired tolerance induction 
include post-HSCT lymphopenia, persistent allo-antigen stimulation, and high BAFF levels, all 
of which contribute to hyper-responsive BCR pathways. SYK inhibition of cGVHD B cells
subsets could antagonize the pro-survival signaling and result in pathogenic B cell deletion that 
could help reestablish B cell homeostasis.
1.2.
Entospletinib (ENTO)
For further information refer to the ENTO Investigator’s Brochure (IB).


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1.2.1.
Preclinical Pharmacology and Toxicology
Entospletinib (ENTO) was evaluated in a standard battery of safety pharmacology studies to 
assess potential effects on central nervous, cardiovascular, and respiratory systems. ENTO had 
no effect on central nervous and respiratory system parameters evaluated in rats. In a 
cardiovascular safety pharmacology study in dogs, small increases in heart rate (up to a 
25% increase) were observed in male dogs given ENTO at 15, 50, or 150 mg/kg. While the 
higher heart rates were considered ENTO related, the relevance of these changes to humans is 
not known. Due to the observed increases in heart rate, a no observed effect level (NOEL) was 
not identified and the lowest observed effect level was 15-mg/kg. ENTO had no effect on ECGs 
or arterial blood pressure values at oral doses up to 150 mg/kg, the highest dose tested. 
Consistent with the lack of effect on ECG parameters, ENTO has no meaningful effect on the 
human-ether-a-go-go related gene (hERG), indicating that ENTO would not be expected to 
induce clinical QT prolongation. 
The toxicity of ENTO has been characterized in animal genotoxicity, embryo-fetal reproductive 
toxicity, and phototoxicity studies. Recently published data demonstrated that species-specific GI 
toxicity and lymphoid changes, similar to that which was observed following ENTO
administration to dogs, can occur in dogs but not rats, cynomolgus monkeys, or humans treated 
with p38 map kinase and mitogen-activated protein (MAP) kinase activated protein kinase-2 
(MK2) small molecule kinase inhibitors that inhibit pathways that overlap with SYK signaling 
pathways {Morris et al 2010}. Oral administration of ENTO to rats for up to 26 weeks or 
cynomolgus monkeys for up to 39 weeks showed no evidence of GI toxicity or lymphoid 
changes at exposures which overlapped with or exceeded those that resulted in acute toxicity in 
dogs. Furthermore, ENTO (administered as Entospletinib methanesulfonate (ENTO MSA)) has 
been previously investigated in healthy human subjects at doses up to 1200 mg twice a day for 
7 days and in subjects with rheumatoid arthritis (RA) at doses up to 900 mg twice a day for 
26 days and no evidence of GI or lymphoid toxicity was observed in these clinical studies. 
Therefore, the relevance of these findings to humans is not known.
ENTO inhibits uridine disphosphate glucuronosyltransferase 1A1 (UGT1A1) with an IC50 of 
2 μM. This enzyme is involved in glucuronidation of bilirubin, and inhibitors of UGT1A1 have 
the potential to produce increased levels of total and indirect (unconjugated) bilirubin in the 
circulation {Zhang et al 2005}. 
ENTO is considered non-genotoxic and administration of ENTO did not result in skin reactions 
indicative of phototoxicity in mice.
Administration of ENTO to pregnant female rats and rabbits from implantation to the closure of 
the hard palate (International Conference on Harmonisation [ICH] Harmonised Tripartite 
Guideline stages C to D) resulted in dose-dependent developmental findings including increased 
incidence of early and late fetal resorptions and reduced fetal weights, and delays in ossification 
of the forelimb phalanges (rats and rabbits) and metacarpals (rabbits only). These fetal findings 
occurred at ENTO doses that caused maternal toxicity as demonstrated in both studies by 
dose-dependent decreases in body weight gain and/or body weight loss and decreased food 
consumption of the dams. Maternal toxicity was also demonstrated in these studies at doses that 
did not result in developmental findings.


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1.2.1.1.
Non Clinical Pharmacology
For further information refer to ENTO Investigator’s Brochure (IB).
1.2.1.2.
Toxicology
In vitro and in vivo nonclinical studies were conducted to examine the potential toxicity of 
ENTO. In vivo studies were conducted in rats and dogs. Oral administration is proposed for the 
initial clinical trials; therefore, multiple-dose studies with ENTO were conducted via the oral 
route (gavage). 
Based on the totality of the data from the standard battery of in vitro and in vivo genotoxicity 
studies, ENTO is considered non-genotoxic. 
Further details can be found in the ENTO IB.
1.2.2.
Clinical Trials of Entospletinib (ENTO) 
To date, 16 clinical studies have been initiated with ENTO including a total of 566 subjects 
(including 328 healthy subjects, 7 subjects with RA, 76 subjects with CLL, 155 subjects with 
NHL; 26 subjects receiving placebo in Phase 1 and Phase 2 clinical studies. Of the 540 subjects 
receiving ENTO in these studies, ENTO has generally been well tolerated.
Positive results have been reported from a Phase 2 clinical trial with the putative SYK inhibitor 
fostamatinib showing objective anti-tumor responses in chronic lymphocytic leukemia (CLL) 
and Non-Hodgkin’s lymphoma (NHL) subjects {Friedberg et al 2010}.  These responses occurred 
despite off target toxicities that limited drug exposure. ENTO is a highly selective inhibitor of 
SYK and hence has the potential for an improved efficacy and tolerability profile in subjects 
with hematologic malignancies. 
ENTO is being evaluated in an ongoing Phase 2 clinical trial in subjects with relapsed or 
refractory CLL/NHL. A Phase 1b/2 clinical trial is being conducted for subjects with ENTO 
monotherapy and in combination with chemotherapy in subjects with acute myeloid leukemia 
(AML) and acute lymphocytic leukemia (ALL).
ENTO has been studied in single and multiple ascending dose studies in 304 healthy subjects, 
7 subjects with rheumatoid arthritis who were on stable doses of methotrexate, 80 subjects with 
CLL and 95 subjects with NHL.  Of these subjects, 460 received ENTO and 26 received placebo.  
In Pharmacokinetic (PK) studies at steady state in healthy subjects, ENTO was well tolerated 
when given in a fasted state for 7 days at doses of 25, 75, 200, 600, 900, and 1200 mg twice daily 
(GS-US-245-0101) and when given in a fed state for 6 days at doses of 100 and 900 mg 
twice daily (GS-US-245-0106), for 4 days at doses of 200 and 600 mg twice daily 
(GS-US-339-0101), and at 1200 mg twice daily for 5 days (GS-US-339-0109).Exposure, as 
measured by AUC and maximum concentration Cmax, did not increase appreciably at doses 
above 600 mg under fasted condition. 


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To provide a margin for inter-patient variability, a dose of 900 mg twice daily was chosen for the 
study of subjects with rheumatoid arthritis receiving stable doses of methotrexate in Study 
GS-US-245-0101.  A dose of 900 mg ENTO twice daily was given in a fasted state for 26 days 
in 7 subjects.  The median AUCtau in these subjects was similar to that of the healthy subjects.  In 
general, this dose was well tolerated.   One subject developed reversible, Grade 2 alkaline 
phosphatase and transaminase elevations starting 7 days after her last dose of ENTO, concurrent 
with new onset of a bronchopneumonia.  One other subject reported not feeling well and 
experienced hot flashes, fever, shivers, rash, headache, dizziness, and fainting 1 day after her last 
dose of ENTO with reversible Grade 1 alkaline phosphatase and Grade 3 transaminase elevations 
which peaked 1 week later.  While these events are potentially confounded by concurrent 
illnesses, hepatic enzymes will be closely monitored during this study.
Consistent with the known inhibition of UGT1A1 by ENTO, 8 of the 178 healthy subjects 
developed asymptomatic indirect bilirubin elevations (6 Grade 1, 1 Grade 2 and 1 Grade 3) that 
resolved following discontinuation of the drug.  Three of the 7 subjects with rheumatoid arthritis 
who received ENTO for 26 days developed asymptomatic indirect bilirubin elevations 
(2 Grade 1, 1 Grade 3) which improved despite continued dosing.
Common AEs from an on-going Phase 2 study evaluating chronic administration of ENTO
monotherapy in 186 subjects with hematologic malignancies are fatigue (53.2%), 
nausea (45.2%), diarrhea (38.7%), decreased appetite (24.7%), constipation (23.7%), 
cough (21.0%), and headache (21.0%) as of 21 November 2014. One out of a total of 
201 subjects (0.5%) experienced pneumonitis in this monotherapy study as of 11 March 2015.
1.2.3.
Interaction with Proton Pump Inhibitors
In Study GS-US-245-1222, omeprazole co-administration reduced ENTO AUCtau by 
59% following ENTO BIS-MSA 400 mg BID (solid dispersion formulation). Available 
solubility and clinical PK data strongly imply that the observed interaction between ENTO and 
PPIs is due to elevated gastric pH, leading to reduced ENTO absorption. ENTO solubility is 
known to be highly pH-dependent, with aqueous solubility of 10 mg/mL at pH 2 but 
<0.15 mg/mL at pH ≥3.0, suggesting that PPIs are likely to reduce ENTO absorption due to 
increased gastric pH. In Study GS-US-245-1222, the ENTO terminal elimination half-life was 
similar when ENTO was administered alone (median [Q1, Q3] 14.89 [11.86, 21.36] hours) or 
with omeprazole (13.65 [10.49, 17.04] hours), demonstrating that the reduced ENTO exposure 
observed with omeprazole is likely a result of reduced absorption, rather than a result of altered 
elimination. Furthermore, omeprazole is a known inhibitor of CYP2C19 {Angiolillo et al 2011}
however in vitro studies did not identify a role of CYP2C19 in ENTO metabolism. In addition, 
CYP inhibition by omeprazole would be expected to result in increased drug exposure of 
susceptible substrates, whereas significantly decreased ENTO exposure was observed with 
omeprazole co-administration in healthy volunteer studies.
Please refer to Section 1.4 of the protocol for further discussion of the dosing implications of PPI 
co-administration with ENTO in this study.


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1.3.
Rationale for This Study
Given the emerging role of B cells in cGVHD (abnormal response to BAFF, errors in B cell 
reconstitution/differentiation, BCR signaling via SYK or BTK, failed induction of B cell 
tolerance), ENTO, in a dose responsive manner, induces ex vivo apoptosis of a population of 
B cells present only in patients with active cGVHD, and the proof-of-concept studies with 
rituximab demonstrating that B cell targeted therapy shows benefit in cGVHD
(see Section 1.1.1.1), Gilead is pursuing an investigation into whether ENTO is an effective 
treatment for cGVHD. Study GS-US-406-1840 is designed to evaluate the efficacy and 
tolerability of ENTO in addition to systemic corticosteroids in subjects at the time of initial 
diagnosis of cGVHD requiring treatment. Safety reviews will be performed in real time and will 
include evaluations of clinical laboratory abnormalities, relapse of primary malignancy, physical 
examinations, vital signs and AE reporting.
1.4.
Rationale for Dose Selection 
Since the target coverage necessary to achieve efficacy in subjects cannot be established in 
ex vivo experiments or animal models, the objective for dose selection is to achieve >50% target 
inhibition (% inhibition in stimulated CD63+ basophils) at trough. At 200 mg twice daily of 
ENTO BIS-MSA, the degree of inhibition of CD63+ cells is ~50% at steady state Ctrough. 
However, the majority of cGVHD subjects are administered proton pump inhibitors (PPIs), 
which would be expected to decrease target inhibition below 50% at this dose. At an ENTO
BIS-MSA dose of 400 mg twice daily in the presence of a PPI, target inhibition at Ctrough is 
~50%. Thus, the selected dose in cGVHD is 400 mg twice daily of ENTO in patients currently 
taking a PPI, and 200 mg twice daily of ENTO in patients not currently taking a PPI.
Furthermore, ENTO has a safety profile that is acceptable for subjects receiving treatment for 
malignancy (including cGVHD subjects). In studies with ENTO, the rate of Grade 3 or 4 
AST/ALT elevations is between 10-14%, and these events are reversible with interruption of 
dosing. Reversible episodes of elevated indirect bilirubin (≥ Grade 1) occur in ~11% of subjects.
1.5.
Risk/Benefit Assessment for the Study
Chronic GVHD remains a highly morbid disease with a high mortality rate, and given the 
cumulative safety data in healthy volunteers and patients with hematologic malignancies, the 
safety profile of ENTO is expected to be similar in cGVHD patients. ENTO is 
immunomodulatory, and even though ENTO has not been associated with an increased rate of 
infections in clinical studies in hematologic malignancy, serious infections are events of interest 
in this population as patients with cGVHD have a high rate of infections. Any 
immunomodulatory agent has a theoretical risk of decreasing the graft versus tumor effect, and 
malignancy relapse is also an event of interest in this study. However, as SYK inhibition affects 
primarily B cell function and not T-cell function, loss of the graft versus tumor effect is not 
expected as a result of treatment with ENTO. ENTO is associated with transaminase elevations 
and bilirubin increases, but these episodes have been reversible. The evaluation of safety of 
ENTO administration in the cGVHD population is facilitated in this study with the inclusion of a
placebo control group.


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Refer to the IB for full details of prior and ongoing pre-clinical and clinical studies including 
summary safety and efficacy data. 
1.6.
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 primaty objective is: 
To evaluate the effect ofENTO on the best overall response rate (BORR) as assessed by the 
cGVHD Activity Assessment (NCAA) by 24 weeks in the setting of add-on to systemic 
cotiicosteroids as patt of first-line therapy for cGVHD 
The key secondaty objectives al'e: 
• 
To evaluate the effect of ENTO on the skin domain of the Lee Symptom Scale (LSS) 
(Appendix 6) at 24 weeks 
• 
To evaluate the effect ofENTO on the mouth domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the eyes domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the total score of the LSS at 24 weeks 
Additional secondaty objectives include: 
• 
To evaluate the effect ofENTO on dmation of response (DOR) 
• 
To evaluate the effect of ENTO on dose reduction of cotiicosteroids 
• 
To evaluate the effect ofENTO on initiation of second-line therapy for cGVHD 
• 
To evaluate the effect of ENTO on progression of cGVHD 
• 
To evaluate the safety and tolerability ofENTO 
Exploratmy objectives include: 
I 
I 
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3. 
STUDY DESIGN 
3.1. 
Endpoints 
The primary endpoint of this study is: 
Final 
Amendment 2.0 Global 
• 
The primary endpoint is BORR as assessed by the NCAA by 24 weeks in the setting of 
add-on to systemic corticosteroids as part of first-line therapy for cGVHD 
The key secondary endpoints are: 
• 
Change from Baseline in the skin domain of the LSS at 24 weeks 
• 
Change from Baseline in the mouth domain ofthe LSS at 24 weeks 
• 
Change from Baseline in the eyes domain ofthe LSS at 24 weeks 
• 
Change from Baseline in the total score ofthe LSS at 24 weeks 
Other secondary endpoints include: 
• 
DOR 
• 
Proportion of subjects who achieve at least 50% reduction in systemic corticosteroid dose 
relative to baseline 
• 
Proportion of subjects who initiate second-line therapy for cGVHD 
• 
Failure-free survival (FFS) 
• 
Safety and tolerability of ENTO 
Exploratory endpoints ofthis study include: 
I 
I 
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3.2.
Study Design
This protocol describes a randomized, double-blind, placebo-controlled multicenter study to 
evaluate the efficacy and safety of ENTO (Treatment Arm 1) vs. placebo (Treatment Arm 2) in 
combination with systemic corticosteroids for subjects with cGVHD.  
A total of 100 eligible subjects will be randomized in a 1:1 manner to ENTO (Treatment Arm 1)
or placebo-to-match (PTM) (Treatment Arm 2), and treated for 48 weeks during the blinded 
phase. Randomization will be stratified by the following 2 factors at the Baseline/Day 1Visit:
Stratification Factor
Stratification Levels
Calcineurin inhibitor or MMF use
Yes vs. No
Disease severity as determined by the 2014 NIH 
Consensus cGVHD criteria
Moderate cGVHD:

≥ 1 organ with score = 2, or

≥ 3 organs with score = 1, or

lung score = 1
Severe cGVHD:

any organ score = 3 or

lung score ≥ 2
The final analysis for BORR is planned when all subjects have been on study for 24 weeks.  All 
subjects will be followed up to 48 weeks for DOR evaluation.  At the Week 48 visit, subjects
who are still on investigational treatment (ENTO or PTM) and are eligible to remain on study
will have the option to receive open-label extension (OLE) with ENTO. This OLE offers patients
who are deriving a benefit from ENTO or those with no alternative treatments the opportunity 
for further therapy for a serious and life threatening disease.
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study, perform interim reviews of safety data at regular intervals approximately every 3 months, 
and perform an interim review of efficacy data for futility when approximately 50% of subjects 
have been on study for 24 weeks, as described in the DMC Charter.  The first DMC meeting will 
be conducted after the 20th subject has been on study for 4 weeks.  The DMC will provide 
recommendations to Gilead as to whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the study in the best interests of 
the participants, whether the study should continue as planned, or the study should continue with 
modifications. 
3.3.
Study Treatments
After 48 weeks of blinded treatment, subjects who are still on investigational treatment (ENTO 
or PTM) and are eligible to remain on study will have the option to receive open-label extension 
(OLE) with ENTO and attend visits per the schedule of assessments (Table 6-1) for an additional 
96 weeks.
Subjects who provide written informed consent and meet all eligibility criteria will be 
randomized in a 1:1 fashion to either Treatment Arm 1 or Treatment Arm 2.  


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Subjects will retum for study visits at Weeks: 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48. At the 
Week 48 visit subjects who aTe still on investigational treatment (ENTO or PTM) and are 
eligible to remain on study will have the option to palticipate in the OLE. If subjects elect not to 
emoll in the OLE phase of the trial, they will retum for a 30-day follow-up visit. 
Subjects that will continue in the OLE phase of the trial will retum for the following study visits 
at Weeks: 50, 52, 56, 60, 64, 72 and visits evety 12 weeks thereafter. NOTE for subjects 
receiving tacrolimus, cyclosporine or MMF: For subjects receiving these medicines at 
emolment and are continuing on these medicines, the blood levels of tacrolimus, cyclosporine or 
the active metabolite ofMMF (MPA) will be monitored at baseline/Day 1 (prior to starting 
ENTO or PTM), on Day 2 or Day 3 and Day 6 or Day 7 after initiating ENTO or PTM, and at 
the end of Week 2 and Week 50 shtdy visit. Beyond these time points, concentration monitoring 
for tacrolimus, cyclosporine and MPA should follow the treating instihttion's protocol and 
therapeutic range for monitoring these medicines. For subjects who initiate these medicines 
while ah·eady receiving ENTO or PTM, concentration monitoring for tacrolimus, cyclosporine 
and NIP A should follow the treating institution's protocol and therapeutic range for monitoring 
these medicines. When a concentration sample is taken at a local lab in accordance with the 
treating institution's protocol for monitoring these medications, a sample may also be requested 
for central lab analysis. 
PPD 
Figure 3-1. 
Study Schema 
Baseline 
(Day 1)1 
Week 2• 
I 
Week48' 
Screening 
Treatment Arm 1: Entospletinib + Systemic corticoids 
for 48 weeks (n=50)b 
30 Day 
F /t; 
Treatment Arm 2: Placebo+ Systemic corticoids 
for 48 weeks (n=50) b 
Open-Label Extension 
Entospletinibd 
a 
Following the Baseline/ Day 1 visit subjects will return to the clinic for visits at Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 
48. 
b 
For subje.cts receiving tacrolinms, cyclosporine or MMF the blood levels of tacrolinms, cyclosporine or the active metabolite 
ofMMF (MPA) will be monitored at baseline/Day 1 (prior to statting ENTO or PTM), on day 2 or day 3 and day 6 or day 7 
after initiating ENTO or PTM, and at the end of Week 2 and Week 50 study visit. Beyond d1ese tin1e points, concentration 
monitoring for tacrolinms, cyclosporine and MPA should follow the treating institutions protocol and tllerapeutic range for 
monitoring these medicines 
c 
Subjects who complete tlle study through Week 48 and do not wish to continue to participate in d1e OLE phase of tlle trial 
will be required to return to d1e clinic 30 days after the completion of study dmg for a 30-Day Follow-up visit 
d 
After Week 48, subj ects who are still on investigational treatment (ENTO or PTM) and are eligible to remain on study will 
have the option to receive OLE for an additional96 weeks. Subjects will attend visits at Weeks: 50, 52, 56, 60, 64, 72 and 
every 12 weeks tllereafter. 
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e      The initial taper of prednisone from the starting dose of 1.0 mg/kg/day (or equivalent) may be attempted 14 days after co-
administration with ENTO/Placebo if there is evidence of improvement in cGVHD 
  
3.4.
Discontinuation Criteria
Subject participation may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree.

Unacceptable toxicity, 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

Relapse of primary disease  

Severity of cGVHD requiring therapy that is not allowed as concomitant therapy on study
(for example JAK inhibitor/BTK inhibitor /mTOR inhibitors/ any cell depletion 
agent/ phototherapy)

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 8

Discontinuation of the study at the request of Gilead, a regulatory agency or an 
Institutional Review Board or Independent Ethics Committee (IRB/IEC)
3.5.
Biomarker Testing
3.5.1.
Biomarker Samples to Address the Study Objectives:
Blood will be collected in this study and will be used to evaluate the effect of ENTO on markers 
relevant to cGVHD and/or the SYK pathway. The specific biomarkers may include, but are not
limited to the following:  cytokines, cell subset analysis, pathway markers, and/or other B-cell 
activating factor, B-cell function immunoglobulin levels, and/or antigen-specific B cell 
responses.
Because biomarker science is a rapidly evolving area of investigation, and adverse events in 
particular are difficult to predict, 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 art knowledge. 
The samples obtained for the study may be stored for 15 years after the end of the study.


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Optional Future Research 
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3.5.3. 
Optional Sub-study to study cellular turnover {Emson et al 2013, Ladell et al 
2008, Messmer et al 2005} 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 subjects who meet the inclusion/exclusion criteria will be enrolled. 
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) The ability to understand and sign a written informed consent form, which must be obtained 
prior to initiation of study procedures
2) 18-75 years of age, inclusive at Screening
3) Newly diagnosed cGVHD defined by: 
a) At least 100 days after receiving any allogeneic hematopoietic stem cell transplant 
AND 
b) Receiving a new course of systemic corticosteroids (1.0 mg/kg/day or prednisone 
equivalent) as first-line cGVHD therapy for at least 1 day and no more than 21 days prior 
to first dose of ENTO/Placebo   
AND
c) Moderate to severe cGVHD as assessed by NCDSC with at least three organ systems 
involved OR one organ system with a score of 2 OR lung organ score = 1 (Appendix 2)
4) Subjects who have undergone transplantation for benign indications are eligible for the study. 
Complete remission is required for subjects who have undergone transplantations for 
hematologic malignancies. 
5) Have either a normal ECG or one with abnormalities that are considered clinically 
insignificant by the investigator in consultation with the Sponsor 
6) A negative serum pregnancy test is required for female subjects (unless permanently sterile 
or greater than two years post-menopausal) 
7) A female subject is eligible to enter the study if it is confirmed that she is: 
a) Not pregnant or nursing
b) Of non-childbearing potential (i.e., women who have had a hysterectomy, have had both 
ovaries removed or medically documented ovarian failure, or are postmenopausal 


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women > 54 years of age with cessation (for 12 months) of previously occurring 
menses), or
c) Of childbearing potential (as defined in Appendix 8) and agrees to utilize a highly 
effective protocol-specified contraceptive method or be non-heterosexually active or 
practice sexual abstinence from Screening throughout the duration of study treatment and 
for 30 days following the last study drug dose
8) Male subjects of childbearing potential who engage in heterosexual intercourse must agree to 
use protocol specified method(s) of contraception as described in Appendix 8.
9) Both female and male subjects of childbearing potential who are receiving mycophenolate 
mofetil (MMF) must agree to utilize contraceptive measures in accordance with the current 
MMF SmPC and the precautions for ENTO outlined in Appendix 8, whichever is stricter. 
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Uncontrolled infection within 4 weeks prior to Randomization
2) History of the following therapies in the post-transplant period:
a) B cell depleting biologic agents
b) CD19 CAR-T cells based therapies 
c) BTK/SYK/JAK/PI3K inhibitors
d) Phototherapy-unless administered for aGVHD 
3) Treatment of cGVHD with anti-thymocyte globulins (ATG), or campath within 60 days of 
Screening visit  unless used for  treatment of acute GVHD
4) Severe organ dysfunction manifest during Screening period: 
a) Requiring supplemental oxygen at more than 2L/min
b) Uncontrolled arrhythmia or heart failure
c) Creatinine clearance (Cockroft-Gault) < 30 mL/min
5) Known hypersensitivity to the Investigational Medicinal Product (IMP), the metabolites, or 
formulation excipient.
6) Laboratory abnormalities including: 


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a) Human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen or hepatitis 
C antibody positive (Subjects with positive HCV antibody and without detectable HCV 
RNA are permitted to enroll) 
b) Aspartate aminotrasferase (AST)/Alanine aminotransferase (ALT) ≥ 2 X upper limit of 
normal (ULN) unless deemed to be secondary to Liver GVHD
c) Total bilirubin ≥2 X ULN unless deemed to be secondary to Liver GVHD
7) Positive serum pregnancy test (for female subjects) 
8) Any other clinical condition or prior therapy that, in the opinion of the investigator, would 
make the subject unsuitable for the study or unable to comply with dosing requirements 
9) Participation in any other clinical trial without prior approval from the sponsor is prohibited 
while participating in this trial 
10) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance or subject safety
11) Subjects receiving ongoing therapy with any of the following medications in the Table 5-2.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
Subjects will be assigned a screening number at the time of consent.  The Randomization and 
Baseline/Day 1 visit cannot occur until the Investigator has received the results of the Screening 
tests and subject eligibility has been confirmed. 
Once eligibility has been confirmed, each subject will be assigned a unique subject number. 
Once a subject number has been assigned to a subject, it will not be reassigned to any other 
subject. Prior to or during the Baseline/Day 1 visit, the investigator or designee will randomize 
the subject using an Interactive Web Response System (IWRS).  Subjects will be randomized in 
a 1:1 ratio to Treatment Arm 1 or Treatment Arm 2. The IWRS will assign blinded study drug 
bottle numbers at each study visit (except Weeks 2, 30 and 42).  Study drug will be dispensed to 
the subject in a blinded fashion until Week 48.  Randomization will be stratified by the following 
2 factors at the Screening and Baseline/Day1 Visit:
Stratification Factor
Stratification Levels
Calcineurin inhibitor or MMF use
Yes vs. No
Disease severity as determined at 
Screening by the NIH cGVHD 
Staging and Diagnosis Criteria 
(NCSDC) Global Severity Score
Moderate cGVHD:
≥ 1 organ with score = 2, or
≥ 3 organs with score = 1, or
lung score = 1
Severe cGVHD:
any organ score = 3 or
lung score ≥ 2
All Baseline/Day 1 tests and procedures must be completed prior the administration of the first 
dose of the study drug. The subject must complete the Baseline procedures prior to 
randomization and drug dispensation. Initiation of treatment with the study drug must take place 
within 24 hours after the Baseline/Day 1 visit.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IXRS system 
for that subject.  Gilead recommends but does not require that the investigator contact the 
Gilead medical monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the case report 
form/ electronic case report form (eCRF), along with the date on which the treatment assignment 
was obtained. The investigator is requested to contact the Gilead medical monitor promptly in 


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case of any treatment unblinding. Blinding of study treatment is critical to the integrity of this 
clinical trial and therefore, if a subject’s treatment assignment is disclosed to the investigator, the 
subject will have study treatment discontinued. All subjects will be followed until study 
completion unless consent to do so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.2.
Description and Handling of Study Drug
5.2.1.
Formulation
ENTO is available as 200-mg strength tablets. ENTO 200 mg tablets are blue, plain-faced, 
capsule-shaped, film-coated tablets. Each tablet contains the equivalent of 200 mg Entospletinib
free base in the form of Entospletinib bismesylate monohydrate (ENTO BIS-MSA). In addition 
to the active ingredient, ENTO tablets contain the following inactive ingredients: 
methanesulfonic acid, hydroxypropyl methylcellulose, mannitol, microcrystalline cellulose, 
crospovidone, poloxamer 188, silicon dioxide, magnesium stearate, polyethylene glycol, 
polyvinyl alcohol, talc, titanium dioxide, and FD&C blue #2 aluminum lake.
Placebo-to-match (PTM) tablets 200 mg are blue, plain-faced, capsule-shaped, film-coated 
tablets. Each tablet contains the following inactive ingredients: lactose monohydrate, 
microcrystalline cellulose, crospovidone, magnesium stearate, polyethylene glycol, polyvinyl 
alcohol, talc, titanium dioxide, and FD&C blue #2 aluminum lake. 
5.2.2.
Packaging and Labeling
ENTO (GS-9973) 200-mg and PTM tablets are packaged in white, high-density polyethylene 
(HDPE) bottles. Each bottle contains 60 tablets, silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant polypropylene 
screw cap with an induction-sealed and aluminum-faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
5.2.3.
Storage and Handling
Study drug (ENTO and PTM) 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. 


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Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure through inhalation when handling.
5.3.
Dosage and Administration 
ENTO and PTM tablets will be provided by Gilead Sciences.  
ENTO or PTM should be taken under fasted conditions. Fasting is defined as no food or liquids 
other than water for 2 hours pre- and 1 hour post-dose. Subjects unable to swallow tablets should 
contact Gilead Medical Monitor for guidance. If vomiting occurs within 30 minutes after IMP 
administration and undissolved tablets are present in the vomitus, the subject should take another 
dose.
Study medication will be adjusted for whether the subject is taking a proton pump inhibitor (PPI) 
per the following table, both at study entry and throughout the study.
PPI status
ENTO or PTM dose
Subject is taking PPI
400 mg (2 x 200 mg tablet) twice daily 
Subject is NOT taking PPI
200 mg (1 x 200 mg tablet) twice daily 
5.4.
Prior and Concomitant Medications 
Systemic corticosteroids are required at study entry. Administration and taper recommendations 
are below:

Prednisone: administered initially as a single early morning dose of 1.0 mg/kg/day 
[or equivalent (Adults: maximum dose 100 mg)]. If due to formulation of prednisone tablets 
1.0 mg/kg/day is not possible, we allow a range of 0.90 to 1.10 mg/kg/day. 

Prednisone therapy continues at the initial dose until there is objective evidence of 
improvement in manifestations of cGVHD (ie, a PR or better), minimum of 14 days of co-
administration of ENTO/Placebo and prednisone. 

The initial taper of prednisone from the starting dose of 1.0 mg/kg/day (or equivalent) may 
be attempted 14 days after co-administration with ENTO/Placebo if there is evidence of 
improvement in cGVHD

If exacerbation or recurrence of cGVHD is evident at any step of the taper, the dose of 
prednisone should be increased promptly by 2 levels, with daily administration for 2 to 
4 weeks, followed by resumption of alternate-day administration. Please see Table 5-1 for 
tapering. 


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Table 5-1.
Tapering of Prednisone after reaching PR/CR
Week 
Dose, mg/kg body weight (example for 80kg patient in mg)
0
1.0 once a day (80)
1-3
1.0/0.5 (to begin within 1 week after objective improvement, 
alternating days) (80/40/80)
4-5
0.5 once a day (40)
6-7
0.5  every other day (40/0/40)
8-9
0.25 every other day  (20/0/20)
10
0.1 every other day (10/0/10) with ultimate goal of complete discontinuation of 
Prednisone

Inhaled and topical steroids (eg, Budesonide/ Beclomethasone) are not considered 
second-line therapy and are permitted throughout the duration of the study. Addition of the 
aforementioned agents will be recorded in the eCRF for posterior analysis.   

Local organ-specific treatment (eg, eye drops) will be recorded in the eCRF and assessment 
of response after local organ-specific treatment will be based on the NCAA.
Co- Administration of ENTO with Other Classes of Immunosuppresant Agents during OLE:

During the extension phase (post 96 weeks of study) or OLE, for patients who are eligible to 
remain on study, the maximum period of co-administration of ENTO with Cyclosporine, 
Tacrolimus or MMF should not exceed 3 months. The sponsor envisions that if the subject 
has stable or refractory disease, they should be transitioned to other forms of therapies within 
this 3 month period.
Disallowed Medications: 
Published clinical data suggests that the combination of ENTO with Idelalisib resulted in an 
unexpected pneumonitis syndrome attributed to excessive mammalian target of rapamycin–like 
activity. Although pneumonitis has been reported with all mTOR inhibitors, the exact incidence 
of this toxicity seems to vary widely from study to study. Therapeutic inhibition of kinases 
involved within the BCR signaling cascade is an emerging field, and many questions remain and 
for this reason, the co-administration of SYK inhibitors with PI3K inhibitors is strongly 
discouraged.
In vivo and in vitro data indicates that ENTO is a substrate of CYP2C9 and CYP3A. 
Co-administration of CYP2C9 inhibitors or inducers may increase or decrease ENTO exposure, 
respectively. As such, co-administration of moderate and strong CYP3A and CYP2C9 inducers
and strong CYP2C9 inhibitors are prohibited in this study. Caution should be exercised when 
co-administering drugs that are moderate inhibitors of CYP2C9 (eg fluconazole, voriconazole or 
amiodarone) as they may increase ENTO exposure. Administration of strong and moderate 
CYP3A and CYP2C9 inducers, and strong CYP2C9 inhibitors, is also prohibited for 2 weeks 
prior to study drug administration. Examples of strong CYP2C9 inhibitors and moderate/strong


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CYP3A and CYP2C9 inducers, PI3K inhibitors, and other medications that are prohibited in this 
study are provided in Table 5-2


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Table 5-2.
Examples of Prohibited Agents
Drug Class
Examples of Prohibited Agents (but not limited to)
mTOR inhibitor
Everolimus, sirolimus
Any cell depleting antibody
Rituxan®
Phototherapy
Phototherapy
BTK agents
Ibrutinib
JAK inhibitors
Tofacitinib, ruxolitinib
Moderate CYP3A/2C9 inducers
Bosentan, modafinil, nafcillin, ritonavir, efavirenz, thioridazine, lopinavir, 
etravirine, lersivirine, talviraline, tipranavir/ritonavir, semagacestat 
Strong CYP3A/2C9 inducers
Rifampin, mitotane, avasimibe, phenytoin, carbamazepine, enzalutamide, St 
John’s Wort, rifabutin, phenobarbital
Strong CYP2C9 inhibitors
Miconazole (systemic)
PI3K inhibitors
Idelalisib
Herbal/Natural Supplements 
St. John’s Wort 
Use with Caution: 
In vitro data indicates that Entospletinib has the potential to inhibit several transporters and the 
metabolizing enzyme UGT1A1, which may affect the plasma concentrations of substrates of 
these transporters and/or enzyme. Caution should be exercised when 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. A list of sensitive substrates of this enzyme and/or transporters 
is provided below; any use of these medicines should be discussed with the medical monitor.
Table 5-3.
List of Sensitive Substrates of UGT1A1, OATP1B1, OATP1B3, P-gp 
and BCRP
Transporter
Substrate
P-gp
Aliskiren, aldosterone, ambrisentan, colchicine, dasatinib, dabigatran etexilate, 
dexamethasone, digoxin, diltiazem, domperidone, etoposide, fexofenadine, imatinib, 
itraconazole, ivermectin, loperamide, lapatinib, maraviroc, methylprednisolone, 
nilotinib, posaconazole, quinidine, ranolazine, saxagliptin, sitagliptin, sparfloxacin, 
talinolol, tolvaptan, topotecan, vinblastine
BCRP
Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, 
sulfasalazine, topotecan
OATP1B1
Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, SN-38 (active metabolite 
of irinotecan), rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide,  
valsartan, olmesartan
OAPT1B3
Atorvastatin, rosuvastatin, pitavastatin, telmisartan, valsartan, olmesartan
UGT1A1
Acetaminophen, atorvastatin, bropirimine, carvedilol, clofibrate, ezetimibe, 
flavopiridol, gemfibrozil, genistein, nalorphine, naltrexone, naringenin, raloxifene, 
SN-38, simvastatin, telmisartan, troglitazone


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In a study in healthy volunteers, Entospletinib 400 mg twice daily increased rosuvastatin 
exposure by approximately 3-4-fold, which may theoretically increase the risk of 
rhabdomyolysis. In reviewing the safety of subjects whom have received a statin with
Entospletinib there have been no reports of rhabdomyolysis nor a different adverse events 
profile, but in the interest of caution, the following restrictions apply to the use of HMG-CoA 
reductase inhibitors with Entospletinib:
HMG-CoA reductase inhibitor
Dose Adjustment Required
Atorvastatin
Maximum dose 20 mg QD
Rosuvastatin
Maximum dose 10 mg QD
Pravastatin
Maximum dose 20 mg QD
Simvastatin
Maximum dose 20 mg QD
Lovastatin
Maximum dose 20 mg QD
Fluvastatin
Maximum dose 20 mg QD
5.5.
Opportunistic Infections and Prophylactic Regimens
Patients with ongoing cGVHD or continued use of immunosuppressive therapy should be 
considered as immune deficient and at risk for significant infectious complications. Thus, 
prophylaxis for opportunistic infection according to institutional treatment standards are 
mandated. For additional questions please refer to IDSA guidelines{Tomblyn et al 2009}. 
Specifically, CMV surveillance is mandated and in case of clinical infection or the need for 
preemptive CMV treatment, investigational treatment must be discontinued.
5.6.
Accountability for Investigational Medicinal Product 
The investigator is responsible for ensuring adequate accountability of all used and unused IMP.
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
Study drug accountability records will be provided by Gilead Sciences (or equivalent 
documentation maintained by the study site) to:

Record the date received and quantity of IMP bottles

Record the date, subject number, subject initials, the IMP bottle number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
5.6.1.
Investigational Medicinal Product Return or Disposal
IMP return and disposal will be performed as outlined in Section 9.1.6.


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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 the schedule of assessment 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).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that each subject is eligible for the study 
before enrollment in the study.  Please refer to Section 5.1 for details about randomization and 
treatment assignment.  
6.2.
Study Assessments 
Study procedures are outlined in Table 6-1.


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Table 6-1.
Schedule of Assessments
Visit
Screeninga
Baseline/
Day1c
END OF WEEK b
Every 12 
Weeks
30 
Day 
Follo
w-up
2t
4
8
12
16
20
24
30
36
42
48/
ESDDd
50
52
56
60
64
72
Visit Window
-30 days
0
3
3
3
3
3
3
3
5
5
5
5
3
3
3
3
3
5
5
Written Informed 
Consent
X
Medical History 
X
Smoking Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete 
Physical Exam
X
X
X
X
X
Symptom-
Directed Physical 
Exame
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
Testf
X
Urine Pregnancy 
testf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum FSHf
X
NIH cGVHD 
Diagnosis and 
Staging Criteria u
X
NIH cGVHD 
Activity 
Assessment
(NCAA) Form  A
with spirometryg
Xg
X
X
X
X
X
Xg
X
X
X
Xg
X
X
X
X
NIH cGVHD 
Activity 
Assessment
(NCAA) Form Bh  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lee Symptom 
Scale (LSS)h 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Visit
Screeninga
Baseline/
Day1c
END OF WEEK b
Every 12 
Weeks
30 
Day 
Follo
w-up
2t
4
8
12
16
20
24
30
36
42
48/
ESDDd
50
52
56
60
64
72
Visit Window
-30 days
0
3
3
3
3
3
3
3
5
5
5
5
3
3
3
3
3
5
5
Primary disease 
assessment per 
institutional 
guidelines  
X
X
   
X
Height 
X
Vital Signs & 
Weighti
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematologyj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistryk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Analysisl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Metabolic Panel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1, HBV, & 
HCV Serologym 
X
12 lead ECG-
performed supine 
X
X
X
PKn
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitoring of 
calcineurin 
inhibitors and 
MPA o
X
X
X
Biomarkersp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PFTs
X
X
X
Randomize 
X
Drug Dispensingq
X
X
X
X
X
X
X
X
X
X
X
X
X
Written Informed 
Consent for OLE
X


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Visit
Screeninga
Baseline/
Day1c
END OF WEEK b
Every 12 
Weeks
30 
Day 
Follo
w-up
2t
4
8
12
16
20
24
30
36
42
48/
ESDDd
50
52
56
60
64
72
Visit Window
-30 days
0
3
3
3
3
3
3
3
5
5
5
5
3
3
3
3
3
5
5
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medicationsr 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Evaluations to be completed within 30 days prior to Day 1. 
b
All study visits are to be scheduled relative to the Day 1 visit date. 
c
Initiation of treatment with the study drug must take place within 24 hours after the Baseline/Day 1 Visit
d
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug 
e
Symptom-directed physical exam as needed 
f
FSH: For female subject post-menopausal for less than two years, if FSH 40 mIU/ mL a serum pregnancy test will be required.  Women determined to be of child bearing 
potential will have a serum pregnancy test performed at screening.  All subsequent visits will have a urine test, and positive urine pregnancy tests will be confirmed with a 
serum test. During OLE, urine pregnancy test will be performed every 4 weeks starting with end of visit Week 64.
g
NCAA Form A (Appendix 5) with spirometry measures will be completed by the Investigator or Sub-I. In the OLE this will be assessed at Weeks 56, 60, 64, 72 and every 12 
weeks thereafter. NCAA should also be performed at the time of initiation of second-line therapy. Walk test to be performed at Baseline/Day 1, Weeks 24 and 48/ESDD when 
medically feasible. Trained study personnel may complete spirometry and walk test portion.
h
LSS (Appendix 6) and the NCAA Form B (Appendix 5) is to be completed by the subject. The subject is to read the questionnaire by himself/herself and write/mark answers 
directly onto the questionnaire. In the OLE this will be assessed at Weeks 56, 60, 64, 72 and every 12 weeks thereafter. The LSS and the NCAA Form B should also be 
administered at the time of initiation of second-line therapy.
i
Vital sign measurements include blood pressure, pulse, respiration rate, weight and temperature
j
Complete blood count (CBC) with differential platelet count 
k
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorous, magnesium, potassium, sodium, uric acid, and amylase and (reflex lipase testing is performed in subjects with total amylase 
> 1.5 ULN) 
l
Urine collection for urinalysis and urine pregnancy test (if applicable) 
m
Subjects with positive HCV antibody and without detectable HCV RNA are permitted to enroll 
n
Randomly timed PK sampling.  Sites should enter the time of the last dose of study medication in the eCRF for sample reconciliation. PK samples will be drawn at Week 60 
and every 12 weeks in the OLE. 
o
For subjects receiving tacrolimus, cyclosporine or MMF the blood levels of tacrolimus, cyclosporine or the active metabolite of MMF (MPA) will be monitored at 
baseline/Day 1 (prior to starting ENTO or PTM), on day 2 or day 3 and day 6 or day 7 after initiating ENTO or PTM, and at the end of Week 2 and Week 50 study visit. 
Beyond these time points, concentration monitoring for tacrolimus, cyclosporine and MPA should follow the treating institutions protocol and therapeutic range for 
monitoring these medicines 
p
Assessments may include but are not limited to: cytokines, cell subset analysis, pathway markers, and/or other B-cell activating factor, B-cell function, immunoglobulin 
levels, and/or antigen-specific B cell response.  Timepoints may differ depending on the specific biomarker and will be outlined in the Central Lab Manual.  
q
At visit 2, 30,  42 and (OLE visit 50), study drug will not be dispensed at these visits 
r
Will include the following: systemic corticosteroid dose, other immunosuppressive, antimicrobials, PPI 


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s
PFTs will include spirometry with bronchodilator, and diffusing capacity of the lungs for carbon monoxide (DLCO). PFTs will be done at ESDD, if ESDD visit greater than 
12 weeks from Baseline. Any PFT done within 30 days prior to randomization can be used in lieu of Screening PFT.
t
The initial taper of prednisone from the starting dose of 1.0 mg/kg/day (or equivalent) may be attempted 14 days after co-administration with ENTO/Placebo if there is 
evidence of improvement in cGVHD
u
Local lab results may be used to establish diagnosis of liver cGVHD


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6.2.1.
Screening Visit
Written informed consent must be obtained from each subject before initiation of any visit 
procedures. After a subject has provided informed consent, the investigator and other study 
personnel (listed on the Form FDA 1572) will determine if the subject is eligible for participation 
in the study.  Subjects will be screened within 30 days before the Baseline/Day 1 visit to 
determine eligibility for the participation in the study.  This assessment will include review of the 
Inclusion/Exclusion criteria and completion of all Screening visits procedures as outlined in 
Table 6-1.  
Screening visit procedures will include the following for all subjects that provide informed 
consent: vital signs (including height and weight), medical history, smoking status, complete 
physical examination, 12-lead ECG (performed supine), concomitant medications, serum 
pregnancy test (for women of child bearing potential), serum FSH (if applicable), primary 
malignancy assessment (if applicable), complete the NCDSC (local lab results may be used to 
establish diagnosis of liver cGVHD), blood draws for the following tests: hematology, 
chemistry, metabolic panel, HIV-1, HBV, and HCV serology unless specified otherwise.  Urine 
will be collected for urinalysis. 
Pulmonary function tests (PFTs) will be required at Screening: spirometry with bronchodilator 
and diffusing capacity of the lungs for carbon monoxide (DLCO). Per institutional guidelines 
Investigators may seek specialist examination for PFTs, ocular and gynecological involvement, 
and other items as described in the NCDSC.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30 days from the Screening visit for randomization into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (eCRF).  All 
other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF.  
See Section 7. for additional details.
6.3.
Baseline/Day 1 Visit 
The following evaluations are to be completed at the Baseline/Day 1 visit. The Investigator must 
confirm subject eligibility prior to randomization. Initiation of treatment with the study drug 
must take place within 24 hours after the Baseline/Day 1 visit. 
Baseline/Day 1 visit procedures will include the following: review of adverse events and 
concomitant medication use.  Sites will obtain: vital signs (including weight), complete physical 
exam, smoking status, primary malignancy assessment (if applicable), NCAA and LSS.  Blood 
will be collected for the following tests: hematology, chemistry, metabolic panel, Blood 
specimens for selected biomarkers will be collected at Baseline, and urine for urine pregnancy 
test (if applicable) and urine analysis. 


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Amendment 2.0 Global 
NCAA Form A should be completed by the Investigator or Sub-Investigator; trained study 
personnel may complete the spirometry and walk test portion. The NCAA Form Band the LSS 
should be completed by the subject. Subject is to read questionnaire by himself/herself and 
write/mark answers directly on the questionnaire. 
Eligible subjects will be randomized in the IXRS to obtain the subject number. Study drug will 
be dispensed in a blinded fashion. Subjects should initiate dosing of study drug within 24 hours 
ofthe Baseline/Day 1 visit. 
ENTO or PTM should be taken under fasted conditions. Fasting is defined as no food or liquids 
other than water for 2 hours pre- and 1 hour post-dose. Subjects should be instructed not to bite 
or chew the tablets. In case of breakage of the tablets in the oral cavity, additional water should 
be taken as a rinse. Subject should be counseled on the importance of taking study medication 
daily and to return study medication bottles to each visit. 
6.4. 
Treatment Assessments (Weeks 2-48 and OLE) 
Evaluations listed in Table 6-1 are to be completed at the end of Weeks: 2, 4, 8, 12, 16, 20, 24, 
30, 36, 42 and 48 in blinded fashion. For subjects continuing in the OLE the evaluations listed in 
Table 6-1 are to be completed at the end of Weeks: 50, 52, 56, 60, 64,72 and every 12 weeks 
thereafter up to Week 144 or, until unacceptable toxicity, withdrawal of consent by subject or 
withdrawal from study by investigator, or until ENTO becomes commercially available. 
Study visits are to be completed within ±3 days, for Weeks 2-24, and Weeks 50-64. Study visits 
are to be completed within ±5 days for Weeks 30-48 and Weeks 72-144. NOTE for subjects 
receiving tacrolimus, cyclosporine or MMF: For subjects receiving these medicines at 
enrolment and are continuing on these medicines, the blood levels oftacrolimus, cyclosporine or 
the active metabolite of MMF (MP A) will be monitored at baseline/Day 1 (prior to starting 
ENTO or PTM), on Day 2 or Day 3 and Day 6 or Day 7 after initiating ENTO or 
placebo-to-match (PTM), and at the end of Week 2 and Week 50 study visit. Beyond these time 
points, concentration monitoring for tacrolimus, cyclosporine and MPA should follow the 
treating institution's protocol and therapeutic range for monitoring these medicines. For subjects 
who initiate these medicines while already receiving ENTO, concentration monitoring for 
tacrolimus, cyclosporine and MPA should follow the treating institution's protocol and 
therapeutic range for monitoring these medicines. When a concentration sample is taken at a 
local lab in accordance with the treating institution's protocol for monitoring these medications, 
a sample may also be requested for central lab analysis. 
At all visits the following will occur: review of adverse events (AEs) and changes in concomitant 
medications, vital signs (including weight), primary malignancy assessment (if applicable), 
blood for hematology, chemistry, metabolic anel, and urine for: regnancy test if applicable), 
and urinalysis. PPD 
~------------------------------------------------~ 
PFTs will be required at on treatment Weeks 24 and 48 only: spirometry with bronchodilator and 
diffusing capacity ofthe lungs for carbon monoxide (DLCO) 
ECG will be performed at on treatment Weeks 24 and 48 only. 
CONFIDENTIAL 
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Blood specimens for selected biomarkers will be collected at Screening, Baseline and at Weeks: 
2, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, 50, 52, 56, 60, 64, 72, every 12 weeks thereafter , 30 Day 
Follow-up and ESDD (if applicable). The timepoints may differ depending on the specific 
biomarker and will be outlined in the Central Lab manual. 
PK blood draws will be collected at Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48 and Week 60 
and every 12 weeks in the OLE. 
Smoking status will be collected at Weeks 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, 52, 56, 60, 64, 72 
and every 12 weeks thereafter.
Women determined to be of child bearing potential will have a urine test as listed in Table 6-1
and every 4 weeks during the OLE starting with Week 64. 
Complete physical exam will be performed at Weeks 12, 24 and 48, symptom directed physical 
exam will be completed as needed at all other visits.
NCAA Form A with spirometry should be completed by the Investigator or Sub-Investigator at 
all study visits (except Week 2) and during the OLE at Weeks 56, 60, 64, 72 and every 12 weeks 
thereafter. The NCAA Form A should also be performed at the time of initiation of second-line 
therapy. Situations where subjects have comorbid or irreversible conditions that may interfere 
with response assessment, the check box on the NCAA indicating that the abnormality is entirely 
explained by a non-GVHD documented cause should be marked. Organ-specific response 
measures may be delayed until the following visit to allow for resolution of a non-GVHD 
issue. All other organs should still be scored. A 2 min or 6 min walk test should be performed at 
Baseline/Day 1, Weeks 24 and 48/ESDD, when medically feasible. Trained study personnel may 
complete spirometry and walk test portion of NCAA Form A.
LSS and NCAA Form B should be completed by the subject.  The Subject is to read the 
questionnaire by himself/herself and write/mark answers directly on the questionnaire. The PROs 
will be completed at all study visits (except Week 2) and during the OLE will be assessed at 
Weeks 56, 60, 64, 72 and every 12 weeks thereafter. One question has been added to the LSS 
which asks which two domains are most impactful to the subject.
Document study drug dispensation and accountability for all study drugs dispensed. No study
drug will be dispensed at Weeks 2, 30, 42 and 50, drug accountability must be done at dispensing 
visits. 
6.5.
Post-treatment Assessments
6.5.1.
Unscheduled Visit 
A subject should attend an unscheduled visit if requested by the Sponsor or the investigator. The
assessments performed are at the investigator’s discretion.  


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For subjects that initiate second line therapy during the study, every attempt should be made to 
collect the NCAA and LSS at an unscheduled visit and to keep the subject in the study and study 
related follow-up procedures should be continued. 
6.5.2.
Early Study Drug Discontinuation (ESDD) 
If the subject discontinues study drug prior to the end of study, the subject will be asked to return 
to the clinic within 72 hours of stopping study drug for the Early Study Drug Discontinuation 
Visit.  The subject will be asked to continue attending the schedule study visits through Week 48. 
Subjects who ESDD will not be eligible for the OLE phase of the study. 
At the ESDD visit, any evaluations showing abnormal results indicating that there is a possible 
or probable causal relationship with the study drug, should be repeated weekly (or as often as 
deemed prudent by the investigator) until the abnormality is resolved, returns to baseline, or is 
otherwise explained. 
Evaluation listed in Table 6-1 will be completed at the ESDD visit.  
The following will be conducted at the ESDD: review of adverse events (AEs) and changes in 
concomitant medications, vital signs (including weight), complete physical exam, primary 
malignancy assessment (if applicable), blood for hematology, chemistry, metabolic panel, 
selected biomarkers and urine for: pregnancy test (if applicable), and urinalysis. The NCAA and 
LSS will be assessed.
PFTs will be required at ESDD: spirometry with bronchodilator and diffusing capacity of the 
lungs for carbon monoxide (DLCO).
6.6.
30 Day Follow-Up Visit 
Subjects who complete through Week 48 visit and who do not wish to participate in the OLE
phase of the study will return to the clinic 30 days after the completion of study drug for the 
30-Day follow-up visit. Subjects who complete the OLE will return to the clinic 30 days after the 
completion of study drug for the 30-Day follow-up visit
Subjects who permanently discontinue study drug and refuse to continue in the study will be 
asked to return to the clinic 30 days after the completion of the ESDD visit for the 30-Day
follow-up visit. 
For the purpose of scheduling a 30-Day follow-up visit, a ± 5 days window may be used. 
Table 6-1 lists all procedures to be completed at the 30-Day Follow-up visit. 
6.7.
End of Study
The definition of the end of the trial is the last visit of the last participant on the trial.


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6.8.
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiration rate, weight and temperature. 
Height will be measured at the Screening visit only. 
6.9.
Biomarker Sample Collection 
Blood for selected biomarkers may include, but not limited to, cytokines, B-cell activating factor, 
B-cell function, SYK pathway markers, immunoglobulin levels, and/or antigen-specific B cell 
responses. Please refer to Table 6-1 for collection timepoints. Samples may be stored for up to 
15 years. 
6.10.
Clinical Laboratory Tests/Assessments 
Blood and urine samples will be collected as outlined in Table 6-1.  All labs will be done 
centrally, local lab results may be used to establish diagnosis of liver cGVHD. 

Hematology profile: completed blood count (CBC) with differential and platelet count 

Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, uric acid

Metabolic assessments: lipid panel (total cholesterol, HDL, direct LDL, and triglycerides).  

Immunoglobulin levels: Immunoglobulin A-E  

Serum and biomarker storage sample for possible additional clinical testing (if subject 
agrees) 

Urine pregnancy test (females of child bearing potential only); positive urine pregnancy tests 
will be confirmed with a serum test. 

Urinalysis 
6.11.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

Unacceptable toxicity, 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

Relapse of primary disease  

Severity of cGVHD requiring therapy that is not allowed as concomitant therapy on study


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
Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 8

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)


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If the investigator considers discontinuing study medication for any reason other than those listed 
above, such as sustained complete remission of cGVHD for more than 3 months, then tapering to 
discontinue ENTO can be considered and should follow the schedule listed below:
Starting Dose
Action
400 mg twice daily
200 mg, twice daily, for 2 weeks
200 mg once daily for 2 weeks
200 mg, once daily, every other day for 2 weeks
Stop Study Medication
200 mg twice daily
200 mg once daily for 2 weeks
200 mg, once daily, every other day for 2 weeks
Stop Study Medication


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Pre-existing 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 (see Section 7.6.2.2)

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

Relapse of primary disease 

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 (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.4.1.
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 (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the modified CTCAE, version 4.03. For each episode, 
the highest grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening) or 
Grade 5 (fatal) to describe the maximum intensity of the adverse event.  For purposes of 
consistency with the CTCAE, these intensity grades are defined in Table 7-1 and Appendix 7.
Table 7-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2
Moderate
Local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL 
Grade 3
Severe
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL  
Grade 4
Life-threatening
Urgent intervention indicated 
Grade 5
Death 
Death related AE 
*
Activities of Daily Living (ADL) Instrumental ADL refer to opening preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden 


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Table 7-2.
Grading of Adverse Event Severity: Upper Respiratory 
The only modification to the CTCAE criteria has been the addition of a Grade 1 upper 
respiratory infection as follows:
CTCAE 
v4.0 Term
Grade 1*
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.03 
AE Term 
Definition
Upper 
respiratory 
infection
Mild 
symptoms; 
symptomatic 
relief (cough 
suppressant, 
decongestant, 
etc.)
Moderate 
symptoms; oral 
intervention 
indicated 
(e.g., antibiotic, 
antifungal, 
antiviral)
IV antibiotic, 
antifungal, or 
antiviral 
intervention 
indicated; 
radiologic, 
endoscopic, or 
operative 
intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder 
characterized by 
an infectious 
process involving 
the upper 
respiratory tract 
(nose, paranasal 
sinuses, pharynx, 
larynx, or 
trachea).
The distinction between the seriousness and the severity of an adverse event 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 one 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 case report form (eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 


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eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur within 30-days of the last dose of study IMP, regardless of 
causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

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 DSPH 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 as described above.

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.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.


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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.4.1.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events Toxicity Management 

All clinical events and clinically significant laboratory toxicities will be managed according 
to uniform guidelines detailed in Appendix 7.

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for Modified CTCAE 4.03 for Severity of Adverse Events and Laboratory 
Abnormalities. 

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose or modified dose that is 
dependent upon discussion with the Gilead Sciences Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.

Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
7.4.2.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue investigational medicinal product at the discretion of the investigator.


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7.4.3.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to Grade 2.If 
a laboratory abnormality recurs to Grade 3 following rechallenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.
7.4.4.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. The subject should be followed as clinically indicated 
until the laboratory abnormality returns to baseline or is otherwise explained, whichever 
occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade.
Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (e.g., Grade 4 CK after strenuous exercise or 
triglyceride elevation that is nonfasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product.
7.5.
Toxicity Management 
Concentration Monitoring of Calcineurin Inhibitors and Mycophenolate Mofetil
ENTO has been shown in vitro to inhibit the drug transporters organic anion transporting 
polypeptides 1B1 and 1B3 (OATP1B1 / OATP1B3), P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP), as well as the drug metabolizing enzyme glucuronosyltransferase 
UGT1A1. Due to the involvement of these pathways in the disposition of the calcineurin 
inhibitors tacrolimus and cyclosporine, and the active (mycophenolic acid [MPA]) and inactive 
metabolites of mycophenolate mofetil, Entospletinib may potentially affect the exposure of these 
medicines.
For subjects receiving these medicines, the blood levels of tacrolimus, cyclosporine or the active 
metabolite of MMF (MPA) will be monitored at baseline/Day 1 (prior to starting ENTO), on day 
2 or day 3 and day 6 or day 7 after initiating ENTO or PTM, and at the end of Week 2 and 
Week 50 study visit. Beyond these time points, concentration monitoring for tacrolimus, 


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cyclosporine and MPA should follow the treating institution’s protocol and therapeutic range for 
monitoring these medicines. When a concentration sample is taken at local lab, in accordance 
with the treating institution’s protocol for monitoring these medications, a sample may also be 
requested for central lab analysis. 
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 DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.


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Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH 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 DSPH, 
fax number +1 650 522-5477 or email Safety_FC@gilead.com. 
Refer to Appendix 8 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 Gilead DSPH 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 Section 7.3 and 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.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primaty objective is: 
To evaluate the effect ofENTO on BORRas assessed by the NCAA by 24 weeks in the setting 
of add-on to systemic corticosteroids as part of first-line therapy for cGVHD 
The key secondaty objectives are: 
• 
To evaluate the effect ofENTO on the skin domain of the LSS at 24 weeks 
• 
To evaluate the effect of ENTO on the mouth domain of the LSS at 24 weeks 
• 
To evaluate the effect of ENTO on the eyes domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the total score of the LSS at 24 weeks 
Additional secondary objectives include: 
• 
To evaluate the effect ofENTO on DOR 
• 
To evaluate the effect of ENTO on dose reduction of cmiicosteroids 
• 
To evaluate the effect of ENTO on initiation of second-line therapy for cGVHD 
• 
To evaluate the effect of ENTO on progression of cGVHD 
• 
To evaluate the safety and tolerability ofENTO 
• 
Exploratmy objectives include: 
I 
I 
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8.1.2.
Primary Endpoint
The primary endpoint is BORR by 24 weeks, defined as the proportion of subjects who achieve a 
complete or partial overall response (CR or PR) as assessed by the NCAA within 24 weeks, in 
the setting of add-on therapy to systemic corticosteroids as part of first-line therapy for cGVHD. 
At each assessment time point, organ-specific responses will be determined according to 
Appendix 4.  An overall time point response across all involved organs will then be determined 
according to Table 8-1.  The best overall response across all time points up to 24 weeks will be 
used to calculate BORR by 24 weeks. 
Table 8-1.
Criteria for time point response determination
Response Category
Response Criteria
Complete response (CR)
Resolution of all cGVHD manifestations in each organ or site as described in the 
NCAA organ response determination table
Partial response (PR)
Improvement of at least 1 organ or site, without progression in any other organ or 
site as described in the NCAA organ response determination table.
Stable disease (SD)
Neither sufficient improvement to qualify for a PR nor sufficient decline to qualify 
for a PD
Progressive disease (PD)

Worsening of signs and symptoms in any organ or site as described in the 
NCAA organ response determination table, taking the current best overall 
response as reference that is not a flare. A flare is defined as acute 
worsening of signs and symptoms in any organ or site that occurs at least 4 
weeks after PR/CR is achieved, which lasts ≤ 4 weeks.  
OR

Increase in systemic corticosteroid dose to ≥ baseline dose (1 mg/kg/day)
OR

Initiation of systemic immunosuppressive therapy other than systemic 
corticosteroids
8.1.3.
Secondary Endpoint
The key secondary endpoints are:

Change from baseline in the skin domain of the LSS at 24 weeks

Change from baseline in the mouth domain of the LSS at 24 weeks

Change from baseline in the eyes domain of the LSS at 24 weeks

Change from baseline in the total score of the LSS at 24 Weeks 


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Other secondaty endpoints include: 
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• 
DOR, defmed as the time from the documentation of BORR to the documentation ofPD as 
defmed in Table 8-1. Note that a flare does not constitute an end to response. 
• 
Proportion of subjects who achieve at least 50% reduction in systemic corticosteroid dose 
relative to baseline, where % reduction is calculated as (systemic cotiicosteroid dose at 
24 weeks - baseline systemic cmiicosteroid dose) I baseline systemic corticosteroid dose 
• 
Proportion of subjects who initiate second-line therapy for cGVHD, defmed as receiving any 
therapy besides systemic corticosteroids or study dmg for the treatment of cGVHD. Inhaled 
and topical steroids are not considered second-line therapy. 
• 
Failure-free smvival (FFS), defined as the time from randomization to the earliest of first 
documentation of systemic therapy change, nonrelapse motiality, or recmTent malignancy 
• 
Safety and tolerability of ENTO 
8.1.4. 
Other Endpoints of Interest 
Exploratmy endpoints include: 
p 
D 
I 
I 
I 
I 
8.2. 
Analysis Conventions 
All individual subject data will be listed as measured. All statistical smnmaries and analyses will 
be perfonned using SAS® software (SAS Institute, Caty, North Carolina, USA). 
In general, data will be described and sUlllillarized by relevant treatment rum, analysis set, and 
time point. As appropriate, changes from baseline to each subsequent time point will be 
described and sUlllillal·ized by treatment ann. Graphical techniques ( eg, Kaplan-Meier cmves, 
waterfall plots, etc.) may be used when such methods m·e appropriate and infmmative. 
Summmy tables for continuous variables will contain the following statistics: N (number in 
analysis set), n (number with data), mean, standard deviation (SD), 95% confidence intetvals 
(Cis) on the mean, median, minimum, first quatiile (Ql), third quartile (Q3), and maximum. 
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Summary tables for categorical variables will include: N, n, percentage, and 95% CIs on the 
percentage. 
Subjects with discrepancies between the stratification factor values at randomization and the 
actual values as documented on data review will be categorized in the analyses according to the 
actual values.
Unless otherwise specified, all statistical tests will be 2-sided.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analyses will be the Intent-to-Treat (ITT), which includes 
data from all randomized subjects, with treatment assignments designated according to 
randomization. 
Selected efficacy endpoints may also be evaluated using the Per-Protocol (PP) analysis set, 
which includes all randomized subjects who received at least one dose of study drug, did not 
violate any major entry criteria, and did not have any major protocol deviations.
8.2.1.2.
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set, which includes data 
from all subjects who received at least one dose of study drug, with treatment assignments 
designated according to actual treatment received. All data collected up to the last dose of study 
drug plus 30 days will be included in the safety summaries. 
8.2.1.3.
Pharmacokinetics (PK)
The PK Analysis Set will include data from subjects in the Safety Analysis Set who have the 
necessary baseline and on-study measurements to provide interpretable results for the specific 
parameters of interest. 
8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial results. In general, values for 
missing data will not be imputed unless methods for handling missing data are specified.
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. 

If a subject received study drug, the subject will be included in the summary of AEs 
according to the treatment received; otherwise, if the subject is not dosed then they will be 
excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.


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Values for missing safety laboratory data will not be imputed; however, a missing 
Baseline/Day 1 result will be replaced with a screening result, if available. If no pre-treatment 
safety laboratory value is available, the Baseline/Day 1 value will be assumed to be normal 
(ie, no grade [Grade 0]) in the summary of graded laboratory abnormalities. Values for missing 
vital signs data will not be imputed; however, a missing Baseline/Day 1 result will be replaced 
with a screening result, if available.
Laboratory data that are continuous in nature but are less than the lower limit of quantitation 
(LOQ) or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used for calculation of descriptive statistics if 
the data is reported in the form of “<x” (x is considered the LOQ). For example, if the values 
are reported as <50 and <5.0, then values of 49 and 4.9 will be used for calculation of
summary statistics, respectively. 

A value that is 1 unit above the LOQ will be used for calculation of descriptive statistics if 
the data is reported in the form of “>x” (x is considered the LOQ). For example, if the values 
are reported as >50 and >5.0, then values of 51 and 5.1 will be used for calculation of 
summary statistics, respectively.

The LOQ will be used for calculation of descriptive statistics if the data is reported in the 
form of “≤ x” or “≥ x” (x is considered as the LOQ).
PK concentration values that are below the limit of quantitation (BLQ) will be presented as 
“BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 at pre-dose time 
points, and one-half the value of the lower limit of quantitation (LLOQ) at post-baseline time 
points, where LLOQ is corrected for the dilution factor (ie, reported LLOQ/dilution factor) for 
determination of summary and order statistics.
The following conventions will be used for the presentation of summary and order statistics: 

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ”

If more than 25% of the subjects have a concentration value of BLQ for a given time point, 
the minimum and Q1 values will be displayed as “BLQ” 

If more than 50% of the subjects have a concentration value of BLQ for a given time point, 
the minimum, Q1, and median values will be displayed as “BLQ” 

If more than 75% of the subjects have a concentration value of BLQ for a given time point, 
the minimum, Q1, median, and Q3 values will be displayed as “BLQ” 

If all subjects have concentration values of BLQ for a given time point, all order statistics 
(minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ”
PK parameters that are BLQ will be imputed as one-half LLOQ before log transformation or 
statistical model fitting.


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8.4.
Demographic Data and Baseline Characteristics
Demographic data and baseline characteristics will be summarized by treatment group and 
overall using standard descriptive statistics for the ITT Analysis Set.
Demographic data will include: age, gender, race, and ethnicity.
Baseline characteristics will include: body weight, height, body mass index, and other covariates 
as necessary.
The number (proportion of subjects) in each stratum will also be summarized.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary endpoint is BORR by 24 weeks in the setting of add-on therapy to systemic 
corticosteroids as part of first-line therapy for cGVHD. The primary analysis will test the null 
hypothesis that there is no difference in response rate between ENTO + systemic corticosteroids 
and placebo + systemic corticosteroids versus the alternative hypothesis that there is a difference.  
Response rate will be summarized by count and percent of subjects with each ordinal response
(CR, PR, and CR + PR).  A stratified Cochran-Mantel-Haenszel (CMH) Chi-square test for 
association will be performed to compare BORR between ENTO and PTM by 24 weeks.  The 
difference in response rates between treatment groups and the corresponding 95% CIs will be 
presented.
8.5.2.
Secondary Analyses
A sequential testing strategy will be implemented to preserve the overall type I error rate across 
the primary and key secondary endpoints of the study at a 2-sided significance level of 0.05.  The 
primary endpoint analysis will serve as the gatekeeper for the key secondary endpoint analyses, 
ie, the primary efficacy endpoint must be met before the key secondary efficacy endpoints can be 
tested. The key secondary endpoints included in this sequential testing approach are (1) change 
from baseline in the skin domain of the LSS at 24 weeks, (2) change from baseline in the mouth
domain of the LSS at 24 weeks, (3) change from baseline in the eyes domain of LSS at 
24 weeks, and (4) change from baseline in the total score of the LSS at 24 weeks.
If the primary hypothesis is rejected, the key secondary endpoints will be sequentially tested at 
the 2-sided 0.05 significance level in the order listed above. If a null hypothesis is not rejected, 
formal sequential testing will stop and only nominal significance will be cited for the remaining 
endpoints. 
The key secondary endpoints will be analyzed using a MMRM model that includes all available 
data at baseline and all post-baseline visits. The model will include terms for baseline value, 
stratification factor, treatment, visit, and treatment-by-visit interaction. The Kenward-Roger
approximation will be used to estimate the denominator degrees of freedom and adjust standard 


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enors. Treatment comparisons will be generated within the lviMRM model based on the linear 
contrast of the least square means at all-time points. Adjusted means and 95% Cis will be 
presented by treatment group. Plots of mean (±SE) change from baseline over time will be 
provided by treatment group. Additional sensitivity analyses to fmther evaluate the impact of 
missing data may be perf01med and will be specified in the statistical analysis plan (SAP). 
Other secondary endpoints will be analyzed as follows: 
DOR and FFS will be analyzed using the Kaplan-Meier (KM) method and stratified logrank test. 
Kaplan-Meier summru.y statistics (median, 95% CI for median, and 25th, 75th percentiles) and 
number and percentage of events will be presented by treatment group. A stratified Cox 
prop01tional hazards model will be used to estimate the hazru.·d ratio and conesponding 95% CI. 
A KM survival plot will also be provided. Data for subjects who do not experience an event will 
be censored at the date of last visit. 
Prop01tion of subjects with at least 50% reduction in systemic c01ticosteroid dose relative to 
baseline and proportion of subjects who initiated second-line therapy for cGVHD will be 
analyzed similarly to the primru.y endpoint. 
8.5.3. 
Exploratory Analyses 
8.5.4. 
Interim Analysis 
An interim analysis for futility is plam1ed when approximately 50% of subjects have been on 
study for 24 weeks. The futility analysis will be perf01med on BORR by 24 weeks in the ITT 
Analysis Set. A non-binding futility mle will be implemented. Based upon the analysis results, 
the DMC may recormnend terminating the study for lack of efficacy if the predictive power of 
obtaining a statistically significant result at the final analysis given the observed interim data is 
:; 5%. A 2-sided alpha of0.001 will be allocated to this futility interim; following the 
Haybittle-Peto approach {Haybittle 1971, Peto et al 1976}, the final analysis alpha level is 
0.05 (2-sided). 
8.5.5. 
Final Analysis 
The fmal analysis for BORR is planned when all subjects have been on study for 24 weeks. 
Duration and quality of response will continue to be assessed up to 48 weeks. 
8.6. 
Safety Analysis 
All safety data collected on or after the date that ENTO/PTM was first administered up to the 
date of last dose of ENTO/PTM plus 30 days will be summarized by treatment group 
(according to the treatment received). Data for the pre-treatment period will be included in 
data listings. 
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8.6.1.
Extent of Exposure
A subject’s extent of exposure to ENTO will be generated from the study drug administration 
eCRF page. Exposure data will be summarized by treatment group. 
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event is defined as any adverse event with onset date on or after the date of first dose of 
study drug up to 30 days after permanent study drug discontinuation, or any adverse events 
leading to premature study drug discontinuation.  Summaries (number and percentage of 
subjects) of treatment-emergent adverse events (by SOC and PT) will be provided by treatment 
group. 
8.6.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using modified CTCAE 4.03.  Maximum 
post-baseline grade will be summarized by count and percentage of subjects with each grade.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post-baseline, will be summarized by treatment 
group. If baseline data are missing, then any graded abnormality (ie, at least a Grade 1) will be 
considered treatment-emergent.
Laboratory abnormalities that occur before the first dose of study drug or after the subject has 
been discontinued from treatment for at least 30 days will be included in data listings.
8.6.4.
Other Safety Evaluations
Individual data for 12-lead ECG, vital signs measurements will be listed by subject and 
summarized by treatment group by incidence of events/abnormalities or descriptive statistical 
summaries (n, mean, SD, median, Q1, Q3, minimum, and maximum), as appropriate. In 
comparison to pre-treatment (either Screening or pre-dose on Day 1) values, vital signs 
measurements and ECG findings will additionally be summarized using predetermined, 
clinically relevant thresholds.
8.7.
Pharmacokinetic Analysis
Concentrations will be listed by subject and summarized using descriptive statistics (eg, n, 
arithmetic mean, geometric mean, % coefficient of variation [CV], SD, median, Q1, Q3, 
minimum, and maximum).


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Descriptive statistics of baseline and change in biomarkers will be provided at each sampling 
time for all subjects and by treatment. 
pp 
PD 
8.9. 
Sample Size 
With 40 subjects per treatment group, there is 75% power to detect a 30% improvement in 
response rate at a 2-sided 0.05 significance level using Fisher's exact test, assuming a placebo 
response rate of 50%. A total of 100 subjects (50 per treatment group) will be emolled assuming 
a 20% dropout rate. 
8.10. 
Data Monitoring Committee 
An extemal multidisciplinruy data monitoring committee (DMC) will review the progress of the 
study, perf01m interim reviews of safety data at regular intervals approximately evety 3 months, 
and perf01m an interim review of efficacy data for futility when approximately 50% of subjects 
have been on study for 24 weeks, as described in the DMC Chruier. The DMC will provide 
recommendations to Gilead as to the whether the nature, frequency, and severity of adverse 
effects associated with study treatment wanant the eru·ly tetmination of the study in the best 
interests of the pruticipants, whether the study should continue as planned, or the study should 
continue with modifications. 
The DMC's specific activities will be defmed by a mutually agreed chruter, which will define the 
DMC's membership, conduct and meeting schedule. 
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study te1mination, Gilead retains fmal decision-making authority on all aspects of 
the study. 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable 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.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an . The investigator will not begin any study subject activities until 
approval from the IRB/EC has been documented and provided as a letter to the investigator.
Before implementation, the Investigator will submit to and receive documented approval from 
the IRB/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/EC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/EC approved consent form for documenting 


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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by the IRB/EC. 
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,., 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 instruction.  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, 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

Participation in study (including study number);


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
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. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 
as described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 


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the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (e.g. data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5. 
9.1.7.
IMP Destruction
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/EC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/EC in 
accordance with local requirements and receive documented IRB/EC 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 agencies. Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.


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


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Vigorito AC, Campregher PV, Storer BE, Carpenter PA, Moravec CK, Kiem HP, et al. 
Evaluation of NIH consensus criteria for classification of late acute and chronic 
GVHD. Blood 2009;114 (3):702-8.
Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. Predominant 
autoantibody production by early human B cell precursors. Science 2003;301 
(5638):1374-7.
Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG. In vitro inhibition of 
UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors 
and the relationship of this property to in vivo bilirubin glucuronidation. Drug 
Metab Dispos 2005;33 (11):1729-39.


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Amendment 2.0 Global 
CONFIDENTIAL
Page 81
31 August 2016
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
For Screening: NIH cGVHD Diagnosis and Staging Criteria, Global Severity Score 
{Jagasia et al 2015}
Appendix 3.
For Screening: NIH cGVHD Diagnosis and Staging Criteria (NCDSC) Form 
{Jagasia et al 2015}
Appendix 4.
For Baseline + Subsequent Visits:  Response Determination for the NIH cGVHD 
Activity Assessment (NCAA) {Lee et al 2015}
Appendix 5.
For Baseline + Subsequent Visits: Chronic GVHD Activity Assessment- Clinician
Appendix 6.
For Baseline + Subsequent Visits: Lee Symptom Scale {Lee et al 2002}
Appendix 7.
Grading of Adverse Event Severity
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 9.
Schedule of Assessments for the Optional Cellular Turnover Sub-study*


Bntospletinib 
Protocol GS-US-406-1840 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment 2.0 Global 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and 
Tolerability ofEntospletinib, a Selective SYK Inhibitor, in Combination with Systemic 
Corticosteroids as First-Line Therapy in Subjects with Chronic Graft Versus Host Disease 
(cGVHD) 
GS-US-406-1840 PROTCOL Amendment 2.0 (Global): 31 August 2016 
This protocol bas been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
~.~JlRtO C). ff/ffl(:wPe5 f(li{D 
arne (Printe<t}Mario Marcondes, MD, 
PhD 
INVESTIGATOR ST ATE:MENT 
l have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator N arne (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 82 
31 August 2016 


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Amendment 2.0 Global 
CONFIDENTIAL
Page 83
31 August 2016
Appendix 2.
For Screening: NIH cGVHD Diagnosis and Staging Criteria, Global 
Severity Score {Jagasia et al 2015}
Mild chronic GVHD
1 or 2 Organs involved with no more than score 1
plus
Lung score 0
Moderate chronic GVHD
3 or More organs involved with no more than score 1
OR
At least 1 organ (not lung) with a score of 2
OR
Lung score 1
Severe chronic GVHD
At least 1 organ with a score of 3
OR
Lung score of 2 or 3
Key points:
In skin: higher of the 2 scores to be used for calculating global severity.
In lung: FEV1 is used instead of clinical score for calculating global severity.
If the entire abnormality in an organ is noted to be unequivocally explained by a non-GVHD documented 
cause, that organ is not included for calculation of the global severity.
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes) the scored 
organ will be used for calculation of the global severity regardless of the contributing causes (no 
downgrading of organ severity score).


Entospletinib 
Protocol GS-US-406-1840 
Gilead Sciences, Inc. 
Final 
Amendment 2.0 Global 
Appendix 3. 
For Screening: NIH cGVHD Diagnosis and Staging Criteria (NCDSC) 
Form {Jagasia et al 2015} 
SCOREO 
P •;RFOR,JA;-;CE 
SCORE: 
I 
KPS ECOG LPS 
0 Asymptomatic and 
fully active (ECOG 
0: KPS or LPS 
100%) 
SKJNt 
SCORE"/o BSA D 
G VHD features to be scored 
0 No BSA 
llJ!...ll.&1.: 
involved 
Check an that apoly: 
0 Maculopapular rasbferytbeJllll 
0 Lichen planus-like features 
0 clerotic fea111res 
0 Papulosquamous lesions or 
icbtl1yosis 
0 Keratosis pilaris-)jke GVRD 
SKIN I'EATL'RES 
sco!U:: 
0 No sclerotic 
features 
Odrer skju G VJJD feature,• {NQT g ored bv BSA) 
Check all thnt apply: 
0 llyperpigmenullion 
0 Hypopig:mcntation 
0 Poikilodenna 
0 Severe or generalized pruritus 
0 Hair involvem.:nl 
0 Nail involvement 
SCOREl 
0 Symptomatic, 
fully ambulatory, 
restricted only rn 
physically 
strenuous <Lctivlty 
(ECOG I, KPS 
or LPS 80..90%) 
0 1-18% BS.A 
SCORE2 
SCORE 3 
0 Symptomatic, 
0 Symptomatic. 
ambulatory, capabl• 
limited self-care, 
of ~df-care. >50% 
>50% of V.".tking 
of v.'<lking hours ou 
hours in bed {ECOG 
of bt:d (ECOG 2, 
3-4, KPS or LPS 
KPS or LPS 60-
<60%) 
70%) 
0 19-50% BSA 
0 SuiWrficial 
sclerotic features 
"not hidebound" 
(able to pinch) 
0 >50% BSA 
Ch£Sk all that applv: 
0 Deep sclerotjc 
features 
o "Hidebound" 
(Lmablc to pinch) 
0 fmpaired mobility 
0 lJlccmtion 
0 Abnormality presellt but explained entirely by non-G VHD tlocumettled cause (specify): __ 
MOUTII 
Lichen planus-like 
features present: 
0 Yes 
ONo 
0 No symptoms 
0 Mild symptoms 
with disease signs 
but not limiting 
oral intake 
significantly 
0 Modcmtc 
symptoms with 
disease signs with 
partial limitation 
o [ oral intake 
0 AbnormaJiiy pre.senl but e.tpfai.ned eniireJy by non-GVJJD tlocumemed cause (specifl): 
0 Severe symptoms with 
disease signs on 
examination with major 
limitation of ora.l in!Jlke 
Figur~ I. Or~n sa. ring o [chronic GVHO. ECOC i nduares Eastl!rn COOpt'rJtM! OlliDlOf:)l Croup; KPS, K.tntol'sky ~ lf'onn.utcr Sl~tus; LPS, Lansky P'~r[omunCl! !i.uus; 
BSA, body Su1f<1<r are~: ADL. activit~ or da1ly hVIIlJ; LFf~ liVI'r fuMDOn ~IS; AP, alkaline phosphaw~: ALT. ~Luti ne .. ninOtrdli.Sf~r-; ULN, 1-.HITIAI UPP"r im1L 
"Wel:ht lOSSWtthln 3 nt<lnoo. ISkin .ronngshould u~ b«h pt'cra!'lltagt'O[BSI\ 11110lvel by disuse .slgns<tnd th~CULdnt!OUs [t.;nures sc.U.,S. When .. doscrrp.mcy ..xnu 
b<!LWren the percen~<~,g• ol tnll.l body s w·race (BSA) =~ 
.utd the skin fe<ttu ~ score. OR if s uperfiCIAl scrrodc fe<ttw-e< a rr p,._nt (Sc~ 2} !Jut rl~,... is imparrld 
motility or ul~ranon (Sc:ore 3), the higher level ~ho uld be ~ 
ror th~ Rn.al skill scori ng. t-ro be <omplerld by speoal"'t or rramO!d m«< ic.al pr0111d~rs (s"" 
Supprrrr rul Rgtn). -·Lung smr11g should be perforrrr d usmglloth the .sympr01ru • nd FEVl sro"'s when...,r poss1ble. ltV! .should~..,;"" m dte ftn<tl lung 
sa.nng wltt!l't' LhPrr is dtstrepariC)' berv....en symjl(oms .md f"EVJ sm-
CONFIDENTIAL 
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Final
Gilead Sciences, Inc. 
Amendment 2.0 Global 
CONFIDENTIAL
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SCOREO 
EY~S 
0 No symptoms 
Ke.ratoconjrmctivitis 
sicca (KCS) confinned 
by ophthalmologist: 
0 Yes 
0 No 
0 Not examined 
SCORE I 
0 Mild dry eye 
symptorus not 
affecting ADL 
(requirement of 
lubricant eye 
drops .::, 3 x per 
day) 
SCORE2 
0 Moderate dry eye 
symptoms partially 
affecting ADL 
(requiring lublicant 
eye drops > 3 x per 
day or puncta) 
plugs), 
WITHOUT new 
vision impairment 
dueto KCS 
0 Abnormality present bwt explained entirely by non-GVHD documented cause (soecifl'): 
Gl Tract 
Check all that apply: 
0 Esophageal web/ 
proximal stricture 
or ring 
0 Dysphagia 
OAnorexia 
0 Nausea 
0 Vomiting 
0 Diarrhea 
0 Weight lo.s 2:_S%* 
0 Failure to thrive 
0 No s}mptoms 
0 Symptoms 
without 
significant weight 
loss• (<5%) 
0 Symptoms 
associated with 
mild to moderate 
weigbl loss• 
(5- 15%) OR 
modcntc diarrhea 
without 
s ignifi ~ant 
interference with 
daily living 
0 Abnormality presentlwt explained entirely by non-G VHD documented cause [.\pec{/YL-
0 NonnaJ tota I 
bilirobin and 
ALTorAP 
< 3xULN 
0 Not·roaJ total 
bilirubin with ALT 
:::;3 to5 x ULN or 
AP2:_3x ULN 
0 Elevated total 
bilirubin but 
.::,3 mgfdL or 
ALT>5 ULN 
0 Ab,tormulity present but explained entire!)' by non-GVHD documented cause (soecify): 
LUNGS .. 
~nnntom score; 
Lung score: 
%FBVJD 
Pulmonary j imction tests 
0 Not perfonned 
0 No symptoms 
0 f'EV1<:80% 
0 Mild symptoms 
(shortness of 
bn:ath at\er 
climbing one Oight 
of steps) 
O FEVI 60..79% 
0 Mode.mte 
symptoms 
(shortrtCSS ofbn:alh 
after ·walking on 
flat grow1d) 
0 FEVJ 40-59% 
SCORE 3 
0 Severe dry eye 
symptoms significantly 
affecting ADL (special 
eyeware to relieve pain) 
OR unable to work 
because of ocular 
symptoms OR Joss of 
vision due to KCS 
0 Symptoms associated 
with significant weight 
loss• > 15%. requires 
nutritional suppJem~nt fOr 
most calorie needs OR 
esophageal dilation OR 
severe dian·hca with 
significant interference-
with daily living 
0 Elevated total 
bilintbin > 3 rog/dL 
0 Severe syroptoms 
(shortness of breath at 
rcs1; requirin.g Oz) 
0 FEV199% 
0 Abnormality present bwt explained entirely by nou-OVf{f) d<)CUmellled cause (specify) .:~-------------, 
f'.gure 1. {oondrrued). 


Entospletinib 
Protocol GS-US-406-1840 
Gilead Sciences, Inc. 
JOIXrS Al\"D FASCIA 
P-ROM score 
(su below) 
Shoulder (1-7):_ 
F.lbow( l-7): _ 
WrisTlnnger (1-7):_ 
Ankle (1 -4) :_ 
SCOREO 
0 No 
symptoms 
SCORE 1 
0 :'vlild rightnes~ of 
arms or legs, 
nonnaJ or mild 
decreased ran,ge of 
motion (ROM) 
AND not affecting 
ADL 
SCORE2 
0 Tightness of arms or 
legs OR joint 
contrucrun:s. 
<:rythcma thought 
due to fasciitis, 
moderate decrease 
ROM AND mild to 
moderate limitation 
ofADL 
Final 
Amendment 2.0 Global 
SCORE 3 
0 Conn·acturcs WITH 
significant decrease of 
ROM AND significant 
limitation of ADL 
(unable to tie shoes, 
button s hirt~, dres.~ self 
etc.) 
0 Abnonnality presenr bu1 l"xplained entirl"ly by non-GVHD documl"nted c.fiJJSl" (specify): __________ __ . 
GENI1'AL TRACJ' 
0 No signs 
0 Mild signs1 and 
0 Moderate signsl and 
(Srr Sunplrmen(al figure' ) 
t'emales with or 
may have 
0 Not examined 
wilbout discomfort 
symptoms with 
Currently sexually aclivt> 
on exam 
discomfo1t on exam 
D Yes 
0 No 
0 Abnonnaliry present bur &p!ained entirely bv non-GVHD documl'nted cause (specify): 
0 Severe signs1 Yooilh 
or wilbouL 
symptoms 
Other indi<:ators, slinicnl fsatnr£f gr sonrglka!fons related to chronic CVllp Cshsck all thai apply and ay,jgn. a 
.scor e IO seyeriry m, :ll hued on functional Impact wh ~re anplicallle nons- 0 mild ·I mod reate - 2 
~C\'IltC- 3) 
0 Ascites. (serositis)_ 
0 Pericar>dial Effusion_ 
0 Pleural Effu,ion(s)_ 
CONFIDENTIAL 
0 Myastbenia Gravis_ 
0 Peripheral Neuropalby_ 
0 Polymyositis_ 
D Wei lloss>S%• wiliJOLit Gl s 
[J NoGVUD 
[J MUd 
Wrtfit,'f'inttr 
Figure J_ (a>n OnUt'd). 
Page 86 
0 Eosinophilia > 500/JII_ 
0 Platelets <100,000/J!I_ 
0 
[J 1\todtratc 
[J Severe 
31 August 2016 


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Protocol GS–US-406-1840
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Gilead Sciences, Inc. 
Amendment 2.0 Global 
CONFIDENTIAL
Page 87
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Supplemenr f igure - Genital Tract Chronic Graft-,·er:.5us-Hosr Assessment and Scoring f orm 
:"'Jame· 
. . 
Date of binb· 
Assessment date· 
" 
. 
SCORE O 
SCORE I 
SCORE 2 
SGORE3 
GE!'<TI.U TR'I.CT 
D No signs 
D Mild signs and 
D Moderate signs 
D Severt signs with 
Check: 
females may have 
and may have 
or without 
symptoms" WITH 
symptoms* with 
symptoms* 
D Male DFema!e 
di3comfort ou exam 
discomfort on cxnm 
Cul'renrh· sexuallY actin: 
D Yes 0
No 
Clu~ck oll ~igus tl1af Dfl2.ll': 
D Erosion'S. 
D Lichen planus-like features 
D Fissures 
D Lichen sclerosis-like features 
D Ulcers 
D Vaginal scarring (female) 
D Phimosi; (male) 
D Clitoral/labial agglutination (female) 
D Urethralme.ants scarring/ stenosis (male) 
D Labial re.:;orption (bm.'lle) 
D Abnormalily present but NOT thought to represent GI'HD (specify cause): 
D Abnormalily thought to represetlt GVHD PLUS other causes(specify cause): 
• Gem tal symptoms are ~tot specific to cGVHD and can represent premaiurt gonadal fOllure or genital tract mfecflon. 
If a gyne('ologist is un~,·aiJable, external examination may be performed to de-te.mline ~'discomfort on exam" as follows: 
a) Spread the labia lllJljora to inspe.ct the. vulva for the above signs. Touch the vestibular gland openings (Skene's and 
Bartholin's), labia minora and majora gently with a qtip. Vulvar pain elicited by the gentle touch of a qrip is 
classified as discoofort on examination. Palpate. the vaginal walls with a single. digit to detect bauds, shortening, 
narrowing or other signs of vaginal scarring. 
b) If the woman is sexually active, detenniue whether qtip palpation or gentle palpation of scarred ridges elicits pain 
similar to that which the woman experiences during intercourse . 
Female g-enitalia: Severity of signs: 
I) Mild (any of the following); erythe.ma on vulvar mucosal surfaces, vulva: lichen-planus or""'"' lichen-sclerosis. 
2) Moderate-(any of the following)~ erosive intlammatOI)' changes of the. \<1llvar mucosa, fissures in vulvar folds 
3) Severe (any of the following); labial fttsion, clitoral hood agglutinatio11, fibrinous vaginal adhesions, circumferential 
fibrous vaginal bandmg, vaginal shorte-ning, synechi~ dense sclerotic dwtges. and complete vaginal stenosis. 
~{ale gtnitalia: Diagn()stic features include lichen planus-like or lichen sclerosis-like feat\lres and phymosis or urethral 
scarring or stenosis. Se\'e-rity of sigru: 
I) .Mild: lichen planus-like featme.; 
2) Moderate: lichen sclerosus-like feature or moderate erythema; 
3) Severe: phimosis or urethraVmeataJ scarring. 
Bi-op-~' obtained: D Ye.~ D !\o 
Site biop.;ied: _____ G\"BD C'onfirmed by hi<i-tology: D Yes 
D No 
Change from prniou<> e'l':tlu:ttion: D No prior or <'Urnnl CYHD D lmprond D St~ble 
D \Yom D 'S/A (b . ...W.t) 
Completed b;- (pl'int n.1me): 
Date fol'm ('Ompleftd: 


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Amendment 2.0 Global
CONFIDENTIAL
Page 88
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Appendix 4.
For Baseline + Subsequent Visits: 
Response Determination for the NIH cGVHD Activity Assessment (NCAA) {Lee et al 2015}
Organ 
Complete Response 
Parlial Response 
Progression 
Skin 
NIH Skin Score 0 after 
Decrease in NIH Skin Score 
Increase in NIH Skin Score by 1 or 
previous involvement 
by 1 OJ' more points 
more points, except 0 to 1 
Eyes 
NIH Eye Score 0 after 
Decrease in NIH Eye Score 
Increase in NIH Eye Score by 1 or 
previous iovolvemem 
by 1 or more points 
more points, except 0 to 1 
Mouth 
NIH Modified OMRS 0 after 
Decrease in NIH Modified OMRS 
Increase in NIH Modified OMRS 
previous involvement 
of 2 or more points 
of 2 or more points 
Esophagus 
NIH Esophagus Score 0 after 
Decrease in NIH Esophagus 
Increase in NIH Esophagus Score 
previous involvement 
Score by 1 or more points 
by 1 or more points. except 0 to I 
Upper Gl 
NIH Upper Gl Score 0 after 
Decrease in NIH Upper Gl 
Increase in NIH Upper Gl Score 
previous involvement 
Score by 1 or more points 
by 1 or more points, except 0 to 1 
!.ower Gl 
NIH tower Gl Score 0 after 
Decrease in NIH tower Gl 
Increase in NIH tower Gl Score by 1 
previous involvement 
Score by 1 or more point~ 
or more points, except from 0 to 1 
Uver 
Normal AL T, alkaline 
Decrease by 50% 
Increase by 2 x ULN 
phosphatase, and Total 
bilirubin after previous 
elevation of 1 or more 
Lungs 
- Normal J FEVl after 
Increase by 1 0% predicted 
- DeCI'ease by 10% pr·edicted 
previous involvement 
absolute value of JFEV1 
absolute value of JFEV1 
- If PFTs nor available, NIH 
• If PFTs nor available, decrease 
• If PFTs not available, increase in 
Lung Symptom Score 0 
in NIH Lung Symptom Score 
NIH Lung Symptom Score by 1 
after previous involvement 
by 1 or more points 
or more points, except 0 to 1 
Joints and fascia 
Both NIH Joint and Fascia 
Decrease in NIH Joint and Fascia 
Increase in NIH joint and Fascia 
Score 0 and P-ROM score 
Score by 1 or more points or 
Score by 1 or more points or 
25 after previous involvement 
increase in P-ROM score by 1 
decrease in P-ROM score by 1 
by at least 1 measure 
point for any site 
point for any site 
Global 
Clinician overall severity score 0 
Clinician overall severily score 
Clinidan overall severily score 
decreases by 2 or more points 
increases by 2 or more points 
on a 0·10 scale 
on a 0-10 scale 
ULN indicates upper limit of normal. 


Entospletinib 
Protocol GS- US-406-1840 
Gilead Sciences, Inc. 
Final 
Amendment 2.0 Global 
Appendix 5. 
I FORMA I 
For Baseline + Subsequent Visits: Chronic GVHD Activity Assessment- Clinician 
Current Patient Weight: ____ _ 
Today's Date: _____ MR#/Name: ---------
CHRONIC GVHD ACTIVITY ASSESSMENT- CLINICIAN 
Health Care Provider 
Since the last assessment would you say that this 
Global Ratings: 
Where would you rate the severity of this patient's chronic GvHD symptoms on 
patient's cGvHD is 
the following scale, where 0 is cGVHD symptoms that are not at all severe and 10 
+3= Very much better 
O=none 
is the most severe cGVHD symptoms possible: 
+ 2= Moderately better 
1= mild 
+ 1 = A little better 
2=moderate 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
0= About the same 
3=severe 
10 
-1 =A little worse 
cGvHD symptoms 
Most 
-2=Moderately worse 
severe cGvHD 
-3=Very much worse 
not at all severe 
svm~ toms possible 
Erythema 
None 
0 
Mild erythema or 
1 
Moderate (<:25%) or 
2 
Severe erythema 
Mouth 
moderate erythema 
Severe erythema 
(2:25%) 
(<25%) 
(<25%) 
Lichenoid 
None 
0 
Lichen-like changes 
1 
Lichen-like changes 
2 
Lichen-like changes 
(<25%) 
(25-50%) 
(>50%) 
Ulcers 
None 
0 
Ulcers involving 
3 
Severe ulcerations 
(520%) 
(>20%) 
Total score for all mucosal changes 
Gastro intestinal-Esophageal 
0= no esophageal symptoms 
• 
Dysphagia 
OR 
1=0ccasional dysphagia or odynophagia with solid food or pills during the past week 
Odynophagia 
2=1ntermittent dysphagia or odynophagia with solid foods or pills, but not for liquids or soft foods, during the past week 
3=Dysphagia or odynophagia for almost a{{ oral intake, on almost everv dav of the oast week 
Gastro intestinal-Upper Gl 
0= no symptoms 
• 
Early satiety OR 
1=mild, occasional symptoms, with little reduction in oral intake during the past week 
• 
Anorexia 
OR 
2=moderate, intermittent symptoms, with some reduction in oral intake during the past week 
3 
3 
6 
• 
Nausea & Vomiting 
3=more severe or persistent symptoms throughout the day, with marked reduction in oral intake, on almost everv day of the past 
week 
Gastro intestinal-Lower Gl 
0= no loose or liquid stools during the past week 
• 
Diarrhea 
1= occasional loose or liquid stools, on some days during the past week 
2=intermittent loose or liquid stools throughout the day, on almost every day of the past week. without requiring intervention to 
prevent or correct volume depletion 
3=voluminous diarrhea on almost every dav of the past week reauirina intervention to prevent or correct volume depletion 
CONFIDENTIAL 
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Gilead Sciences, Inc. 
Amendment 2.0 Global
CONFIDENTIAL
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Lungs (Liters and % 
predicted)

Bronchiolitis Obliterans
FEV1
FVC
Single Breath DLCO (adjusted for 
hemoglobin)
TLC
RV
Liver Values
Total serum bilirubin
                            
mg/dL
ULN
                           
                     mg/dL
ALT
                          
U/L
   ULN                   
                                 
U/L
A kaline Phosphatase
                                  
U/L
ULN
                       
                              U/L
Baseline Values
Total Distance Walked in 2 or 6 Mins: 
                                                 2 min        
6 min
Karnofsky or 
Lansky 
Platelet Count              
                                    
K/uL
Total WBC                      
                                      
K/uL
Eosinophils
                           
                            %        
. Abnormality present but explained entirely by non-GVHD documented cause (specify site/alternate 
cause):_______________________________
 Abnormality present but explained entirely by non-GVHD documented cause (specify site/alternate 
cause):_______________________________
 Abnormality present but explained entirely by non-GVHD documented cause (specify site/alternate 
cause):_______________________________


Entospletinib 
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Gilead Sciences, Inc. 
Amendment 2.0 Global
CONFIDENTIAL
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CHRONIC GVHD ACTIVITY ASSESSMENT- CLINICIAN (FORM A)
SCORE 0
SCORE 1
SCORE 2
SCORE 3
SKIN
GVHD features to be scored     
by BSA:
Check all that apply:
 Maculopapular rash / erythema
 Lichen planus-like features 
 Sclerotic features
 Papulosquamous lesions or
    ichthyosis
 Keratosis pilaris-like
  No BSA   involved
  1-18% BSA 
  19-50% BSA  
  >50% BSA
 Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________
SKIN FEATURES 
SCORE:
 No sclerotic 
features
 Superficial 
   sclerotic features “not 
hidebound” (able to pinch)
Check all that apply:
 Deep sclerotic                         
features 
 “Hidebound”                          
(unable to pinch) 
 Impaired mobility 
 Ulceration
If skin features score = 3, BSA% of non-moveable sclerosis/fasciitis  ___________
How would you rate the severity of this patient’s skin and/or joint tightening on the following scale, where 0 is not at all severe and 10 is the most severe 
symptoms possible:
             0       1         2         3         4         5         6         7         8          9         10
Symptoms
                                                                                                  Most severe
not at all severe                                                                                             symptoms possible


Entospletinib 
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Gilead Sciences, Inc. 
Amendment 2.0 Global
CONFIDENTIAL
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EYES
  No symptoms 
     symptoms 
  Mild dry eye symptoms 
not affecting ADL 
(requirement of 
lubricant eye drops < 3 
x per day) 
  Moderate dry eye symptoms 
partially affecting ADL 
(requiring lubricant eye drops 
> 3 x per day or punctal 
plugs), WITHOUT new 
vision impairment due to KCS
  Severe dry eye symptoms 
significantly affecting 
ADL (special eyeware to 
relieve pain) OR unable to 
work because of ocular 
symptoms OR loss of 
vision due to KCS
 Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________
LUNGS
 No symptoms
  Mild symptoms 
(shortness of breath 
after climbing one 
flight of steps)
  Moderate symptoms 
(shortness of breath after 
walking on flat ground)
  Severe symptoms 
(shortness of breath  at rest; 
requiring 02)
 Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________
JOINTS AND FASCIA
  No symptoms
  Mild tightness of arms or 
legs, normal or mild 
decreased range of motion 
(ROM) AND not affecting 
ADL
  Tightness of arms or legs OR 
joint contractures, erythema 
thought due to fasciitis, moderate 
decrease ROM AND mild to 
moderate limitation of ADL
  Contractures WITH 
significant decrease of ROM 
AND significant limitation of 
ADL (unable to tie shoes, 
button shirts, dress self etc.) 
 Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________


Entospletinib 
Protocol GS-US-406-1840 
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1 (Wors t) 
Shoulder 
Elbow 
Wrist/finger 
Ankle 
CONFIDENTIAL 
2 
3 
2 
3 
2 
3 
4 
5 
6 
4 
5 
6 
4 (Normal) 
Page 93 
7 <Normal) 
7 (Normal) 
0 Not done 
0 Not done 
0 Not done 
0 Not done 
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                        Today’s Date: ________________________
MR#/Name: ________________________
CHRONIC GVHD ACTIVITY ASSESSMENT-PATIENT SELF REPORT
Symptoms
Not                                                                                                                                           As Bad As You
Present                                                                                                                                     Can Imagine
   
 0           1         2         3          4         5         6         7         8          9         10
Please rate how severe the following symptoms 
have been in the last seven days.  Please fill in the 
circle below from 0 (symptom has not been 
present) to 10 (the symptom was as bad as you 
can imagine it could be) for each item.
Your skin itching at its WORST?
O
O
O
O
O
O
O
O
O
O
O
Your skin and/or joint tightening at their 
WORST?
O
O
O
O
O
O
O
O
O
O
O
Your mouth sensitivity at its WORST?
O
O
O
O
O
O
O
O
O
O
O
Your genital discomfort at its WORST?
(Women – vagina, vulva, or labia)
(Men – penis)
O
O
O
O
O
O
O
O
O
O
O
Eyes
What is your main complaint with regard to your eyes?
Please rate how severe this symptom is, from 0 (not at all 
severe) to 10 (most severe):
0    1     2     3     4     5     6     7     8      9    10
FORM B


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Patient Global Ratings:
1. Overall, do you think that your chronic graft versus host disease is mild, moderate or severe?
1= mild
2=moderate
3=severe
2. Please circle the number indicating how severe your chronic graft versus host disease symptoms are, where 0 is cGvHD symptoms that are not at all 
severe and 10 is the most severe chronic GvHD symptoms possible.
          0         1           2           3           4           5           6           7           8            9           10
cGvHD symptoms                                                                                                                                       Most severe cGvHD                                                                                                                                           
not at all severe                                                                                                                                           symptoms  possible
                                                                                                                                                                           
3. Compared to a month ago, overall would you say that your cGvHD symptoms are:
+3= Very much better
+2= Moderately better
+1=A little better
0= About the same
-1=A little worse
-2=Moderately worse
-3=Very much worse


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Appendix 6.
For Baseline + Subsequent Visits: Lee Symptom Scale {Lee et al 2002}
By circling one (1) number per line, please indicate how much you have been bothered by the 
following problems in the past 7 days: 
SKIN: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
1. 
Abnormal skin color. ................... 
0 
2 
3 
4 
2. 
Rashes .................. ···············-·· 
0 
2 
3 
4 
3. 
Thickened skin ........ ... ............ 
0 
2 
3 
4 
4. 
Sores on ski11.. ..........•... ·····- ····· 
0 
2 
3 
4 
5. 
Itchy skin ...... .............. .......... 
0 
2 
3 
4 
EYES AND MOUTH: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
6. 
Dry eyes ....•............................. 
0 
2 
3 
4 
7. 
Need to use eye drops frequently .. 
0 
2 
3 
4 
8. 
Difficulty seeing cleal'fy ........... , ... 
0 
2 
3 
4 
9. 
Need to avoid certain foods due to 
0 
2 
3 
4 
mouth pain .•........ 
. ............ 
10. Ulc.ers in mouth ......................... 
0 
2 
3 
4 
1"1. Receiving nutrition from an 
intravenous line or feeding tube .... 
0 
2 
3 
4 
BREATHING: 
rJot at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
12. 
Frequent coogh .......•... , ......•...... 
0 
2 
3 
4 
13. Colored sputum ......................... 
0 
2 
3 
4 
14. Shortness of breath with exereise .. 
0 
2 
3 
4 
15. Shortness of breath at rest. ........ 
0 
2 
3 
4 
16. Need to use oxygen ................. 
0 
2 
3 
4 


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EATING AND DIGESTION: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
17. Difficulty swallo"'ing solid foods .... 
0 
1 
2 
3 
4 
18. Difficulty swallowing liquids ......... 
0 
2 
3 
4 
19. Vomiting ............................ 
0 
1 
2 
3 
4 
20. Weight loss .........•... 
0 
2 
3 
4 
MUSCLES AND JOINTS: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
21. Joint and muscle aches ........... 
~. ~ 
0 
1 
2 
3 
4 
22. 
Lim~ed joint movement ............. 
0 
2 
3 
4 
23. Muscle cramps ................. 
0 
2 
3 
4 
24. Weak muscles ... ....... 
·· ~ ........ 
0 
2 
3 
4 
ENERGY: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
25. 
Loss of energy ....................•.... 
0 
1 
2 
3 
4 
26. 
Need to sleep more/take naps ..... 
0 
1 
2 
3 
4 
27. 
Fevers ........................ ........... 
0 
1 
2 
3 
4 
MENTAL AND EMOTIONAL: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
28. 
Depression ........• .................... 
0 
1 
2 
3 
4 
29. 
Anxiety .............. ..................... 
0 
2 
3 
4 
30. 
Difficulty sleeping .. ................... 
0 
1 
2 
3 
4 


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Summary of the Lee Symptom Scale
Which 2 of the following organs/systems have you found to affect you the most in the last seven 
days:
1) Skin
2) Eyes 
3) Mouth
4) Breathing
5) Eating and Digestion
6) Muscles and Joints
7) Energy
8) Mental and Emotional


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Appendix 7.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated 
Grade 2
Moderate
Local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL 
Grade 3
Severe
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADL  
Grade 4
Life-threatening
Urgent intervention indicated 
Grade 5
Death 
Death related AE 
*
Activities of Daily Living (ADL) Instrumental ADL refer to opening preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden


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Gilead Sciences, Inc. 
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Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
ENTO is contraindicated in pregnancy as animal studies in rats and rabbits have shown that 
study drug is teratogenic. Pregnancy must be excluded before the start of treatment with study 
drug and prevented thereafter by reliable contraceptive methods. Pregnancy tests will be 
performed regularly throughout this study per Table 6-1. Please refer to the latest version of the 
investigator’s brochure for additional information.
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 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
ENTO is contraindicated in pregnancy as there is a strong suspicion of human 
teratogenicity/fetotoxicity in early pregnancy based on non-clinical data. In addition, ENTO has 
insufficient data 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. 
Please refer to the latest version of the investigator’s brochure for additional information.
b) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must also not rely on hormone-containing contraceptives as a 
form of birth control during the study.  They must have a negative serum pregnancy test at


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screening and a negative pregnancy test on the Baseline/Day 1 Visit.  Pregnancy tests will be 
performed on the protocol-specified schedule thereafter.  Female subjects must agree to one of 
the following methods to avoid pregnancy from Screening until 30 days from the last dose of 
ENTO:

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.
a) Intrauterine device (IUD) with a failure rate of <1% per year
b) Tubal sterilization
c) Essure micro-insert system (provided confirmation of success 3 months after procedure)
d) 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 from the last dose of ENTO.
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 from the 
last dose of ENTO.  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 
from the last dose of ENTO.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose.  Subjects who 


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become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator.  Instructions for reporting pregnancy, partner pregnancy, and pregnancy 
outcome are outlined in Section 7.6.


PPD 
Entospletinib 
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Prot_002.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Clinical Program 
Manager: 
Gilead Medical 
Monitor: 
(!') GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Efficacy and Tolerability ofEntospletinib, a Selective 
SYK Inhibitor, in Combination with Systemic Cmiicosteroids as 
First-Line Therapy in Subjects with Chronic Graft Versus Host 
Disease ( cGVHD) 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
129907 
2015-004572-30 
NCT02701634 
Chronic Graft Versus Host Disease (cGVHD) 
GS-US-406-1840 
Name: 
Telephone: 
Name: 
Telephone: 
Fax: 
Mobile: 
PPD 
t-'t-'U 
Mario Marcondes, MD, PhD 
PPD 
PPD 
PPD 
Protocol Version/Date: 
Original 
11 November 2015 
14 March 2016 
Amendment 1.0 (UK only) 
Amendment 1.0 (Global) 
02 May2016 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, pmi icularly unpublished data, is the prope11y 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 info1mation is only to be used by you in 
com1ection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infmm ation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infmm ed consent from those 
persons to whom the dmg 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
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................13
1.
INTRODUCTION ..............................................................................................................................................17
1.1.
Background ............................................................................................................................................17
1.1.1.
Background on Chronic Graft Versus Host Disease ............................................................17
1.2.
Entospletinib (ENTO)............................................................................................................................20
1.2.1.
Preclinical Pharmacology and Toxicology...........................................................................21
1.2.2.
Clinical Trials of Entospletinib (ENTO) ..............................................................................22
1.2.3.
Interaction with Proton Pump Inhibitors ..............................................................................23
1.3.
Rationale for This Study ........................................................................................................................24
1.4.
Rationale for Dose Selection..................................................................................................................24
1.5.
Risk/Benefit Assessment for the Study..................................................................................................24
1.6.
Compliance ............................................................................................................................................25
2.
OBJECTIVES.....................................................................................................................................................26
3.
STUDY DESIGN................................................................................................................................................27
3.1.
Endpoints ...............................................................................................................................................27
3.2.
Study Design..........................................................................................................................................28
3.3.
Study Treatments ...................................................................................................................................28
3.4.
Discontinuation Criteria.........................................................................................................................30
3.5.
Biomarker Testing..................................................................................................................................30
3.5.1.
Biomarker Samples to Address the Study Objectives:.........................................................30
3.5.2.
Optional Future Research.....................................................................................................31
3.5.3.
Optional Sub-study to study cellular turnover {Emson et al 2013, Ladell 
et al 2008, Messmer et al 2005}...........................................................................................31
4.
SUBJECT POPULATION..................................................................................................................................32
4.1.
Number of Subjects and Subject Selection ............................................................................................32
4.2.
Inclusion Criteria....................................................................................................................................32
4.3.
Exclusion Criteria...................................................................................................................................33
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................35
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................35
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................35
5.2.
Description and Handling of Study Drug...............................................................................................36
5.2.1.
Formulation..........................................................................................................................36
5.2.2.
Packaging and Labeling .......................................................................................................36
5.2.3.
Storage and Handling...........................................................................................................36
5.3.
Dosage and Administration....................................................................................................................37
5.4.
Prior and Concomitant Medications.......................................................................................................37
5.5.
Opportunistic Infections and Prophylactic Regimens ............................................................................40
5.6.
Accountability for Investigational Medicinal Product ...........................................................................40
5.6.1.
Investigational Medicinal Product Return or Disposal.........................................................40
6.
STUDY PROCEDURES ....................................................................................................................................41


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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................41
6.2.
Study Assessments.................................................................................................................................41
6.2.1.
Screening Visit .....................................................................................................................45
6.3.
Baseline/Day 1 Visit ..............................................................................................................................45
6.4.
Treatment Assessments (Weeks 2-48 and OLE)....................................................................................46
6.5.
Post-treatment Assessments ...................................................................................................................47
6.5.1.
Unscheduled Visit ................................................................................................................47
6.5.2.
Early Study Drug Discontinuation (ESDD) .........................................................................48
6.6.
30 Day Follow-Up Visit.........................................................................................................................48
6.7.
End of Study...........................................................................................................................................48
6.8.
Vital Signs..............................................................................................................................................48
6.9.
Biomarker Sample Collection ................................................................................................................49
6.9.1.
Clinical Laboratory Tests/Assessments................................................................................49
6.10.
Criteria for Discontinuation of Study Treatment....................................................................................49
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................51
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................51
7.1.1.
Adverse Events.....................................................................................................................51
7.1.2.
Serious Adverse Events........................................................................................................51
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................52
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................52
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................52
7.2.2.
Assessment of Severity ........................................................................................................53
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................54
7.4.
Gilead Reporting Requirements.............................................................................................................56
7.4.1.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events Toxicity Management .....................................56
7.4.2.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................56
7.4.3.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................57
7.4.4.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................57
7.5.
Toxicity Management ............................................................................................................................57
7.6.
Special Situations Reports......................................................................................................................58
7.6.1.
Definitions of Special Situations..........................................................................................58
7.6.2.
Instructions for Reporting Special Situations.......................................................................58
8.
STATISTICAL CONSIDERATIONS................................................................................................................60
8.1.
Analysis Objectives and Endpoints........................................................................................................60
8.1.1.
Analysis Objectives..............................................................................................................60
8.1.2.
Primary Endpoint .................................................................................................................61
8.1.3.
Secondary Endpoint .............................................................................................................61
8.1.4.
Other Endpoints of Interest ..................................................................................................62
8.2.
Analysis Conventions.............................................................................................................................62
8.2.1.
Analysis Sets ........................................................................................................................63
8.3.
Data Handling Conventions ...................................................................................................................63
8.4.
Demographic Data and Baseline Characteristics ...................................................................................65
8.5.
Efficacy Analysis ...................................................................................................................................65
8.5.1.
Primary Analysis..................................................................................................................65
8.5.2.
Secondary Analyses .............................................................................................................65
8.5.3.
Exploratory Analyses ...........................................................................................................66
8.5.4.
Interim Analysis ...................................................................................................................66
8.5.5.
Final Analysis.......................................................................................................................66
8.6.
Safety Analysis.......................................................................................................................................66


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8.6.1.
Extent of Exposure...............................................................................................................67
8.6.2.
Adverse Events.....................................................................................................................67
8.6.3.
Laboratory Evaluations ........................................................................................................67
8.6.4.
Other Safety Evaluations......................................................................................................67
8.7.
Pharmacokinetic Analysis......................................................................................................................67
8.8.
Biomarker Analysis................................................................................................................................68
8.9.
Sample Size............................................................................................................................................68
8.10.
Data Monitoring Committee ..................................................................................................................68
9.
RESPONSIBILITIES..........................................................................................................................................69
9.1.
Investigator Responsibilities ..................................................................................................................69
9.1.1.
Good Clinical Practice..........................................................................................................69
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................69
9.1.3.
Informed Consent.................................................................................................................69
9.1.4.
Confidentiality......................................................................................................................70
9.1.5.
Study Files and Retention of Records ..................................................................................70
9.1.6.
Case Report Forms...............................................................................................................71
9.1.7.
IMP Destruction ...................................................................................................................72
9.1.8.
Inspections............................................................................................................................72
9.1.9.
Protocol Compliance............................................................................................................72
9.2.
Sponsor Responsibilities ........................................................................................................................72
9.2.1.
Protocol Modifications.........................................................................................................72
9.2.2.
Study Report and Publications .............................................................................................73
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................73
9.3.1.
Payment Reporting...............................................................................................................73
9.3.2.
Access to Information for Monitoring..................................................................................73
9.3.3.
Access to Information for Auditing or Inspections ..............................................................74
9.3.4.
Study Discontinuation..........................................................................................................74
10.
REFERENCES ...................................................................................................................................................75
11.
APPENDICES ....................................................................................................................................................78
Appendix 1.
Investigator Signature Page....................................................................................................79
Appendix 2.
For Screening: NIH cGVHD Diagnosis and Staging Criteria, Global Severity Score 
{Jagasia et al 2015}................................................................................................................80
Appendix 3.
For Screening: NIH cGVHD Diagnosis and Staging Criteria (NCDSC) Form 
{Jagasia et al 2015}................................................................................................................81
Appendix 4.
For Baseline + Subsequent Visits:  Response Determination for the NIH cGVHD 
Activity Assessment (NCAA) {Herskowitz et al 1992} ........................................................85
Appendix 5.
For Baseline + Subsequent Visits: Chronic GVHD Activity Assessment- Clinician.............86
Appendix 6.
For Baseline + Subsequent Visits: Lee Symptom Scale {Lee et al 2002} .............................93
Appendix 7.
Grading of Adverse Event Severity........................................................................................96
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................97
Appendix 9.
Schedule of Assessments for the Optional Cellular Turnover Sub-study*..........................100


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Amendment 1.0 Global 
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LIST OF IN-TEXT TABLES
Table 5-1.
Tapering of Prednisone after reaching PR/CR .......................................................................38
Table 5-2.
Examples of Prohibited Agents ..............................................................................................39
Table 5-3.
List of Sensitive Substrates of UGT1A1, OATP1B1, OATP1B3, P-gp and BCRP...............39
Table 6-1.
Schedule of Assessments........................................................................................................42
Table 7-1.
Grading of Adverse Event Severity........................................................................................53
Table 7-2.
Grading of Adverse Event Severity: Upper Respiratory ........................................................54
Table 8-1.
Criteria for time point response determination.......................................................................61
LIST OF IN-TEXT FIGURES
Figure 1-1.
cGVHD prophylaxis with rituximab.  (A) Cumulative incidence of cGVHD. 
(B) Non-relapse mortality & GVHD recurrence. (C) Overall survival ..................................18
Figure 1-2.
Entospletinib Induces Apoptosis in B Cells from cGVHD Patients.......................................20
Figure 3-1.
Study Schema.........................................................................................................................29


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Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Amendment 1.0 Global 
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02 May 2016
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Efficacy and Tolerability of Entospletinib, a Selective 
SYK Inhibitor, in Combination with Systemic Corticosteroids as 
First-Line Therapy in Subjects with Chronic Graft Versus Host 
Disease (cGVHD)
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
129907
2015-004572-30
NCT02701634
Study Centers 
Planned:
Approximately 30 centers in the North America, Europe, Asia and 
Australia 
Objectives:
The primary objective is:
To evaluate the effect of ENTO on the best overall response rate 
(BORR) as assessed by the NIH cGVDH Activity Assessment 
(NCAA) {Herskowitz et al 1992} by 24 weeks in the setting of add-on 
to systemic corticosteroids as part of first-line therapy for cGVHD
The key secondary objectives are:

To evaluate the effect of ENTO on the skin domain of the Lee 
Symptom Scale (LSS)  (Appendix 6) at 24 weeks

To evaluate the effect of ENTO on the mouth domain of the LSS 
at 24 weeks

To evaluate the effect of ENTO on the eyes domain of the LSS at 
24 weeks

To evaluate the effect of ENTO on the total score of the LSS at 
24 weeks
Additional secondary objectives include:

To evaluate the effect of ENTO on duration of response (DOR)

To evaluate the effect of ENTO on dose reduction of 
corticosteroids


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Study Design: 
Number of Subjects 
Planned: 
Target Population: 
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• 
To evaluate the effect ofENTO on initiation of second-line 
therapy for cGVHD 
• 
To evaluate the effect ofENTO on progression of cGVHD 
• 
To evaluate the safety and tolerability ofENTO 
Exploratmy objectives include: 
~ 
I 
I 
Randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the efficacy and safety ofENTO (Treatment Alm 1) 
vs. placebo (Treatment Alm 2) in combination with systemic 
cmticosteroids for subjects with cGVHD. 
An interim analysis for futility is planned when approximately 50% of 
subjects have been on study for 24 weeks. The primary endpoint will 
be evaluated when all subjects complete 24 weeks of treatment. 
Duration and quality of response will be evaluated up to 48 weeks of 
blinded treatment. 
After 48 weeks, subjects who are still on investigational treatment 
(ENTO or PTM) and ar·e eligible to remain on study will have the 
option to receive open-label extension (OLE) with ENTO and attend 
visits per the schedule of assessments (Table 6-1) for an additional 
96 weeks. 
Subjects who complete the study through Week 48 and do not wish to 
patiicipate in the OLE will be required to retum to the clinic after 
completion of study dmg for a 30-Day Follow-up Visit. 
Approximately 100 subjects. Randomization will be stratified 
by 1) calcineurin inhibitor or mycophenolate mofetil (MMF) use 
(no vs. yes) and 2) moderate vs. severe cGVHD as detetmined by the 
NIH cGVHD Diagnosis and Staging Criteria (NCDSC) at the 
Screening visit. 
Adult males or non-pregnant, non-lactating, female subjects with 
cGVHD 
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Duration of 
Treatment:
48 weeks in the double-blind, placebo-controlled period.  After 
48 weeks subjects who are still on investigational treatment (ENTO or 
PTM) and are eligible to remain on study will have the option to 
receive OLE with ENTO and attend visits per the schedule of 
assessments (Table 6-1) for an additional 96 weeks.
Diagnosis and Main 
Eligibility Criteria:
The following are a summary of the key criteria: 
Key Inclusion Criteria: 

Male or non-pregnant, non-lactating, female subjects 

18-75 years of age, inclusive at Screening

Newly diagnosed cGVHD defined by:
a) At least 100 days after receiving any allogeneic hematopoietic 
stem cell transplant 
AND 
b) Receiving new course of systemic corticosteroids 
(1.0 mg/kg/day or prednisone equivalent) as first-line therapy 
for cGVHD within 10 days of screening 
AND
c) Moderate to severe cGVHD as assessed by NCDSC with at 
least three organ systems involved OR one organ system with 
a score of 2 OR lung organ score = 1 (Appendix 2) 

Subjects who have undergone transplant for hematologic 
malignancy are required to be in complete remission. 

Have either a normal ECG or one with abnormalities that are 
considered clinically insignificant by the investigator in 
consultation with the Sponsor 
Key Exclusion Criteria:

Uncontrolled infection within  4 weeks of Screening

History of the following therapies in the post-transplant period:
B cell depleting biologic agents 
CD19 CAR-T cells based therapies 
BTK/SYK/JAK/PI3K inhibitors
Phototherapy-unless administered for acute GVHD 


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
Treatment of cGVHD with anti-thymocyte globulins (ATG), or 
campath within 60 days of Screening visit  unless used for  
treatment of acute GVHD

Severe organ dysfunction manifested during Screening period: 
Requiring supplemental oxygen at more than 2 L/min
Uncontrolled arrhythmia or heart failure
Study Procedures/
Frequency:
Eligible subjects will be randomized 1:1 to Treatment Arm 1 or 
Treatment Arm 2 to receive study drug for 48 weeks.  Following 
Screening and Baseline/Day 1 Visits, subjects will return for study 
visits at Weeks: 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48.  Subjects 
that participate in the OLE will return for visits at Weeks: 50, 52, 56, 
60, 64, 72 and visits every 12 weeks thereafter. During the OLE, the 
maximum period of co-administration of ENTO with Cyclosporine, 
Tacrolimus or MMF should not exceed 3 months. Subjects who do 
not wish to participate in the OLE will have a 30-day Follow-Up visit 
after their week 48 visit. 
NOTE for subjects receiving tacrolimus, cyclosporine or MMF: 
For subjects receiving these medicines at enrolment and are
continuing on these medicines, the blood levels of tacrolimus, 
cyclosporine or the active metabolite of MMF (MPA) will be 
monitored at Baseline/Day 1 (prior to starting ENTO or 
placebo-to-match [PTM]), on Day 2 or Day 3 and Day 6 or Day 7 
after initiating ENTO or PTM, and at the end of Week 2 and 
Week 50 study visit. Beyond these time points, concentration 
monitoring for tacrolimus, and cyclosporine should follow the treating 
institution’s protocol and therapeutic range for monitoring these 
medicines. For subjects who initiate these medicines while already 
receiving ENTO, concentration monitoring for tacrolimus, 
cyclosporine and MPA should follow the treating institution’s 
protocol and therapeutic range for monitoring these medicines. When 
a concentration sample is taken at a local lab in accordance with the 
treating institution’s protocol for monitoring these medications, a
sample may also be requested for central lab analysis.
At Screening the NIH cGVHD Diagnosis and Staging Criteria 
(NCDSC) (Appendix 3) will be administered. At Baseline/Day1 and 
Weeks 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, 56, 60, 64, 72, 96 and Early 
Study Drug Discontinuation (ESDD) the NCAA (Appendix 5), and 
the LSS (Appendix 6) will be administered. Serological screening for 
HIV antibody (Ab), hepatitis B antigen, hepatitis C Antibody will be 
collected at the Screening visit.  For subjects with hematologic
malignancy, assessments of residual disease will be followed per the 
institutional guidelines.  


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Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
CONFIDENTIAL 
Final 
Amendment 1.0 Global 
Blood and urine will be collected at all study visits per the schedule of 
assessments(Table 6-1 ). 
Blood for selected biomarkers will be collected at all study visits per 
the Schedule of Assessments (Table 6-1). 
PPD 
I 
I 
Treatment Alm 1: ENTO 400 mg twice daily: 2 X 200 mg tablets 
twice daily, for subjects cunently on proton pump inhibitors (PPI)* 
Treatment Alm 2: Placebo-to-match (PTM) twice daily 
Both treatment atms will be administered orally without food (in a 
fasted state) for 48 weeks. 
*For subjects NOT cmTently taking a PPI, the dose will be adjusted to 
ENTO 200 mg twice daily: 1 X 200 mg tablet orally twice daily 
without food (in a fasted state) for 48 weeks. 
Systemic c01ticosteroids at a dose and route consistent with first-line 
therapy for newly diagnosed cGVHD. 
Systemic c01ticosteroids will be administered per provided treatment 
schema. 
Safety evaluations include documentation of AEs, physical 
examination, vital signs, ECGs, and clinical laboratory evaluations. 
The primru.y endpoint is BORR by 24 weeks, as assessed by the 
NCAA{Herskowitz et al 1992}, in the setting of add-on therapy to 
systemic c01ticosteroids as part of first-line therapy for cGVHD. 
The key secondru.y endpoints are: 
• 
Change from Baseline in the skin domain of the LSS at 24 weeks 
• 
Change from Baseline in the mouth domain of the LSS at 
24 weeks 
• 
Change from Baseline in the eyes domain ofLSS at 24 weeks 
• 
Change from Baseline in the total score of the LSS at 24 weeks 
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Phmmacokinetics: 
Statistical Methods: 
CONFIDENTIAL 
Other secondary endpoints include: 
• 
DOR 
Final 
Amendment 1.0 Global 
• 
Prop011ion of subjects who achieve at least 50% reduction in 
systemic c01ticosteroid dose relative to baseline 
• 
Prop011ion of subjects who initiate second-line therapy for 
cGVHD 
• 
Failme-free-smvival (FFS) 
• 
Safety and tolerability ofENTO 
Explorat01y endpoints of this study include: 
~ 
D 
I 
I 
I 
PK blood sampling will occm at Weeks 2 through Week 48 and then 
eve1y 12 weeks thereafter. 
The primmy endpoint ofBORR by 24 weeks is defmed as the 
proportion of subjects who achieve a complete or pmtial response 
(CR or PR) within 24 weeks, as assessed by the NCAA. A CR is 
achieved when all signs and symptoms of cGVHD have resolved. A 
PR is achieved when an objective response is observed in any organ 
system without progression in another organ system, and no 
additional systemic therapy is needed. 
The primmy analysis for BORR will be perf01med in the 
intent-to-treat (ITT) Analysis Set, which includes all subjects who 
were randomized. Response rate will be summarized by cmmt and 
percent of subjects with each ordinal response (CR, PR, and 
CR + PR). A stratified Cochran-Mantel-Haenszel (CMH) Chi-squm·e 
test will be pe1f01med to compm·e BORR between ENTO and PTM by 
24 weeks. The difference in response rates between treatment groups 
and the conesponding 95% Cis will be presented. 
Change from Baseline in the LSS scores will be analyzed using a 
mixed model repeated measmes (MMRM) model. Dmation of 
response (DOR) will be analyzed using the Kaplan-Meier method. 
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A sequential testing strategy will be implemented to preserve the 
overall type I error rate across the primary and key secondary 
endpoints of the study at a 2-sided significance level of 0.05.  If the 
primary hypothesis is rejected, the key secondary endpoints will be 
sequentially tested at the 2-sided 0.05 significance level in the
following order: (1) change from Baseline in the skin domain of the 
LSS, (2) change from Baseline in the mouth domain of the LSS, 
(3) change from Baseline in the eyes domain of the LSS, and 
(4) change from Baseline in the total score of the LSS.  If a null 
hypothesis is not rejected, formal sequential testing will stop and only 
nominal significance will be cited for the remaining endpoints.
With 40 subjects per treatment group, there is 75% power to detect a 
30% improvement in response rate at the 2-sided 0.05 significance 
level using a Fisher’s exact test, assuming a placebo response rate of 
50%. A total of 100 subjects (50 per treatment group) will be enrolled 
assuming a 20% dropout rate.  
Safety data will be listed by subject and summarized by treatment and 
frequency of event/abnormality or descriptive statistical summaries, 
as appropriate. The endpoints to be evaluated will include AEs, 
physical examination, clinical laboratory test findings, ECG 
abnormalities and interval measurements, and vital signs 
measurements.
An external multidisciplinary data monitoring committee (DMC) will 
review the progress of the study, perform interim reviews of safety 
data at regular intervals approximately every 3 months, and perform 
an interim review of efficacy data for futility when approximately 
50% of subjects have been on study for 24 weeks, as described in the 
DMC Charter.  The DMC will provide recommendations to Gilead as 
to whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the 
study in the best interests of the participants, whether the study should 
continue as planned, or the study should continue with modifications.
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
aGVHD
Acute Graph Versus Host Disease 
ADL
Activities of daily living 
AKT
Protein kinase B
ALT
alanine aminotransferase
AML
acute myeloid leukemia 
APC
antigen presenting cell 
AST
aspartate aminotransferase
ATG
anti-thymocyte globulins
AUC
area under curve versus time
BAFF
B cell Activating Factor
BCMA
B cell maturation antigen
BCR
B cell receptor
BCRP
breast cancer resistance protein
BLNK
B cell linker protein
BLQ
below limit of quantitation
BTK
Bruton’s tyrosine kinase
BORR
best overall response rate
cGMP
Current Good Manufacturing Practice
CI
confidence interval
cGVHD
Chronic Graft Versus Host Disease
Clast
last observed quantifiable concentration
CL
systemic clearance following IV administration
CLL 
chronic lymphocytic leukemia
Cmax
maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
concentration at the end of the dosing interval
CONMED
concomitant medication
CPK
creatine phosphokinase
CR
complete response
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
DSPH
Drug Safety and Public Health
DMC
Data Monitoring Committee
DOR
duration of response
E2
Estradiol
ECG
Electrocardiogram


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eCRF
electronic case report form(s)
ENTO
Entospletinib 
ENTO BIS-MSA
Entospletinib bismesylate monohydrate
ENTO MSA
Entospletinib methanesulfonate
ENTO SSD
Entospletinib spray-dried dispersion tablet
ERK
Extracellular signal regulated kinase
ESR
erythrocyte sedimentation rate
ET
early termination
FDA
(United States) Food and Drug Administration
FFS
failure-free survival
FSH
follicle-stimulating hormone
cGVHD
Chronic Graph Versus Host Disease 
GCP
Good Clinical Practice (Guidelines)
GGT
Gamma-glutamyl transferase
GVHD
Graph Versus Host Disease 
GSI
Gilead Sciences, Inc.
Hb
Hemoglobin
HBV
Hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDPE
high-density polyethylene
hERG
human-ether-a-go-go related gene
HIV
Human immunodeficiency virus
HSCT
hematopoietic stem cell transplant
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IgG
immunoglobulin G
IgM
immunoglobulin M
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
IRB
institutional review board
ITT
intent-to-treat 
IUD
intrauterine device
IV
Intravenous
IxRS
interactive voice/web response system
JAK
janus kinase
LDL
low-density lipoprotein


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LLN
lower limit of the normal range
LLOQ
lower limit of quantitation
LOCF
last observation carried forward
LOEL
lowest observed effect level
LOQ
limit of quantitation
LSS
Lee Symptom Scale 
MAD
multiple ascending dose
MAP
mitogen-activated protein
MedDRA
Medical Dictionary for Regulatory Activities
MK2
MAP kinase activated protein kinase-2
MMF
mycophenolate mofetil
MMP9
Matrix metallopeptidase-9
MMRM
mixed model repeated measures
µm
Micro millimeter
NDA
New Drug Application
NCAA
NIH cGVHD Activity Assessment
NCDSA
NIH cGVHD Diagnosis and Staging Criteria
NIH
National Institute of Health
NOAEL
no observable adverse effect level
NRI
non-responder imputation
PE
physical examination
PFT 
pulmonary function tests 
PI3K
phosphatidylinositol-4,5-bisphosphate 3-kinase
PK
Pharmacokinetic
PP
per-protocol
PR
pulse rate
PPI
proton pump inhibitor
PTM
placebo-to-match
Q1
first quartile
Q3
third quartile
QTcF
Quantum Tunnelling Composite Fridericia
RA
rheumatoid arthritis
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SEM
standard error of measure
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction


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SYK
Spleen tyrosine kinase
TACI
Transmembrane activator and CAML interactor
TLC
total lung capacity
tmax
the time (observed time point) of Cmax
t½
an estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant 
(λz)
UGT1A1
uridine disphosphate glucuronosyltransferase 1A1
ULN
upper limit of the normal range
US
United States
Vz
apparent volume of distribution following IV administration
WBC
White blood cell
WHO
World Health Organization
λz 
terminal phase rate constant


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1.
INTRODUCTION
1.1.
Background
1.1.1.
Background on Chronic Graft Versus Host Disease
Chronic Graft Versus Host Disease (cGVHD) is a disease observed in recipients of allogeneic 
hematopoietic stem cells, where the new immune system is reconstituted without complete 
tolerance to the host and begins to attack multiple organ systems including eyes, skin, mucosa, 
lungs, gut, and liver. Classic acute GVHD (aGVHD) occurs in episodes with donor cell 
engraftment before 100 days post-transplant and is thought to be mediated by donor T cells. 
Acute GVHD is observed in 35-50% of patients receiving hematopoietic stem cell transplant 
(HCT) {Jacobsohn et al 2007}. Acute GVHD is a risk factor for developing cGVHD, but 
cGVHD can develop without history of aGVHD. Chronic GVHD occurs in 35-70% of patients 
receiving allogeneic transplants. In the U.S., the incidence of cGVHD is estimated at 
~3000-5000 patients per year, with prevalence at approximately 10,000 {Vigorito et al 2009}. 
Initial therapy for cGVHD consists of high dose systemic corticosteroids, however 50 to 60% of 
patients fail to have a complete response to this line of therapy. 
No agents are currently approved for cGVHD. A combination of calcineurin inhibitors, mTOR 
inhibitors and mycophenolate mofetil (MMF) are frequently added as second-line therapy with 
an initial response rate of 20-70% {Flowers et al 2015}. The majority of responses are not 
durable, and cGVHD is associated with a 5-year mortality of 30-50% {Blazar et al 2012}. 
Current immunosuppressive treatments also increase the rate of life-threatening infections and 
cancer relapse due to presumably the loss of graft versus tumor effect. The absence of effective 
therapies is attributed to the limited understanding of disease pathophysiology and limited 
directed development by industry.  
1.1.1.1.
Role of SYK in cGVHD
Unlike aGVHD which is believed to be mediated by allo-reactive T cells; the current biological 
and clinical evidence implicates that dysregulated B cell homeostasis is involved in 
establishment of the chronic phase of GVHD.  B cell depletion in the peri-HSCT period is 
correlated with a reduction in the incidence of cGVHD.  In addition, antibodies against minor 
histocompatibility antigens have been associated with the occurrence of cGVHD.  In murine 
models of cGVHD, donor B cell alloantibodies have been shown to be responsible for the 
pathogenesis of the disease.   A single open label study with the CD20 B cell depleting 
agent -rituximab- evaluated the potential of prophylactic therapy for development of cGVHD 
post-transplant period {Cutler et al 2013}  . This study demonstrated clinically relevant 
differences in the cumulative incidence of cGVHD and overall survival (Figure 1-1).


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Figure 1-1.
cGVHD prophylaxis with rituximab. 
(A) Cumulative incidence of cGVHD.
(B) Non-relapse mortality & GVHD recurrence.
(C) Overall survival
In a subsequent study, subjects with steroid-refractory cGVHD received open-label rituximab 
{Cutler et al 2006} and an overall response rate of 70% was observed. This is in comparison to 
an expected response rate of ~50% for those receiving standard of care alone {Cutler et al 2013, 
Inamoto et al 2014}. These efficacy data with rituximab in cGVHD represent clinical validation
that therapy targeting B cells in this disease indication is effective. However, treatment of 
cGVHD with rituximab is suboptimal. The treatment effect is not durable as altered B cell 
populations recover {Sarantopoulos et al 2011}, and non-selective depletion of B cells results in 
complications such as hypogammaglobulinemia {Cutler et al 2013}. Targeting the pathogenic
B cell subpopulation that drives cGVHD may therefore yield enhanced efficacy and safety.
Emerging data also indicates that alterations in B cell homeostasis play a pathogenic role in 
cGVHD {Sarantopoulos et al 2015}. In healthy individuals, newly generated B cells emerge 
from the bone marrow as transitional B cells and must complete maturation and selection in the 
periphery {Wardemann et al 2003}. About 40% of these newly emerged B cells are auto 
reactive. Transitional B cells are dependent upon both BAFF (B cell Activating Factor) and BCR 
signaling for their differentiation/maturation and survival.  Low BAFF levels facilitate deletion 


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of autoreactive B cells.  Following HSCT, donor B cell reconstitution occurs in the presence of a 
high foreign antigen load and high BAFF levels. This unique setting promotes the survival of 
activated, potentially allo- and auto-reactive B cells that would normally undergo negative 
selection.   These donor-derived B cells can react with recipient tissue, facilitate tissue damage, 
produce inflammatory cytokines and serve as antigen presenting cell (APCs).   Importantly, 
patients with cGVHD treated with anti-CD20 who have persistent B cell lymphopenia after 
treatment experience worsening symptoms, suggesting that both high BAFF levels and limited 
capacity to generate sufficient native and transitional B cells contribute to the abnormal B cell 
homeostasis that underlies the disease pathology.  High numbers of native and transitional 
B cells protect from cGVHD development, possibly by binding and decreasing BAFF levels.  
These results further support the hypothesis that normal B cell homeostasis is required for 
protection from cGVHD.  
As described, BAFF and B cell receptor (BCR) signaling play critical roles in the establishment 
of B cell homeostasis by regulating the auto-reactive B cell population.  Patients with cGVHD 
have significantly increased BAFF levels versus B cell numbers {Sarantopoulos et al 2011}.  
Circulating CD27+ B cell subsets are increased and have high expression levels of the BAFF 
receptors.  These cells are present in patients with autoimmune disease, but are absent in healthy 
individuals.  These CD27+ cells are able to constitutively produce IgG and potentially mediate 
anti-recipient tissue responses.  In the cGVHD murine model, elevated BAFF was shown to 
maintain B cells in a state of heightened sensitivity to antigen stimulation following BCR 
stimulation. This observation led to the hypothesis that B cells of cGVHD patients become more 
sensitive to antigen stimulation via BCR stimulation, resulting in loss of peripheral tolerance and 
survival of autoreactive B cell clones.  In vitro studies in human B cells from cGVHD patients
vs. those without cGVHD, revealed that cGVHD B cells have increased proliferative responses 
to BCR stimulation and reduced apoptosis {Allen et al 2012}.   
A mechanistic understanding of BAFF and BCR signaling in cGVHD is currently being 
investigated and highlights that therapeutic kinase inhibition may benefit cGVHD patients with 
altered B cell homeostasis.  The aberrant B cell survival in cGVHD patients is postulated to 
involve BAFF signaling via a SYK-AKT-ERK axis {Allen et al 2012}.  Following HSCT, 
peripheral B cells isolated from cGVHD patients signal through protein kinase B and ERK and 
have decreased expression of the proapoptotic molecule, BIM, resulting in heightened 
metabolism and resistance to apoptosis {Allen et al 2012}.  Importantly, B cells from cGVHD 
patients also have increased proliferative responses to BCR stimulation, with concomitant 
elevations in B cell linker protein (BLNK) and SYK phosphorylation compared to patients 
without cGVHD {Allen et al 2014}.  Pharmacologically blocking SYK kinase activity with 
fostamatinib in vitro in cGVHD donor B cells, prevented BCR hyper-responsiveness of B cells 
to BCR stimulation with anti-IgM {Allen et al 2014}.  Inhibition of Burton’s tyrosine kinase 
(BTK) activity by ibrutinib blocked PLC- gamma 2 activation in cGVHD patient B cells; 
impacting survival of cGVHD B cells in a BTK dependent manner {Dubovsky et al 2014, 
Miklos et al 2015}. These data suggest that BAFF and BCR cooperate to prime cGVHD B cells 
for survival and antigen responsiveness by lowering the threshold for BCR activation in cGVHD.  
Blockade of BCR signaling, therefore, could be of therapeutic benefit by reestablishing normal 
B cell homeostasis. Therefore, both SYK and BTK inhibition have potential to modulate aberrant 


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B cell function in cGVHD. In contrast to SYK, there are no published data to indicate that BTK 
is activated in cGVHD patient samples. Preliminary unpublished data from the 
Sarantopoulos Lab at Duke University with ENTO in the same assay with active cGVHD patient 
samples demonstrates a dose-dependent effect of ENTO to induce apoptosis of B cells vs. in 
samples from patients without active cGVHD (Figure 1-2).
Figure 1-2.
Entospletinib Induces Apoptosis in B Cells from cGVHD Patients
In summary, failed induction of B cell tolerance after HSCT is postulated to underlie the 
pathophysiology of human cGVHD.  Factors contributing to impaired tolerance induction 
include post-HSCT lymphopenia, persistent allo-antigen stimulation, and high BAFF levels, all 
of which contribute to hyper-responsive BCR pathways. SYK inhibition of cGVHD B cells
subsets could antagonize the pro-survival signaling and result in pathogenic B cell deletion that 
could help reestablish B cell homeostasis.
1.2.
Entospletinib (ENTO)
For further information refer to Entospletinib Investigator’s Brochure (IB).


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1.2.1.
Preclinical Pharmacology and Toxicology
Entospletinib (ENTO) was evaluated in a standard battery of safety pharmacology studies to 
assess potential effects on central nervous, cardiovascular, and respiratory systems. ENTO had 
no effect on central nervous and respiratory system parameters evaluated in rats. In a 
cardiovascular safety pharmacology study in dogs, small increases in heart rate (up to a 
25% increase) were observed in male dogs given ENTO at 15, 50, or 150 mg/kg. While the 
higher heart rates were considered ENTO related, the relevance of these changes to humans is 
not known. Due to the observed increases in heart rate, a no observed effect level (NOEL) was 
not identified and the lowest observed effect level was 15-mg/kg. ENTO had no effect on ECGs 
or arterial blood pressure values at oral doses up to 150 mg/kg, the highest dose tested. 
Consistent with the lack of effect on ECG parameters, ENTO has no meaningful effect on the 
human-ether-a-go-go related gene (hERG), indicating that ENTO would not be expected to 
induce clinical QT prolongation. 
The toxicity of ENTO has been characterized in animal genotoxicity, embryo-fetal reproductive 
toxicity, and phototoxicity studies. Recently published data demonstrated that species-specific GI 
toxicity and lymphoid changes, similar to that which was observed following ENTO
administration to dogs, can occur in dogs but not rats, cynomolgus monkeys, or humans treated 
with p38 map kinase and mitogen-activated protein (MAP) kinase activated protein kinase-2 
(MK2) small molecule kinase inhibitors that inhibit pathways that overlap with SYK signaling 
pathways {Morris et al 2010}. Oral administration of ENTO to rats for up to 26 weeks or 
cynomolgus monkeys for up to 39 weeks showed no evidence of GI toxicity or lymphoid 
changes at exposures which overlapped with or exceeded those that resulted in acute toxicity in 
dogs. Furthermore, ENTO (administered as Entospletinib methanesulfonate (ENTO MSA)) has 
been previously investigated in healthy human subjects at doses up to 1200 mg twice a day for 
7 days and in subjects with rheumatoid arthritis (RA) at doses up to 900 mg twice a day for 
26 days and no evidence of GI or lymphoid toxicity was observed in these clinical studies. 
Therefore, the relevance of these findings to humans is not known.
ENTO inhibits uridine disphosphate glucuronosyltransferase 1A1 (UGT1A1) with an IC50 of 
2 μM. This enzyme is involved in glucuronidation of bilirubin, and inhibitors of UGT1A1 have 
the potential to produce increased levels of total and indirect (unconjugated) bilirubin in the 
circulation {Zhang et al 2005}. 
ENTO is considered non-genotoxic and administration of ENTO did not result in skin reactions 
indicative of phototoxicity in mice.
Administration of ENTO to pregnant female rats and rabbits from implantation to the closure of 
the hard palate (International Conference on Harmonisation [ICH] Harmonised Tripartite 
Guideline stages C to D) resulted in dose-dependent developmental findings including increased 
incidence of early and late fetal resorptions and reduced fetal weights, and delays in ossification 
of the forelimb phalanges (rats and rabbits) and metacarpals (rabbits only). These fetal findings 
occurred at ENTO doses that caused maternal toxicity as demonstrated in both studies by 
dose-dependent decreases in body weight gain and/or body weight loss and decreased food 
consumption of the dams. Maternal toxicity was also demonstrated in these studies at doses that 
did not result in developmental findings.


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1.2.1.1.
Non Clinical Pharmacology
For further information refer to ENTO Investigator’s Brochure (IB).
1.2.1.2.
Toxicology
In vitro and in vivo nonclinical studies were conducted to examine the potential toxicity of 
ENTO. In vivo studies were conducted in rats and dogs. Oral administration is proposed for the 
initial clinical trials; therefore, multiple-dose studies with ENTO were conducted via the oral 
route (gavage). 
Based on the totality of the data from the standard battery of in vitro and in vivo genotoxicity 
studies, ENTO is considered non-genotoxic. 
Further details can be found in the ENTO IB.
1.2.2.
Clinical Trials of Entospletinib (ENTO) 
To date, 11 clinical studies have been initiated with ENTO including a total of 566 subjects 
(including 328 healthy subjects, 7 subjects with RA, 76 subjects with CLL, 155 subjects with 
NHL; 26 subjects receiving placebo in Phase 1 and Phase 2 clinical studies. Of the 566 subjects 
receiving ENTO in these studies, ENTO has generally been well tolerated.
Positive results have been reported from a Phase 2 clinical trial with the putative SYK inhibitor 
fostamatinib showing objective anti-tumor responses in chronic lymphocytic leukemia (CLL) 
and Non-Hodgkin’s lymphoma (NHL) subjects {Friedberg et al 2010}.  These responses occurred 
despite off target toxicities that limited drug exposure. ENTO is a highly selective inhibitor of 
SYK and hence has the potential for an improved efficacy and tolerability profile in subjects 
with hematologic malignancies. 
ENTO is being evaluated in an ongoing Phase 2 clinical trial in subjects with relapsed or 
refractory CLL/NHL. A Phase 1b/2 clinical trial is being conducted for subjects with ENTO 
monotherapy and in combination with chemotherapy in subjects with acute myeloid leukemia 
(AML) and acute lymphocytic leukemia (ALL).
ENTO has been studied in single and multiple ascending dose studies in 304 healthy subjects, 
7 subjects with rheumatoid arthritis who were on stable doses of methotrexate, 80 subjects with 
CLL and 95 subjects with NHL.  Of these subjects, 460 received ENTO and 26 received placebo.  
In Pharmacokinetic (PK) studies at steady state in healthy subjects, ENTO was well tolerated 
when given in a fasted state for 7 days at doses of 25, 75, 200, 600, 900, and 1200 mg twice daily 
(GS-US-245-0101) and when given in a fed state for 6 days at doses of 100 and 900 mg 
twice daily (GS-US-245-0106), for 4 days at doses of 200 and 600 mg twice daily 
(GS-US-339-0101), and at 1200 mg twice daily for 5 days (GS-US-339-0109).Exposure, as 
measured by AUC and maximum concentration Cmax, did not increase appreciably at doses 
above 600 mg under fasted condition. 


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To provide a margin for inter-patient variability, a dose of 900 mg twice daily was chosen for the 
study of subjects with rheumatoid arthritis receiving stable doses of methotrexate in Study 
GS-US-245-0101.  A dose of 900 mg ENTO twice daily was given in a fasted state for 26 days 
in 7 subjects.  The median AUCtau in these subjects was similar to that of the healthy subjects.  In 
general, this dose was well tolerated.   One subject developed reversible, Grade 2 alkaline 
phosphatase and transaminase elevations starting 7 days after her last dose of ENTO, concurrent 
with new onset of a bronchopneumonia.  One other subject reported not feeling well and 
experienced hot flashes, fever, shivers, rash, headache, dizziness, and fainting 1 day after her last 
dose of ENTO with reversible Grade 1 alkaline phosphatase and Grade 3 transaminase elevations 
which peaked 1 week later.  While these events are potentially confounded by concurrent 
illnesses, hepatic enzymes will be closely monitored during this study.
Consistent with the known inhibition of UGT1A1 by ENTO, 8 of the 178 healthy subjects 
developed asymptomatic indirect bilirubin elevations (6 Grade 1, 1 Grade 2 and 1 Grade 3) that 
resolved following discontinuation of the drug.  Three of the 7 subjects with rheumatoid arthritis 
who received ENTO for 26 days developed asymptomatic indirect bilirubin elevations 
(2 Grade 1, 1 Grade 3) which improved despite continued dosing.
Common AEs from an on-going Phase 2 study evaluating chronic administration of ENTO
monotherapy in 186 subjects with hematologic malignancies are fatigue (53.2%), 
nausea (45.2%), diarrhea (38.7%), decreased appetite (24.7%), constipation (23.7%), 
cough (21.0%), and headache (21.0%) as of 21 November 2014. One out of a total of 
201 subjects (0.5%) experienced pneumonitis in this monotherapy study as of 11 March 2015.
1.2.3.
       Interaction with Proton Pump Inhibitors
In Study GS-US-245-1222, omeprazole co-administration reduced ENTO AUCtau by 
59% following ENTO BIS-MSA 400 mg BID (solid dispersion formulation). Available 
solubility and clinical PK data strongly imply that the observed interaction between ENTO and 
PPIs is due to elevated gastric pH, leading to reduced ENTO absorption. ENTO solubility is 
known to be highly pH-dependent, with aqueous solubility of 10 mg/mL at pH 2 but 
<0.15 mg/mL at pH ≥3.0, suggesting that PPIs are likely to reduce ENTO absorption due to 
increased gastric pH. In Study GS-US-245-1222, the ENTO terminal elimination half-life was 
similar when ENTO was administered alone (median [Q1, Q3] 14.89 [11.86, 21.36] hours) or 
with omeprazole (13.65 [10.49, 17.04] hours), demonstrating that the reduced ENTO exposure 
observed with omeprazole is likely a result of reduced absorption, rather than a result of altered 
elimination. Furthermore, omeprazole is a known inhibitor of CYP2C19 {Angiolillo et al 2011}
however in vitro studies did not identify a role of CYP2C19 in ENTO metabolism. In addition, 
CYP inhibition by omeprazole would be expected to result in increased drug exposure of 
susceptible substrates, whereas significantly decreased ENTO exposure was observed with 
omeprazole co-administration in healthy volunteer studies.
Please refer to Section 1.4 of the protocol for further discussion of the dosing implications of PPI 
co-administration with ENTO in this study.


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1.3.
Rationale for This Study
Given the emerging role of B cells in cGVHD (abnormal response to BAFF, errors in B cell 
reconstitution/differentiation, BCR signaling via SYK or BTK, failed induction of B cell 
tolerance), ENTO, in a dose responsive manner, induces ex vivo apoptosis of a population of 
B cells present only in patients with active cGVHD, and the proof-of-concept studies with 
rituximab demonstrating that B cell targeted therapy shows benefit in cGVHD
(see Section 1.1.1.1), Gilead is pursuing an investigation into whether ENTO is an effective 
treatment for cGVHD. Study GS-US-406-1840 is designed to evaluate the efficacy and 
tolerability of ENTO in addition to systemic corticosteroids in subjects at the time of initial 
diagnosis of cGVHD requiring treatment. Safety reviews will be performed in real time and will 
include evaluations of clinical laboratory abnormalities, relapse of primary malignancy, physical 
examinations, vital signs and AE reporting.
1.4.
Rationale for Dose Selection 
Since the target coverage necessary to achieve efficacy in subjects cannot be established in 
ex vivo experiments or animal models, the objective for dose selection is to achieve >50% target 
inhibition (% inhibition in stimulated CD63+ basophils) at trough. At 200 mg twice daily of 
ENTO BIS-MSA, the degree of inhibition of CD63+ cells is ~50% at steady state Ctrough. 
However, the majority of cGVHD subjects are administered proton pump inhibitors (PPIs), 
which would be expected to decrease target inhibition below 50% at this dose. At an ENTO
BIS-MSA dose of 400 mg twice daily in the presence of a PPI, target inhibition at Ctrough is 
~50%. Thus, the selected dose in cGVHD is 400 mg twice daily of ENTO in patients currently 
taking a PPI, and 200 mg twice daily of ENTO in patients not currently taking a PPI.
Furthermore, ENTO has a safety profile that is acceptable for subjects receiving treatment for 
malignancy (including cGVHD subjects). In studies with ENTO, the rate of Grade 3 or 4 
AST/ALT elevations is between 10-14%, and these events are reversible with interruption of 
dosing. Reversible episodes of elevated indirect bilirubin (≥ Grade 1) occur in ~11% of subjects.
1.5.
Risk/Benefit Assessment for the Study
Chronic GVHD remains a highly morbid disease with a high mortality rate, and given the 
cumulative safety data in healthy volunteers and patients with hematologic malignancies, the 
safety profile of ENTO is expected to be similar in cGVHD patients. ENTO is 
immunomodulatory, and even though ENTO has not been associated with an increased rate of 
infections in clinical studies in hematologic malignancy, serious infections are events of interest 
in this population as patients with cGVHD have a high rate of infections. Any 
immunomodulatory agent has a theoretical risk of decreasing the graft versus tumor effect, and 
malignancy relapse is also an event of interest in this study. However, as SYK inhibition affects 
primarily B cell function and not T-cell function, loss of the graft versus tumor effect is not 
expected as a result of treatment with ENTO. ENTO is associated with transaminase elevations 
and bilirubin increases, but these episodes have been reversible. The evaluation of safety of 
ENTO administration in the cGVHD population is facilitated in this study with the inclusion of a
placebo control group.


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Refer to the IB for full details of prior and ongoing pre-clinical and clinical studies including 
summary safety and efficacy data. 
1.6.
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 primaty objective is: 
To evaluate the effect ofENTO on the best overall response rate (BORR) as assessed by the 
cGVHD Activity Assessment (NCAA) {Herskowitz et all992} by 24 weeks in the setting of 
add-on to systemic corticosteroids as prut of first-line therapy for cGVHD 
The key secondaty objectives al'e: 
• 
To evaluate the effect of ENTO on the skin domain of the Lee Symptom Scale (LSS) 
(Appendix 6) at 24 weeks 
• 
To evaluate the effect ofENTO on the mouth domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the eyes domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the total score of the LSS at 24 weeks 
Additional secondruy objectives include: 
• 
To evaluate the effect ofENTO on duration of response (DOR) 
• 
To evaluate the effect of ENTO on dose reduction of c01ticosteroids 
• 
To evaluate the effect ofENTO on initiation of second-line therapy for cGVHD 
• 
To evaluate the effect of ENTO on progression of cGVHD 
• 
To evaluate the safety and tolerability ofENTO 
Explorat01y objectives include: 
I 
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3. 
STUDY DESIGN 
3.1. 
Endpoints 
The primary endpoint of this study is: 
Final 
Amendment 1.0 Global 
• 
The primary endpoint is BORR as assessed by the NCAA by 24 weeks in the setting of 
add-on to systemic corticosteroids as part of first-line therapy for cGVHD 
The key secondary endpoints are: 
• 
Change from Baseline in the skin domain of the LSS at 24 weeks 
• 
Change from Baseline in the mouth domain ofthe LSS at 24 weeks 
• 
Change from Baseline in the eyes domain ofthe LSS at 24 weeks 
• 
Change from Baseline in the total score ofthe LSS at 24 weeks 
Other secondary endpoints include: 
• 
DOR 
• 
Proportion of subjects who achieve at least 50% reduction in systemic corticosteroid dose 
relative to baseline 
• 
Proportion of subjects who initiate second-line therapy for cGVHD 
• 
Failure-free survival (FFS) 
• 
Safety and tolerability of ENTO 
Exploratory endpoints ofthis study include: 
I 
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3.2.
Study Design
This protocol describes a randomized, double-blind, placebo-controlled multicenter study to 
evaluate the efficacy and safety of ENTO (Treatment Arm 1) vs. placebo (Treatment Arm 2) in 
combination with systemic corticosteroids for subjects with cGVHD.  
A total of 100 eligible subjects will be randomized in a 1:1 manner to ENTO (Treatment Arm 1)
or placebo-to-match (PTM) (Treatment Arm 2), and treated for 48 weeks during the blinded 
phase. Randomization will be stratified by the following 2 factors at the Baseline/Day 1Visit:
Stratification Factor
Stratification Levels
Calcineurin inhibitor or MMF use
Yes vs. No
Disease severity as determined by the 2014 NIH 
Consensus cGVHD criteria
Moderate cGVHD:

≥ 1 organ with score = 2, or

≥ 3 organs with score = 1, or

lung score = 1
Severe cGVHD:

any organ score = 3 or

lung score ≥ 2
The final analysis for BORR is planned when all subjects have been on study for 24 weeks.  All 
subjects will be followed up to 48 weeks for DOR evaluation.  At the Week 48 visit, subjects
who are still on investigational treatment (ENTO or PTM) and are eligible to remain on study
will have the option to receive open-label extension (OLE) with ENTO. This OLE offers patients
who are deriving a benefit from ENTO or those with no alternative treatments the opportunity 
for further therapy for a serious and life threatening disease.
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study, perform interim reviews of safety data at regular intervals approximately every 3 months, 
and perform an interim review of efficacy data for futility when approximately 50% of subjects 
have been on study for 24 weeks, as described in the DMC Charter.  The first DMC meeting will 
be conducted after the 20th subject has been on study for 4 weeks.  The DMC will provide 
recommendations to Gilead as to whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the study in the best interests of 
the participants, whether the study should continue as planned, or the study should continue with 
modifications. 
3.3.
Study Treatments
After 48 weeks of blinded treatment, subjects who are still on investigational treatment (ENTO 
or PTM) and are eligible to remain on study will have the option to receive open-label extension 
(OLE) with ENTO and attend visits per the schedule of assessments (Table 6-1) for an additional 
96 weeks.
Subjects who provide written informed consent and meet all eligibility criteria will be 
randomized in a 1:1 fashion to either Treatment Arm 1 or Treatment Arm 2.  


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Subjects will retum for study visits at Weeks: 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48. At the 
Week 48 visit subjects who are still on investigational treatment (ENTO or PTM) and are 
eligible to remain on study will have the option to palticipate in the OLE. If subjects elect not to 
emoll in the OLE phase of the trial, they will retum for a 30-day follow-up visit. 
Subjects that will continue in the OLE phase of the trial will retum for the following study visits 
at Weeks: 50, 52, 56, 60, 64, 72 and visits evety 12 weeks thereafter. NOTE for subjects 
receiving tacrolimus, cyclosporine or MMF: For subjects receiving these medicines at 
emolment and are continuing on these medicines, the blood levels of tacrolimus, cyclosporine or 
the active metabolite of MMF (MPA) will be monitored at baseline/Day 1 (prior to statting 
ENTO or PTM), on Day 2 or Day 3 and Day 6 or Day 7 after initiating ENTO or PTM, and at 
the end of Week 2 and Week 50 study visit. Beyond these time points, concentration monitoring 
for tacrolimus, cyclosporine and MPA should follow the treating institution's protocol and 
therapeutic range for monitoring these medicines. For subjects who initiate these medicines 
while already receiving ENTO or PTM, concentration monitoring for tacrolimus, cyclosporine 
and MP A should follow the treating institution's protocol and therapeutic range for monitoring 
these medicines. When a concentration sample is taken at a local lab in accordance with the 
treating institution's protocol for monitoring these medications, a sample may also be requested 
for central lab analysis. 
PD 
Figure 3-1. 
Scru.ni.ng 
9 0 days prior 
to Baseline 
Study Schema 
Baseline 
(Day 1)• 
Week48• 
T re.;atmen t Arm. l; Ento-spletinib + Sy!>tem:ic corticoids 
for 48 weeks (n=50)" 
30Day 
FlU 
Treatment Arm 2: Placebo +Systemic corticoid'S 
for 48 "'-eeks (n=50)" 
Open-Label Lrtension 
I.ntospletinibd 
a 
Following the Baseline/ Day 1 visit subjects willrettun to the clinic for visits at Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 
48. 
b 
For subjects receiving tacrolimus, cyclosporine or MMF the blood levels of tacrolinms, cyclosporine or the active metabolite 
ofMMF (MPA) will be monitored at baseline/Day 1 (prior to struting ENTO or PTM), on day 2 or day 3 and day 6 or day 7 
aftet· initiating ENTO or PTM, and at d1e end of Week 2 and Week 50 study visit. Beyond these time points, concentration 
monitoring for tacrolimus, cyclosporine and MP A should follow the treating institutions protocol and therapeutic range for 
monitoring these medicines 
c 
Subjects who c.omplete the stt1dy through Week 48 and do not wish to continue to patticipate in the OLE phase of the trial 
will be requu·ed to rettu11 to the clinic 30 days after the completion of stt1dy dmg for a 30-Day Follow-up visit 
d Aftet· Week 48, subjects who are still on investigational treatment (ENTO or PTM) and ru·e eligible to remau1 on study will 
have the option to receive OLE for an additional 96 we.eks. Subjects will attend visits at Weeks: 50, 52, 56, 60, 64, 72 and 
every 12 weeks thereafter. 
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3.4.
Discontinuation Criteria
Subject participation may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree.

Unacceptable toxicity, 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

Relapse of primary disease  

Severity of cGVHD requiring therapy that is not allowed as concomitant therapy on study
(for example JAK inhibitor/BTK inhibitor /mTOR inhibitors/ any cell depletion 
agent/ phototherapy)

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 8

Discontinuation of the study at the request of Gilead, a regulatory agency or an 
Institutional Review Board or Independent Ethics Committee (IRB/IEC)
3.5.
Biomarker Testing
3.5.1.
Biomarker Samples to Address the Study Objectives:
Blood will be collected in this study and will be used to evaluate the effect of ENTO on markers 
relevant to cGVHD and/or the SYK pathway. The specific biomarkers may include, but are not
limited to the following:  cytokines, cell subset analysis , pathway markers, and/or other B-cell 
activating factor, B-cell function immunoglobulin levels, and/or antigen-specific B cell 
responses.
Because biomarker science is a rapidly evolving area of investigation, and adverse events in 
particular are difficult to predict, 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 art knowledge. 
The samples obtained for the study may be stored for 15 years after the end of the study.


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Optional Future Research 
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3.5.3. 
Optional Sub-study to study cellular turnover {Emson et al 2013, Ladell et al 
2008, Messmer et al 2005} 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 subjects who meet the inclusion/exclusion criteria will be enrolled. 
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) The ability to understand and sign a written informed consent form, which must be obtained 
prior to initiation of study procedures
2) 18-75 years of age, inclusive at Screening
3) Newly diagnosed cGVHD defined by: 
a) At least 100 days after receiving any allogeneic hematopoietic stem cell transplant 
AND 
b) Receiving new course of systemic corticosteroids (1.0 mg/kg/day or prednisone 
equivalent) as first-line therapy for cGVHD within 10 days of screening 
AND
c) Moderate to severe cGVHD as assessed by NCDSC with at least three organ systems 
involved OR one organ system with a score of 2 OR lung organ score = 1 (Appendix 2)
4) Subjects who have undergone transplantation for benign indications are eligible for the study. 
Complete remission is required for subjects who have undergone transplantations for 
hematologic malignancies. 
5) Have either a normal ECG or one with abnormalities that are considered clinically 
insignificant by the investigator in consultation with the Sponsor 
6) A negative serum pregnancy test is required for female subjects (unless permanently sterile 
or greater than two years post-menopausal) 
7) A female subject is eligible to enter the study if it is confirmed that she is: 
a) Not pregnant or nursing
b) Of non-childbearing potential (i.e., women who have had a hysterectomy, have had both 
ovaries removed or medically documented ovarian failure, or are postmenopausal 
women > 54 years of age with cessation (for 12 months) of previously occurring 
menses), or


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c) Of childbearing potential (as defined in Appendix 8) and agrees to utilize a highly 
effective protocol-specified contraceptive method or be non-heterosexually active or 
practice sexual abstinence from Screening throughout the duration of study treatment and 
for 30 days following the last study drug dose
8) Male subjects of childbearing potential who engage in heterosexual intercourse must agree to 
use protocol specified method(s) of contraception as described in Appendix 8.
9) Both female and male subjects of childbearing potential who are receiving mycophenolate 
mofetil (MMF) must agree to utilize contraceptive measures in accordance with the current 
MMF SmPC and the precautions for ENTO outlined in Appendix 8, whichever is stricter. 
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Uncontrolled infection within 4 weeks of Screening
2) History of the following therapies in the post-transplant period:
a) B cell depleting biologic agents
b) CD19 CAR-T cells based therapies 
c) BTK/SYK/JAK/PI3K inhibitors
d) Phototherapy-unless administered for aGVHD 
3) Treatment of cGVHD with anti-thymocyte globulins (ATG), or campath within 60 days of 
Screening visit  unless used for  treatment of acute GVHD
4) Severe organ dysfunction manifest during Screening period: 
a) Requiring supplemental oxygen at more than 2L/min
b) Uncontrolled arrhythmia or heart failure
c) Creatinine clearance (Cockroft-Gault) < 30 mL/min
5) Known hypersensitivity to the Investigational Medicinal Product (IMP), the metabolites, or 
formulation excipient.
6) Laboratory abnormalities including: 
a) Human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen or hepatitis 
C antibody positive (Subjects with positive HCV antibody and without detectable HCV 
RNA are permitted to enroll) 


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b) Aspartate aminotrasferase (AST)/Alanine aminotransferase (ALT) ≥ 2 X upper limit of 
normal (ULN) unless deemed to be secondary to Liver GVHD
c) Total bilirubin ≥2 X ULN unless deemed to be secondary to Liver GVHD
7) Positive serum pregnancy test (for female subjects) 
8) Any other clinical condition or prior therapy that, in the opinion of the investigator, would 
make the subject unsuitable for the study or unable to comply with dosing requirements 
9) Participation in any other clinical trial without prior approval from the sponsor is prohibited 
while participating in this trial 
10) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance or subject safety
11) Subjects receiving ongoing therapy with any of the following medications in the Table 5-2.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
Subjects will be assigned a screening number at the time of consent.  The Randomization and 
Baseline/Day 1 visit cannot occur until the Investigator has received the results of the Screening 
tests and subject eligibility has been confirmed. 
Once eligibility has been confirmed, each subject will be assigned a unique subject number. 
Once a subject number has been assigned to a subject, it will not be reassigned to any other 
subject. Prior to or during the Baseline/Day 1 visit, the investigator or designee will randomize 
the subject using an Interactive Web Response System (IWRS).  Subjects will be randomized in 
a 1:1 ratio to Treatment Arm 1 or Treatment Arm 2. The IWRS will assign blinded study drug 
bottle numbers at each study visit (except Weeks 2, 30 and 42).  Study drug will be dispensed to 
the subject in a blinded fashion until Week 48.  Randomization will be stratified by the following 
2 factors at the Screening and Baseline/Day1 Visit:
Stratification Factor
Stratification Levels
Calcineurin inhibitor or MMF use
Yes vs. No
Disease severity as determined at 
Screening by the NIH cGVHD 
Staging and Diagnosis Criteria 
(NCSDC) Global Severity Score
Moderate cGVHD:
≥ 1 organ with score = 2, or
≥ 3 organs with score = 1, or
lung score = 1
Severe cGVHD:
any organ score = 3 or
lung score ≥ 2
All Baseline/Day1 tests and procedures must be completed prior the administration of the first 
dose of the study drug. The subject must complete the Baseline procedures prior to 
randomization and drug dispensation.  Initiation of treatment with the study drug must take 
place within 24 hours after the Baseline/Day 1 visit.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IXRS system 
for that subject.  Gilead recommends but does not require that the investigator contact the 
Gilead medical monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the case report 
form/ electronic case report form (eCRF), along with the date on which the treatment assignment 
was obtained. The investigator is requested to contact the Gilead medical monitor promptly in 


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case of any treatment unblinding. Blinding of study treatment is critical to the integrity of this 
clinical trial and therefore, if a subject’s treatment assignment is disclosed to the investigator, the 
subject will have study treatment discontinued. All subjects will be followed until study 
completion unless consent to do so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.2.
Description and Handling of Study Drug
5.2.1.
Formulation
ENTO is available as 200-mg strength tablets. ENTO 200 mg tablets are blue, plain-faced, 
capsule-shaped, film-coated tablets. Each tablet contains the equivalent of 200 mg Entospletinib
free base in the form of Entospletinib bismesylate monohydrate (ENTO BIS-MSA). In addition 
to the active ingredient, ENTO tablets contain the following inactive ingredients: 
methanesulfonic acid, hydroxypropyl methylcellulose, mannitol, microcrystalline cellulose, 
crospovidone, poloxamer 188, silicon dioxide, magnesium stearate, polyethylene glycol, 
polyvinyl alcohol, talc, titanium dioxide, and FD&C blue #2 aluminum lake.
Placebo-to-match (PTM) tablets 200 mg are blue, plain-faced, capsule-shaped, film-coated 
tablets. Each tablet contains the following inactive ingredients: lactose monohydrate, 
microcrystalline cellulose, crospovidone, magnesium stearate, polyethylene glycol, polyvinyl 
alcohol, talc, titanium dioxide, and FD&C blue #2 aluminum lake. 
5.2.2.
Packaging and Labeling
ENTO (GS-9973) 200-mg and PTM tablets are packaged in white, high-density polyethylene 
(HDPE) bottles. Each bottle contains 60 tablets, silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant polypropylene 
screw cap with an induction-sealed and aluminum-faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
5.2.3.
Storage and Handling
Study drug (ENTO and PTM) 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. 


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Consideration should be given to handling, preparation, and disposal through measures that
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure through inhalation when handling.
5.3.
Dosage and Administration 
ENTO and PTM tablets will be provided by Gilead Sciences.  
ENTO or PTM should be taken under fasted conditions. Fasting is defined as no food or liquids 
other than water for 2 hours pre- and 1 hour post-dose. Subjects unable to swallow tablets should 
contact Gilead Medical Monitor for guidance. If vomiting occurs within 30 minutes after IMP 
administration and undissolved tablets are present in the vomitus, the subject should take another 
dose.
Study medication will be adjusted for whether the subject is taking a proton pump inhibitor (PPI) 
per the following table, both at study entry and throughout the study.
PPI status
ENTO or PTM dose
Subject is taking PPI
400 mg (2 x 200 mg tablet) twice daily 
Subject is NOT taking PPI
200 mg (1 x 200 mg tablet) twice daily 
5.4.
Prior and Concomitant Medications 
Systemic corticosteroids are required at study entry. Administration and taper recommendations 
are below:

Prednisone: administered initially as a single early morning dose of 1.0 mg/kg/day 
[or equivalent (Adults: maximum dose 100 mg)]. 

Prednisone therapy continues at the initial dose until there is objective evidence of 
improvement in manifestations of cGVHD (ie, a PR or better), minimum of 14 days. 

The initial taper of prednisone from the starting dose of 1.0 mg/kg/day (or equivalent) is 
attempted within 2 weeks after the first evidence of improvement in cGVHD

If exacerbation or recurrence of cGVHD is evident at any step of the taper, the dose of 
prednisone should be increased promptly by 2 levels, with daily administration for 2 to 
4 weeks, followed by resumption of alternate-day administration. Please see Table 5-1 for 
tapering. 


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Table 5-1.
Tapering of Prednisone after reaching PR/CR
Week 
Dose, mg/kg body weight (example for 80kg patient in mg)
0
1.0 qday (80)
1-3
1.0/0.5 (to begin within 1 week after objective improvement, 
alternating days) (80/40/80)
4-5
0.5 qday (40)
6-7
0.5  every other day (40/0/40)
8-9
0.25 every other day  (20/0/20)
10
0.1 every other day (10/0/10)

Inhaled and topical steroids (eg, Budesonide/ Beclomethasone) are not considered 
second-line therapy and are permitted throughout the duration of the study. Addition of the 
aforementioned agents will be recorded in the eCRF for posterior analysis.   

Local organ-specific treatment (eg, eye drops) will be recorded in the eCRF and assessment 
of response after local organ-specific treatment will be based on the NCAA.
Co- Administration of ENTO with Other Classes of Immunosuppresant Agents during OLE:

During the extension phase (post 96 weeks of study) or OLE, for patients who are eligible to 
remain on study, the maximum period of co-administration of ENTO with Cyclosporine, 
Tacrolimus or MMF should not exceed 3 months. The sponsor envisions that if the subject 
has stable or refractory disease, they should be transitioned to other forms of therapies within 
this 3 month period.
Disallowed Medications: 
Published clinical data suggests that the combination of ENTO with Idelalisib resulted in an 
unexpected pneumonitis syndrome attributed to excessive mammalian target of rapamycin–like 
activity. Although pneumonitis has been reported with all mTOR inhibitors, the exact incidence 
of this toxicity seems to vary widely from study to study. Therapeutic inhibition of kinases 
involved within the BCR signaling cascade is an emerging field, and many questions remain and 
for this reason, the co-administration of SYK inhibitors with PI3K inhibitors is strongly 
discouraged.
In vivo and in vitro data indicates that ENTO is a substrate of CYP2C9 and CYP3A. 
Co-administration of CYP2C9 inhibitors or inducers may increase or decrease ENTO exposure, 
respectively. As such, co-administration of moderate and strong CYP3A and CYP2C9 inducers
and strong CYP2C9 inhibitors are prohibited in this study. Caution should be exercised when 
co-administering drugs that are moderate inhibitors of CYP2C9 (eg fluconazole, voriconazole or 
amiodarone) as they may increase ENTO exposure. Administration of strong and moderate 
CYP3A and CYP2C9 inducers, and strong CYP2C9 inhibitors, is also prohibited for 2 weeks 
prior to study drug administration. Examples of strong CYP2C9 inhibitors and moderate/strong 
CYP3A and CYP2C9 inducers, PI3K inhibitors, and other medications that are prohibited in this 
study are provided in Table 5-2


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Table 5-2.
Examples of Prohibited Agents
Drug Class
Examples of Prohibited Agents (but not limited to)
mTOR inhibitor
Everolimus, sirolimus
Any cell depleting antibody
Rituxan®
Phototherapy
Phototherapy
BTK agents
Ibrutinib
JAK inhibitors
Tofacitinib, ruxolitinib
Moderate CYP3A/2C9 inducers
Bosentan, modafinil, nafcillin, ritonavir, efavirenz, thioridazine, lopinavir, 
etravirine, lersivirine, talviraline, tipranavir/ritonavir, semagacestat 
Strong CYP3A/2C9 inducers
Rifampin, mitotane, avasimibe, phenytoin, carbamazepine, enzalutamide, St 
John’s Wort, rifabutin, phenobarbital
Strong CYP2C9 inhibitors
Miconazole (systemic)
PI3K inhibitors
Idelalisib
Herbal/Natural Supplements 
St. John’s Wort 
Use with Caution: 
In vitro data indicates that Entospletinib has the potential to inhibit several transporters and the 
metabolizing enzyme UGT1A1, which may affect the plasma concentrations of substrates of 
these transporters and/or enzyme. Caution should be exercised when 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. A list of sensitive substrates of this enzyme and/or transporters 
is provided below; any use of these medicines should be discussed with the medical monitor.
Table 5-3.
List of Sensitive Substrates of UGT1A1, OATP1B1, OATP1B3, P-gp 
and BCRP
Transporter
Substrate
P-gp
Aliskiren, aldosterone, ambrisentan, colchicine, dasatinib, dabigatran etexilate, 
dexamethasone, digoxin, diltiazem, domperidone, etoposide, fexofenadine, imatinib, 
itraconazole, ivermectin, loperamide, lapatinib, maraviroc, methylprednisolone, 
nilotinib, posaconazole, quinidine, ranolazine, saxagliptin, sitagliptin, sparfloxacin, 
talinolol, tolvaptan, topotecan, vinblastine
BCRP
Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, 
sulfasalazine, topotecan
OATP1B1
Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, SN-38 (active metabolite 
of irinotecan), rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide,  
valsartan, olmesartan
OAPT1B3
Atorvastatin, rosuvastatin, pitavastatin, telmisartan, valsartan, olmesartan
UGT1A1
Acetaminophen, atorvastatin, bropirimine, carvedilol, clofibrate, ezetimibe, 
flavopiridol, gemfibrozil, genistein, nalorphine, naltrexone, naringenin, raloxifene, 
SN-38, simvastatin, telmisartan, troglitazone


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In a study in healthy volunteers, Entospletinib 400 mg twice daily increased rosuvastatin 
exposure by approximately 3-4-fold, which may theoretically increase the risk of 
rhabdomyolysis. In reviewing the safety of subjects whom have received a statin with 
Entospletinib there have been no reports of rhabdomyolysis nor a different adverse events 
profile, but in the interest of caution, the following restrictions apply to the use of HMG-CoA 
reductase inhibitors with Entospletinib:
HMG-CoA reductase inhibitor
Dose Adjustment Required
Atorvastatin
Maximum dose 20 mg QD
Rosuvastatin
Maximum dose 10 mg QD
Pravastatin
Maximum dose 20 mg QD
Simvastatin
Maximum dose 20 mg QD
Lovastatin
Maximum dose 20 mg QD
Fluvastatin
Maximum dose 20 mg QD
5.5.
Opportunistic Infections and Prophylactic Regimens
Patients with ongoing cGVHD or continued use of immunosuppressive therapy should be 
considered as immune deficient and at risk for significant infectious complications. Thus, 
prophylaxis for opportunistic infection according to institutional treatment standards are 
mandated For additional questions please refer to IDSA guidelines{Tomblyn et al 2009}. 
Specifically, CMV surveillance is mandated and in case of clinical infection or the need for 
preemptive CMV treatment, investigational treatment must be discontinued.
5.6.
Accountability for Investigational Medicinal Product 
The investigator is responsible for ensuring adequate accountability of all used and unused IMP.
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
Study drug accountability records will be provided by Gilead Sciences (or equivalent 
documentation maintained by the study site) to:

Record the date received and quantity of IMP bottles

Record the date, subject number, subject initials, the IMP bottle number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
5.6.1.
Investigational Medicinal Product Return or Disposal
IMP return and disposal will be performed as outlined in Section 9.1.6.


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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 the schedule of assessment 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).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that each subject is eligible for the study 
before enrollment in the study.  Please refer to Section 5.1 for details about randomization and 
treatment assignment.  
6.2.
Study Assessments 
Study procedures are outlined in Table 6-1.


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Table 6-1.
Schedule of Assessments
Visit
Screeninga
Baseline/
Day1c
END OF WEEK b
Every 12 
Weeks
30 
Day 
Follo
w-up
2
4
8
12
16
20
24
30
36
42
48/
ESDDd
50
52
56
60
64
72
Visit Window
-30 days
0
3
3
3
3
3
3
3
5
5
5
5
3
3
3
3
3
5
5
Written Informed 
Consent
X
Medical History 
X
Complete 
Physical Exam
X
X
X
X
X
Symptom-
Directed Physical 
Exame
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
Testf
X
Urine Pregnancy 
testf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum FSHf
X
NIH cGVHD 
Diagnosis and 
Staging Criteria
X
NIH cGVHD 
Activity 
Assessment
(NCAA) Form  
Ag
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NIH cGVHD 
Activity 
Assessment
(NCAA) Form Bh  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lee Symptom 
Scale (LSS)h 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Amendment 1.0 Global 
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Visit
Screeninga
Baseline/
Day1c
END OF WEEK b
Every 12 
Weeks
30 
Day 
Follo
w-up
2
4
8
12
16
20
24
30
36
42
48/
ESDDd
50
52
56
60
64
72
Visit Window
-30 days
0
3
3
3
3
3
3
3
5
5
5
5
3
3
3
3
3
5
5
Primary disease 
assessment per 
institutional 
guidelines  
X
X
   
X
Height 
X
Vital Signs & 
Weighti
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematologyj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistryk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Analysisl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Metabolic Panel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1, HBV, & 
HCV Serologym 
X
12 lead ECG-
performed supine 
X
X
X
PKn
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitoring of 
calcineurin 
inhibitors and 
MPA o
X
X
X
Biomarkersp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PFTs
X
X
X
Randomize 
X
Drug Dispensingq
X
X
X
X
X
X
X
X
X
X
X
X
X
Written Informed 
Consent for OLE
X


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Amendment 1.0 Global 
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Visit
Screeninga
Baseline/
Day1c
END OF WEEK b
Every 12 
Weeks
30 
Day 
Follo
w-up
2
4
8
12
16
20
24
30
36
42
48/
ESDDd
50
52
56
60
64
72
Visit Window
-30 days
0
3
3
3
3
3
3
3
5
5
5
5
3
3
3
3
3
5
5
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medicationsr 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Evaluations to be completed within 30 days prior to Day 1. 
b
All study visits are to be scheduled relative to the Day 1 visit date. 
c
Initiation of treatment with the study drug must take place within 24 hours after the Baseline/Day 1 Visit
d
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug 
e
Symptom-directed physical exam as needed 
f
FSH: For female subject post-menopausal for less than two years, if FSH 40 mIU/ mL a serum pregnancy test will be required.  Women determined to be of child bearing 
potential will have a serum pregnancy test performed at screening.  All subsequent visits will have a urine test, and positive urine pregnancy tests will be confirmed with a 
serum test. During OLE, urine pregnancy test will be performed every 4 weeks starting with end of visit Week 64.
g
NCAA Form A (Appendix 5) with spirometry measures will be completed by the Investigator or Sub-I. In the OLE this will be assessed at Weeks 56, 60, 64, 72 and 96. 
NCAA should also be performed at the time of initiation of second-line therapy.
h
LSS (Appendix 6) and the NCAA Form B (Appendix 5) is to be completed by the subject. The subject is to read the questionnaire by himself/herself and write/mark answers 
directly onto the questionnaire. In the OLE this will be assessed at Weeks 56, 60, 64, 72 and 96. The LSS and the NCAA Form B should also be administered at the time of 
initiation of second-line therapy.
i
Vital sign measurements include blood pressure, pulse, respiration rate, weight and temperature
j
Complete blood count (CBC) with differential platelet count 
k
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorous, magnesium, potassium, sodium, uric acid, and amylase and (reflex lipase testing is performed in subjects with total amylase 
> 1.5 ULN) 
l
Urine collection for urinalysis and urine pregnancy test (if applicable) 
m
Subjects with positive HCV antibody and without detectable HCV RNA are permitted to enroll 
n
Randomly timed PK sampling.  Sites should enter the time of the last dose of study medication in the eCRF for sample reconciliation. PK samples will be drawn at Week 60 
and every 12 weeks in the OLE. 
o
For subjects receiving tacrolimus, cyclosporine or MMF the blood levels of tacrolimus, cyclosporine or the active metabolite of MMF (MPA) will be monitored at 
baseline/Day 1 (prior to starting ENTO or PTM), on day 2 or day 3 and day 6 or day 7 after initiating ENTO or PTM, and at the end of Week 2 and Week 50 study visit. 
Beyond these time points, concentration monitoring for tacrolimus, cyclosporine and MPA should follow the treating institutions protocol and therapeutic range for 
monitoring these medicines 
p
Assessments may include but are not limited to: cytokines, cell subset analysis, pathway markers, and/or other B-cell activating factor, B-cell function, immunoglobulin 
levels, and/or antigen-specific B cell response.  Timepoints may differ depending on the specific biomarker and will be outlined in the Central Lab Manual.  
q
At visit 2, 30,  42 and (OLE visit 50) drug accountability only, study drug will not be dispensed at these visits 
r
Will include the following: systemic corticosteroid dose, other immunosuppressive, antimicrobials, PPI 
s
PFTs will include spirometry with bronchodilator, and diffusing capacity of the lungs for carbon monoxide (DLCO). PFTs will be done at ESDD, if ESDD visit greater than 
12 weeks from Baseline. 


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6.2.1.
Screening Visit
Written informed consent must be obtained from each subject before initiation of any visit 
procedures. After a subject has provided informed consent, the investigator and other study 
personnel (listed on the Form FDA 1572) will determine if the subject is eligible for participation 
in the study.  Subjects will be screened within 30 days before the Baseline/Day 1 visit to 
determine eligibility for the participation in the study.  This assessment will include review of the 
Inclusion/Exclusion criteria and completion of all Screening visits procedures as outlined in 
Table 6-1.  
Screening visit procedures will include the following for all subjects that provide informed 
consent: vital signs (including height and weight), medical history, complete physical 
examination, 12-lead ECG (performed supine), concomitant medications, serum pregnancy test 
(for women of child bearing potential), serum FSH (if applicable), primary malignancy 
assessment (if applicable), complete the NCDSC, blood draws for the following tests: 
hematology, chemistry, metabolic panel, HIV-1, HBV, and HCV serology unless specified 
otherwise.  Urine will be collected for urinalysis. 
Pulmonary function tests (PFTs) will be required at Screening: spirometry with bronchodilator 
and diffusing capacity of the lungs for carbon monoxide (DLCO). Investigators will be required 
to seek specialist examination for PFTs, ocular and gynecological involvement, and other items 
as described in the NCDSC.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30 days from the Screening visit for randomization into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (eCRF).  All 
other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF.  
See Section 7. for additional details.
6.3.
Baseline/Day 1 Visit 
The following evaluations are to be completed at the Baseline/Day 1 visit. The Investigator must 
confirm subject eligibility prior to randomization. Initiation of treatment with the study drug 
must take place within 24 hours after the Baseline/Day 1 visit. 
Baseline/Day 1 visit procedures will include the following: review of adverse events and 
concomitant medication use.  Sites will obtain: vital signs (including weight), complete physical 
exam, primary malignancy assessment (if applicable), NCAA and LSS.  Blood will be collected 
for the following tests: hematology, chemistry, metabolic panel, Blood specimens for selected 
biomarkers will be collected at Baseline, and urine for urine pregnancy test (if applicable) and 
urine analysis. 


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Final 
Amendment 1.0 Global 
NCAA Form A with spirometry should be completed by the Investigator or Sub-Investigator. 
The NCAA Form Band the LSS should be completed by the subject. Subject is to read 
questionnaire by himself/herself and write/mark answers directly on the questionnaire. 
Eligible subjects will be randomized in the IXRS to obtain the subject number. Study drug will 
be dispensed in a blinded fashion. Subjects should initiate dosing of study drug within 24 hours 
ofthe Baseline/Day 1 visit. 
ENTO or PTM should be taken under fasted conditions. Fasting is defined as no food or liquids 
other than water for 2 hours pre- and 1 hour post-dose. Subjects should be instructed not to bite 
or chew the tablets. In case of breakage of the tablets in the oral cavity, additional water should 
be taken as a rinse. Subject should be counseled on the importance of taking study medication 
daily and to return study medication bottles to each visit. 
6.4. 
Treatment Assessments (Weeks 2-48 and OLE) 
Evaluations listed in Table 6-1 are to be completed at the end of Weeks: 2, 4, 8, 12, 16, 20, 24, 
30 36, 42 and 48 in blinded fashion. For subjects continuing in the OLE the evaluations listed in 
Table 6-1 are to be completed at the end of Weeks: 50, 52, 56, 60, 64, and every 12 weeks post 
Week 72 up to Week 96 or, until unacceptable toxicity, withdrawal of consent by subject or 
withdrawal from study by investigator, or until ENTO becomes commercially available. 
Study visits are to be completed within ±3 days ofthe Baseline/Day 1 visit for Weeks 2-20; 
50-64 and ±5 days for Weeks 24-48. NOTE for subjects receiving tacrolimus, cyclosporine or 
MMF: For subjects receiving these medicines at enrolment and are continuing on these 
medicines, the blood levels oftacrolimus, cyclosporine or the active metabolite of MMF (MP A) 
will be monitored at baseline/Day 1 (prior to starting ENTO or PTM), on Day 2 or Day 3 and 
Day 6 or Day 7 after initiating ENTO or placebo-to-match (PTM), and at the end of Week 2 and 
Week 50 study visit. Beyond these time points, concentration monitoring for tacrolimus, 
cyclosporine and MPA should follow the treating institution's protocol and therapeutic range for 
monitoring these medicines. For subjects who initiate these medicines while already receiving 
ENTO, concentration monitoring for tacrolimus, cyclosporine and MP A should follow the 
treating institution's protocol and therapeutic range for monitoring these medicines. When a 
concentration sample is taken at a local lab in accordance with the treating institution's protocol 
for monitoring these medications, a sample may also be requested for central lab analysis. 
At all visits the following will occur: review of adverse events (AEs) and changes in concomitant 
medications, vital signs (including weight), primary malignancy assessment (if applicable), 
blood for hematology, chemistry, metabolic anel, and urine for: regnancy test if applicable), 
and urinalysis. PPD 
~--------------------------------------------------
PFTs will be required at on treatment Weeks 24 and 48 only: spirometry with bronchodilator 
and diffusing capacity of the lungs for carbon monoxide (DLCO) 
ECG will be performed at on treatment Weeks 24 and 48 only. 
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Blood specimens for selected biomarkers will be collected at Screening, Baseline and at Weeks: 
2, 4, 8, 12, 16, 20, 24,30, 36, 42, 48, 50, 52, 56, 60, 64, 72, F/up and ESDD (if applicable). The 
timepoints may differ depending on the specific biomarker and will be outlined in the Central 
Lab manual. 
PK blood draws will be collected at Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48 and Week 60 
and every 12 weeks in the OLE. 
Women determined to be of child bearing potential will have a urine test as listed in Table 6-1
and every 4 weeks during the OLE starting with Week 64. 
Complete physical exam will be performed at Weeks 12, 24 and 48, symptom directed physical 
exam will be completed as needed at all other visits.
NCAA Form A with spirometry should be completed by the Investigator or Sub-Investigator at 
all study visits (except Week 2) and during the OLE at Weeks 56, 60, 64, 72 and 96. The NCAA 
Form A should also be performed at the time of initiation of second-line therapy. Situations 
where subjects have comorbid or irreversible conditions that may interfere with response 
assessment, the check box on the NCAA indicating that the abnormality is entirely explained by 
a non-GVHD documented cause should be marked. Organ-specific response measures may be 
delayed until the following visit to allow for resolution of a non-GVHD issue. All other organs 
should still be scored.
LSS and NCAA Form B should be completed by the subject.  The Subject is to read the 
questionnaire by himself/herself and write/mark answers directly on the questionnaire. The PROs 
will be completed at all study visits (except Week 2) and during the OLE will be assessed at 
Weeks 56, 60, 64, 72 and 96. One question has been added to the LSS which asks which 
two domains are most impactful to the subject.
Document study drug dispensation and accountability for all study drugs dispensed. No study
drug will be dispensed at the Weeks 2, 30, 42 and 50 visits, only drug accountability will be done 
at those visits. 
6.5.
Post-treatment Assessments
6.5.1.
Unscheduled Visit 
A subject should attend an unscheduled visit if requested by the Sponsor or the investigator. The
assessments performed are at the investigator’s discretion.  
For subjects that initiate second line therapy during the study, every attempt should be made to 
collect the NCAA and LSS at an unscheduled visit and to keep the subject in the study and study 
related follow-up procedures should be continued. 


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6.5.2.
Early Study Drug Discontinuation (ESDD) 
If the subject discontinues study drug prior to the end of study, the subject will be asked to return 
to the clinic within 72 hours of stopping study drug for the Early Study Drug Discontinuation 
Visit.  The subject will be asked to continue attending the schedule study visits through Week 48. 
Subjects who ESDD will not be eligible for the OLE phase of the study. 
At the ESDD visit, any evaluations showing abnormal results indicating that there is a possible 
or probable causal relationship with the study drug, should be repeated weekly (or as often as 
deemed prudent by the investigator) until the abnormality is resolved, returns to baseline, or is 
otherwise explained. 
Evaluation listed in Table 6-1 will be completed at the ESDD visit.  
The following will be conducted at the ESDD: review of adverse events (AEs) and changes in 
concomitant medications, vital signs (including weight), complete physical exam, primary 
malignancy assessment (if applicable), blood for hematology, chemistry, metabolic panel, 
selected biomarkers and urine for: pregnancy test (if applicable), and urinalysis. The NCAA and 
LSS will be assessed.
PFTs will be required at ESDD: spirometry with bronchodilator and diffusing capacity of the 
lungs for carbon monoxide (DLCO).
6.6.
30 Day Follow-Up Visit 
Subjects who complete through Week 48 visit and who do not wish to participate in the OLE
phase of the study will return to the clinic 30 days after the completion of study drug for the 
30-Day follow-up visit. Subjects who complete the OLE will return to the clinic 30 days after the 
completion of study drug for the 30-Day follow-up visit
Subjects who permanently discontinue study drug and refuse to continue in the study will be 
asked to return to the clinic 30 days after the completion of the ESDD visit for the 30-Day
follow-up visit. 
For the purpose of scheduling a 30-Day follow-up visit, a ± 5 days window may be used. 
Table 6-1 lists all procedures to be completed at the 30-Day Follow-up visit. 
6.7.
End of Study
The definition of the end of the trial is the last visit of the last participant on the trial.
6.8.
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiration rate, weight and temperature. 
Height will be measured at the Screening visit only. 


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6.9.
Biomarker Sample Collection 
Blood for selected biomarkers may include, but not limited to, cytokines, B-cell activating factor, 
B-cell function, SYK pathway markers, immunoglobulin levels, and/or antigen-specific B cell 
responses. Please refer to Table 6-1 for collection timepoints. Samples may be stored for up to 
15 years. 
6.9.1.
Clinical Laboratory Tests/Assessments 
Blood and urine samples will be collected as outlined in Table 6-1.  

Hematology profile: completed blood count (CBC) with differential and platelet count 

Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, uric acid

Metabolic assessments: lipid panel (total cholesterol, HDL, direct LDL, and triglycerides).  

Immunoglobulin levels: Immunoglobulin A-E  

Serum and biomarker storage sample for possible additional clinical testing (if subject 
agrees) 

Urine pregnancy test (females of child bearing potential only); positive urine pregnancy tests 
will be confirmed with a serum test. 

Urinalysis 
6.10.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

Unacceptable toxicity, 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

Relapse of primary disease  

Severity of cGVHD requiring therapy that is not allowed as concomitant therapy on study

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 8

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)


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If the investigator considers discontinuing study medication for any reason other than those listed 
above, such as sustained complete remission of cGVHD for more than 3 months, then tapering to 
discontinue ENTO can be considered and should follow the schedule listed below:
Starting Dose
Action
400 mg twice daily
200 mg, twice daily, for 2 weeks
200 mg once daily for 2 weeks
200 mg, once daily, every other day for 2 weeks
Stop Study Medication
200 mg twice daily
200 mg once daily for 2 weeks
200 mg, once daily, every other day for 2 weeks
Stop Study Medication


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Pre-existing 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 (see Section 7.6.2.2)

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

Relapse of primary disease 

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 (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.4.1.
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 (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the modified CTCAE, version 4.03.  For each episode, 
the highest grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening) or 
Grade 5 (fatal) to describe the maximum intensity of the adverse event.  For purposes of 
consistency with the CTCAE, these intensity grades are defined in Table 7-1 and Appendix 7.
Table 7-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2
Moderate
Local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL
Grade 3
Severe
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL  
Grade 4
Life-threatening
Urgent intervention indicated 
Grade 5
Death 
Death related AE 
*
Activities of Daily Living (ADL) Instrumental ADL refer to opening preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden 


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Table 7-2.
Grading of Adverse Event Severity: Upper Respiratory 
The only modification to the CTCAE criteria has been the addition of a Grade 1 upper 
respiratory infection as follows:
CTCAE 
v4.0 Term
Grade 1*
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.03 
AE Term 
Definition
Upper 
respiratory 
infection
Mild 
symptoms; 
symptomatic 
relief (cough 
suppressant, 
decongestant, 
etc.)
Moderate 
symptoms; oral 
intervention 
indicated 
(e.g., antibiotic, 
antifungal, 
antiviral)
IV antibiotic, 
antifungal, or 
antiviral 
intervention 
indicated; 
radiologic, 
endoscopic, or 
operative 
intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder 
characterized by 
an infectious 
process involving 
the upper 
respiratory tract 
(nose, paranasal 
sinuses, pharynx, 
larynx, or 
trachea).
The distinction between the seriousness and the severity of an adverse event 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 one 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 case report form (eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 


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eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur within 30-days of the last dose of study IMP, regardless of 
causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

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 DSPH 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 as described above.

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.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.


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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.4.1.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events Toxicity Management 

All clinical events and clinically significant laboratory toxicities will be managed according 
to uniform guidelines detailed in Appendix 7.

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for Modified CTCAE 4.03 for Severity of Adverse Events and Laboratory 
Abnormalities. 

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose or modified dose that is 
dependent upon discussion with the Gilead Sciences Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.

Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
7.4.2.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue investigational medicinal product at the discretion of the investigator.


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7.4.3.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to Grade 2.If 
a laboratory abnormality recurs to Grade 3 following rechallenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.
7.4.4.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. The subject should be followed as clinically indicated 
until the laboratory abnormality returns to baseline or is otherwise explained, whichever 
occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade.
Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (e.g., Grade 4 CK after strenuous exercise or 
triglyceride elevation that is nonfasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product.
7.5.
Toxicity Management 
Concentration Monitoring of Calcineurin Inhibitors and Mycophenolate Mofetil
ENTO has been shown in vitro to inhibit the drug transporters organic anion transporting 
polypeptides 1B1 and 1B3 (OATP1B1 / OATP1B3), P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP), as well as the drug metabolizing enzyme glucuronosyltransferase 
UGT1A1. Due to the involvement of these pathways in the disposition of the calcineurin 
inhibitors tacrolimus and cyclosporine, and the active (mycophenolic acid [MPA]) and inactive 
metabolites of mycophenolate mofetil, Entospletinib may potentially affect the exposure of these 
medicines.
For subjects receiving these medicines, the blood levels of tacrolimus, cyclosporine or the active 
metabolite of MMF (MPA) will be monitored at baseline/Day 1 (prior to starting ENTO), on day 
2 or day 3 and day 6 or day 7 after initiating ENTO or PTM, and at the end of Week 2 and 
Week 50 study visit. Beyond these time points, concentration monitoring for tacrolimus, 


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cyclosporine and MPA should follow the treating institution’s protocol and therapeutic range for 
monitoring these medicines. When a concentration sample is taken at local lab, in accordance 
with the treating institution’s protocol for monitoring these medications, a sample may also be 
requested for central lab analysis. 
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 DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.


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Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH 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 DSPH, 
fax number +1 650 522-5477 or email Safety_FC@gilead.com. 
Refer to Appendix 8 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 Gilead DSPH 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 Section 7.3 and 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.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primaty objective is: 
To evaluate the effect ofENTO on BORRas assessed by the NCAA {Herskowitz et all992} by 
24 weeks in the setting of add-on to systemic corticosteroids as part of first-line therapy for 
cGVHD 
The key secondaty objectives are: 
• 
To evaluate the effect of ENTO on the skin domain of the LSS at 24 weeks 
• 
To evaluate the effect of ENTO on the mouth domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the eyes domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the total score of the LSS at 24 weeks 
Additional secondmy objectives include: 
• 
To evaluate the effect of ENTO on DOR 
• 
To evaluate the effect of ENTO on dose reduction of cotiicosteroids 
• 
To evaluate the effect of ENTO on initiation of second-line therapy for cGVHD 
• 
To evaluate the effect of ENTO on progression of cGVHD 
• 
To evaluate the safety and tolerability of ENTO 
• 
Exploratmy objectives include: 
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8.1.2.
Primary Endpoint
The primary endpoint is BORR by 24 weeks, defined as the proportion of subjects who achieve a 
complete or partial overall response (CR or PR) as assessed by the NCAA {Herskowitz et al 
1992} within 24 weeks, in the setting of add-on therapy to systemic corticosteroids as part of 
first-line therapy for cGVHD. 
At each assessment time point, organ-specific responses will be determined according to 
Appendix 4.  An overall time point response across all involved organs will then be determined 
according to Table 8-1.  The best overall response across all time points up to 24 weeks will be 
used to calculate BORR by 24 weeks. 
Table 8-1.
Criteria for time point response determination
Response Category
Response Criteria
Complete response (CR)
Resolution of all cGVHD manifestations in each organ or site as described in the 
NCAA organ response determination table
Partial response (PR)
Improvement of at least 1 organ or site, without progression in any other organ or 
site as described in the NCAA organ response determination table.
Stable disease (SD)
Neither sufficient improvement to qualify for a PR nor sufficient decline to qualify 
for a PD
Progressive disease (PD)

Worsening of signs and symptoms in any organ or site as described in the 
NCAA organ response determination table, taking the current best overall 
response as reference that is not a flare. A flare is defined as acute 
worsening of signs and symptoms in any organ or site that occurs at least 4 
weeks after PR/CR is achieved, which lasts ≤ 4 weeks.  
OR

Increase in systemic corticosteroid dose to ≥ baseline dose (1 mg/kg/day)
OR

Initiation of systemic immunosuppressive therapy other than systemic 
corticosteroids
8.1.3.
Secondary Endpoint
The key secondary endpoints are:

Change from baseline in the skin domain of the LSS at 24 weeks

Change from baseline in the mouth domain of the LSS at 24 weeks

Change from baseline in the eyes domain of the LSS at 24 weeks

Change from baseline in the total score of the LSS at 24 Weeks 


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• 
DOR, defmed as the time from the documentation of BORR to the documentation ofPD as 
defmed in Table 8-1. Note that a flare does not constitute an end to response. 
• 
Proportion of subjects who achieve at least 50% reduction in systemic corticosteroid dose 
relative to baseline, where % reduction is calculated as (systemic cotiicosteroid dose at 
24 weeks - baseline systemic cmiicosteroid dose) I baseline systemic corticosteroid dose 
• 
Proportion of subjects who initiate second-line therapy for cGVHD, defmed as receiving any 
therapy besides systemic cmticosteroids or study drug for the treatment of cGVHD. Inhaled 
and topical steroids are not considered second-line therapy. 
• 
Failure-free smvival (FFS), defined as the time from randomization to the earliest of first 
documentation of systemic therapy change, nonrelapse motiality, or recmTent malignancy 
• 
Safety and tolerability of ENTO 
8.1.4. 
Other Endpoints of Interest 
Exploratmy endpoints include: 
p 
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8.2. 
Analysis Conventions 
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be perfonned using SAS® software (SAS Institute, Caty, North Carolina, USA). 
In general, data will be described and summarized by relevant treatment rum, analysis set, and 
time point. As appropriate, changes from baseline to each subsequent time point will be 
described and summa1·ized by treatment ann. Graphical techniques ( eg, Kaplan-Meier cmves, 
waterfall plots, etc.) may be used when such methods m·e appropriate and infmmative. 
Summmy tables for continuous variables will contain the following statistics: N (number in 
analysis set), n (number with data), mean, standard deviation (SD), 95% confidence intetvals 
(Cis) on the mean, median, minimmn, first qum1ile (Ql), third qum1ile (Q3), and maximum. 
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Summary tables for categorical variables will include: N, n, percentage, and 95% CIs on the 
percentage. 
Subjects with discrepancies between the stratification factor values at randomization and the 
actual values as documented on data review will be categorized in the analyses according to the 
actual values.
Unless otherwise specified, all statistical tests will be 2-sided.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analyses will be the Intent-to-Treat (ITT), which includes 
data from all randomized subjects, with treatment assignments designated according to 
randomization. 
Selected efficacy endpoints may also be evaluated using the Per-Protocol (PP) analysis set, 
which includes all randomized subjects who received at least one dose of study drug, did not 
violate any major entry criteria, and did not have any major protocol deviations.
8.2.1.2.
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set, which includes data 
from all subjects who received at least one dose of study drug, with treatment assignments 
designated according to actual treatment received. All data collected up to the last dose of study 
drug plus 30 days will be included in the safety summaries. 
8.2.1.3.
Pharmacokinetics (PK)
The PK Analysis Set will include data from subjects in the Safety Analysis Set who have the 
necessary baseline and on-study measurements to provide interpretable results for the specific 
parameters of interest. 
8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial results. In general, values for 
missing data will not be imputed unless methods for handling missing data are specified.
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. 

If a subject received study drug, the subject will be included in the summary of AEs 
according to the treatment received; otherwise, if the subject is not dosed then they will be 
excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.


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Values for missing safety laboratory data will not be imputed; however, a missing 
Baseline/Day 1 result will be replaced with a screening result, if available. If no pre-treatment 
safety laboratory value is available, the Baseline/Day 1 value will be assumed to be normal 
(ie, no grade [Grade 0]) in the summary of graded laboratory abnormalities. Values for missing 
vital signs data will not be imputed; however, a missing Baseline/Day 1 result will be replaced 
with a screening result, if available.
Laboratory data that are continuous in nature but are less than the lower limit of quantitation 
(LOQ) or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used for calculation of descriptive statistics if 
the data is reported in the form of “<x” (x is considered the LOQ). For example, if the values 
are reported as <50 and <5.0, then values of 49 and 4.9 will be used for calculation of 
summary statistics, respectively. 

A value that is 1 unit above the LOQ will be used for calculation of descriptive statistics if 
the data is reported in the form of “>x” (x is considered the LOQ). For example, if the values 
are reported as >50 and >5.0, then values of 51 and 5.1 will be used for calculation of 
summary statistics, respectively.

The LOQ will be used for calculation of descriptive statistics if the data is reported in the 
form of “≤ x” or “≥ x” (x is considered as the LOQ).
PK concentration values that are below the limit of quantitation (BLQ) will be presented as 
“BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 at pre-dose time 
points, and one-half the value of the lower limit of quantitation (LLOQ) at post-baseline time 
points, where LLOQ is corrected for the dilution factor (ie, reported LLOQ/dilution factor) for 
determination of summary and order statistics.
The following conventions will be used for the presentation of summary and order statistics: 

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ”

If more than 25% of the subjects have a concentration value of BLQ for a given time point, 
the minimum and Q1 values will be displayed as “BLQ” 

If more than 50% of the subjects have a concentration value of BLQ for a given time point, 
the minimum, Q1, and median values will be displayed as “BLQ” 

If more than 75% of the subjects have a concentration value of BLQ for a given time point, 
the minimum, Q1, median, and Q3 values will be displayed as “BLQ” 

If all subjects have concentration values of BLQ for a given time point, all order statistics 
(minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ”
PK parameters that are BLQ will be imputed as one-half LLOQ before log transformation or 
statistical model fitting.


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8.4.
Demographic Data and Baseline Characteristics
Demographic data and baseline characteristics will be summarized by treatment group and 
overall using standard descriptive statistics for the ITT Analysis Set.
Demographic data will include: age, gender, race, and ethnicity.
Baseline characteristics will include: body weight, height, body mass index, and other covariates 
as necessary.
The number (proportion of subjects) in each stratum will also be summarized.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary endpoint is BORR by 24 weeks in the setting of add-on therapy to systemic 
corticosteroids as part of first-line therapy for cGVHD. The primary analysis will test the null 
hypothesis that there is no difference in response rate between ENTO + systemic corticosteroids 
and placebo + systemic corticosteroids versus the alternative hypothesis that there is a difference.  
Response rate will be summarized by count and percent of subjects with each ordinal response
(CR, PR, and CR + PR).  A stratified Cochran-Mantel-Haenszel (CMH) Chi-square test for 
association will be performed to compare BORR between ENTO and PTM by 24 weeks.  The 
difference in response rates between treatment groups and the corresponding 95% CIs will be 
presented.
8.5.2.
Secondary Analyses
A sequential testing strategy will be implemented to preserve the overall type I error rate across 
the primary and key secondary endpoints of the study at a 2-sided significance level of 0.05.  The 
primary endpoint analysis will serve as the gatekeeper for the key secondary endpoint analyses, 
ie, the primary efficacy endpoint must be met before the key secondary efficacy endpoints can be 
tested. The key secondary endpoints included in this sequential testing approach are (1) change 
from baseline in the skin domain of the LSS at 24 weeks, (2) change from baseline in the mouth
domain of the LSS at 24 weeks, (3) change from baseline in the eyes domain of LSS at 
24 weeks, and (4) change from baseline in the total score of the LSS at 24 weeks.
If the primary hypothesis is rejected, the key secondary endpoints will be sequentially tested at 
the 2-sided 0.05 significance level in the order listed above. If a null hypothesis is not rejected, 
formal sequential testing will stop and only nominal significance will be cited for the remaining 
endpoints. 
The key secondary endpoints will be analyzed using a MMRM model that includes all available 
data at baseline and all post-baseline visits. The model will include terms for baseline value, 
stratification factor, treatment, visit, and treatment-by-visit interaction. The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom and adjust standard 


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enors. Treatment comparisons will be generated within the lviMRM model based on the linear 
contrast of the least square means at all-time points. Adjusted means and 95% Cis will be 
presented by treatment group. Plots of mean (±SE) change from baseline over time will be 
provided by treatment group. Additional sensitivity analyses to fmther evaluate the impact of 
missing data may be perf01med and will be specified in the statistical analysis plan (SAP). 
Other secondary endpoints will be analyzed as follows: 
DOR and FFS will be analyzed using the Kaplan-Meier (KM) method and stratified logrank test. 
Kaplan-Meier summru.y statistics (median, 95% CI for median, and 25th, 75th percentiles) and 
number and percentage of events will be presented by treatment group. A stratified Cox 
prop01tional hazards model will be used to estimate the hazru.·d ratio and conesponding 95% CI. 
A KM survival plot will also be provided. Data for subjects who do not experience an event will 
be censored at the date of last visit. 
Prop01tion of subjects with at least 50% reduction in systemic c01ticosteroid dose relative to 
baseline and proportion of subjects who initiated second-line therapy for cGVHD will be 
analyzed similarly to the primru.y endpoint. 
8.5.3. 
Exploratory Analyses 
8.5.4. 
Interim Analysis 
An interim analysis for futility is plam1ed when approximately 50% of subjects have been on 
study for 24 weeks. The futility analysis will be perf01med on BORR by 24 weeks in the ITT 
Analysis Set. A non-binding futility mle will be implemented. Based upon the analysis results, 
the DMC may recormnend terminating the study for lack of efficacy if the predictive power of 
obtaining a statistically significant result at the final analysis given the observed interim data is 
:; 5%. A 2-sided alpha of0.001 will be allocated to this futility interim; following the 
Haybittle-Peto approach {Haybittle 1971, Peto et al 1976}, the final analysis alpha level is 
0.05 (2-sided). 
8.5.5. 
Final Analysis 
The fmal analysis for BORR is planned when all subjects have been on study for 24 weeks. 
Duration and quality of response will continue to be assessed up to 48 weeks. 
8.6. 
Safety Analysis 
All safety data collected on or after the date that ENTO/PTM was first administered up to the 
date of last dose of ENTO/PTM plus 30 days will be summarized by treatment group 
(according to the treatment received). Data for the pre-treatment period will be included in 
data listings. 
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8.6.1.
Extent of Exposure
A subject’s extent of exposure to ENTO will be generated from the study drug administration 
eCRF page. Exposure data will be summarized by treatment group. 
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event is defined as any adverse event with onset date on or after the date of first dose of 
study drug up to 30 days after permanent study drug discontinuation, or any adverse events 
leading to premature study drug discontinuation.  Summaries (number and percentage of 
subjects) of treatment-emergent adverse events (by SOC and PT) will be provided by treatment 
group. 
8.6.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using modified CTCAE 4.03.  Maximum 
post-baseline grade will be summarized by count and percentage of subjects with each grade.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post-baseline, will be summarized by treatment 
group. If baseline data are missing, then any graded abnormality (ie, at least a Grade 1) will be 
considered treatment-emergent.
Laboratory abnormalities that occur before the first dose of study drug or after the subject has 
been discontinued from treatment for at least 30 days will be included in data listings.
8.6.4.
Other Safety Evaluations
Individual data for 12-lead ECG, vital signs measurements will be listed by subject and 
summarized by treatment group by incidence of events/abnormalities or descriptive statistical 
summaries (n, mean, SD, median, Q1, Q3, minimum, and maximum), as appropriate. In 
comparison to pre-treatment (either Screening or pre-dose on Day 1) values, vital signs 
measurements and ECG findings will additionally be summarized using predetermined, 
clinically relevant thresholds.
8.7.
Pharmacokinetic Analysis
Plasma concentrations of ENTO (and metabolite, if applicable) will be displayed as individual 
concentration vs. time using scheduled sampling times, as appropriate. Concentrations will be 
listed by subject and summarized using descriptive statistics (eg, n, arithmetic mean, geometric 
mean, % coefficient of variation [CV], SD, median, Q1, Q3, minimum, and maximum). Plasma 


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concentration vs. time cmves may also be plotted in semi-logarithmic and linear f01mats as mean 
(± SD) and median (Ql, Q3). Available PK parameters will be listed and smnmarized for 
GS-9973 using descriptive statistics. 
8.8. 
Biomarker Analysis 
Descriptive statistics of baseline and change in biomarkers will be provided at each sampling 
time for all subjects and by treatment. 
PD 
PD 
8.9. 
Sample Size 
With 40 subjects per treatment group, there is 75% power to detect a 30% improvement in 
response rate at a 2-sided 0.05 significance level using Fisher's exact test, assuming a placebo 
response rate of 50%. A total of 100 subjects (50 per treatment group) will be enrolled assuming 
a 20% dropout rate. 
8.10. 
Data Monitoring Committee 
An extemal multidisciplinru.y data monitoring committee (DMC) will review the progress of the 
study, perf01m interim reviews of safety data at regular intervals approximately evety 3 months, 
ru.1d perf01m an interim review of efficacy data for futility when approximately 50% of subjects 
have been on study for 24 weeks, as described in the DMC Chru.ter. The DMC will provide 
recommendations to Gilead as to the whether the natme, frequency, and severity of adverse 
effects associated with study treatment wanant the early tetmination of the study in the best 
interests of the pru.iicipants, whether the study should continue as planned, or the study should 
continue with modifications. 
The DMC's specific activities will be defined by a mutually agreed charter, which will define the 
DMC's membership, conduct and meeting schedule. 
While the DMC will be asked to advise Gilead regarding futme conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study. 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable 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.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an . The investigator will not begin any study subject activities until 
approval from the IRB/EC has been documented and provided as a letter to the investigator.
Before implementation, the Investigator will submit to and receive documented approval from 
the IRB/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/EC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/EC approved consent form for documenting 


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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by the IRB/EC. 
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,., 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 instruction.  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, 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

Participation in study (including study number);


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
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. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 
as described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 


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the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (e.g. data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5. 
9.1.7.
IMP Destruction
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/EC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/EC in 
accordance with local requirements and receive documented IRB/EC 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 agencies. Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation.
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.


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


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10.
REFERENCES
Allen JL, Fore MS, Wooten J, Roehrs PA, Bhuiya NS, Hoffert T, et al. B cells from patients with 
chronic GVHD are activated and primed for survival via BAFF-mediated 
pathways. Blood 2012;120 (12):2529-36.
Allen JL, Tata PV, Fore MS, Wooten J, Rudra S, Deal AM, et al. Increased BCR responsiveness 
in B cells from patients with chronic GVHD. Blood 2014;123 (13):2108-15.
Angiolillo DJ, Gibson CM, Cheng S, Ollier C, Nicolas O, Bergougnan L, et al. Differential 
effects of omeprazole and pantoprazole on the pharmacodynamics and 
pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-
controlled, crossover comparison studies. Clin Pharmacol Ther 2011;89 (1):65-
74.
Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. 
Nature reviews 2012;12 (6):443-58.
Cutler C, Kim HT, Bindra B, Sarantopoulos S, Ho VT, Chen YB, et al. Rituximab prophylaxis 
prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood 
stem cell transplantation: results of a phase 2 trial. Blood 2013;122 (8):1510-7.
Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D, et al. Rituximab for steroid-
refractory chronic graft-versus-host disease. Blood 2006;108 (2):756-62.
Dubovsky JA, Flynn R, Du J, Harrington BK, Zhong Y, Kaffenberger B, et al. Ibrutinib 
treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest 
2014;124 (11):4867-76.
Emson CL, Fitzmaurice S, Lindwall G, Li KW, Hellerstein MK, Maibach HI, et al. A pilot study 
demonstrating a non-invasive method for the measurement of protein turnover in 
skin disorders: application to psoriasis. Clinical and translational medicine 
2013;2:12.
Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood 2015;125 
(4):606-15.
Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al. Inhibition of 
Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin 
lymphoma and chronic lymphocytic leukemia. Blood 2010;115 (13):2578-85.
Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol 
1971;44 (526):793-7.


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Gilead Sciences, Inc. 
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Herskowitz A, Willoughby SB, Baughman KL, Schulman SP, Bartlett JD. Cardiomyopathy 
associated with antiretroviral therapy in patients with HIV infection: a report of 
six cases. Ann Intern Med 1992;116 (4):311-3.
Inamoto Y, Flowers ME, Sandmaier BM, Aki SZ, Carpenter PA, Lee SJ, et al. Failure-free 
survival after initial systemic treatment of chronic graft-versus-host disease. 
Blood 2014;124 (8):1363-71.
Jacobsohn DA, Vogelsang GB. Acute graft versus host disease. Orphanet J Rare Dis 2007;2:35.
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes 
of Health Consensus Development Project on Criteria for Clinical Trials in 
Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working 
Group Report. Biol Blood Marrow Transplant 2015;21 (3):389-401 e1.
Ladell K, Hellerstein MK, Cesar D, Busch R, Boban D, McCune JM. Central memory CD8+ T 
cells appear to have a shorter lifespan and reduced abundance as a function of 
HIV disease progression. J Immunol 2008;180 (12):7907-18.
Lee S, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure 
symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant 
2002;8 (8):444-52.
Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesar D, et al. In vivo 
measurements document the dynamic cellular kinetics of chronic lymphocytic 
leukemia B cells. J Clin Invest 2005;115 (3):755-64.
Miklos DB, Arora M, Cutler CS, Nakamura R, Juretic M, Li Y, et al. A multicenter open-label 
phase 1b/2 study of ibrutinib in steroid dependent or refractory chronic graft 
versus host disease (cGVHD) [Abstract 7024]. American Society of Clinical 
Oncology (ASCO) Annual Meeting; 2015 29 May - 02 June; Chicago, IL. 
Morris DL, O'Neil SP, Devraj RV, Portanova JP, Gilles RW, Gross CJ, et al. Acute lymphoid 
and gastrointestinal toxicity induced by selective p38alpha map kinase and map 
kinase-activated protein kinase-2 (MK2) inhibitors in the dog. Toxicol Pathol 
2010;38 (4):606-18.
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of 
randomized clinical trials requiring prolonged observation of each patient. I. 
Introduction and design. Br J Cancer 1976;34 (6):585-612.
Sarantopoulos S, Ritz J. Aberrant B cell homeostasis in chronic GVHD. Blood 2015.
Sarantopoulos S, Stevenson KE, Kim HT, Washel WS, Bhuiya NS, Cutler CS, et al. Recovery of 
B-cell homeostasis after rituximab in chronic graft-versus-host disease. Blood 
2011;117 (7):2275-83.


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Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for 
preventing infectious complications among hematopoietic cell transplantation 
recipients: a global perspective. Biol Blood Marrow Transplant 2009;15 
(10):1143-238.
Vigorito AC, Campregher PV, Storer BE, Carpenter PA, Moravec CK, Kiem HP, et al. 
Evaluation of NIH consensus criteria for classification of late acute and chronic 
GVHD. Blood 2009;114 (3):702-8.
Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. Predominant 
autoantibody production by early human B cell precursors. Science 2003;301 
(5638):1374-7.
Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG. In vitro inhibition of 
UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors 
and the relationship of this property to in vivo bilirubin glucuronidation. Drug 
Metab Dispos 2005;33 (11):1729-39.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
For Screening: NIH cGVHD Diagnosis and Staging Criteria, Global Severity Score 
{Jagasia et al 2015}
Appendix 3.
For Screening: NIH cGVHD Diagnosis and Staging Criteria (NCDSC) Form 
{Jagasia et al 2015}
Appendix 4.
For Baseline + Subsequent Visits:  Response Determination for the NIH cGVHD 
Activity Assessment (NCAA) {Herskowitz et al 1992}
Appendix 5.
For Baseline + Subsequent Visits: Chronic GVHD Activity Assessment- Clinician
Appendix 6.
For Baseline + Subsequent Visits: Lee Symptom Scale {Lee et al 2002}
Appendix 7.
Grading of Adverse Event Severity
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 9.
Schedule of Assessments for the Optional Cellular Turnover Sub-study*


Entospletinib 
Protocol GS- US-406-1840 
Gilead Sciences, lnc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment 1.0 Global 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and 
Tolerability ofEntospletinib, a Selective SYK Inhibjtor, in Combination with Systemic 
Corticosteroids as First-Line Therapy in Subjects with Chronic Graft Versus Host Disease 
(cGVHD) 
GS-US-406-1840 PROTCOL Amendment 1.0 (Global): 02 May 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approvaL 
Name (Printed) Mario Marcondes, MD, 
PhD 
Date 
~STIGATORSTATEMENT 
I have read the protocol, including all appendices, and I agree that it contains aU necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
1 will provide all study personnel under my supervision copies of the protocol and access lo all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully infonned about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
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02 May2016 


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Appendix 2.
For Screening: NIH cGVHD Diagnosis and Staging Criteria, Global 
Severity Score {Jagasia et al 2015}
Mild chronic GVHD
1 or 2 Organs involved with no more than score 1
plus
Lung score 0
Moderate chronic GVHD
3 or More organs involved with no more than score 1
OR
At least 1 organ (not lung) with a score of 2
OR
Lung score 1
Severe chronic GVHD
At least 1 organ with a score of 3
OR
Lung score of 2 or 3
Key points:
In skin: higher of the 2 scores to be used for calculating global severity.
In lung: FEV1 is used instead of clinical score for calculating global severity.
If the entire abnormality in an organ is noted to be unequivocally explained by a non-GVHD documented 
cause, that organ is not included for calculation of the global severity.
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes) the scored 
organ will be used for calculation of the global severity regardless of the contributing causes (no 
downgrading of organ severity score).


Entospletinib 
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Final 
Amendment 1.0 Global 
Appendix 3. 
For Screening: NIH cGVHD Diagnosis and Staging Criteria (NCDSC) 
Form {Jagasia et al 2015} 
SCOREO 
P •;RFOR,JA;-;CE 
SCORE: 
I 
KPS ECO G LPS 
0 Asymptomatic and 
fully active (ECOG 
0: KPS or LPS 
100%) 
SKJNt 
SCORE"/o BSA D 
G VHD features to be scored 
0 No BSA 
llJ!...ll.&1.: 
involved 
Check an that apoly: 
0 Maculopapular rasbferytbeJllll 
0 Lichen planus-like features 
0 clerotic fea111res 
0 Papulosquamous lesions or 
icbtl1yosis 
0 Keratosis pilaris-)jke GVRD 
SKIN I'EATL'RES 
sco!U:: 
0 No sclerotic 
features 
Odrer skju G VJJD feature,• {NQT g ored bv BSA) 
Check all thnt apply: 
0 llyperpigmenullion 
0 Hypopig:mcntation 
0 Poikilodenna 
0 Severe or generalized pruritus 
0 Hair involvem.:nl 
0 Nail involvement 
SCOREl 
0 Symptomatic, 
fully ambulatory, 
restricted only rn 
physically 
strenuous <Lctivlty 
(ECOG I, KPS 
or LPS 80..90%) 
0 1-18% BS.A 
SCORE2 
SCORE 3 
0 Symptomatic, 
0 Symptomatic. 
ambulatory, capabl• 
limited self-care, 
of ~df-care. >50% 
>50% of V.".tking 
of v.'<lking hours ou 
hours in bed {ECOG 
of bt:d (ECOG 2, 
3-4, KPS or LPS 
KPS or LPS 60-
<60%) 
70%) 
0 19-50% BSA 
0 SuiWrficial 
sclerotic features 
"not hidebound" 
(able to pinch) 
0 >50% BSA 
Ch£Sk all that applv: 
0 Deep sclerotjc 
features 
o "Hidebound" 
(Lmablc to pinch) 
0 fmpaired mobility 
0 lJlccmtion 
0 Abnormality presellt but explained entirely by non-G VHD tlocumettled cause (specify): __ 
MOUTII 
Lichen planus-like 
features present: 
0 Yes 
ONo 
0 No symptoms 
0 Mild symptoms 
with d isease signs 
but not limiting 
oral intake 
significantly 
0 Modcmtc 
symptoms with 
disease signs with 
partial limitation 
o [ oral intake 
0 AbnormaJiiy pre.senl but e.tpfai.ned eniireJy by non-GVJJD tlocumemed cause (specifl): 
0 Severe symptoms with 
disease signs on 
examination with major 
limitation of ora.l in!Jlke 
Figur~ I. Or~n sa. ring of chronic GVHO. ECOC i nduares Eastl!rn COOpt'rJtM! OlliDlOf:)l Croup; KPS, K.tntol'sky ~ lf'onn.utcr Sl~tus; LPS, Lansky P'~rfomunCl! !i.uus; 
BSA, body Su1f<1<r are~: ADL. activit~ of da1ly hVIIlJ; LFf~ liVI'r fuMDOn ~IS; AP, alkaline phosphaw~: ALT. ~Luti ne .. ninOtrdli.Sf~r.ue; ULN, 1-.HITIAI UflP"r im1L 
"Wel:ht lOSSWtthln 3 nt<ln oo. ISkin .ronngshould u~ b«h pt'cra!'lltagt'OfBSII 11110lvel by disuse .slgns<tnd th~CULdnt!OUs ft.;nures sc.U.,S. When .. doscrrp.mcy ..xnu 
b<!LWrert the percen~<~,g• o( lD!l.i body s w·face ( BSA) -~ 
.utd the Skin re<ttu ~ score. OR if s uperfiCIAl scrrodc fe<ttll"l!S a rr p,._nt (Sc~ 2} !Jut ri~l't' is imparrld 
motility or ul~ranon (Sc:ore 3), the higher level ~ho uld be ~ 
for th~ Rn.al skill scori ng. t-ro be <omplerld by speoal"'t or rramO!d m«< ic.al pr0111d~rs (s"" 
Supprrrr rul Rgtn). -·Lung smr11g should be perforrrr d usmglloth the .sympr01ru • nd FEVl sro"'s when...,r poss1ble. ltV! .should~..,;"" m dte ftn<tl lung 
sa.nng wltt!l't' LhPrr is dtstrepariC)' berv....en symjl(oms .md f"EVJ sm-
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SCOREO 
EY~S 
0 No symptoms 
Ke.ratoconjrmctivitis 
sicca (KCS) confinned 
by ophthalmologist: 
0 Yes 
0 No 
0 Not examined 
SCORE I 
0 Mild dry eye 
symptorus not 
affecting ADL 
(requirement of 
lubricant eye 
drops .::, 3 x per 
day) 
SCORE2 
0 Moderate dry eye 
symptoms partially 
affecting ADL 
(requiring lublicant 
eye drops > 3 x per 
day or puncta) 
plugs), 
WITHOUT new 
vision impairment 
dueto KCS 
0 Abnormality present bwt explained entirely by non-GVHD documented cause (soecifl'): 
Gl Tract 
Check all that apply: 
0 Esophageal web/ 
proximal stricture 
or ring 
0 Dysphagia 
OAnorexia 
0 Nausea 
0 Vomiting 
0 Diarrhea 
0 Weight lo.s 2:_S%* 
0 Failure to thrive 
0 No s}mptoms 
0 Symptoms 
without 
significant weight 
loss• (<5%) 
0 Symptoms 
associated with 
mild to moderate 
weigbl loss• 
(5- 15%) OR 
modcntc diarrhea 
without 
s ignifi ~ant 
interference with 
daily living 
0 Abnormality presentlwt explained entirely by non-G VHD documented cause [.\pec{/YL-
0 NonnaJ tota I 
bilirobin and 
ALTorAP 
< 3xULN 
0 Not·roaJ total 
bilirubin with ALT 
:::;3 to5 x ULN or 
AP2:_3x ULN 
0 Elevated total 
bilirubin but 
.::,3 mgfdL or 
ALT>5 ULN 
0 Ab,tormulity present but explained entire!)' by non-GVHD documented cause (soecify): 
LUNGS .. 
~nnntom score; 
Lung score: 
%FBVJD 
Pulmonary j imction tests 
0 Not perfonned 
0 No symptoms 
0 f'EV1<:80% 
0 Mild symptoms 
(shortness of 
bn:ath at\er 
climbing one Oight 
of steps) 
O FEVI 60..79% 
0 Mode.mte 
symptoms 
(shortrtCSS ofbn:alh 
after ·walking on 
flat grow1d) 
0 FEVJ 40-59% 
SCORE 3 
0 Severe dry eye 
symptoms significantly 
affecting ADL (special 
eyeware to relieve pain) 
OR unable to work 
because of ocular 
symptoms OR Joss of 
vision due to KCS 
0 Symptoms associated 
with significant weight 
loss• > 15%. requires 
nutritional suppJem~nt fOr 
most calorie needs OR 
esophageal dilation OR 
severe dian·hca with 
significant interference-
with daily living 
0 Elevated total 
bilintbin > 3 rog/dL 
0 Severe syroptoms 
(shortness of breath at 
rcs1; requirin.g Oz) 
0 FEV199% 
0 Abnormality present bwt explained entirely by nou-OVf{f) d<)CUmellled cause (specify) .:~-------------, 
f'.gure 1. {oondrrued). 


Entospletinib 
Protocol GS-US-406-1840 
Gilead Sciences, Inc. 
JOIXrS Al\"D FASCIA 
P-ROM score 
(su below) 
Shoulder (1-7):_ 
F.lbow( l-7): _ 
WrisTlnnger (1-7):_ 
Ankle (1 -4) :_ 
SCOREO 
0 No 
symptoms 
SCORE 1 
0 :'vlild rightnes~ of 
arms or legs, 
nonnaJ or mild 
decreased ran,ge of 
motion (ROM) 
AND not affecting 
ADL 
SCORE2 
0 Tightness of arms or 
legs OR joint 
contrucrun:s. 
<:rythcma thought 
due to fasciitis, 
moderate decrease 
ROM AND mild to 
moderate limitation 
ofADL 
Final 
Amendment 1.0 Global 
SCORE 3 
0 Conn·acturcs WITH 
significant decrease of 
ROM AND significant 
limitation of ADL 
(unable to tie shoes, 
button s hirt~, dres.~ self 
etc.) 
0 Abnonnality presenr bu1 l"xplained entirl"ly by non-GVHD documl"nted c.fiJJSl" (specify): __________ __ . 
GENI1'AL TRACJ' 
0 No signs 
0 Mild signs1 and 
0 Moderate signsl and 
(Srr Sunplrmen(al figure' ) 
t'emales with or 
may have 
0 Not examined 
wilbout discomfort 
symptoms with 
Currently sexually aclivt> 
on exam 
discomfo1t on exam 
D Yes 
0 No 
D Abnonnaliry present bur &p!ained entirely bv non-GVHD documl'nted cause (specify): 
0 Severe signs1 Yooilh 
or wilbouL 
symptoms 
Other indi<:ators, slinicnl fsatnr£f gr sonrglka!fons related to chronic CVllp Cshsck all thai apply and ay,jgn. a 
.score IO seyeriry m,:ll hued on functional Impact wh ~re anplicallle nons- 0 mild ·I moderate - 2 
~C\'IltC- 3) 
0 Ascites. (serositis)_ 
0 Pericar>dial Effusion_ 
0 Pleural Effu,ion(s)_ 
CONFIDENTIAL 
0 Myastbenia Gravis_ 
0 Peripheral Neuropalby_ 
0 Polymyositis_ 
D Wei lloss>S%• w iliJOLit Gl s 
[J NoGVUD 
[J MUd 
Wrtfit,'f'inttr 
Figure J_ (a>n OnUt'd). 
Page 83 
0 Eosinophilia > 500/JII_ 
0 Platelets <100,000/J!I_ 
0 
[J 1\todtratc 
[J Severe 
02 May 2016 


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Supplemenr f igure - Genital Tract Chronic Graft-,·er:.5us-Hosr Assessment and Scoring f orm 
:"'Jame· 
. . 
Date of binb· 
Assessment date· 
" 
. 
SCORE O 
SCORE I 
SCORE 2 
SGORE3 
GE!'<TI.U TR'I.CT 
D No signs 
D Mild signs and 
D Moderate signs 
D Severt signs with 
Check: 
females may have 
and may have 
or without 
symptoms" WITH 
symptoms* with 
symptoms* 
D Male DFema!e 
di3comfort ou exam 
discomfort on cxnm 
Cul'renrh· sexuallY actin: 
D Yes 0
No 
Clu~ck oll ~igus tl1af Dfl2.ll': 
D Erosion'S. 
D Lichen planus-like features 
D Fissures 
D Lichen sclerosis-like features 
D Ulcers 
D Vaginal scarring (female) 
D Phimosi; (male) 
D Clitoral/labial agglutination (female) 
D Urethralme.ants scarring/ stenosis (male) 
D Labial re.:;orption (bm.'lle) 
D Abnormalily present but NOT thought to represent GI'HD (specify cause): 
D Abnormalily thought to represetlt GVHD PLUS other causes(specify cause): 
• Gem tal symptoms are ~tot specific to cGVHD and can represent premaiurt gonadal fOllure or genital tract mfecflon. 
If a gyne('ologist is un~,·aiJable, external examination may be performed to de-te.mline ~'discomfort on exam" as follows: 
a) Spread the labia lllJljora to inspe.ct the. vulva for the above signs. Touch the vestibular gland openings (Skene's and 
Bartholin's), labia minora and majora gently with a qtip. Vulvar pain elicited by the gentle touch of a qrip is 
classified as discoofort on examination. Palpate. the vaginal walls with a single. digit to detect bauds, shortening, 
narrowing or other signs of vaginal scarring. 
b) If the woman is sexually active, detenniue whether qtip palpation or gentle palpation of scarred ridges elicits pain 
similar to that which the woman experiences during intercourse . 
Female g-enitalia: Severity of signs: 
I) Mild (any of the following); erythe.ma on vulvar mucosal surfaces, vulva: lichen-planus or""'"' lichen-sclerosis. 
2) Moderate-(any of the following)~ erosive intlammatOI)' changes of the. \<1llvar mucosa, fissures in vulvar folds 
3) Severe (any of the following); labial fttsion, clitoral hood agglutinatio11, fibrinous vaginal adhesions, circumferential 
fibrous vaginal bandmg, vaginal shorte-ning, synechi~ dense sclerotic dwtges. and complete vaginal stenosis. 
~{ale gtnitalia: Diagn()stic features include lichen planus-like or lichen sclerosis-like feat\lres and phymosis or urethral 
scarring or stenosis. Se\'e-rity of sigru: 
I) .Mild: lichen planus-like featme.; 
2) Moderate: lichen sclerosus-like feature or moderate erythema; 
3) Severe: phimosis or urethraVmeataJ scarring. 
Bi-op-~' obtained: D Ye.~ D !\o 
Site biop.;ied: _____ G\"BD C'onfirmed by hi<i-tology: D Yes 
D No 
Change from prniou<> e'l':tlu:ttion: D No prior or <'Urnnl CYHD D lmprond D St~ble 
D \Yom D 'S/A (b . ...W.t) 
Completed b;- (pl'int n.1me): 
Date fol'm ('Ompleftd: 


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Appendix 4.
For Baseline + Subsequent Visits: 
Response Determination for the NIH cGVHD Activity Assessment (NCAA) {Herskowitz et al 1992}
Organ 
Complete Response 
Parlial Response 
Progression 
Skin 
NIH Skin Score 0 after 
Decrease in NIH Skin Score 
Increase in NIH Skin Score by 1 or 
previous involvement 
by 1 OJ' more points 
more points, except 0 to 1 
Eyes 
NIH Eye Score 0 after 
Decrease in NIH Eye Score 
Increase in NIH Eye Score by 1 or 
previous iovolvemem 
by 1 or more points 
more points, except 0 to 1 
Mouth 
NIH Modified OMRS 0 after 
Decrease in NIH Modified OMRS 
Increase in NIH Modified OMRS 
previous involvement 
of 2 or more points 
of 2 or more points 
Esophagus 
NIH Esophagus Score 0 after 
Decrease in NIH Esophagus 
Increase in NIH Esophagus Score 
previous involvement 
Score by 1 or more points 
by 1 or more points. except 0 to I 
Upper Gl 
NIH Upper Gl Score 0 after 
Decrease in NIH Upper Gl 
Increase in NIH Upper Gl Score 
previous involvement 
Score by 1 or more points 
by 1 or more points, except 0 to 1 
!.ower Gl 
NIH tower Gl Score 0 after 
Decrease in NIH tower Gl 
Increase in NIH tower Gl Score by 1 
previous involvement 
Score by 1 or more point~ 
or more points, except from 0 to 1 
Uver 
Normal AL T, alkaline 
Decrease by 50% 
Increase by 2 x ULN 
phosphatase, and Total 
bilirubin after previous 
elevation of 1 or more 
Lungs 
- Normal J FEVl after 
Increase by 1 0% predicted 
- DeCI'ease by 10% pr·edicted 
previous involvement 
absolute value of JFEV1 
absolute value of JFEV1 
- If PFTs nor available, NIH 
• If PFTs nor available, decrease 
• If PFTs not available, increase in 
Lung Symptom Score 0 
in NIH Lung Symptom Score 
NIH Lung Symptom Score by 1 
after previous involvement 
by 1 or more points 
or more points, except 0 to 1 
Joints and fascia 
Both NIH Joint and Fascia 
Decrease in NIH Joint and Fascia 
Increase in NIH joint and Fascia 
Score 0 and P-ROM score 
Score by 1 or more points or 
Score by 1 or more points or 
25 after previous involvement 
increase in P-ROM score by 1 
decrease in P-ROM score by 1 
by at least 1 measure 
point for any site 
point for any site 
Global 
Clinician overall severity score 0 
Clinician overall severily score 
Clinidan overall severily score 
decreases by 2 or more points 
increases by 2 or more points 
on a 0·10 scale 
on a 0-10 scale 
ULN indicates upper limit of normal. 


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Gilead Sciences, Inc. 
Final 
Amendment 1.0 Global 
Appendix 5. 
I FORMA I 
For Baseline+ Subsequent Visits: Chronic GVHD Activity Assessment- Clinician 
Cu rrent Patient Weight: ____ _ 
Today's Date: _____ MR#/Name: ---------
CHRONIC GVHD ACTIVITY ASSESSMENT- CLINICIAN 
Health Care Provider 
Since the last assessment would you say that this 
Global Ratings: 
Where would you rate the severity of this patient's chronic GvHD symptoms on 
patient's cGvHD is 
the following scale, where 0 is cGVHD symptoms that are not at all severe and 10 
+3= Very much better 
O=none 
is the most severe cGVHD symptoms possible: 
+ 2= Moderately better 
1= mild 
+ 1 = A little better 
2=moderate 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
0= About the same 
3=severe 
10 
-1 =A little worse 
cGvHD symptoms 
Most 
-2=Moderately worse 
severe cGvHD 
-3=Very much worse 
not at all severe 
svm~toms possible 
Erythema 
None 
0 
Mild erythema or 
1 
Moderate (<:25%) or 
2 
Severe erythema 
Mouth 
moderate erythema 
Severe erythema 
(2:25%) 
(<25%) 
(<25%) 
Lichenoid 
None 
0 
Lichen-like changes 
1 
Lichen-like changes 
2 
Lichen-like changes 
(<25%) 
(25-50%) 
(>50%) 
Ulcers 
None 
0 
Ulcers involving 
3 
Severe ulcerations 
(520%) 
(>20%) 
Total score for all mucosal changes 
Gastrointestinal-Esophageal 
0= no esophageal symptoms 
• 
Dysphagia 
OR 
1=0ccasional dysphagia or odynophagia with solid food or pills during the past week 
Odynophagia 
2=1ntermittent dysphagia or odynophagia with solid foods or pills, but not for liquids or soft foods, during the past week 
3=Dysphagia or odynophagia for almost a{{ oral intake, on almost everv dav of the oast week 
Gastrointestinal-Upper Gl 
0= no symptoms 
• 
Early satiety OR 
1=mild, occasional symptoms, with little reduction in oral intake during the past week 
• 
Anorexia 
OR 
2=moderate, intermittent symptoms, with some reduction in oral intake during the past week 
3 
3 
6 
• 
Nausea & Vomiting 
3=more severe or persistent symptoms throughout the day, with marked reduction in oral intake, on almost everv day of the past 
week 
Gastrointestinal-Lower Gl 
0= no loose or liquid stools during the past week 
• 
Diarrhea 
1= occasional loose or liquid stools, on some days during the past week 
2=intermittent loose or liquid stools throughout the day, on almost every day of the past week. without requiring intervention to 
prevent or correct volume depletion 
3=voluminous diarrhea on almost every dav of the oast week reauirina intervention to orevent or correct volume deoletion 
CONFIDENTIAL 
Page 86 
02 May 2016 


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Amendment 1.0 Global
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Lungs (Liters and % 
predicted)

Bronchiolitis Obliterans
FEV1
FVC
Single Breath DLCO (adjusted for 
hemoglobin)
TLC
RV
Liver Values
Total serum bilirubin
                            
mg/dL
ULN
                           
                     mg/dL
ALT
                          
U/L
   ULN                   
                                 
U/L
A kaline Phosphatase
                                  
U/L
ULN
                       
                              U/L
Baseline Values
Total Distance Walked in 2 or 6 Mins: 
                                                 2 min        
6 min
Karnofsky or 
Lansky 
Platelet Count              
                                    
K/uL
Total WBC                      
                                      
K/uL
Eosinophils
                           
                            %        
 Abnormality present but explained entirely by non-GVHD documented cause (specify site/alternate 
cause):_______________________________
 Abnormality present but explained entirely by non-GVHD documented cause (specify site/alternate 
cause):_______________________________
 Abnormality present but explained entirely by non-GVHD documented cause (specify site/alternate 
cause):_______________________________


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CONFIDENTIAL
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CHRONIC GVHD ACTIVITY ASSESSMENT- CLINICIAN (FORM A)
SCORE 0
SCORE 1
SCORE 2
SCORE 3
SKIN
GVHD features to be scored     
by BSA:
Check all that apply:
 Maculopapular rash / erythema
 Lichen planus-like features 
 Sclerotic features
 Papulosquamous lesions or
    ichthyosis
 Keratosis pilaris-like
  No BSA   involved
  1-18% BSA 
  19-50% BSA  
  >50% BSA
 Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________
SKIN FEATURES 
SCORE:
 No sclerotic 
features
 Superficial 
   sclerotic features “not 
hidebound” (able to pinch)
Check all that apply:
 Deep sclerotic                         
features 
 “Hidebound”                          
(unable to pinch) 
 Impaired mobility 
 Ulceration
If skin features score = 3, BSA% of non-moveable sclerosis/fasciitis  ___________
How would you rate the severity of this patient’s skin and/or joint tightening on the following scale, where 0 is not at all severe and 10 is the most severe 
symptoms possible:
             0       1         2         3         4         5         6         7         8          9         10
Symptoms
                                                                                                  Most severe
not at all severe                                                                                             symptoms possible


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EYES
  No symptoms 
     symptoms 
  Mild dry eye symptoms 
not affecting ADL 
(requirement of 
lubricant eye drops < 3 
x per day) 
  Moderate dry eye symptoms 
partially affecting ADL 
(requiring lubricant eye drops 
> 3 x per day or punctal 
plugs), WITHOUT new 
vision impairment due to KCS
  Severe dry eye symptoms 
significantly affecting 
ADL (special eyeware to 
relieve pain) OR unable to 
work because of ocular 
symptoms OR loss of 
vision due to KCS
 Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________
LUNGS
 No symptoms
  Mild symptoms 
(shortness of breath 
after climbing one 
flight of steps)
  Moderate symptoms 
(shortness of breath after 
walking on flat ground)
  Severe symptoms 
(shortness of breath  at rest; 
requiring 02)
 Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________
JOINTS AND FASCIA
  No symptoms
  Mild tightness of arms or 
legs, normal or mild 
decreased range of motion 
(ROM) AND not affecting 
ADL
  Tightness of arms or legs OR 
joint contractures, erythema 
thought due to fasciitis, moderate 
decrease ROM AND mild to 
moderate limitation of ADL
  Contractures WITH 
significant decrease of ROM 
AND significant limitation of 
ADL (unable to tie shoes, 
button shirts, dress self etc.) 
 Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________


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Not done
Not done
Not done
Not done


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                        Today’s Date: ________________________
MR#/Name: ________________________
CHRONIC GVHD ACTIVITY ASSESSMENT-PATIENT SELF REPORT
Symptoms
Not                                                                                                                                           As Bad As You
Present                                                                                                                                     Can Imagine
   
 0           1         2         3          4         5         6         7         8          9         10
Please rate how severe the following symptoms 
have been in the last seven days.  Please fill in the 
circle below from 0 (symptom has not been 
present) to 10 (the symptom was as bad as you 
can imagine it could be) for each item.
Your skin itching at its WORST?
O
O
O
O
O
O
O
O
O
O
O
Your skin and/or joint tightening at their 
WORST?
O
O
O
O
O
O
O
O
O
O
O
Your mouth sensitivity at its WORST?
O
O
O
O
O
O
O
O
O
O
O
Your genital discomfort at its WORST?
(Women – vagina, vulva, or labia)
(Men – penis)
O
O
O
O
O
O
O
O
O
O
O
Eyes
What is your main complaint with regard to your eyes?
Please rate how severe this symptom is, from 0 (not at all 
severe) to 10 (most severe):
0    1     2     3     4     5     6     7     8      9    10
FORM B


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Amendment 1.0 Global
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Patient Global Ratings:
1. Overall, do you think that your chronic graft versus host disease is mild, moderate or severe?
1= mild
2=moderate
3=severe
2. Please circle the number indicating how severe your chronic graft versus host disease symptoms are, where 0 is cGvHD symptoms that are not at all 
severe and 10 is the most severe chronic GvHD symptoms possible.
          0         1           2           3           4           5           6           7           8            9           10
cGvHD symptoms                                                                                                                                       Most severe cGvHD                                                                                                                                           
not at all severe                                                                                                                                           symptoms  possible
                                                                                                                                                                           
3. Compared to a month ago, overall would you say that your cGvHD symptoms are:
+3= Very much better
+2= Moderately better
+1=A little better
0= About the same
-1=A little worse
-2=Moderately worse
-3=Very much worse


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Gilead Sciences, Inc. 
Amendment 1.0 Global
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Appendix 6.
For Baseline + Subsequent Visits: Lee Symptom Scale {Lee et al 2002}
By circling one (1) number per line, please indicate how much you have been bothered by the 
following problems in the past 7 days: 
SKIN: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
1. 
Abnormal skin color. ................... 
0 
2 
3 
4 
2. 
Rashes .................. ···············-·· 
0 
2 
3 
4 
3. 
Thickened skin ........ ... ............ 
0 
2 
3 
4 
4. 
Sores on ski11.. ..........•... ·····- ····· 
0 
2 
3 
4 
5. 
Itchy skin ...... .............. .......... 
0 
2 
3 
4 
EYES AND MOUTH: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
6. 
Dry eyes ....•............................. 
0 
2 
3 
4 
7. 
Need to use eye drops frequently .. 
0 
2 
3 
4 
8. 
Difficulty seeing cleal'fy ........... , ... 
0 
2 
3 
4 
9. 
Need to avoid certain foods due to 
0 
2 
3 
4 
mouth pain .•........ 
. ............ 
10. Ulc.ers in mouth ......................... 
0 
2 
3 
4 
1"1. Receiving nutrition from an 
intravenous line or feeding tube .... 
0 
2 
3 
4 
BREATHING: 
rJot at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
12. 
Frequent coogh .......•... , ......•...... 
0 
2 
3 
4 
13. Colored sputum ......................... 
0 
2 
3 
4 
14. Shortness of breath with exereise .. 
0 
2 
3 
4 
15. Shortness of breath at rest. ........ 
0 
2 
3 
4 
16. Need to use oxygen ................. 
0 
2 
3 
4 


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EATING AND DIGESTION: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
17. Difficulty swallo"'ing solid foods .... 
0 
1 
2 
3 
4 
18. Difficulty swallowing liquids ......... 
0 
2 
3 
4 
19. Vomiting ............................ 
0 
1 
2 
3 
4 
20. Weight loss .........•... 
0 
2 
3 
4 
MUSCLES AND JOINTS: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
21. Joint and muscle aches ........... 
~. ~ 
0 
1 
2 
3 
4 
22. 
Lim~ed joint movement ............. 
0 
2 
3 
4 
23. Muscle cramps ................. 
0 
2 
3 
4 
24. Weak muscles ... ....... 
·· ~ ........ 
0 
2 
3 
4 
ENERGY: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
25. 
Loss of energy ....................•.... 
0 
1 
2 
3 
4 
26. 
Need to sleep more/take naps ..... 
0 
1 
2 
3 
4 
27. 
Fevers ........................ ........... 
0 
1 
2 
3 
4 
MENTAL AND EMOTIONAL: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
28. 
Depression ........• .................... 
0 
1 
2 
3 
4 
29. 
Anxiety .............. ..................... 
0 
2 
3 
4 
30. 
Difficulty sleeping .. ................... 
0 
1 
2 
3 
4 


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Amendment 1.0 Global
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Summary of the Lee Symptom Scale
Which 2 of the following organs/systems have you found to affect you the most in the last seven 
days:
1) Skin
2) Eyes 
3) Mouth
4) Breathing
5) Eating and Digestion
6) Muscles and Joints
7) Energy
8) Mental and Emotional


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Appendix 7.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated 
Grade 2
Moderate
Local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL 
Grade 3
Severe
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADL  
Grade 4
Life-threatening
Urgent intervention indicated 
Grade 5
Death 
Death related AE 
*
Activities of Daily Living (ADL) Instrumental ADL refer to opening preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden


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Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
ENTO is contraindicated in pregnancy as animal studies in rats and rabbits have shown that 
study drug is teratogenic. Pregnancy must be excluded before the start of treatment with study 
drug and prevented thereafter by reliable contraceptive methods. Pregnancy tests will be 
performed regularly throughout this study per Table 6-1. Please refer to the latest version of the 
investigator’s brochure for additional information.
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 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
ENTO is contraindicated in pregnancy as there is a strong suspicion of human 
teratogenicity/fetotoxicity in early pregnancy based on non-clinical data. In addition, ENTO has 
insufficient data 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. 
Please refer to the latest version of the investigator’s brochure for additional information.
b) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must also not rely on hormone-containing contraceptives as a 
form of birth control during the study.  They must have a negative serum pregnancy test at


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Amendment 1.0 Global
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screening and a negative pregnancy test on the Baseline/Day 1 Visit.  Pregnancy tests will be 
performed on the protocol-specified schedule thereafter.  Female subjects must agree to one of 
the following methods to avoid pregnancy from Screening until 30 days from the last dose of 
ENTO:

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.
a) Intrauterine device (IUD) with a failure rate of <1% per year
b) Tubal sterilization
c) Essure micro-insert system (provided confirmation of success 3 months after procedure)
d) 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 from the last dose of ENTO.
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 from the 
last dose of ENTO.  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 
from the last dose of ENTO.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose.  Subjects who 


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become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator.  Instructions for reporting pregnancy, partner pregnancy, and pregnancy 
outcome are outlined in Section 7.6.


Entospletinib 
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Gilead Sciences, Inc. 
_wendix9. 
PPD 
CONFIDENTIAL 
Final 
Amendment 1.0 Global 
Schedule of Assessments for the 0 tional Cellular Turnover Sub-study* 
·-----------------------------------, 
Page 100 
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Prot_004.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Clinical Program 
Manager: 
(!') GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess 
the Efficacy and Tolerability ofEntospletinib, a Selective SYK Inhibitor, in 
Combination with Systemic COiticosteroids as First-Line Therapy in 
Subjects with Chronic Graft Versus Host Disease (cGVHD) 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
129907 
2015-004572-30 
NCT02701634 
Chronic Graft Versus Host Disease (cGVHD) 
GS-US-406-1840 
Name: 
Telephone: 
Gilead Medic.al Monitor: 
Name: 
Matio Marcondes, MD, PhD 
PPD 
Protocol Version/Date: 
Telephone: 
Fax: 
PPD 
Mobile: 
PPD 
Original 
Amendment 1.0 (UK only) 
Amendment 1.0 (Global) 
Amendment 2.0 (Global) 
Amendment 3.0 (Global) 
11 November 2015 
14 March 2016 
02 May 2016 
31 August2016 
30 January 2017 
CONFIDENTIALITY STATEMENT 
The inf01mation 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 infotmation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the inf01m ation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaty to obtain infotmed consent from those 
persons to whom the dm g 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
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................13
1.
INTRODUCTION ..............................................................................................................................................17
1.1.
Background ............................................................................................................................................17
1.1.1.
Background on Chronic Graft Versus Host Disease ............................................................17
1.2.
Entospletinib (ENTO)............................................................................................................................20
1.2.1.
Preclinical Pharmacology and Toxicology...........................................................................21
1.2.2.
Clinical Trials of Entospletinib (ENTO) ..............................................................................22
1.2.3.
Interaction with Proton Pump Inhibitors ..............................................................................23
1.3.
Rationale for This Study ........................................................................................................................24
1.4.
Rationale for Dose Selection..................................................................................................................24
1.5.
Risk/Benefit Assessment for the Study..................................................................................................24
1.6.
Compliance ............................................................................................................................................25
2.
OBJECTIVES.....................................................................................................................................................26
3.
STUDY DESIGN................................................................................................................................................27
3.1.
Endpoints ...............................................................................................................................................27
3.2.
Study Design..........................................................................................................................................28
3.3.
Study Treatments ...................................................................................................................................28
3.4.
Discontinuation Criteria.........................................................................................................................30
3.5.
Biomarker Testing..................................................................................................................................30
3.5.1.
Biomarker Samples to Address the Study Objectives:.........................................................30
3.5.2.
Optional Future Research.....................................................................................................30
3.5.3.
Optional Sub-study to study cellular turnover {Emson et al 2013, Ladell 
et al 2008, Messmer et al 2005}...........................................................................................31
4.
SUBJECT POPULATION..................................................................................................................................32
4.1.
Number of Subjects and Subject Selection ............................................................................................32
4.2.
Inclusion Criteria....................................................................................................................................32
4.3.
Exclusion Criteria...................................................................................................................................33
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................35
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................35
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................35
5.2.
Description and Handling of Study Drug...............................................................................................36
5.2.1.
Formulation..........................................................................................................................36
5.2.2.
Packaging and Labeling .......................................................................................................36
5.2.3.
Storage and Handling...........................................................................................................37
5.3.
Dosage and Administration....................................................................................................................37
5.4.
Prior and Concomitant Medications.......................................................................................................37
5.5.
Opportunistic Infections and Prophylactic Regimens ............................................................................40
5.6.
Accountability for Investigational Medicinal Product ...........................................................................41
5.6.1.
Investigational Medicinal Product Return or Disposal.........................................................41
6.
STUDY PROCEDURES ....................................................................................................................................42


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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................42
6.2.
Study Assessments.................................................................................................................................42
6.2.1.
Screening Visit .....................................................................................................................47
6.3.
Baseline/Day 1 Visit ..............................................................................................................................47
6.4.
Treatment Assessments (Weeks 2-48 and OLE)....................................................................................48
6.5.
Post-treatment Assessments ...................................................................................................................49
6.5.1.
Unscheduled Visit ................................................................................................................49
6.5.2.
Early Study Drug Discontinuation (ESDD) .........................................................................50
6.6.
30 Day Follow-Up Visit.........................................................................................................................50
6.7.
End of Study...........................................................................................................................................50
6.8.
Vital Signs..............................................................................................................................................51
6.9.
Biomarker Sample Collection ................................................................................................................51
6.9.1.
Clinical Laboratory Tests/Assessments................................................................................51
6.10.
Criteria for Discontinuation of Study Treatment....................................................................................51
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................53
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................53
7.1.1.
Adverse Events.....................................................................................................................53
7.1.2.
Serious Adverse Events........................................................................................................53
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................54
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................54
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................54
7.2.2.
Assessment of Severity ........................................................................................................55
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................56
7.4.
Gilead Reporting Requirements.............................................................................................................57
7.4.1.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events Toxicity Management .....................................58
7.4.2.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................58
7.4.3.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................58
7.4.4.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................59
7.5.
Toxicity Management ............................................................................................................................59
7.6.
Special Situations Reports......................................................................................................................60
7.6.1.
Definitions of Special Situations..........................................................................................60
7.6.2.
Instructions for Reporting Special Situations.......................................................................60
8.
STATISTICAL CONSIDERATIONS................................................................................................................62
8.1.
Analysis Objectives and Endpoints........................................................................................................62
8.1.1.
Analysis Objectives..............................................................................................................62
8.1.2.
Primary Endpoint .................................................................................................................63
8.1.3.
Secondary Endpoint .............................................................................................................63
8.1.4.
Other Endpoints of Interest ..................................................................................................64
8.2.
Analysis Conventions.............................................................................................................................64
8.2.1.
Analysis Sets ........................................................................................................................65
8.3.
Data Handling Conventions ...................................................................................................................65
8.4.
Demographic Data and Baseline Characteristics ...................................................................................67
8.5.
Efficacy Analysis ...................................................................................................................................67
8.5.1.
Primary Analysis..................................................................................................................67
8.5.2.
Secondary Analyses .............................................................................................................67
8.5.3.
Exploratory Analyses ...........................................................................................................68
8.5.4.
Interim Analysis ...................................................................................................................68
8.5.5.
Final Analysis.......................................................................................................................68
8.6.
Safety Analysis.......................................................................................................................................68


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8.6.1.
Extent of Exposure...............................................................................................................69
8.6.2.
Adverse Events.....................................................................................................................69
8.6.3.
Laboratory Evaluations ........................................................................................................69
8.6.4.
Other Safety Evaluations......................................................................................................69
8.7.
Pharmacokinetic Analysis......................................................................................................................69
8.8.
Biomarker Analysis................................................................................................................................70
8.9.
Sample Size............................................................................................................................................70
8.10.
Data Monitoring Committee ..................................................................................................................70
9.
RESPONSIBILITIES..........................................................................................................................................71
9.1.
Investigator Responsibilities ..................................................................................................................71
9.1.1.
Good Clinical Practice..........................................................................................................71
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................71
9.1.3.
Informed Consent.................................................................................................................71
9.1.4.
Confidentiality......................................................................................................................72
9.1.5.
Study Files and Retention of Records ..................................................................................72
9.1.6.
Case Report Forms...............................................................................................................73
9.1.7.
IMP Destruction ...................................................................................................................74
9.1.8.
Inspections............................................................................................................................74
9.1.9.
Protocol Compliance............................................................................................................74
9.2.
Sponsor Responsibilities ........................................................................................................................74
9.2.1.
Protocol Modifications.........................................................................................................74
9.2.2.
Study Report and Publications .............................................................................................75
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................75
9.3.1.
Payment Reporting...............................................................................................................75
9.3.2.
Access to Information for Monitoring..................................................................................75
9.3.3.
Access to Information for Auditing or Inspections ..............................................................76
9.3.4.
Study Discontinuation..........................................................................................................76
10.
REFERENCES ...................................................................................................................................................77
11.
APPENDICES ....................................................................................................................................................80
Appendix 1.
Investigator Signature Page....................................................................................................81
Appendix 2.
For Screening: NIH cGVHD Diagnosis and Staging Criteria, Global Severity Score 
{Jagasia et al 2015}................................................................................................................82
Appendix 3.
For Screening: NIH cGVHD Diagnosis and Staging Criteria (NCDSC) Form 
{Jagasia et al 2015}................................................................................................................83
Appendix 4.
For Baseline + Subsequent Visits:  Response Determination for the NIH cGVHD 
Activity Assessment (NCAA) {Lee et al 2015}.....................................................................87
Appendix 5.
For Baseline + Subsequent Visits: Chronic GVHD Activity Assessment- Clinician 
{Lee et al 2015} .....................................................................................................................88
Appendix 6.
For Baseline + Subsequent Visits: Lee Symptom Scale {Lee et al 2002} .............................95
Appendix 7.
Grading of Adverse Event Severity........................................................................................98
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and
Contraceptive Requirements...................................................................................................99
Appendix 9.
Schedule of Assessments for the Optional Cellular Turnover Sub-study*..........................101


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LIST OF IN-TEXT TABLES
Table 5-1.
Tapering of Systemic Corticosteroid after reaching PR/CR based on 1 mg/kg/day*.............38
Table 5-2.
Examples of Prohibited Agents ..............................................................................................39
Table 5-3.
List of Sensitive Substrates of UGT1A1, OATP1B1, OATP1B3, P-gp and BCRP...............40
Table 6-1.
Schedule of Assessments........................................................................................................43
Table 7-1.
Grading of Adverse Event Severity........................................................................................55
Table 7-2.
Grading of Adverse Event Severity: Upper Respiratory ........................................................56
Table 8-1.
Criteria for time point response determination.......................................................................63
LIST OF IN-TEXT FIGURES
Figure 1-1.
cGVHD prophylaxis with rituximab.  (A) Cumulative incidence of cGVHD. 
(B) Non-relapse mortality & GVHD recurrence. (C) Overall survival ..................................18
Figure 1-2.
Entospletinib Induces Apoptosis in B Cells from cGVHD Patients.......................................20
Figure 3-1.
Study Schema.........................................................................................................................29


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Efficacy and Tolerability of Entospletinib, a Selective SYK 
Inhibitor, in Combination with Systemic Corticosteroids as First-Line 
Therapy in Subjects with Chronic Graft Versus Host Disease (cGVHD)
IND Number:
EudraCT 
Number:
Clinical Trials.gov 
Identifier:
129907
2015-004572-30
NCT02701634
Study Centers 
Planned:
Approximately 65 centers in the North America, Europe, Asia and 
Australia 
Objectives:
The primary objective is:
To evaluate the effect of ENTO on the best overall response rate (BORR) 
as assessed by the NIH cGVHD Activity Assessment (NCAA) by 24 
weeks in the setting of add-on to systemic corticosteroids as part of first-
line therapy for cGVHD
The key secondary objectives are:

To evaluate the effect of ENTO on the skin domain of the Lee 
Symptom Scale (LSS)  (Appendix 6) at 24 weeks

To evaluate the effect of ENTO on the mouth domain of the LSS at 
24 weeks

To evaluate the effect of ENTO on the eyes domain of the LSS at 
24 weeks

To evaluate the effect of ENTO on the total score of the LSS at 
24 weeks
Additional secondary objectives include:

To evaluate the effect of ENTO on duration of response (DOR)

To evaluate the effect of ENTO on dose reduction of corticosteroids


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Study Design: 
Nmnberof 
Subjects 
Planned: 
Target 
Population: 
CONFIDENTIAL 
• 
To evaluate the effect ofENTO on initiation of second-line therapy for 
cGVHD 
• 
To evaluate the effect ofENTO on progression of cGVHD 
• 
To evaluate the safety and tolerability ofENTO 
Explorat01y objectives include: 
~ 
D 
I 
I 
Randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the efficacy and safety ofENTO (Treatment Ann 1) vs. placebo 
(Treatment Aim 2) in combination with systemic c01ticosteroids for 
subjects with cGVHD. 
An interim analysis for futility is planned when approximately 50% of 
subjects have been on study for 24 weeks. The primaty endpoint will be 
evaluated when all subjects complete 24 weeks of treatment. Dmation and 
quality of response will be evaluated up to 48 weeks ofblinded treatment. 
After 48 weeks, subjects who are still on investigational treatment (ENTO 
or PTM) and are eligible to remain on study will have the option to 
receive open-label extension (OLE) with ENTO and attend visits per the 
schedule of assessments (Table 6-1) for an additional 96 weeks. 
Subjects who complete the study through Week 48 and do not wish to 
patticipate in the OLE will be required to retmn to the clinic after 
completion of study drug for a 30-Day Follow-up Visit. 
Approximately 100 subjects. Randomization will be stratified 
by 1) calcinemin inhibitor or mycophenolate mofetil (MMF) use 
(no vs. yes) and 2) moderate vs. severe cGVHD as detennined by the NIH 
cGVHD Diagnosis and Staging Criteria (NCDSC) at the Screening visit. 
Adult males or non-pregnant, non-lactating, female subjects with cGVHD 
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Study Schema
Duration of 
Treatment:
48 weeks in the double-blind, placebo-controlled period.  After 48 weeks 
subjects who are still on investigational treatment (ENTO or PTM) and
are eligible to remain on study will have the option to receive OLE with
ENTO and attend visits per the schedule of assessments (Table 6-1) for an 
additional 96 weeks.
Diagnosis and 
Main Eligibility 
Criteria:
The following are a summary of the key criteria: 
Key Inclusion Criteria: 

Male or non-pregnant, non-lactating, female subjects 

18-75 years of age, inclusive at Screening 

Newly diagnosed cGVHD defined by: 
a) At least 100 days after receiving any allogeneic hematopoietic 
stem cell transplant 
AND 
b) Requiring a new course of systemic corticosteroids 
(≥0.5 mg/kg/day) as first-line cGVHD therapy for at least 1 day 
and no more than 21 days  prior to first dose of ENTO/Placebo  
AND
c) Moderate to severe cGVHD as assessed by NCDSC with at least 
three organ systems involved OR one organ system with a score 
of 2 OR lung organ score = 1 (Appendix 2)

Subjects who have undergone transplant for hematologic malignancy 
are required to be in complete remission. 

Have either a normal ECG or one with abnormalities that are 
considered clinically insignificant by the investigator in consultation 
with the Sponsor 
Key Exclusion Criteria:

Inability to begin systemic corticosteroids therapy at a dose 
of ≥0.5 mg/kg/day (or equivalent)

Uncontrolled infection within 4 weeks prior to Randomization


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
History of the following therapies in the post-transplant period:
B cell depleting biologic agents 
CD19 CAR-T cells based therapies 
BTK/SYK/JAK/PI3K inhibitors
Phototherapy-unless administered for acute GVHD 

Treatment of cGVHD with anti-thymocyte globulins (ATG), or 
campath within 60 days of Screening visit  unless used for  treatment 
of acute GVHD

Severe organ dysfunction manifested during Screening period: 
Requiring supplemental oxygen at more than 2 L/min
Uncontrolled arrhythmia or heart failure
Study 
Procedures/
Frequency:
Eligible subjects will be randomized 1:1 to Treatment Arm 1 or Treatment 
Arm 2 to receive study drug for 48 weeks.  Following Screening and 
Baseline/Day 1 Visits, subjects will return for study visits at Weeks: 2, 4, 
8, 12, 16, 20, 24, 30, 36, 42 and 48.  Subjects that participate in the OLE 
will return for visits at Weeks: 50, 52, 56, 60, 64, 72 and visits every 
12 weeks thereafter. During the OLE, the maximum period of 
co-administration of ENTO with Cyclosporine, Tacrolimus or MMF 
should not exceed 3 months. Subjects who do not wish to participate in 
the OLE will have a 30-day Follow-Up visit after their week 48 visit. 
NOTE for subjects receiving tacrolimus, cyclosporine or MMF: For 
subjects receiving these medicines at enrollment and are continuing on 
these medicines, the blood levels of tacrolimus, cyclosporine or the active 
metabolite of MMF (MPA) will be monitored at Baseline/Day 1 (prior to 
starting ENTO or placebo-to-match [PTM]), on Day 2 (optional) or Day 3 
(optional) and Day 6 or Day 7 after initiating ENTO or PTM, and at the 
end of Week 2 and Week 50 study visit. Beyond these time points, 
concentration monitoring for tacrolimus, and cyclosporine should follow 
the treating institution’s protocol and therapeutic range for monitoring 
these medicines. For subjects who initiate these medicines while already 
receiving ENTO, concentration monitoring for tacrolimus, cyclosporine 
and MPA should follow the treating institution’s protocol and therapeutic 
range for monitoring these medicines. When a concentration sample is 
taken at a local lab in accordance with the treating institution’s protocol 
for monitoring these medications, a sample may also be requested for 
central lab analysis. 
At Screening the NIH cGVHD Diagnosis and Staging Criteria (NCDSC) 
(Appendix 3) will be administered. At Baseline/Day1 and Weeks 4, 8, 12, 
16, 20, 24, 30, 36, 42, 48, 56, 60, 64, 72, every 12 weeks thereafter and 
Early Study Drug Discontinuation (ESDD) the NCAA (Appendix 5), and 


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Test Product, 
Dose, and Mode of 
Administration: 
Reference 
Therapy, Dose, 
and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
CONFIDENTIAL 
the LSS (Appendix 6) will be administered. Serological screening for HIV 
antibody (Ab ), hepatitis B antigen, hepatitis C Antibody will be collected 
at the Screening visit. For subjects with hematologic malignancy, 
assessments of residual disease will be followed per the institutional 
guidelines. 
Blood and urine will be collected at all study visits per the schedule of 
assessments (Table 6-1 ). 
Blood for selected biomarkers will be collected at all study visits per the 
Schedule of Assessments (Table 6-1 ). 
PD 
Treatment Aim 1: ENTO 400 mg twice daily: 2 X 200 mg tablets twice 
daily, for subjects cmTently on proton pump inhibitors (PPI)* 
Treatment Aim 2: Placebo-to-match (PTM) twice daily 
Both treatment mms will be administered orally without food (in a fasted 
state) for 48 weeks. 
*For subjects NOT c1mently taking a PPI, the dose will be adjusted to 
ENTO 200 mg twice daily: 1 X 200 mg tablet orally twice daily without 
food (in a fasted state) for 48 weeks. 
Systemic c01ticosteroids at a dose and route consistent with first-line 
therapy for newly diagnosed cGVHD. 
Systemic c01ticosteroids will be administered per provided treatment 
schema. 
Safety evaluations include documentation of AEs, physical exainination, 
vital signs, ECGs, and clinicallaborat01y evaluations. 
The primaty endpoint is BORR by 24 weeks, as assessed by the NCAA, in 
the setting of add-on therapy to systemic c01ticosteroids as pmi of first-
line therapy for cGVHD. 
The key secondaiy endpoints are: 
• 
Change from Baseline in the skin domain of the LSS at 24 weeks 
• 
Change from Baseline in the mouth domain of the LSS at 24 weeks 
• 
Change from Baseline in the eyes domain of LSS at 24 weeks 
• 
Change from Baseline in the total score of the LSS at 24 weeks 
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Phatmacokinetics: 
Statistical 
Methods: 
CONFIDENTIAL 
Other secondmy endpoints include: 
• 
DOR 
• 
Prop01tion of subjects who achieve at least 50% reduction in systemic 
c01ticosteroid dose relative to baseline 
• 
Prop01tion of subjects who initiate second-line therapy for cGVHD 
• 
Failure-free-survival (FFS) 
• 
Safety and tolerability ofENTO 
Explorat01y endpoints of this study include: 
~ 
D 
I 
I 
I 
PK blood sampling will occm at Weeks 2 through Week 48 and then 
evety 12 weeks thereafter. 
The primary endpoint ofBORR by 24 weeks is defined as the proportion 
of subjects who achieve a complete or pattial response (CR or PR) within 
24 weeks, as assessed by the NCAA. A CR is achieved when all signs and 
symptoms of cGVHD have resolved. A PR is achieved when an objective 
response is observed in any organ system without progression in another 
organ system, and no additional systemic therapy is needed. 
The primaty analysis for BORR will be perfonned in the intent-to-treat 
(ITT) Analysis Set, which includes all subjects who were randomized. 
Response rate will be summarized by cmmt and percent of subjects with 
each ordinal response (CR, PR, and CR + PR). A stratified 
Cochran-Mantel-Haenszel (CMH) Chi-square test will be perf01med to 
compare BORR between ENTO and PTM by 24 weeks. The difference in 
response rates between treatment groups and the con esponding 95% Cis 
will be presented. 
Change from Baseline in the LSS scores will be analyzed using a mixed 
model repeated measmes (MMRM) model. Dmation of response (DOR) 
will be analyzed using the Kaplan-Meier method. 
A sequential testing strategy will be implemented to preserve the overall 
type I en or rate across the primaty and key secondmy endpoints of the 
study at a 2-sided significance level of0.05. If the primaty hypothesis is 
rejected, the key secondaty endpoints will be sequentially tested at the 
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2-sided 0.05 significance level in the following order: (1) change from 
Baseline in the skin domain of the LSS, (2) change from Baseline in the 
mouth domain of the LSS, (3) change from Baseline in the eyes domain of 
the LSS, and (4) change from Baseline in the total score of the LSS. If a 
null hypothesis is not rejected, formal sequential testing will stop and only 
nominal significance will be cited for the remaining endpoints.
With 40 subjects per treatment group, there is 75% power to detect a 
30% improvement in response rate at the 2-sided 0.05 significance level 
using a Fisher’s exact test, assuming a placebo response rate of 50%. A 
total of 100 subjects (50 per treatment group) will be enrolled assuming a 
20% dropout rate.  
Safety data will be listed by subject and summarized by treatment and 
frequency of event/abnormality or descriptive statistical summaries, as 
appropriate. The endpoints to be evaluated will include AEs, physical 
examination, clinical laboratory test findings, ECG abnormalities and 
interval measurements, and vital signs measurements.
An external multidisciplinary data monitoring committee (DMC) will 
review the progress of the study, perform interim reviews of safety data at 
regular intervals approximately every 3 months, and perform an interim 
review of efficacy data for futility when approximately 50% of subjects 
have been on study for 24 weeks, as described in the DMC Charter.  The 
DMC will provide recommendations to Gilead as to whether the nature, 
frequency, and severity of adverse effects associated with study treatment 
warrant the early termination of the study in the best interests of the 
participants, whether the study should continue as planned, or the study 
should continue with modifications.
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
aGVHD
Acute Graft Versus Host Disease 
ADL
Activities of daily living 
AKT
Protein kinase B
ALT
alanine aminotransferase
AML
acute myeloid leukemia 
APC
antigen presenting cell 
AST
aspartate aminotransferase
ATG
anti-thymocyte globulins
AUC
area under curve versus time
BAFF
B cell Activating Factor
BCMA
B cell maturation antigen
BCR
B cell receptor
BCRP
breast cancer resistance protein
BLNK
B cell linker protein
BLQ
below limit of quantitation
BTK
Bruton’s tyrosine kinase
BORR
best overall response rate
cGMP
Current Good Manufacturing Practice
CI
confidence interval
cGVHD
Chronic Graft Versus Host Disease
Clast
last observed quantifiable concentration
CL
systemic clearance following IV administration
CLL 
chronic lymphocytic leukemia
Cmax
maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
concentration at the end of the dosing interval
CONMED
concomitant medication
CPK
creatine phosphokinase
CR
complete response
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
DSPH
Drug Safety and Public Health
DMC
Data Monitoring Committee
DOR
duration of response
E2
Estradiol
ECG
Electrocardiogram


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eCRF
electronic case report form(s)
ENTO
Entospletinib 
ENTO BIS-MSA
Entospletinib bismesylate monohydrate
ENTO MSA
Entospletinib methanesulfonate
ERK
Extracellular signal regulated kinase
ESR
erythrocyte sedimentation rate
ET
early termination
FDA
(United States) Food and Drug Administration
FFS
failure-free survival
FSH
follicle-stimulating hormone
cGVHD
Chronic Graft Versus Host Disease 
GCP
Good Clinical Practice (Guidelines)
GGT
Gamma-glutamyl transferase
GVHD
Graft Versus Host Disease 
GSI
Gilead Sciences, Inc.
Hb
Hemoglobin
HBV
Hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDPE
high-density polyethylene
hERG
human-ether-a-go-go related gene
HIV
Human immunodeficiency virus
HSCT
hematopoietic stem cell transplant
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IgG
immunoglobulin G
IgM
immunoglobulin M
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
IRB
institutional review board
ITT
intent-to-treat 
IUD
intrauterine device
IV
Intravenous
IxRS
interactive voice/web response system
JAK
janus kinase
LDL
low-density lipoprotein
LLN
lower limit of the normal range


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LLOQ
lower limit of quantitation
LOCF
last observation carried forward
LOEL
lowest observed effect level
LOQ
limit of quantitation
LSS
Lee Symptom Scale 
MAD
multiple ascending dose
MAP
mitogen-activated protein
MedDRA
Medical Dictionary for Regulatory Activities
MK2
MAP kinase activated protein kinase-2
MMF
mycophenolate mofetil
MMP9
Matrix metallopeptidase-9
MMRM
mixed model repeated measures
µm
Micro millimeter
NDA
New Drug Application
NCAA
NIH cGVHD Activity Assessment
NCDSC
NIH cGVHD Diagnosis and Staging Criteria
NIH
National Institute of Health
NOAEL
no observable adverse effect level
NRI
non-responder imputation
PE
physical examination
PFT 
pulmonary function tests 
PI3K
phosphatidylinositol-4,5-bisphosphate 3-kinase
PK
Pharmacokinetic
PP
per-protocol
PR
pulse rate
PPI
proton pump inhibitor
PTM
placebo-to-match
Q1
first quartile
Q3
third quartile
QTcF
Quantum Tunnelling Composite Fridericia
RA
rheumatoid arthritis
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SEM
standard error of measure
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
SYK
Spleen tyrosine kinase


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TACI
Transmembrane activator and CAML interactor
TLC
total lung capacity
tmax
the time (observed time point) of Cmax
t½
an estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant 
(λz)
UGT1A1
uridine disphosphate glucuronosyltransferase 1A1
ULN
upper limit of the normal range
US
United States
Vz
apparent volume of distribution following IV administration
WBC
White blood cell
WHO
World Health Organization
λz 
terminal phase rate constant


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1.
INTRODUCTION
1.1.
Background
1.1.1.
Background on Chronic Graft Versus Host Disease
Chronic Graft Versus Host Disease (cGVHD) is a disease observed in recipients of allogeneic 
hematopoietic stem cells, where the new immune system is reconstituted without complete 
tolerance to the host and begins to attack multiple organ systems including eyes, skin, mucosa, 
lungs, gut, and liver. Classic acute GVHD (aGVHD) occurs in episodes with donor cell 
engraftment before 100 days post-transplant and is thought to be mediated by donor T cells. 
Acute GVHD is observed in 35-50% of patients receiving hematopoietic stem cell transplant 
(HCT) {Jacobsohn et al 2007}. Acute GVHD is a risk factor for developing cGVHD, but 
cGVHD can develop without history of aGVHD. Chronic GVHD occurs in 35-70% of patients 
receiving allogeneic transplants. In the U.S., the incidence of cGVHD is estimated at 
~3000-5000 patients per year, with prevalence at approximately 10,000 {Vigorito et al 2009}. 
Initial therapy for cGVHD consists of high dose systemic corticosteroids, however 50 to 60% of 
patients fail to have a complete response to this line of therapy. 
No agents are currently approved for cGVHD. A combination of calcineurin inhibitors, mTOR 
inhibitors and mycophenolate mofetil (MMF) are frequently added as second-line therapy with 
an initial response rate of 20-70% {Flowers et al 2015}. The majority of responses are not 
durable, and cGVHD is associated with a 5-year mortality of 30-50% {Blazar et al 2012}. 
Current immunosuppressive treatments also increase the rate of life-threatening infections and 
cancer relapse due to presumably the loss of graft versus tumor effect. The absence of effective 
therapies is attributed to the limited understanding of disease pathophysiology and limited 
directed development by industry.  
1.1.1.1.
Role of SYK in cGVHD
Unlike aGVHD which is believed to be mediated by allo-reactive T cells; the current biological 
and clinical evidence implicates that dysregulated B cell homeostasis is involved in 
establishment of the chronic phase of GVHD.  B cell depletion in the peri-HSCT period is 
correlated with a reduction in the incidence of cGVHD. In addition, antibodies against minor 
histocompatibility antigens have been associated with the occurrence of cGVHD.  In murine 
models of cGVHD, donor B cell alloantibodies have been shown to be responsible for the 
pathogenesis of the disease.  A single open label study with the CD20 B cell depleting 
agent -rituximab- evaluated the potential of prophylactic therapy for development of cGVHD 
post-transplant period {Cutler et al 2013}. This study demonstrated clinically relevant 
differences in the cumulative incidence of cGVHD and overall survival (Figure 1-1).


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Figure 1-1.
cGVHD prophylaxis with rituximab. 
(A) Cumulative incidence of cGVHD.
(B) Non-relapse mortality & GVHD recurrence.
(C) Overall survival
In a subsequent study, subjects with steroid-refractory cGVHD received open-label rituximab 
{Cutler et al 2006} and an overall response rate of 70% was observed. This is in comparison to 
an expected response rate of ~50% for those receiving standard of care alone {Cutler et al 2013, 
Inamoto et al 2014}. These efficacy data with rituximab in cGVHD represent clinical validation 
that therapy targeting B cells in this disease indication is effective. However, treatment of 
cGVHD with rituximab is suboptimal. The treatment effect is not durable as altered B cell 
populations recover {Sarantopoulos et al 2011}, and non-selective depletion of B cells results in 
complications such as hypogammaglobulinemia {Cutler et al 2013}. Targeting the pathogenic
B cell subpopulation that drives cGVHD may therefore yield enhanced efficacy and safety.
Emerging data also indicates that alterations in B cell homeostasis play a pathogenic role in 
cGVHD {Sarantopoulos et al 2015}. In healthy individuals, newly generated B cells emerge 
from the bone marrow as transitional B cells and must complete maturation and selection in the 
periphery {Wardemann et al 2003}. About 40% of these newly emerged B cells are auto 
reactive. Transitional B cells are dependent upon both BAFF (B cell Activating Factor) and BCR 
signaling for their differentiation/maturation and survival.  Low BAFF levels facilitate deletion 


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of autoreactive B cells.  Following HSCT, donor B cell reconstitution occurs in the presence of a 
high foreign antigen load and high BAFF levels. This unique setting promotes the survival of 
activated, potentially allo- and auto-reactive B cells that would normally undergo negative 
selection. These donor-derived B cells can react with recipient tissue, facilitate tissue damage, 
produce inflammatory cytokines and serve as antigen presenting cell (APCs). Importantly, 
patients with cGVHD treated with anti-CD20 who have persistent B cell lymphopenia after 
treatment experience worsening symptoms, suggesting that both high BAFF levels and limited 
capacity to generate sufficient native and transitional B cells contribute to the abnormal B cell 
homeostasis that underlies the disease pathology.  High numbers of native and transitional 
B cells protect from cGVHD development, possibly by binding and decreasing BAFF levels.  
These results further support the hypothesis that normal B cell homeostasis is required for 
protection from cGVHD.  
As described, BAFF and B cell receptor (BCR) signaling play critical roles in the establishment 
of B cell homeostasis by regulating the auto-reactive B cell population.  Patients with cGVHD 
have significantly increased BAFF levels versus B cell numbers {Sarantopoulos et al 2011}.  
Circulating CD27+ B cell subsets are increased and have high expression levels of the BAFF 
receptors.  These cells are present in patients with autoimmune disease, but are absent in healthy 
individuals.  These CD27+ cells are able to constitutively produce IgG and potentially mediate 
anti-recipient tissue responses.  In the cGVHD murine model, elevated BAFF was shown to 
maintain B cells in a state of heightened sensitivity to antigen stimulation following BCR 
stimulation. This observation led to the hypothesis that B cells of cGVHD patients become more 
sensitive to antigen stimulation via BCR stimulation, resulting in loss of peripheral tolerance and 
survival of autoreactive B cell clones.  In vitro studies in human B cells from cGVHD patients
vs. those without cGVHD, revealed that cGVHD B cells have increased proliferative responses 
to BCR stimulation and reduced apoptosis {Allen et al 2012}.   
A mechanistic understanding of BAFF and BCR signaling in cGVHD is currently being 
investigated and highlights that therapeutic kinase inhibition may benefit cGVHD patients with 
altered B cell homeostasis.  The aberrant B cell survival in cGVHD patients is postulated to 
involve BAFF signaling via a SYK-AKT-ERK axis {Allen et al 2012}.  Following HSCT, 
peripheral B cells isolated from cGVHD patients signal through protein kinase B and ERK and 
have decreased expression of the proapoptotic molecule, BIM, resulting in heightened 
metabolism and resistance to apoptosis {Allen et al 2012}.  Importantly, B cells from cGVHD 
patients also have increased proliferative responses to BCR stimulation, with concomitant 
elevations in B cell linker protein (BLNK) and SYK phosphorylation compared to patients 
without cGVHD {Allen et al 2014}.  Pharmacologically blocking SYK kinase activity with 
fostamatinib in vitro in cGVHD donor B cells, prevented BCR hyper-responsiveness of B cells 
to BCR stimulation with anti-IgM {Allen et al 2014}.  Inhibition of Bruton’s tyrosine kinase 
(BTK) activity by ibrutinib blocked PLC- gamma 2 activation in cGVHD patient B cells; 
impacting survival of cGVHD B cells in a BTK dependent manner {Dubovsky et al 2014, 
Miklos et al 2015}. These data suggest that BAFF and BCR cooperate to prime cGVHD B cells 
for survival and antigen responsiveness by lowering the threshold for BCR activation in cGVHD.  
Blockade of BCR signaling, therefore, could be of therapeutic benefit by reestablishing normal 
B cell homeostasis. Therefore, both SYK and BTK inhibition have potential to modulate aberrant 


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B cell function in cGVHD. In contrast to SYK, there are no published data to indicate that BTK 
is activated in cGVHD patient samples. Preliminary unpublished data from the 
Sarantopoulos Lab at Duke University with ENTO in the same assay with active cGVHD patient 
samples demonstrates a dose-dependent effect of ENTO to induce apoptosis of B cells vs. in 
samples from patients without active cGVHD (Figure 1-2).
Figure 1-2.
Entospletinib Induces Apoptosis in B Cells from cGVHD Patients
In summary, failed induction of B cell tolerance after HSCT is postulated to underlie the 
pathophysiology of human cGVHD.  Factors contributing to impaired tolerance induction 
include post-HSCT lymphopenia, persistent allo-antigen stimulation, and high BAFF levels, all 
of which contribute to hyper-responsive BCR pathways. SYK inhibition of cGVHD B cells
subsets could antagonize the pro-survival signaling and result in pathogenic B cell deletion that 
could help reestablish B cell homeostasis.
1.2.
Entospletinib (ENTO)
For further information refer to the ENTO Investigator’s Brochure (IB).


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1.2.1.
Preclinical Pharmacology and Toxicology
Entospletinib (ENTO) was evaluated in a standard battery of safety pharmacology studies to 
assess potential effects on central nervous, cardiovascular, and respiratory systems. ENTO had 
no effect on central nervous and respiratory system parameters evaluated in rats. In a 
cardiovascular safety pharmacology study in dogs, small increases in heart rate (up to a 
25% increase) were observed in male dogs given ENTO at 15, 50, or 150 mg/kg. While the 
higher heart rates were considered ENTO related, the relevance of these changes to humans is 
not known. Due to the observed increases in heart rate, a no observed effect level (NOEL) was 
not identified and the lowest observed effect level was 15 mg/kg. ENTO had no effect on ECGs 
or arterial blood pressure values at oral doses up to 150 mg/kg, the highest dose tested. 
Consistent with the lack of effect on ECG parameters, ENTO has no meaningful effect on the 
human-ether-a-go-go related gene (hERG), indicating that ENTO would not be expected to 
induce clinical QT prolongation. 
The toxicity of ENTO has been characterized in animal genotoxicity, embryo-fetal reproductive 
toxicity, and phototoxicity studies. Recently published data demonstrated that species-specific GI 
toxicity and lymphoid changes, similar to that which was observed following ENTO
administration to dogs, can occur in dogs but not rats, cynomolgus monkeys, or humans treated 
with p38 map kinase and mitogen-activated protein (MAP) kinase activated protein kinase-2 
(MK2) small molecule kinase inhibitors that inhibit pathways that overlap with SYK signaling 
pathways {Morris et al 2010}. Oral administration of ENTO to rats for up to 26 weeks or 
cynomolgus monkeys for up to 39 weeks showed no evidence of GI toxicity or lymphoid 
changes at exposures which overlapped with or exceeded those that resulted in acute toxicity in 
dogs. Furthermore, ENTO (administered as Entospletinib methanesulfonate (ENTO MSA)) has 
been previously investigated in healthy human subjects at doses up to 1200 mg twice a day for 
7 days and in subjects with rheumatoid arthritis (RA) at doses up to 900 mg twice a day for 
26 days and no evidence of GI or lymphoid toxicity was observed in these clinical studies. 
Therefore, the relevance of these findings to humans is not known.
ENTO inhibits uridine disphosphate glucuronosyltransferase 1A1 (UGT1A1) with an IC50 of 
2 μM. This enzyme is involved in glucuronidation of bilirubin, and inhibitors of UGT1A1 have 
the potential to produce increased levels of total and indirect (unconjugated) bilirubin in the 
circulation {Zhang et al 2005}. 
ENTO is considered non-genotoxic and administration of ENTO did not result in skin reactions 
indicative of phototoxicity in mice.
Administration of ENTO to pregnant female rats and rabbits from implantation to the closure of 
the hard palate (International Conference on Harmonisation [ICH] Harmonised Tripartite 
Guideline stages C to D) resulted in dose-dependent developmental findings including increased 
incidence of early and late fetal resorptions and reduced fetal weights, and delays in ossification 
of the forelimb phalanges (rats and rabbits) and metacarpals (rabbits only). These fetal findings 
occurred at ENTO doses that caused maternal toxicity as demonstrated in both studies by 
dose-dependent decreases in body weight gain and/or body weight loss and decreased food 
consumption of the dams. Maternal toxicity was also demonstrated in these studies at doses that 
did not result in developmental findings.


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1.2.1.1.
Non Clinical Pharmacology
For further information refer to ENTO Investigator’s Brochure (IB).
1.2.1.2.
Toxicology
In vitro and in vivo nonclinical studies were conducted to examine the potential toxicity of 
ENTO. In vivo studies were conducted in rats and dogs. Oral administration is proposed for the 
initial clinical trials; therefore, multiple-dose studies with ENTO were conducted via the oral 
route (gavage). 
Based on the totality of the data from the standard battery of in vitro and in vivo genotoxicity 
studies, ENTO is considered non-genotoxic. 
Further details can be found in the ENTO IB.
1.2.2.
Clinical Trials of Entospletinib (ENTO) 
To date, 16 clinical studies have been initiated with ENTO including a total of 566 subjects 
(including 328 healthy subjects, 7 subjects with RA, 76 subjects with CLL, 155 subjects with 
NHL; 26 subjects receiving placebo in Phase 1 and Phase 2 clinical studies. Of the 540 subjects 
receiving ENTO in these studies, ENTO has generally been well tolerated.
Positive results have been reported from a Phase 2 clinical trial with the putative SYK inhibitor 
fostamatinib showing objective anti-tumor responses in chronic lymphocytic leukemia (CLL) 
and Non-Hodgkin’s lymphoma (NHL) subjects {Friedberg et al 2010}.  These responses 
occurred despite off target toxicities that limited drug exposure. ENTO is a highly selective 
inhibitor of SYK and hence has the potential for an improved efficacy and tolerability profile in 
subjects with hematologic malignancies. 
ENTO is being evaluated in an ongoing Phase 2 clinical trial in subjects with relapsed or 
refractory CLL/NHL. A Phase 1b/2 clinical trial is being conducted for subjects with ENTO 
monotherapy and in combination with chemotherapy in subjects with acute myeloid leukemia 
(AML) and acute lymphocytic leukemia (ALL).
ENTO has been studied in single and multiple ascending dose studies in 304 healthy subjects, 
7 subjects with rheumatoid arthritis who were on stable doses of methotrexate, 80 subjects with 
CLL and 95 subjects with NHL.  Of these subjects, 460 received ENTO and 26 received placebo.  
In Pharmacokinetic (PK) studies at steady state in healthy subjects, ENTO was well tolerated 
when given in a fasted state for 7 days at doses of 25, 75, 200, 600, 900, and 1200 mg twice daily 
(GS-US-245-0101) and when given in a fed state for 6 days at doses of 100 and 900 mg 
twice daily (GS-US-245-0106), for 4 days at doses of 200 and 600 mg twice daily 
(GS-US-339-0101), and at 1200 mg twice daily for 5 days (GS-US-339-0109).Exposure, as 
measured by AUC and maximum concentration Cmax, did not increase appreciably at doses 
above 600 mg under fasted condition. 


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To provide a margin for inter-patient variability, a dose of 900 mg twice daily was chosen for the 
study of subjects with rheumatoid arthritis receiving stable doses of methotrexate in Study 
GS-US-245-0101.  A dose of 900 mg ENTO twice daily was given in a fasted state for 26 days 
in 7 subjects.  The median AUCtau in these subjects was similar to that of the healthy subjects.  In 
general, this dose was well tolerated.   One subject developed reversible, Grade 2 alkaline 
phosphatase and transaminase elevations starting 7 days after her last dose of ENTO, concurrent 
with new onset of a bronchopneumonia.  One other subject reported not feeling well and 
experienced hot flashes, fever, shivers, rash, headache, dizziness, and fainting 1 day after her last 
dose of ENTO with reversible Grade 1 alkaline phosphatase and Grade 3 transaminase elevations 
which peaked 1 week later.  While these events are potentially confounded by concurrent 
illnesses, hepatic enzymes will be closely monitored during this study.
Consistent with the known inhibition of UGT1A1 by ENTO, 8 of the 178 healthy subjects 
developed asymptomatic indirect bilirubin elevations (6 Grade 1, 1 Grade 2 and 1 Grade 3) that 
resolved following discontinuation of the drug.  Three of the 7 subjects with rheumatoid arthritis 
who received ENTO for 26 days developed asymptomatic indirect bilirubin elevations 
(2 Grade 1, 1 Grade 3) which improved despite continued dosing.
Common AEs from an on-going Phase 2 study evaluating chronic administration of ENTO
monotherapy in 186 subjects with hematologic malignancies are fatigue (53.2%), 
nausea (45.2%), diarrhea (38.7%), decreased appetite (24.7%), constipation (23.7%), 
cough (21.0%), and headache (21.0%) as of 21 November 2014. One out of a total of 
201 subjects (0.5%) experienced pneumonitis in this monotherapy study as of 11 March 2015.
1.2.3.
Interaction with Proton Pump Inhibitors
In Study GS-US-245-1222, omeprazole co-administration reduced ENTO AUCtau by 
59% following ENTO BIS-MSA 400 mg BID (solid dispersion formulation). Available 
solubility and clinical PK data strongly imply that the observed interaction between ENTO and 
PPIs is due to elevated gastric pH, leading to reduced ENTO absorption. ENTO solubility is 
known to be highly pH-dependent, with aqueous solubility of 10 mg/mL at pH 2 but 
<0.15 mg/mL at pH ≥3.0, suggesting that PPIs are likely to reduce ENTO absorption due to 
increased gastric pH. In Study GS-US-245-1222, the ENTO terminal elimination half-life was 
similar when ENTO was administered alone (median [Q1, Q3] 14.89 [11.86, 21.36] hours) or 
with omeprazole (13.65 [10.49, 17.04] hours), demonstrating that the reduced ENTO exposure 
observed with omeprazole is likely a result of reduced absorption, rather than a result of altered 
elimination. Furthermore, omeprazole is a known inhibitor of CYP2C19 {Angiolillo et al 2011}
however in vitro studies did not identify a role of CYP2C19 in ENTO metabolism. In addition, 
CYP inhibition by omeprazole would be expected to result in increased drug exposure of 
susceptible substrates, whereas significantly decreased ENTO exposure was observed with 
omeprazole co-administration in healthy volunteer studies.
Please refer to Section 1.4 of the protocol for further discussion of the dosing implications of PPI 
co-administration with ENTO in this study.


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1.3.
Rationale for This Study
Given the emerging role of B cells in cGVHD (abnormal response to BAFF, errors in B cell 
reconstitution/differentiation, BCR signaling via SYK or BTK, failed induction of B cell 
tolerance), ENTO, in a dose responsive manner, induces ex vivo apoptosis of a population of 
B cells present only in patients with active cGVHD, and the proof-of-concept studies with 
rituximab demonstrating that B cell targeted therapy shows benefit in cGVHD
(see Section 1.1.1.1), Gilead is pursuing an investigation into whether ENTO is an effective 
treatment for cGVHD. Study GS-US-406-1840 is designed to evaluate the efficacy and 
tolerability of ENTO in addition to systemic corticosteroids in subjects at the time of initial 
diagnosis of cGVHD requiring treatment. Safety reviews will be performed in real time and will 
include evaluations of clinical laboratory abnormalities, relapse of primary malignancy, physical 
examinations, vital signs and AE reporting.
1.4.
Rationale for Dose Selection 
Since the target coverage necessary to achieve efficacy in subjects cannot be established in 
ex vivo experiments or animal models, the objective for dose selection is to achieve >50% target 
inhibition (% inhibition in stimulated CD63+ basophils) at trough. At 200 mg twice daily of 
ENTO BIS-MSA, the degree of inhibition of CD63+ cells is ~50% at steady state Ctrough. 
However, the majority of cGVHD subjects are administered proton pump inhibitors (PPIs), 
which would be expected to decrease target inhibition below 50% at this dose. At an ENTO
BIS-MSA dose of 400 mg twice daily in the presence of a PPI, target inhibition at Ctrough is 
~50%. Thus, the selected dose in cGVHD is 400 mg twice daily of ENTO in patients currently 
taking a PPI, and 200 mg twice daily of ENTO in patients not currently taking a PPI.
Furthermore, ENTO has a safety profile that is acceptable for subjects receiving treatment for 
malignancy (including cGVHD subjects). In studies with ENTO, the rate of Grade 3 or 4 
AST/ALT elevations is between 10-14%, and these events are reversible with interruption of 
dosing. Reversible episodes of elevated indirect bilirubin (≥ Grade 1) occur in ~11% of subjects.
1.5.
Risk/Benefit Assessment for the Study
Chronic GVHD remains a highly morbid disease with a high mortality rate, and given the 
cumulative safety data in healthy volunteers and patients with hematologic malignancies, the 
safety profile of ENTO is expected to be similar in cGVHD patients. ENTO is 
immunomodulatory, and even though ENTO has not been associated with an increased rate of 
infections in clinical studies in hematologic malignancy, serious infections are events of interest 
in this population as patients with cGVHD have a high rate of infections. Any 
immunomodulatory agent has a theoretical risk of decreasing the graft versus tumor effect, and 
malignancy relapse is also an event of interest in this study. However, as SYK inhibition affects 
primarily B cell function and not T-cell function, loss of the graft versus tumor effect is not 
expected as a result of treatment with ENTO. ENTO is associated with transaminase elevations 
and bilirubin increases, but these episodes have been reversible. The evaluation of safety of 
ENTO administration in the cGVHD population is facilitated in this study with the inclusion of a 
placebo control group.


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Refer to the IB for full details of prior and ongoing pre-clinical and clinical studies including 
summary safety and efficacy data. 
1.6.
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 primaty objective is: 
To evaluate the effect ofENTO on the best overall response rate (BORR) as assessed by the 
cGVHD Activity Assessment (NCAA) by 24 weeks in the setting of add-on to systemic 
cotiicosteroids as pati of first-line therapy for cGVHD 
The key secondaty objectives al'e: 
• 
To evaluate the effect of ENTO on the skin domain of the Lee Symptom Scale (LSS) 
(Appendix 6) at 24 weeks 
• 
To evaluate the effect ofENTO on the mouth domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the eyes domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the total score of the LSS at 24 weeks 
Additional secondaty objectives include: 
• 
To evaluate the effect ofENTO on duration of response (DOR) 
• 
To evaluate the effect of ENTO on dose reduction of cotiicosteroids 
• 
To evaluate the effect ofENTO on initiation of second-line therapy for cGVHD 
• 
To evaluate the effect of ENTO on progression of cGVHD 
• 
To evaluate the safety and tolerability ofENTO 
Exploratmy objectives include: 
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STUDY DESIGN 
3.1. 
Endpoints 
The primary endpoint of this study is: 
Final 
Amendment 3.0 Global 
• 
The primary endpoint is BORR as assessed by the NCAA by 24 weeks in the setting of 
add-on to systemic corticosteroids as part of first-line therapy for cGVHD 
The key secondary endpoints are: 
• 
Change from Baseline in the skin domain of the LSS at 24 weeks 
• 
Change from Baseline in the mouth domain ofthe LSS at 24 weeks 
• 
Change from Baseline in the eyes domain ofthe LSS at 24 weeks 
• 
Change from Baseline in the total score ofthe LSS at 24 weeks 
Other secondary endpoints include: 
• 
DOR 
• 
Proportion of subjects who achieve at least 50% reduction in systemic corticosteroid dose 
relative to baseline 
• 
Proportion of subjects who initiate second-line therapy for cGVHD 
• 
Failure-free survival (FFS) 
• 
Safety and tolerability of ENTO 
Exploratory endpoints ofthis study include: 
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3.2.
Study Design
This protocol describes a randomized, double-blind, placebo-controlled multicenter study to 
evaluate the efficacy and safety of ENTO (Treatment Arm 1) vs. placebo (Treatment Arm 2) in 
combination with systemic corticosteroids for subjects with cGVHD.  
A total of 100 eligible subjects will be randomized in a 1:1 manner to ENTO (Treatment Arm 1)
or placebo-to-match (PTM) (Treatment Arm 2), and treated for 48 weeks during the blinded 
phase. Randomization will be stratified by the following 2 factors at the Baseline/Day 1Visit:
Stratification Factor
Stratification Levels
Calcineurin inhibitor or MMF use
Yes vs. No
Disease severity as determined by the 2014 NIH 
Consensus cGVHD criteria
Moderate cGVHD:

≥ 1 organ with score = 2, or

≥ 3 organs with score = 1, or

lung score = 1
Severe cGVHD:

any organ score = 3 or

lung score ≥ 2
The final analysis for BORR is planned when all subjects have been on study for 24 weeks.  All 
subjects will be followed up to 48 weeks for DOR evaluation.  At the Week 48 visit, subjects
who are still on investigational treatment (ENTO or PTM) and are eligible to remain on study
will have the option to receive open-label extension (OLE) with ENTO. This OLE offers patients
who are deriving a benefit from ENTO or those with no alternative treatments the opportunity 
for further therapy for a serious and life threatening disease.
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study, perform interim reviews of safety data at regular intervals approximately every 3 months, 
and perform an interim review of efficacy data for futility when approximately 50% of subjects 
have been on study for 24 weeks, as described in the DMC Charter.  The first DMC meeting will 
be conducted after the 20th subject has been on study for 8 weeks.  The DMC will provide 
recommendations to Gilead as to whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the study in the best interests of 
the participants, whether the study should continue as planned, or the study should continue with 
modifications. 
3.3.
Study Treatments
After 48 weeks of blinded treatment, subjects who are still on investigational treatment (ENTO 
or PTM) and are eligible to remain on study will have the option to receive open-label extension 
(OLE) with ENTO and attend visits per the schedule of assessments (Table 6-1) for an additional 
96 weeks.
Subjects who provide written informed consent and meet all eligibility criteria will be 
randomized in a 1:1 fashion to either Treatment Arm 1 or Treatment Arm 2.  


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Subjects will retum for study visits at Weeks: 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48. At the 
Week 48 visit subjects who aTe still on investigational treatment (ENTO or PTM) and are 
eligible to remain on study will have the option to palticipate in the OLE. If subjects elect not to 
emoll in the OLE phase of the trial, they will retum for a 30-day follow-up visit. 
Subjects that will continue in the OLE phase of the trial will retum for the following study visits 
at Weeks: 50, 52, 56, 60, 64, 72 and visits evety 12 weeks thereafter. NOTE for subjects 
receiving tacrolimus, cyclosporine or MMF: For subjects receiving these medicines at 
emollment and are continuing on these medicines, the blood levels of tacrolimus, cyclosporine or 
the active metabolite of MMF (MPA) will be monitored at baseline/Day 1 (prior to sta1ting 
ENTO or PTM), on Day 2 (optional) or Day 3 (optional) and Day 6 or Day 7 aft.er initiating 
ENTO or PTM, and at the end of Week 2 and Week 50 study visit. Beyond these time points, 
concentration monitoring for tacrolimus, cyclosporine and MPA should follow the treating 
institution's protocol and therapeutic range for monitoring these medicines. For subjects who 
initiate these medicines while already receiving ENTO or PTM, concentration monitoring for 
tacrolimus, cyclosporine and MPA should follow the treating institution's protocol and 
therapeutic range for monitoring these medicines. When a concentration sample is taken at a 
local lab in accordance with the treating institution's protocol for monitoring these medications, 
a sample may also be requested for central lab analysis. 
PPD 
Figure 3-1. 
Study Schema 
Baseline 
(Day 1)1 
Week2• 
Week48' 
I 
Screening 
Treatment Arm 1: Entospletirub + Systemic corticoids 
for 48 weeks (n=50)b 
JODay 
F/li 
Treatment Arm 2: Placebo+ Systemic corticoids 
for 48 weeks (n=50) b 
Open-Label Enensloo 
Entospletinibd 
a 
Following the Baseline/ Day 1 visit subjects will return to the clinic for visits at Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 
48. 
b 
For subjects receiving tacrolimus, cyclosporine or MMF the blood levels of tacrolimus, cyclosporine or the active metabolite 
ofMMF (MPA) will be monitored at baseline/Day 1 (prior to starting ENTO or PTM), on day 2 (optional) or day 3 
(optional) and day 6 or day 7 after initiating ENTO or PTM, and at the end of Week 2 and Week 50 study visit. Beyond 
these time points. concentmtionmonitoring for tacrolimus, cyclosporine and MPA should follow the treating institutions 
protocol and therapeutic range for monitoring these medicines 
c 
Subjects who complete the study through Week 48 and do not wish to continue to patticipate in the OLE phase of the trial 
will be required to return to the clinic 30 days after the completion of study dmg for a 30-Day Follow-up visit 
d 
Aftet· Week 48, subjects who are still on investigational treatment (ENTO or PTM) and are eligible to remain on study \\rill 
have the option to receive OLE for an additional 96 weeks. Subjects will attend visits at Weeks: 50, 52, 56, 60, 64, 72 and 
every 12 weeks thereafter. 
e 
The initial taper of systetnic cotticosteroid from the starting dose of:;:: 0.5 mglkg/day may be attempted 14 days after co-
adtninistration with ENTO/Placebo if there is evidence of improvement in cGVHD 
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3.4. 
Discontinuation Criteria 
Subject pruiicipation may be discontinued in the following instances: 
Final 
Amendment 3.0 Global 
• 
Intercunent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. 
• 
Unacceptable toxicity, 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 
• 
Relapse of primruy disease 
• 
Severity of cGVHD requiring therapy that is not allowed as concomitant therapy on study 
(for exrunple JAK inhibitor/BTK inhibitor /mTOR inhibitors/ any cell depletion 
agent/ phototherapy) 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy during the study; refer to Appendix 8 
• 
Discontinuation of the study at the request of Gilead, a regulatoty agency or an 
Institutional Review Boru·d or Independent Ethics Committee (IRBIIEC) 
3.5. 
Biomarker Testing 
3.5.1. 
Biomarker Samples to Address the Study Objectives: 
Blood will be collected in this study and will be used to evaluate the effect ofENTO on markers 
relevant to cGVHD and/or the SYK pathway. The specific biomru·kers may include, but are not 
limited to the following: cytokines, cell subset analysis, pathway markers, and/or other B-cell 
activating factor, B-cell ftmction immunoglobulin levels, and/or antigen-specific B cell 
responses. 
Because biomarker science is a rapidly evolving area of investigation, and adverse events in 
particular ru·e difficult to predict, it is not possible to specify prospectively all tests that will be 
done on the specimens provided. The testing outlined above is based upon the cmTent 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 a1t knowledge. 
The samples obtained for the study may be stored for 15 years after the end of the study. 
3.5.2. 
Optional Future Research 
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3.5.3. 
Optional Sub-study to study cellular turnover {Emson et al 2013, Ladell et al 
2008, Messmer et al 2005} 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 subjects who meet the inclusion/exclusion criteria will be enrolled. 
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) The ability to understand and sign a written informed consent form, which must be obtained 
prior to initiation of study procedures
2) 18-75 years of age, inclusive at Screening
3) Newly diagnosed cGVHD defined by: 
a) At least 100 days after receiving any allogeneic hematopoietic stem cell transplant 
AND 
b) Receiving a new course of systemic corticosteroids (≥0.5 mg/kg/day) as first-line 
cGVHD therapy for at least 1 day and no more than 21 days prior to first dose of 
ENTO/Placebo   
AND
c) Moderate to severe cGVHD as assessed by NCDSC with at least three organ systems 
involved OR one organ system with a score of 2 OR lung organ score = 1 (Appendix 2)
4) Subjects who have undergone transplantation for benign indications are eligible for the study. 
Complete remission is required for subjects who have undergone transplantations for 
hematologic malignancies. 
5) Have either a normal ECG or one with abnormalities that are considered clinically 
insignificant by the investigator in consultation with the Sponsor 
6) A negative serum pregnancy test is required for female subjects (unless permanently sterile 
or greater than two years post-menopausal) 
7) A female subject is eligible to enter the study if it is confirmed that she is: 
a) Not pregnant or nursing


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b) Of non-childbearing potential (i.e., women who have had a hysterectomy, have had both 
ovaries removed or medically documented ovarian failure, or are postmenopausal 
women > 54 years of age with cessation (for 12 months) of previously occurring 
menses), or
c) Of childbearing potential (as defined in Appendix 8) and agrees to utilize a highly 
effective protocol-specified contraceptive method or be non-heterosexually active or 
practice sexual abstinence from Screening throughout the duration of study treatment and 
for 30 days following the last study drug dose
8) Male subjects of childbearing potential who engage in heterosexual intercourse must agree to 
use protocol specified method(s) of contraception as described in Appendix 8.
9) Both female and male subjects of childbearing potential who are receiving mycophenolate 
mofetil (MMF) must agree to utilize contraceptive measures in accordance with the current 
MMF SmPC and the precautions for ENTO outlined in Appendix 8, whichever is stricter. 
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Inability to begin systemic corticosteroids therapy at a dose of ≥ 0.5 mg/kg/day (or 
equivalent)
2) Uncontrolled infection within 4 weeks prior to Randomization
3) History of the following therapies in the post-transplant period:
a) B cell depleting biologic agents
b) CD19 CAR-T cells based therapies 
c) BTK/SYK/JAK/PI3K inhibitors
d) Phototherapy-unless administered for aGVHD 
4) Treatment of cGVHD with anti-thymocyte globulins (ATG), or campath within 60 days of 
Screening visit  unless used for  treatment of acute GVHD
5) Severe organ dysfunction manifest during Screening period: 
a) Requiring supplemental oxygen at more than 2L/min
b) Uncontrolled arrhythmia or heart failure
c) Creatinine clearance (Cockroft-Gault) < 30 mL/min


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6) Known hypersensitivity to the Investigational Medicinal Product (IMP), the metabolites, or 
formulation excipient.
7) Laboratory abnormalities including: 
a) Human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen or hepatitis 
C antibody positive (Subjects with positive HCV antibody and without detectable HCV 
RNA are permitted to enroll) 
b) Aspartate aminotrasferase (AST)/Alanine aminotransferase (ALT) ≥ 2 X upper limit of 
normal (ULN) unless deemed to be secondary to Liver GVHD
c) Total bilirubin ≥2 X ULN unless deemed to be secondary to Liver GVHD
8) Positive serum pregnancy test (for female subjects) 
9) Any other clinical condition or prior therapy that, in the opinion of the investigator, would 
make the subject unsuitable for the study or unable to comply with dosing requirements 
10) Participation in any other clinical trial without prior approval from the sponsor is prohibited 
while participating in this trial 
11) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance or subject safety
12) Subjects receiving ongoing therapy with any of the following medications in the Table 5-2.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
Subjects will be assigned a screening number at the time of consent.  The Randomization and 
Baseline/Day 1 visit cannot occur until the Investigator has received the results of the Screening 
tests and subject eligibility has been confirmed. 
Once eligibility has been confirmed, each subject will be assigned a unique subject number. 
Once a subject number has been assigned to a subject, it will not be reassigned to any other 
subject. Prior to or during the Baseline/Day 1 visit, the investigator or designee will randomize
the subject using an Interactive Web Response System (IWRS).  Subjects will be randomized in 
a 1:1 ratio to Treatment Arm 1 or Treatment Arm 2. The IWRS will assign blinded study drug 
bottle numbers at each study visit (except Weeks 2, 30 and 42).  Study drug will be dispensed to 
the subject in a blinded fashion until Week 48.  Randomization will be stratified by the following 
2 factors at the Screening and Baseline/Day1 Visit:
Stratification Factor
Stratification Levels
Calcineurin inhibitor or MMF use
Yes vs. No
Disease severity as determined at 
Screening by the NIH cGVHD 
Staging and Diagnosis Criteria 
(NCSDC) Global Severity Score
Moderate cGVHD:
≥ 1 organ with score = 2, or
≥ 3 organs with score = 1, or
lung score = 1
Severe cGVHD:
any organ score = 3 or
lung score ≥ 2
All Baseline/Day 1 tests and procedures must be completed prior the administration of the first 
dose of the study drug. The subject must complete the Baseline procedures prior to 
randomization and drug dispensation. Initiation of treatment with the study drug must take place 
within 24 hours after the Baseline/Day 1 visit.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IXRS system 
for that subject.  Gilead recommends but does not require that the investigator contact the 
Gilead medical monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the case report 
form/ electronic case report form (eCRF), along with the date on which the treatment assignment 
was obtained. The investigator is requested to contact the Gilead medical monitor promptly in 


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case of any treatment unblinding. Blinding of study treatment is critical to the integrity of this 
clinical trial and therefore, if a subject’s treatment assignment is disclosed to the investigator, the 
subject will have study treatment discontinued. All subjects will be followed until study 
completion unless consent to do so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.2.
Description and Handling of Study Drug
5.2.1.
Formulation
ENTO tablets, 200 mg strength, are available as blue, capsule-shaped film-coated tablets that are 
plain-faced. In addition to the active ingredient, ENTO 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.
ENTO 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, ENTO 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.
Placebo to match ENTO tablets, 200 mg strength, are available as blue, capsule-shaped 
film-coated tablets that are plain-faced. The placebo to match ENTO tablets contain the 
following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, 
magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and FD&C 
blue #2 aluminum lake.
Placebo to match ENTO 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. The placebo 
to match ENTO tablets contain the following inactive ingredients: lactose monohydrate, 
microcrystalline cellulose, crospovidone, magnesium stearate, polyethylene glycol, polyvinyl 
alcohol, talc, titanium dioxide, ferrosoferric oxide/black iron oxide, iron oxide red, and iron 
oxide yellow.
5.2.2.
Packaging and Labeling
ENTO (GS-9973) 200-mg and PTM tablets are packaged in white, high-density polyethylene 
(HDPE) bottles. Each bottle contains 60 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.


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Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
5.2.3.
Storage and Handling
Study drug (ENTO and PTM) should be stored at controlled room temperature of 25°C (77°F); 
excursions are permitted between 15°C and 30°C (59°F and 86°F).  Storage conditions are 
specified on the label.  Until dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel. To ensure the stability and 
proper identification, study drug(s) should not be stored in a container other than the container in 
which they were supplied. 
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure through inhalation when handling.
5.3.
Dosage and Administration 
ENTO and PTM tablets will be provided by Gilead Sciences.  
ENTO or PTM should be taken under fasted conditions. Fasting is defined as no food or liquids 
other than water for 2 hours pre- and 1 hour post-dose. Subjects unable to swallow tablets should 
contact Gilead Medical Monitor for guidance. If vomiting occurs within 30 minutes after IMP 
administration and undissolved tablets are present in the vomitus, the subject should take another 
dose.
Study medication will be adjusted for whether the subject is taking a proton pump inhibitor (PPI) 
per the following table, both at study entry and throughout the study.
PPI status
ENTO or PTM dose
Subject is taking PPI
400 mg (2 x 200 mg tablet) twice daily 
Subject is NOT taking PPI
200 mg (1 x 200 mg tablet) twice daily 
5.4.
Prior and Concomitant Medications 
Systemic corticosteroids are required at study entry. Administration and taper recommendations 
are below:

Systemic corticosteroid: administered initially as a single early morning dose 
of ≥0.5 mg/kg/day [or equivalent (Adults: maximum dose 100 mg)]. 

The initial taper of systemic corticosteroid from the starting dose of ≥0.5 mg/kg/day may be
attempted 14 days after co-administration with ENTO/Placebo if there is evidence of 
improvement in cGVHD. More rapid tapering of systemic corticosteroid dose is allowed if 
clinically recommended.


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Steroid tapering should be completed prior to tapering of immunosuppressants 
(Cyclosporine, Tacrolimus and MMF) unless the clinical condition of the subject dictates 
tapering/discontinuing other medications sooner (eg, toxicity associated with the use of the 
medication). 
• If exacerbation or recunence of cGVHD is evident at any step of the taper, the dose of 
systemic corticosteroid should be increased promptly by 2 levels, with daily administration 
for 2 to 4 weeks, followed by resumption of altemate-day administration. Please see 
Table 5-1 for tapering. 
Table 5-1. 
Tape ring of Systemic Corticosteroid after reaching PR/CR based on 1 
mg/kg/day* 
Week 
Dose, mg/kg body weight (example for 80kg patient in mg) 
0 
1-3 
4-5 
6-7 
8-9 
10 
* 
• 
• 
1.0 once a day (80) 
1.0/0.5 (to begin within 1 week after objective improvement, 
altemating days) (80/40/80) 
0.5 once a day (40) 
0.5 eve1y other day (40/0/40) 
0.25 eve1y other day (20/0/20) 
0.1 eve1y other day (10/0/10) with ultimate goal of complete discontinuation of 
systemic co1ticosteroid 
If initial dose is not hug/kg/day, adjust tapering schedule based on percentage of initial dose (e.g. 50% of initial dose, 25% 
of initial dose, I 0% of initial dose) 
Inhaled and topical steroids ( eg, Budesonide/ Beclomethasone) are not considered 
second-line theragy and are ennitted throuahout the duration of the study/PD.------. 
Local organ-specific treatment ( eg, eye drops) will be recorded in the eCRF and assessment 
of response after local organ-specific treatment will be based on the NCAA. 
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Co- Administration of ENTO with Other Classes of Immunosuppresant Agents during OLE:

During the extension phase (post 96 weeks of study) or OLE, for patients who are eligible to 
remain on study, the maximum period of co-administration of ENTO with Cyclosporine, 
Tacrolimus or MMF should not exceed 3 months. The sponsor envisions that if the subject 
has stable or refractory disease, they should be transitioned to other forms of therapies within 
this 3 month period.
Disallowed Medications: 
Published clinical data suggests that the combination of ENTO with Idelalisib resulted in an 
unexpected pneumonitis syndrome attributed to excessive mammalian target of rapamycin–like 
activity. Although pneumonitis has been reported with all mTOR inhibitors, the exact incidence 
of this toxicity seems to vary widely from study to study. Therapeutic inhibition of kinases 
involved within the BCR signaling cascade is an emerging field, and many questions remain and 
for this reason, the co-administration of SYK inhibitors with PI3K inhibitors is strongly 
discouraged.
In vivo and in vitro data indicates that ENTO is a substrate of CYP2C9 and CYP3A. In a study 
in healthy subjects, co-administration of the strong CYP3A4/CYP2C9 inducer rifampin resulted 
in an approximately 70% decrease in ENTO exposure. 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 ENTO exposure. Examples 
of medications that are prohibited in this study are provided in Table 5-2.
Table 5-2.
Examples of Prohibited Agents
Drug Class
Examples of Prohibited Agents (but not limited to)
mTOR inhibitor
Everolimus, sirolimus
Any cell depleting antibody
Rituxan®
Phototherapy
Phototherapy
BTK agents
Ibrutinib
JAK inhibitors
Tofacitinib, ruxolitinib
Moderate 2C9 inducers
Carbamazepine, rifampin, ritonavir, enzalutamide
Strong CYP3A or 2C9 inducers
Rifampin, mitotane, avasimibe, phenytoin, carbamazepine, enzalutamide, St 
John’s Wort, rifabutin, phenobarbital
PI3K inhibitors
Idelalisib
Herbal/Natural Supplements 
St. John’s Wort 
Use with Caution: 
In vitro data indicates that Entospletinib has the potential to inhibit several transporters and the 
metabolizing enzyme UGT1A1, which may affect the plasma concentrations of substrates of 


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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. A list of sensitive substrates of this enzyme and/or transporters 
is provided below; any use of these medicines should be discussed with the medical monitor.
Table 5-3.
List of Sensitive Substrates of UGT1A1, OATP1B1, OATP1B3, P-gp 
and BCRP
Transporter
Substrate
P-gp
Aliskiren, aldosterone, ambrisentan, colchicine, dasatinib, dabigatran etexilate, 
dexamethasone, digoxin, diltiazem, domperidone, etoposide, fexofenadine, imatinib, 
itraconazole, ivermectin, loperamide, lapatinib, maraviroc, methylprednisolone, 
nilotinib, posaconazole, quinidine, ranolazine, saxagliptin, sitagliptin, sparfloxacin, 
talinolol, tolvaptan, topotecan, vinblastine
BCRP
Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, 
sulfasalazine, topotecan
OATP1B1
Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, SN-38 (active metabolite 
of irinotecan), rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide,  
valsartan, olmesartan
OAPT1B3
Atorvastatin, rosuvastatin, pitavastatin, telmisartan, valsartan, olmesartan
UGT1A1
Acetaminophen, atorvastatin, bropirimine, carvedilol, clofibrate, ezetimibe, 
flavopiridol, gemfibrozil, genistein, nalorphine, naltrexone, naringenin, raloxifene, 
SN-38, simvastatin, telmisartan, troglitazone
In a study in healthy volunteers, Entospletinib 400 mg twice daily increased rosuvastatin 
exposure by approximately 3.8-fold, which may theoretically increase the risk of 
rhabdomyolysis. In reviewing the safety of subjects whom have received a statin with 
Entospletinib there have been no reports of rhabdomyolysis nor a different adverse events 
profile, but in the interest of caution, the following restrictions apply to the use of HMG-CoA 
reductase inhibitors with Entospletinib:
Concomitant Medication
Restriction
Atorvastatin
Maximum dose 20 mg once a day 
Rosuvastatin
Maximum dose 10 mg once a day
Pravastatin
Maximum dose 40 mg once a day
Simvastatin
Maximum dose 20 mg once a day
Lovastatin
Maximum dose 20 mg once a day
Fluvastatin
Maximum dose 20 mg twice a day or 40 mg once a 
day
Pitavastatin
Maximum dose 1 mg once a day
5.5.
Opportunistic Infections and Prophylactic Regimens
Patients with ongoing cGVHD or continued use of immunosuppressive therapy should be 
considered as immune deficient and at risk for significant infectious complications. Thus, 


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prophylaxis for opportunistic infection according to institutional treatment standards are 
mandated. For additional questions please refer to IDSA guidelines{Tomblyn et al 2009}. CMV 
surveillance must be conducted while receiving treatment with ENTO/Placebo following 
institutional guidelines.  If a subject tests positive for CMV PP65 antigen or quantitative CMV 
PCR testing shows an unequivocal increase in viral load, the subject must discontinue 
ENTO/Placebo and begin effective antiviral therapy per institutional guidelines. Weekly 
monitoring should continue for a minimum of 2 weeks and thereafter until clearance of CMV.
Monitoring of CMV should be done through local lab. Re-institution of ENTO/Placebo may
start following CMV viral clearance.
5.6.
Accountability for Investigational Medicinal Product 
The investigator is responsible for ensuring adequate accountability of all used and unused IMP.
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
Study drug accountability records will be provided by Gilead Sciences (or equivalent 
documentation maintained by the study site) to:

Record the date received and quantity of IMP bottles

Record the date, subject number, subject initials, the IMP bottle number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
5.6.1.
Investigational Medicinal Product Return or Disposal
IMP return and disposal will be performed as outlined in Section 9.1.6.


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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 the schedule of assessment 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).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that each subject is eligible for the study 
before enrollment in the study.  Please refer to Section 5.1 for details about randomization and 
treatment assignment.  
6.2.
Study Assessments 
Study procedures are outlined in Table 6-1.


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Table 6-1.
Schedule of Assessments
Visit
Screeninga
Baseline/
Day1c
END OF WEEK b
Every 12 
Weeks
30 
Day 
Follo
w-up
2t
4
8
12
16
20
24
30
36
42
48/
ESDDd
50
52
56
60
64
72
Visit Window
-30 days
0
3
3
3
3
3
3
3
5
5
5
5
3
3
3
3
3
5
5
Written Informed 
Consent
X
Medical History 
X
Smoking Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete 
Physical Exam
X
X
X
X
X
Symptom-
Directed Physical 
Exame
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
Testf
X
Urine Pregnancy 
testf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum FSHf
X
NIH cGVHD 
Diagnosis and 
Staging Criteriau
X
NIH cGVHD 
Activity 
Assessment
(NCAA) Form  A
with spirometryg
Xg
X
X
X
X
X
Xg
X
X
X
Xg
X
X
X
X
NIH cGVHD 
Activity 
Assessment
(NCAA) Form Bh  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Gilead Sciences, Inc. 
Amendment 3.0 Global 
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Visit
Screeninga
Baseline/
Day1c
END OF WEEK b
Every 12 
Weeks
30 
Day 
Follo
w-up
2t
4
8
12
16
20
24
30
36
42
48/
ESDDd
50
52
56
60
64
72
Visit Window
-30 days
0
3
3
3
3
3
3
3
5
5
5
5
3
3
3
3
3
5
5
Lee Symptom 
Scale (LSS)h 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Primary disease 
assessment per 
institutional 
guidelines  
X
X
X
Height 
X
Vital Signs & 
Weighti
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematologyj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistryk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Analysisl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Metabolic Panel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1, HBV, & 
HCV Serologym 
X
12 lead ECG-
performed supine 
X
X
X
PKn
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitoring of 
calcineurin 
inhibitors and 
MPA o
X
X
X
Biomarkersp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PFTs
X
X
X
Randomize 
X


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Amendment 3.0 Global 
CONFIDENTIAL
Page 45
30 January 2017
Visit
Screeninga
Baseline/
Day1c
END OF WEEK b
Every 12 
Weeks
30 
Day 
Follo
w-up
2t
4
8
12
16
20
24
30
36
42
48/
ESDDd
50
52
56
60
64
72
Visit Window
-30 days
0
3
3
3
3
3
3
3
5
5
5
5
3
3
3
3
3
5
5
Drug Dispensingq
X
X
X
X
X
X
X
X
X
X
X
X
X
Written Informed 
Consent for OLE
X
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medicationsr 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Evaluations to be completed within 30 days prior to Day 1. 
b
All study visits are to be scheduled relative to the Day 1 visit date. 
c
Initiation of treatment with the study drug must take place within 24 hours after the Baseline/Day 1 Visit
d
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug. Subjects with an Early Study Drug Discontinuation visit should continue attending 
study visits through Week 48.
e
Symptom-directed physical exam as needed 
f
FSH: For female subject post-menopausal for less than two years, if FSH 40 mIU/ mL a serum pregnancy test will be required.  Women determined to be of child bearing 
potential will have a serum pregnancy test performed at screening.  All subsequent visits will have a urine test, and positive urine pregnancy tests will be confirmed with a 
serum test. During OLE, urine pregnancy test will be performed every 4 weeks starting with end of visit Week 64.
g
NCAA Form A (Appendix 5) with spirometry measures will be completed by the Investigator or Sub-I. In the OLE this will be assessed at Weeks 56, 60, 64, 72 and every 
12 weeks thereafter. NCAA should also be performed at the time of initiation of second-line therapy. Walk test to be performed at Baseline/Day 1, Weeks 24 and 48/ESDD
when medically feasible. Trained study personnel may complete spirometry and walk test portion.
h
LSS (Appendix 6) and the NCAA Form B (Appendix 5) is to be completed by the subject. The subject is to read the questionnaire by himself/herself and write/mark answers 
directly onto the questionnaire. In the OLE this will be assessed at Weeks 56, 60, 64, 72 and every 12 weeks thereafter. The LSS and the NCAA Form B should also be 
administered at the time of initiation of second-line therapy.
i
Vital sign measurements include blood pressure, pulse, respiration rate, weight and temperature
j
Complete blood count (CBC) with differential platelet count 
k
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorous, magnesium, potassium, sodium, uric acid, and amylase and (reflex lipase testing is performed in subjects with total amylase 
> 1.5 ULN) 
l
Urine collection for urinalysis and urine pregnancy test (if applicable) 
m
Subjects with positive HCV antibody and without detectable HCV RNA are permitted to enroll 
n
Randomly timed PK sampling. Sites should enter the time of the last dose of study medication in the eCRF for sample reconciliation. PK samples will be drawn at Week 60 
and every 12 weeks in the OLE. 


Entospletinib 
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Gilead Sciences, Inc. 
Amendment 3.0 Global 
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o
For subjects receiving tacrolimus, cyclosporine or MMF the blood levels of tacrolimus, cyclosporine or the active metabolite of MMF (MPA) will be monitored at 
baseline/Day 1 (prior to starting ENTO or PTM), on day 2 (optional) or day 3 (optional) and day 6 or day 7 after initiating ENTO or PTM, and at the end of Week 2 and Week 
50 study visit. Beyond these time points, concentration monitoring for tacrolimus, cyclosporine and MPA should follow the treating institutions protocol and therapeutic range 
for monitoring these medicines 
p
Assessments may include but are not limited to: cytokines, cell subset analysis, pathway markers, and/or other B-cell activating factor, B-cell function, immunoglobulin 
levels, and/or antigen-specific B cell response.  Timepoints may differ depending on the specific biomarker and will be outlined in the Central Lab Manual.  
q
At visit 2, 30,  42, OLE visits 50 and 64 study drug will not be dispensed at these visits 
r
Will include the following: systemic corticosteroid dose, other immunosuppressive, antimicrobials, PPI 
s
PFTs will include spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO). PFTs will be done at ESDD, if ESDD visit greater than 12 weeks from 
Baseline. Any PFT done within 30 days prior to randomization can be used in lieu of Screening PFT.
t
The initial taper of systemic corticosteroid from the starting dose of ≥ 0.5 mg/kg/day  may be attempted 14 days after co-administration with ENTO/Placebo if there is 
evidence of improvement in cGVHD
u
Local lab results may be used to establish diagnosis of liver cGVHD


Entospletinib 
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Final
Gilead Sciences, Inc. 
Amendment 3.0 Global 
CONFIDENTIAL
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6.2.1.
Screening Visit
Written informed consent must be obtained from each subject before initiation of any visit 
procedures. After a subject has provided informed consent, the investigator and other study 
personnel (listed on the Form FDA 1572) will determine if the subject is eligible for participation 
in the study.  Subjects will be screened within 30 days before the Baseline/Day 1 visit to 
determine eligibility for the participation in the study.  This assessment will include review of the 
Inclusion/Exclusion criteria and completion of all Screening visits procedures as outlined in 
Table 6-1.  
Screening visit procedures will include the following for all subjects that provide informed 
consent: vital signs (including height and weight), medical history, smoking status, complete 
physical examination, 12-lead ECG (performed supine), concomitant medications, serum 
pregnancy test (for women of child bearing potential), serum FSH (if applicable), primary 
malignancy assessment (if applicable), complete the NCDSC (local lab results may be used to 
establish diagnosis of liver cGVHD), blood draws for the following tests: hematology, 
chemistry, metabolic panel, HIV-1, HBV, and HCV serology unless specified otherwise.  Urine 
will be collected for urinalysis. 
Pulmonary function tests (PFTs) will be required at Screening: spirometry and diffusing capacity 
of the lungs for carbon monoxide (DLCO). Bronchodilators should be used when clinically 
indicated. Per institutional guidelines Investigators may seek specialist examination for PFTs,
ocular and gynecological involvement, and other items as described in the NCDSC.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30 days from the Screening visit for randomization into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (eCRF).  All 
other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF.  
See Section 7. for additional details.
6.3.
Baseline/Day 1 Visit 
The following evaluations are to be completed at the Baseline/Day 1 visit. The Investigator must 
confirm subject eligibility prior to randomization. Initiation of treatment with the study drug 
must take place within 24 hours after the Baseline/Day 1 visit. 
Baseline/Day 1 visit procedures will include the following: review of adverse events and 
concomitant medication use.  Sites will obtain: vital signs (including weight), complete physical 
exam, smoking status, primary malignancy assessment (if applicable), NCAA and LSS.  Blood 
will be collected for the following tests: hematology, chemistry, metabolic panel, Blood 
specimens for selected biomarkers will be collected at Baseline, and urine for urine pregnancy 
test (if applicable) and urine analysis. 


Entospletinib 
Protocol GS-US-406-1840 
Gilead Sciences, Inc. 
Final 
Amendment 3.0 Global 
NCAA Form A should be completed by the Investigator or Sub-Investigator; trained study 
personnel may complete the spirometry and walk test portion. The NCAA Form Band the LSS 
should be completed by the subject. Subject is to read questionnaire by himself/herself and 
write/mark answers directly on the questionnaire. 
Eligible subjects will be randomized in the IXRS to obtain the subject number. Study drug will 
be dispensed in a blinded fashion. Subjects should initiate dosing of study drug within 24 hours 
ofthe Baseline/Day 1 visit. 
ENTO or PTM should be taken under fasted conditions. Fasting is defined as no food or liquids 
other than water for 2 hours pre- and 1 hour post-dose. Subjects should be instructed not to bite 
or chew the tablets. In case of breakage of the tablets in the oral cavity, additional water should 
be taken as a rinse. Subject should be counseled on the importance of taking study medication 
daily and to return study medication bottles to each visit. 
6.4. 
Treatment Assessments (Weeks 2-48 and OLE) 
Evaluations listed in Table 6-1 are to be completed at the end of Weeks: 2, 4, 8, 12, 16, 20, 24, 
30, 36, 42 and 48 in blinded fashion. For subjects continuing in the OLE the evaluations listed in 
Table 6-1 are to be completed at the end of Weeks: 50, 52, 56, 60, 64,72 and every 12 weeks 
thereafter up to Week 144 or, until unacceptable toxicity, withdrawal of consent by subject or 
withdrawal from study by investigator, or until ENTO becomes commercially available. 
Study visits are to be completed within ±3 days, for Weeks 2-24, and Weeks 50-64. Study visits 
are to be completed within ±5 days for Weeks 30-48 and Weeks 72-144. NOTE for subjects 
receiving tacrolimus, cyclosporine or MMF: For subjects receiving these medicines at 
enrollment and are continuing on these medicines, the blood levels oftacrolimus, cyclosporine or 
the active metabolite of MMF (MP A) will be monitored centrally at baseline/Day 1 (prior to 
starting ENTO or PTM), on Day 2 (optional) or Day 3 (optional) and Day 6 or Day 7 after 
initiating ENTO or placebo-to-match (PTM), and at the end of Week 2 and Week 50 study visit. 
Beyond these time points, concentration monitoring for tacrolimus, cyclosporine and MP A 
should follow the treating institution's protocol and therapeutic range for monitoring these 
medicines. For subjects who initiate these medicines while already receiving ENTO, 
concentration monitoring for tacrolimus, cyclosporine and MP A should follow the treating 
institution's protocol and therapeutic range for monitoring these medicines. When a 
concentration sample is taken at a local lab in accordance with the treating institution's protocol 
for monitoring these medications, a sample may also be requested for central lab analysis. 
At all visits the following will occur: review of adverse events (AEs) and changes in concomitant 
medications, vital signs (including weight), primary malignancy assessment (if applicable), 
blood for hematology, chemistry, metabolic anel, and urine for: regnancy test if applicable), 
and urinalysis. PPD 
~------------------------------------------------~ 
PFTs will be required at on treatment Weeks 24 and 48 only: spirometry and diffusing capacity 
ofthe lungs for carbon monoxide (DLCO). Bronchodilators should be used when clinically 
indicated. 
CONFIDENTIAL 
Page 48 
30 January 2017 


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Gilead Sciences, Inc. 
Amendment 3.0 Global 
CONFIDENTIAL
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ECG will be performed at on treatment Weeks 24 and 48 only.  
Blood specimens for selected biomarkers will be collected at Screening, Baseline and at Weeks: 
2, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, 50, 52, 56, 60, 64, 72, every 12 weeks thereafter , 30 Day 
Follow-up and ESDD (if applicable). The timepoints may differ depending on the specific 
biomarker and will be outlined in the Central Lab manual. 
PK blood draws will be collected at Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48 and Week 60 
and every 12 weeks in the OLE. 
Smoking status will be collected at Weeks 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, 52, 56, 60, 64, 72 
and every 12 weeks thereafter.
Women determined to be of child bearing potential will have a urine test as listed in Table 6-1
and every 4 weeks during the OLE starting with Week 64. 
Complete physical exam will be performed at Weeks 12, 24 and 48, symptom directed physical 
exam will be completed as needed at all other visits.
NCAA Form A with spirometry should be completed by the Investigator or Sub-Investigator at 
all study visits (except Week 2) and during the OLE at Weeks 56, 60, 64, 72 and every 12 weeks 
thereafter. The NCAA Form A should also be performed at the time of initiation of second-line 
therapy. Situations where subjects have comorbid or irreversible conditions that may interfere 
with response assessment, the check box on the NCAA indicating that the abnormality is entirely 
explained by a non-GVHD documented cause should be marked. Organ-specific response 
measures may be delayed until the following visit to allow for resolution of a non-GVHD 
issue. All other organs should still be scored. A 2 min or 6 min walk test should be performed at 
Baseline/Day 1, Weeks 24 and 48/ESDD, when medically feasible. Trained study personnel may 
complete spirometry and walk test portion of NCAA Form A.
LSS and NCAA Form B should be completed by the subject.  The Subject is to read the 
questionnaire by himself/herself and write/mark answers directly on the questionnaire. The PROs 
will be completed at all study visits (except Week 2) and during the OLE will be assessed at 
Weeks 56, 60, 64, 72 and every 12 weeks thereafter. One question has been added to the LSS 
which asks which two domains are most impactful to the subject.
Document study drug dispensation and accountability for all study drugs dispensed. No study
drug will be dispensed at Weeks 2, 30, 42 and 50, drug accountability must be done at dispensing 
visits. 
6.5.
Post-treatment Assessments
6.5.1.
Unscheduled Visit 
A subject should attend an unscheduled visit if requested by the Sponsor or the investigator. The
assessments performed are at the investigator’s discretion.  


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Gilead Sciences, Inc. 
Amendment 3.0 Global 
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For subjects that initiate second line therapy during the study, every attempt should be made to 
collect the NCAA and LSS at an unscheduled visit and to keep the subject in the study and study 
related follow-up procedures should be continued. 
6.5.2.
Early Study Drug Discontinuation (ESDD) 
If the subject discontinues study drug prior to the end of study, the subject will be asked to return 
to the clinic within 72 hours of stopping study drug for the Early Study Drug Discontinuation 
Visit.  The subject will be asked to continue attending the schedule study visits through Week 48. 
Subjects with ESDD will not be eligible for the OLE phase of the study. 
At the ESDD visit, any evaluations showing abnormal results indicating that there is a possible 
or probable causal relationship with the study drug, should be repeated weekly (or as often as 
deemed prudent by the investigator) until the abnormality is resolved, returns to baseline, or is 
otherwise explained. 
Evaluation listed in Table 6-1 will be completed at the ESDD visit.  
The following will be conducted at the ESDD: review of adverse events (AEs) and changes in 
concomitant medications, vital signs (including weight), complete physical exam, primary 
malignancy assessment (if applicable), blood for hematology, chemistry, metabolic panel, 
selected biomarkers and urine for: pregnancy test (if applicable), and urinalysis. The NCAA and 
LSS will be assessed.
PFTs will be required at ESDD: spirometry and diffusing capacity of the lungs for carbon 
monoxide (DLCO). Bronchodilators should be used when clinically indicated.
6.6.
30 Day Follow-Up Visit 
Subjects who complete through Week 48 visit and who do not wish to participate in the OLE
phase of the study will return to the clinic 30 days after the completion of study drug for the 
30-Day follow-up visit. Subjects who complete the OLE will return to the clinic 30 days after the 
completion of study drug for the 30-Day follow-up visit
Subjects who permanently discontinue study drug and refuse to continue in the study will be 
asked to return to the clinic 30 days after the completion of the ESDD visit for the 30-Day
follow-up visit. 
For the purpose of scheduling a 30-Day follow-up visit, a ± 5 days window may be used. 
Table 6-1 lists all procedures to be completed at the 30-Day Follow-up visit. 
6.7.
End of Study
The definition of the end of the trial is the last visit of the last participant on the trial.


Entospletinib 
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Gilead Sciences, Inc. 
Amendment 3.0 Global 
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6.8.
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiration rate, weight and temperature. 
Height will be measured at the Screening visit only. 
6.9.
Biomarker Sample Collection 
Blood for selected biomarkers may include, but not limited to, cytokines, B-cell activating factor, 
B-cell function, SYK pathway markers, immunoglobulin levels, and/or antigen-specific B cell 
responses. Please refer to Table 6-1 for collection timepoints. Samples may be stored for up to 
15 years. 
6.9.1.
Clinical Laboratory Tests/Assessments 
Blood and urine samples will be collected as outlined in Table 6-1.  All labs will be done 
centrally, local lab results may be used to establish diagnosis of liver cGVHD. 

Hematology profile: completed blood count (CBC) with differential and platelet count 

Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, uric acid

Metabolic assessments: lipid panel (total cholesterol, HDL, direct LDL, and triglycerides).  

Immunoglobulin levels: Immunoglobulin A-E  

Serum and biomarker storage sample for possible additional clinical testing (if subject 
agrees) 

Urine pregnancy test (females of child bearing potential only); positive urine pregnancy tests 
will be confirmed with a serum test. 

Urinalysis 
6.10.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

Unacceptable toxicity, 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


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Final
Gilead Sciences, Inc. 
Amendment 3.0 Global 
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
Relapse of primary disease  

Severity of cGVHD requiring therapy that is not allowed as concomitant therapy on study

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 8

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)
If the subject discontinues study drug prior to the end of study, the subject will be asked to return 
to the clinic within 72 hours of stopping study drug for the Early Study Drug Discontinuation 
Visit.  The subject will be asked to continue attending the schedule study visits through Week 48. 
Subjects with ESDD will not be eligible for the OLE phase of the study.  
If the investigator considers discontinuing study medication for any reason other than those listed 
above, such as sustained complete remission of cGVHD for more than 3 months, then tapering to 
discontinue ENTO can be considered and should follow the schedule listed below:
Starting Dose
Action
400 mg twice daily
200 mg, twice daily, for 2 weeks
200 mg once daily for 2 weeks
200 mg, once daily, every other day for 2 weeks
Stop Study Medication
200 mg twice daily
200 mg once daily for 2 weeks
200 mg, once daily, every other day for 2 weeks
Stop Study Medication


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Protocol GS–US-406-1840
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Gilead Sciences, Inc. 
Amendment 3.0 Global 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Pre-existing 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 (see Section 7.6.2.2)

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

Relapse of primary disease 

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.)


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Amendment 3.0 Global 
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
In-patient hospitalization or prolongation of existing hospitalization

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 (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.4.1.
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 (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the modified CTCAE, version 4.03.  For each episode, 
the highest grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening) or 
Grade 5 (fatal) to describe the maximum intensity of the adverse event.  For purposes of 
consistency with the CTCAE, these intensity grades are defined in Table 7-1 and Appendix 7.
Table 7-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2
Moderate
Local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL 
Grade 3
Severe
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL  
Grade 4
Life-threatening
Urgent intervention indicated 
Grade 5
Death 
Death related AE 
*
Activities of Daily Living (ADL) Instrumental ADL refer to opening preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden 
The only modification to the CTCAE criteria has been the addition of a Grade 1 upper 
respiratory infection as follows:


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Table 7-2.
Grading of Adverse Event Severity: Upper Respiratory 
CTCAE 
v4.0 Term
Grade 1*
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.03 
AE Term 
Definition
Upper 
respiratory 
infection
Mild 
symptoms; 
symptomatic 
relief (cough 
suppressant, 
decongestant, 
etc.)
Moderate 
symptoms; oral 
intervention 
indicated 
(e.g., antibiotic, 
antifungal, 
antiviral)
IV antibiotic, 
antifungal, or 
antiviral 
intervention 
indicated; 
radiologic, 
endoscopic, or 
operative 
intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder 
characterized by 
an infectious 
process involving 
the upper 
respiratory tract 
(nose, paranasal 
sinuses, pharynx, 
larynx, or 
trachea).
The distinction between the seriousness and the severity of an adverse event 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 one 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 case report form (eCRF): all SAEs as well as adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
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Any SAEs and deaths that occur within 30-days of the last dose of study IMP, regardless of 
causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

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 DSPH 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 as described above. Gilead DSPH contact information is as 
follows: Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477

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.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 

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 


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worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.4.1.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events Toxicity Management 

All clinical events and clinically significant laboratory toxicities will be managed according 
to uniform guidelines detailed in Appendix 7.

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for Modified CTCAE 4.03 for Severity of Adverse Events and Laboratory 
Abnormalities. 

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose or modified dose that is 
dependent upon discussion with the Gilead Sciences Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.

Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
7.4.2.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue investigational medicinal product at the discretion of the investigator.
7.4.3.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.


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
For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to Grade 2.If 
a laboratory abnormality recurs to Grade 3 following rechallenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.
7.4.4.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. The subject should be followed as clinically indicated 
until the laboratory abnormality returns to baseline or is otherwise explained, whichever 
occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade.
Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (e.g., Grade 4 CK after strenuous exercise or 
triglyceride elevation that is nonfasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product.
7.5.
Toxicity Management 
Concentration Monitoring of Calcineurin Inhibitors and Mycophenolate Mofetil
ENTO has been shown in vitro to inhibit the drug transporters organic anion transporting 
polypeptides 1B1 and 1B3 (OATP1B1 / OATP1B3), P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP), as well as the drug metabolizing enzyme glucuronosyltransferase 
UGT1A1. Due to the involvement of these pathways in the disposition of the calcineurin 
inhibitors tacrolimus and cyclosporine, and the active (mycophenolic acid [MPA]) and inactive 
metabolites of mycophenolate mofetil, Entospletinib may potentially affect the exposure of these 
medicines.
For subjects receiving these medicines, the blood levels of tacrolimus, cyclosporine or the active 
metabolite of MMF (MPA) will be monitored at baseline/Day 1 (prior to starting ENTO), on day 
2 (optional) or day 3 (optional) and day 6 or day 7 after initiating ENTO or PTM, and at the end 
of Week 2 and Week 50 study visit. Beyond these time points, concentration monitoring for 
tacrolimus, cyclosporine and MPA should follow the treating institution’s protocol and 
therapeutic range for monitoring these medicines. When a concentration sample is taken at local 
lab, in accordance with the treating institution’s protocol for monitoring these medications, a 
sample may also be requested for central lab analysis. 


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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 DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.


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The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH 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 DSPH, 
fax number +1 650 522-5477 or email Safety_FC@gilead.com. 
Refer to Appendix 8 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 Gilead DSPH 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 Section 7.3 and 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.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primaty objective is: 
To evaluate the effect ofENTO on BORRas assessed by the NCAA by 24 weeks in the setting 
of add-on to systemic corticosteroids as part first-line therapy for cGVHD 
The key secondaty objectives are: 
• 
To evaluate the effect ofENTO on the skin domain of the LSS at 24 weeks 
• 
To evaluate the effect of ENTO on the mouth domain of the LSS at 24 weeks 
• 
To evaluate the effect of ENTO on the eyes domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the total score of the LSS at 24 weeks 
Additional secondmy objectives include: 
• 
To evaluate the effect ofENTO on DOR 
• 
To evaluate the effect of ENTO on dose reduction of cmiicosteroids 
• 
To evaluate the effect of ENTO on initiation of second-line therapy for cGVHD 
• 
To evaluate the effect of ENTO on progression of cGVHD 
• 
To evaluate the safety and tolerability ofENTO 
• 
Exploratmy objectives include: 
I 
I 
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8.1.2.
Primary Endpoint
The primary endpoint is BORR by 24 weeks, defined as the proportion of subjects who achieve a 
complete or partial overall response (CR or PR) as assessed by the NCAA within 24 weeks, in 
the setting of add-on therapy to systemic corticosteroids as part of first-line therapy for cGVHD. 
At each assessment time point, organ-specific responses will be determined according to 
Appendix 4.  An overall time point response across all involved organs will then be determined 
according to Table 8-1.  The best overall response across all time points up to 24 weeks will be 
used to calculate BORR by 24 weeks. 
Table 8-1.
Criteria for time point response determination
Response Category
Response Criteria
Complete response (CR)
Resolution of all cGVHD manifestations in each organ or site as described in the 
NCAA organ response determination table
Partial response (PR)
Improvement of at least 1 organ or site, without progression in any other organ or 
site as described in the NCAA organ response determination table.
Stable disease (SD)
Neither sufficient improvement to qualify for a PR nor sufficient decline to qualify 
for a PD
Progressive disease (PD)

Worsening of signs and symptoms in any organ or site as described in the 
NCAA organ response determination table, taking the current best overall 
response as reference that is not a flare. A flare is defined as acute 
worsening of signs and symptoms in any organ or site that occurs at least 4 
weeks after PR/CR is achieved, which lasts ≤ 4 weeks.  
OR

Increase in systemic corticosteroid dose to ≥ baseline dose
OR

Initiation of systemic immunosuppressive therapy other than systemic 
corticosteroids
8.1.3.
Secondary Endpoint
The key secondary endpoints are:

Change from baseline in the skin domain of the LSS at 24 weeks

Change from baseline in the mouth domain of the LSS at 24 weeks

Change from baseline in the eyes domain of the LSS at 24 weeks

Change from baseline in the total score of the LSS at 24 Weeks 


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Other secondaty endpoints include: 
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Amendment 3.0 Global 
• 
DOR, defmed as the time from the documentation of BORR to the documentation ofPD as 
defmed in Table 8-1. Note that a flare does not constitute an end to response. 
• 
Proportion of subjects who achieve at least 50% reduction in systemic corticosteroid dose 
relative to baseline, where % reduction is calculated as (systemic cotiicosteroid dose at 
24 weeks - baseline systemic cmiicosteroid dose) I baseline systemic corticosteroid dose 
• 
Proportion of subjects who initiate second-line therapy for cGVHD, defmed as receiving any 
therapy besides systemic cmticosteroids or study drug for the treatment of cGVHD. Inhaled 
and topical steroids are not considered second-line therapy. 
• 
Failure-free smvival (FFS), defined as the time from randomization to the earliest of first 
documentation of systemic therapy change, nonrelapse motiality, or recmTent malignancy 
• 
Safety and tolerability of ENTO 
8.1.4. 
Other Endpoints of Interest 
Exploratmy endpoints include: 
p 
D 
I 
I 
I 
I 
8.2. 
Analysis Conventions 
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be perfonned using SAS® software (SAS Institute, Caty, North Carolina, USA). 
In general, data will be described and summarized by relevant treatment rum, analysis set, and 
time point. As appropriate, changes from baseline to each subsequent time point will be 
described and summa1·ized by treatment ann. Graphical techniques ( eg, Kaplan-Meier cmves, 
waterfall plots, etc.) may be used when such methods m·e appropriate and infmmative. 
Summmy tables for continuous variables will contain the following statistics: N (number in 
analysis set), n (number with data), mean, standard deviation (SD), 95% confidence intetvals 
(Cis) on the mean, median, minimmn, first qum1ile (Ql), third qum1ile (Q3), and maximum. 
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Summary tables for categorical variables will include: N, n, percentage, and 95% CIs on the 
percentage. 
Subjects with discrepancies between the stratification factor values at randomization and the 
actual values as documented on data review will be categorized in the analyses according to the 
actual values.
Unless otherwise specified, all statistical tests will be 2-sided.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analyses will be the Intent-to-Treat (ITT), which includes 
data from all randomized subjects, with treatment assignments designated according to 
randomization. 
Selected efficacy endpoints may also be evaluated using the Per-Protocol (PP) analysis set, 
which includes all randomized subjects who received at least one dose of study drug, did not 
violate any major entry criteria, and did not have any major protocol deviations.
8.2.1.2.
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set, which includes data 
from all subjects who received at least one dose of study drug, with treatment assignments 
designated according to actual treatment received. All data collected up to the last dose of study 
drug plus 30 days will be included in the safety summaries. 
8.2.1.3.
Pharmacokinetics (PK)
The PK Analysis Set will include data from subjects in the Safety Analysis Set who have the 
necessary baseline and on-study measurements to provide interpretable results for the specific 
parameters of interest. 
8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial results. In general, values for 
missing data will not be imputed unless methods for handling missing data are specified.
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. 

If a subject received study drug, the subject will be included in the summary of AEs 
according to the treatment received; otherwise, if the subject is not dosed then they will be 
excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.


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Values for missing safety laboratory data will not be imputed; however, a missing 
Baseline/Day 1 result will be replaced with a screening result, if available. If no pre-treatment 
safety laboratory value is available, the Baseline/Day 1 value will be assumed to be normal 
(ie, no grade [Grade 0]) in the summary of graded laboratory abnormalities. Values for missing 
vital signs data will not be imputed; however, a missing Baseline/Day 1 result will be replaced 
with a screening result, if available.
Laboratory data that are continuous in nature but are less than the lower limit of quantitation 
(LOQ) or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used for calculation of descriptive statistics if 
the data is reported in the form of “<x” (x is considered the LOQ). For example, if the values 
are reported as <50 and <5.0, then values of 49 and 4.9 will be used for calculation of
summary statistics, respectively. 

A value that is 1 unit above the LOQ will be used for calculation of descriptive statistics if 
the data is reported in the form of “>x” (x is considered the LOQ). For example, if the values 
are reported as >50 and >5.0, then values of 51 and 5.1 will be used for calculation of 
summary statistics, respectively.

The LOQ will be used for calculation of descriptive statistics if the data is reported in the 
form of “≤ x” or “≥ x” (x is considered as the LOQ).
PK concentration values that are below the limit of quantitation (BLQ) will be presented as 
“BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 at pre-dose time 
points, and one-half the value of the lower limit of quantitation (LLOQ) at post-baseline time 
points, where LLOQ is corrected for the dilution factor (ie, reported LLOQ/dilution factor) for 
determination of summary and order statistics.
The following conventions will be used for the presentation of summary and order statistics: 

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ”

If more than 25% of the subjects have a concentration value of BLQ for a given time point, 
the minimum and Q1 values will be displayed as “BLQ” 

If more than 50% of the subjects have a concentration value of BLQ for a given time point, 
the minimum, Q1, and median values will be displayed as “BLQ” 

If more than 75% of the subjects have a concentration value of BLQ for a given time point, 
the minimum, Q1, median, and Q3 values will be displayed as “BLQ” 

If all subjects have concentration values of BLQ for a given time point, all order statistics 
(minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ”
PK parameters that are BLQ will be imputed as one-half LLOQ before log transformation or 
statistical model fitting.


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8.4.
Demographic Data and Baseline Characteristics
Demographic data and baseline characteristics will be summarized by treatment group and 
overall using standard descriptive statistics for the ITT Analysis Set.
Demographic data will include: age, gender, race, and ethnicity.
Baseline characteristics will include: body weight, height, body mass index, and other covariates 
as necessary.
The number (proportion of subjects) in each stratum will also be summarized.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary endpoint is BORR by 24 weeks in the setting of add-on therapy to systemic 
corticosteroids as part of first-line therapy for cGVHD. The primary analysis will test the null 
hypothesis that there is no difference in response rate between ENTO + systemic corticosteroids 
and placebo + systemic corticosteroids versus the alternative hypothesis that there is a difference.  
Response rate will be summarized by count and percent of subjects with each ordinal response
(CR, PR, and CR + PR).  A stratified Cochran-Mantel-Haenszel (CMH) Chi-square test for 
association will be performed to compare BORR between ENTO and PTM by 24 weeks.  The 
difference in response rates between treatment groups and the corresponding 95% CIs will be 
presented.
8.5.2.
Secondary Analyses
A sequential testing strategy will be implemented to preserve the overall type I error rate across 
the primary and key secondary endpoints of the study at a 2-sided significance level of 0.05.  The 
primary endpoint analysis will serve as the gatekeeper for the key secondary endpoint analyses, 
ie, the primary efficacy endpoint must be met before the key secondary efficacy endpoints can be 
tested. The key secondary endpoints included in this sequential testing approach are (1) change 
from baseline in the skin domain of the LSS at 24 weeks, (2) change from baseline in the mouth
domain of the LSS at 24 weeks, (3) change from baseline in the eyes domain of LSS at 
24 weeks, and (4) change from baseline in the total score of the LSS at 24 weeks.
If the primary hypothesis is rejected, the key secondary endpoints will be sequentially tested at 
the 2-sided 0.05 significance level in the order listed above. If a null hypothesis is not rejected, 
formal sequential testing will stop and only nominal significance will be cited for the remaining 
endpoints. 
The key secondary endpoints will be analyzed using a MMRM model that includes all available 
data at baseline and all post-baseline visits. The model will include terms for baseline value, 
stratification factor, treatment, visit, and treatment-by-visit interaction. The Kenward-Roger
approximation will be used to estimate the denominator degrees of freedom and adjust standard 


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enors. Treatment comparisons will be generated within the lviMRM model based on the linear 
contrast of the least square means at all-time points. Adjusted means and 95% Cis will be 
presented by treatment group. Plots of mean (±SE) change from baseline over time will be 
provided by treatment group. Additional sensitivity analyses to fmther evaluate the impact of 
missing data may be perf01med and will be specified in the statistical analysis plan (SAP). 
Other secondary endpoints will be analyzed as follows: 
DOR and FFS will be analyzed using the Kaplan-Meier (KM) method and stratified logrank test. 
Kaplan-Meier summru.y statistics (median, 95% CI for median, and 25th, 75th percentiles) and 
number and percentage of events will be presented by treatment group. A stratified Cox 
prop01tional hazards model will be used to estimate the hazru.·d ratio and conesponding 95% CI. 
A KM survival plot will also be provided. Data for subjects who do not experience an event will 
be censored at the date of last visit. 
Prop01tion of subjects with at least 50% reduction in systemic c01ticosteroid dose relative to 
baseline and proportion of subjects who initiated second-line therapy for cGVHD will be 
analyzed similarly to the primru.y endpoint. 
8.5.3. 
Exploratory Analyses 
8.5.4. 
Interim Analysis 
An interim analysis for futility is plam1ed when approximately 50% of subjects have been on 
study for 24 weeks. The futility analysis will be perf01med on BORR by 24 weeks in the ITT 
Analysis Set. A non-binding futility mle will be implemented. Based upon the analysis results, 
the DMC may recormnend terminating the study for lack of efficacy if the predictive power of 
obtaining a statistically significant result at the final analysis given the observed interim data is 
:; 5%. A 2-sided alpha of0.001 will be allocated to this futility interim; following the 
Haybittle-Peto approach {Haybittle 1971, Peto et al 1976}, the final analysis alpha level is 
0.05 (2-sided). 
8.5.5. 
Final Analysis 
The fmal analysis for BORR is planned when all subjects have been on study for 24 weeks. 
Duration and quality of response will continue to be assessed up to 48 weeks. 
8.6. 
Safety Analysis 
All safety data collected on or after the date that ENTO/PTM was first administered up to the 
date of last dose of ENTO/PTM plus 30 days will be summarized by treatment group 
(according to the treatment received). Data for the pre-treatment period will be included in 
data listings. 
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8.6.1.
Extent of Exposure
A subject’s extent of exposure to ENTO will be generated from the study drug administration 
eCRF page. Exposure data will be summarized by treatment group. 
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event is defined as any adverse event with onset date on or after the date of first dose of 
study drug up to 30 days after permanent study drug discontinuation, or any adverse events 
leading to premature study drug discontinuation.  Summaries (number and percentage of 
subjects) of treatment-emergent adverse events (by SOC and PT) will be provided by treatment 
group. 
8.6.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using modified CTCAE 4.03.  Maximum 
post-baseline grade will be summarized by count and percentage of subjects with each grade.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post-baseline, will be summarized by treatment 
group. If baseline data are missing, then any graded abnormality (ie, at least a Grade 1) will be 
considered treatment-emergent.
Laboratory abnormalities that occur before the first dose of study drug or after the subject has 
been discontinued from treatment for at least 30 days will be included in data listings.
8.6.4.
Other Safety Evaluations
Individual data for 12-lead ECG, vital signs measurements will be listed by subject and 
summarized by treatment group by incidence of events/abnormalities or descriptive statistical 
summaries (n, mean, SD, median, Q1, Q3, minimum, and maximum), as appropriate. In 
comparison to pre-treatment (either Screening or pre-dose on Day 1) values, vital signs 
measurements and ECG findings will additionally be summarized using predetermined, 
clinically relevant thresholds.
8.7.
Pharmacokinetic Analysis
Concentrations will be listed by subject and summarized using descriptive statistics (eg, n, 
arithmetic mean, geometric mean, % coefficient of variation [CV], SD, median, Q1, Q3, 
minimum, and maximum).


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Descriptive statistics of baseline and change in biomarkers will be provided at each sampling 
time for all subjects and by treatment. 
pp 
PD 
8.9. 
Sample Size 
With 40 subjects per treatment group, there is 75% power to detect a 30% improvement in 
response rate at a 2-sided 0.05 significance level using Fisher's exact test, assuming a placebo 
response rate of 50%. A total of 100 subjects (50 per treatment group) will be emolled assuming 
a 20% dropout rate. 
8.10. 
Data Monitoring Committee 
An extemal multidisciplinruy data monitoring committee (DMC) will review the progress of the 
study, perf01m interim reviews of safety data at regular intervals approximately evety 3 months, 
and perf01m an interim review of efficacy data for futility when approximately 50% of subjects 
have been on study for 24 weeks, as described in the DMC Chruier. The DMC will provide 
recommendations to Gilead as to the whether the nature, frequency, and severity of adverse 
effects associated with study treatment wanant the eru·ly tetmination of the study in the best 
interests of the pruticipants, whether the study should continue as planned, or the study should 
continue with modifications. 
The DMC's specific activities will be defmed by a mutually agreed chruter, which will define the 
DMC's membership, conduct and meeting schedule. 
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study te1mination, Gilead retains fmal decision-making authority on all aspects of 
the study. 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable 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.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an . The investigator will not begin any study subject activities until 
approval from the IRB/EC has been documented and provided as a letter to the investigator.
Before implementation, the Investigator will submit to and receive documented approval from 
the IRB/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/EC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/EC approved consent form for documenting 


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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by the IRB/EC. 
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,., 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 instruction.  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, 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

Participation in study (including study number);


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
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. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 
as described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 


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the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (e.g. data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5. 
9.1.7.
IMP Destruction
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/EC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/EC in 
accordance with local requirements and receive documented IRB/EC 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 agencies. Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.


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


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10.
REFERENCES
Allen JL, Fore MS, Wooten J, Roehrs PA, Bhuiya NS, Hoffert T, et al. B cells from patients with 
chronic GVHD are activated and primed for survival via BAFF-mediated 
pathways. Blood 2012;120 (12):2529-36.
Allen JL, Tata PV, Fore MS, Wooten J, Rudra S, Deal AM, et al. Increased BCR responsiveness 
in B cells from patients with chronic GVHD. Blood 2014;123 (13):2108-15.
Angiolillo DJ, Gibson CM, Cheng S, Ollier C, Nicolas O, Bergougnan L, et al. Differential 
effects of omeprazole and pantoprazole on the pharmacodynamics and 
pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-
controlled, crossover comparison studies. Clin Pharmacol Ther 2011;89 (1):65-
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Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. 
Nature reviews 2012;12 (6):443-58.
Cutler C, Kim HT, Bindra B, Sarantopoulos S, Ho VT, Chen YB, et al. Rituximab prophylaxis 
prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood 
stem cell transplantation: results of a phase 2 trial. Blood 2013;122 (8):1510-7.
Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D, et al. Rituximab for steroid-
refractory chronic graft-versus-host disease. Blood 2006;108 (2):756-62.
Dubovsky JA, Flynn R, Du J, Harrington BK, Zhong Y, Kaffenberger B, et al. Ibrutinib 
treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest 
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Emson CL, Fitzmaurice S, Lindwall G, Li KW, Hellerstein MK, Maibach HI, et al. A pilot study 
demonstrating a non-invasive method for the measurement of protein turnover in 
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Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood 2015;125 
(4):606-15.
Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al. Inhibition of 
Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin 
lymphoma and chronic lymphocytic leukemia. Blood 2010;115 (13):2578-85.
Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol 
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Herskowitz A, Willoughby SB, Baughman KL, Schulman SP, Bartlett JD. Cardiomyopathy 
associated with antiretroviral therapy in patients with HIV infection: a report of 
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survival after initial systemic treatment of chronic graft-versus-host disease. 
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Jacobsohn DA, Vogelsang GB. Acute graft versus host disease. Orphanet J Rare Dis 2007;2:35.
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes 
of Health Consensus Development Project on Criteria for Clinical Trials in 
Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working 
Group Report. Biol Blood Marrow Transplant 2015;21 (3):389-401 e1.
Ladell K, Hellerstein MK, Cesar D, Busch R, Boban D, McCune JM. Central memory CD8+ T 
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HIV disease progression. J Immunol 2008;180 (12):7907-18.
Lee S, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure 
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Lee S, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M,  Pidala J, Olivieri A, Martin P, 
Przepiorka D, Pusic I, Dignan F, Mitchell S, Lawitschka A, Jacobsohn D, Hall A, 
Flowers M, Schultz K, Vogelsang G, Pavletic S.  Measuring Therapeutic 
Response in Chronic Graft-versus-Host Disease. National Institutes of Health 
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Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesar D, et al. In vivo 
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Miklos DB, Arora M, Cutler CS, Nakamura R, Juretic M, Li Y, et al. A multicenter open-label 
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Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of 
randomized clinical trials requiring prolonged observation of each patient. I. 
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Metab Dispos 2005;33 (11):1729-39.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
For Screening: NIH cGVHD Diagnosis and Staging Criteria, Global Severity Score 
{Jagasia et al 2015}
Appendix 3.
For Screening: NIH cGVHD Diagnosis and Staging Criteria (NCDSC) Form 
{Jagasia et al 2015}
Appendix 4.
For Baseline + Subsequent Visits:  Response Determination for the NIH cGVHD 
Activity Assessment (NCAA) {Herskowitz et al 1992}
Appendix 5.
For Baseline + Subsequent Visits: Chronic GVHD Activity Assessment- Clinician
Appendix 6.
For Baseline + Subsequent Visits: Lee Symptom Scale {Lee et al 2002}
Appendix 7.
Grading of Adverse Event Severity
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 9.
Schedule of Assessments for the Optional Cellular Turnover Sub-study*


Entospletinib 
Protocol G8-US-406-l840 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
.\mendment 3.0 Global 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and 
Tolerability ofEntospletinib, a Selective SYK Inhibitor, in Combination with Systemic 
Corticosteroids as First-Line Therapy in Subjects with Chronic Graft Versus Host Disease 
(cGVHD) 
GS-US-406-1840 Protocol Amendment 3.0 (Global): 30 January 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approvaL 
PPD 
f), If~ 
c§lvtJe~Q!J ~if 
Nime (Printed) Mario Marcondes, MD, PPD-
PhD 
Date 
INVESTIGATOR STATEMENT 
[ have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I wiU discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 81 
30 January 2017 


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Amendment 3.0 Global 
CONFIDENTIAL
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Appendix 2.
For Screening: NIH cGVHD Diagnosis and Staging Criteria, Global 
Severity Score {Jagasia et al 2015}
Mild chronic GVHD
1 or 2 Organs involved with no more than score 1
plus
Lung score 0
Moderate chronic GVHD
3 or More organs involved with no more than score 1
OR
At least 1 organ (not lung) with a score of 2
OR
Lung score 1
Severe chronic GVHD
At least 1 organ with a score of 3
OR
Lung score of 2 or 3
Key points:
In skin: higher of the 2 scores to be used for calculating global severity.
In lung: FEV1 is used instead of clinical score for calculating global severity.
If the entire abnormality in an organ is noted to be unequivocally explained by a non-GVHD documented 
cause, that organ is not included for calculation of the global severity.
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes) the scored 
organ will be used for calculation of the global severity regardless of the contributing causes (no 
downgrading of organ severity score).


Entospletinib 
Protocol GS-US-406-1840 
Gilead Sciences, Inc. 
Final 
Amendment 3.0 Global 
Appendix 3. 
For Screening: NIH cGVHD Diagnosis and Staging Criteria (NCDSC) 
Form {Jagasia et al 2015} 
SCORE O 
P •;RFOR, JA;-;CE 
SCORE: 
I 
KPS ECOG L PS 
0 Asymptomatic and 
fully active (ECOG 
0: KPS or LPS 
100%) 
SKJNt 
SCORE"/o BSA D 
G VHD features to be scored 
0 No BSA 
llJ!...ll.&1.: 
involved 
Check an that apoly : 
0 Maculopapular rasbferytbeJllll 
0 Lichen planus-like features 
0 clerotic fea111res 
0 Papulosquamous lesions or 
icbtl1yosis 
0 Keratosis pilaris-)jke GVRD 
SKIN I'EATL'RES 
sco!U:: 
0 No sclerotic 
features 
Odrer skju G VJJD feature,• {NQT g ored bv BSA) 
Check all thnt apply : 
0 llyperpigmenullion 
0 Hypopig:mcntation 
0 Poikilodenna 
0 Severe or generalized pruritus 
0 Hair involvem.:nl 
0 Nail involvement 
SCOREl 
0 Symptomatic, 
fully ambulatory, 
restricted only rn 
physically 
strenuous <Lctivlty 
(ECOG I, KPS 
or LPS 80..90%) 
0 1-18% BS.A 
SCO RE 2 
SCORE3 
0 Symptomatic, 
0 Symptomatic. 
ambulatory, capabl• 
limited self-care, 
of ~df-care. >50% 
>50% of V.".tking 
of v.'<lking hours ou 
hours in bed {ECOG 
of bt:d (ECOG 2, 
3-4, KPS or LPS 
KPS or LPS 60-
<60%) 
70%) 
0 19-50% BSA 
0 SuiWrficial 
sclerotic features 
"not hidebound" 
(able to pinch) 
0 >50% BSA 
Ch£Sk all that applv: 
0 Deep sclerotjc 
features 
o "Hidebound" 
(Lmablc to pinch) 
0 fmpaired mobility 
0 lJlccmtion 
0 Abnormality presellt but explained entirely by non-G VHD tlocumettled cause (specify): __ 
M OUTII 
Lichen planus-like 
features present: 
0 Yes 
ONo 
0 No symptoms 
0 Mild symptoms 
with disease signs 
but not limiting 
oral intake 
significantly 
0 Modcmtc 
symptoms with 
disease signs with 
partial limitation 
o [ oral intake 
0 AbnormaJiiy pre.senl but e.tpfai.ned eniireJy by non-GVJJD tlocumemed cause (specifl): 
0 Severe symptoms with 
disease signs on 
examination with major 
limitation of ora.l in!Jlke 
Figur~ I. Or~n sa. ring o [chronic GVHO. ECOC i nduares Eastl!rn COOpt'rJtM! OlliDlOf:)l Croup; KPS, K.tntol'sky ~ lf'onn.utcr Sl~tus; LPS, Lansky P'~r[omunCl! !i.uus; 
BSA, body Su1f<1<r are~: ADL. activit~ or da1ly hVIIlJ; LFf~ liVI'r fuMDOn ~IS; AP, alkaline phosphaw~: ALT. ~Luti ne .. ninOtrdli.Sf~r-; ULN, 1-.HITIAI UPP"r im1L 
"Wel:ht lOSSWtthln 3 nt<lnoo. ISkin .ronngshould u~ b«h pt'cra!'lltagt'O[BSI\ 11110lvel by disuse .slgns<tnd th~CULdnt!OUs [t.;nures sc.U.,S. When .. doscrrp.mcy ..xnu 
b<!LWren the percen~<~,g• ol tnll.l body s w·race (BSA) =~ 
.utd the skin fe<ttu ~ score. OR if s uperfiCIAl scrrodc fe<ttw-e< a rr p,._nt (Sc~ 2} !Jut rl~,... is imparrld 
motility or ul~ranon (Sc:ore 3), the higher level ~ho uld be ~ 
ror th~ Rn.al skill scori ng. t-ro be <omplerld by speoal"'t or rramO!d m«< ic.al pr0111d~rs (s"" 
Supprrrr rul Rgtn). -·Lung smr11g should be perforrrr d usmglloth the .sympr01ru • nd FEVl sro"'s when...,r poss1ble. ltV! .should~..,;"" m dte ftn<tl lung 
sa.nng wltt!l't' LhPrr is dtstrepariC)' berv....en symjl(oms .md f"EVJ sm-
CONFIDENTIAL 
Page 83 
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Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Amendment 3.0 Global 
CONFIDENTIAL
Page 84
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SCOREO 
EY~S 
0 No symptoms 
Ke.ratoconjrmctivitis 
sicca (KCS) confinned 
by ophthalmologist: 
0 Yes 
0 No 
0 Not examined 
SCORE I 
0 Mild dry eye 
symptorus not 
affecting ADL 
(requirement of 
lubricant eye 
drops .::, 3 x per 
day) 
SCORE2 
0 Moderate dry eye 
symptoms partially 
affecting ADL 
(requiring lublicant 
eye drops > 3 x per 
day or puncta) 
plugs), 
WITHOUT new 
vision impairment 
dueto KCS 
0 Abnormality present bwt explained entirely by non-GVHD documented cause (soecifl'): 
Gl Tract 
Check all that apply: 
0 Esophageal web/ 
proximal stricture 
or ring 
0 Dysphagia 
OAnorexia 
0 Nausea 
0 Vomiting 
0 Diarrhea 
0 Weight lo.s 2:_S%* 
0 Failure to thrive 
0 No s}mptoms 
0 Symptoms 
without 
significant weight 
loss• (<5%) 
0 Symptoms 
associated with 
mild to moderate 
weigbl loss• 
(5- 15%) OR 
modcntc diarrhea 
without 
s ignifi ~ant 
interference with 
daily living 
0 Abnormality presentlwt explained entirely by non-G VHD documented cause [.\pec{/YL-
0 NonnaJ tota I 
bilirobin and 
ALTorAP 
< 3xULN 
0 Not·roaJ total 
bilirubin with ALT 
:::;3 to5 x ULN or 
AP2:_3x ULN 
0 Elevated total 
bilirubin but 
.::,3 mgfdL or 
ALT>5 ULN 
0 Ab,tormulity present but explained entire!)' by non-GVHD documented cause (soecify): 
LUNGS .. 
~nnntom score; 
Lung score: 
%FBVJD 
Pulmonary j imction tests 
0 Not perfonned 
0 No symptoms 
0 f'EV1<:80% 
0 Mild symptoms 
(shortness of 
bn:ath at\er 
climbing one Oight 
of steps) 
O FEVI 60..79% 
0 Mode.mte 
symptoms 
(shortrtCSS ofbn:alh 
after ·walking on 
flat grow1d) 
0 FEVJ 40-59% 
SCORE 3 
0 Severe dry eye 
symptoms significantly 
affecting ADL (special 
eyeware to relieve pain) 
OR unable to work 
because of ocular 
symptoms OR Joss of 
vision due to KCS 
0 Symptoms associated 
with significant weight 
loss• > 15%. requires 
nutritional suppJem~nt fOr 
most calorie needs OR 
esophageal dilation OR 
severe dian·hca with 
significant interference-
with daily living 
0 Elevated total 
bilintbin > 3 rog/dL 
0 Severe syroptoms 
(shortness of breath at 
rcs1; requirin.g Oz) 
0 FEV199% 
0 Abnormality present bwt explained entirely by nou-OVf{f) d<)CUmellled cause (specify) .:~-------------, 
f'.gure 1. {oondrrued). 


Entospletinib 
Protocol GS-US-406-1840 
Gilead Sciences, Inc. 
JOIXrS Al\"D FASCIA 
P-ROM score 
(su below) 
Shoulder (1-7):_ 
F.lbow( l-7): _ 
WrisTlnnger (1-7):_ 
Ankle (1 -4) :_ 
SCOREO 
0 No 
symptoms 
SCORE 1 
0 :'vlild rightnes~ of 
arms or legs, 
nonnaJ or mild 
decreased ran,ge of 
motion (ROM) 
AND not affecting 
ADL 
SCORE2 
0 Tightness of arms or 
legs OR joint 
contrucrun:s. 
<:rythcma thought 
due to fasciitis, 
moderate decrease 
ROM AND mild to 
moderate limitation 
ofADL 
Final 
Amendment 3.0 Global 
SCORE 3 
0 Conn·acturcs WITH 
significant decrease of 
ROM AND significant 
limitation of ADL 
(unable to tie shoes, 
button s hirt~, dres.~ self 
etc.) 
0 Abnonnality presenr bu1 l"xplained entirl"ly by non-GVHD documl"nted c.fiJJSl" (specify): __________ __ . 
GENI1'AL TRACJ' 
0 No signs 
0 Mild signs1 and 
0 Moderate signsl and 
(Srr Sunplrmen(al figure' ) 
t'emales with or 
may have 
0 Not examined 
wilbout discomfort 
symptoms with 
Currently sexually aclivt> 
on exam 
discomfo1t on exam 
D Yes 
0 No 
0 Abnonnaliry present bur &p!ained entirely bv non-GVHD documl'nted cause (specify): 
0 Severe signs1 Yooilh 
or wilbouL 
symptoms 
Other indi<:ators, slinicnl fsatnr£f gr sonrglka!fons related to chronic CVllp Cshsck all thai apply and ay,jgn. a 
.score IO seyeriry m, :ll hued on functional Impact wh ~re anplicallle nons- 0 mild ·I mod reate - 2 
~C\'IltC- 3) 
0 Ascites. (serositis)_ 
0 Pericar>dial Effusion_ 
0 Pleural Effu,ion(s)_ 
CONFIDENTIAL 
0 Myastbenia Gravis_ 
0 Peripheral Neuropalby_ 
0 Polymyositis_ 
0 Wei lloss>S%• w iliJOI.Il Gl s 
[J NoGVUD 
[J MUd 
Wrtfit,'f'inttr 
Figure J_ (a>n OnUt'd). 
Page 85 
0 Eosinophilia > 500/JII_ 
0 Platelets <100,000/J!I_ 
0 
[J 1\todtratc 
[J Severe 
30 Januaty 2017 


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Amendment 3.0 Global 
CONFIDENTIAL
Page 86
30 January 2017
Supplemenr f igure - Genital Tract Chronic Graft-,·er:.5us-Hosr Assessment and Scoring f orm 
:"'Jame· 
. . 
Date of binb· 
Assessment date· 
" 
. 
SCORE O 
SCORE I 
SCORE 2 
SGORE3 
GE!'<TI.U TR'I.CT 
D No signs 
D Mild signs and 
D Moderate signs 
D Severt signs with 
Check: 
females may have 
and may have 
or without 
symptoms" WITH 
symptoms* with 
symptoms* 
D Male DFema!e 
di3comfort ou exam 
discomfort on cxnm 
Cul'renrh· sexuallY actin: 
D Yes 0
No 
Clu~ck oll ~igus tl1af Dfl2.ll': 
D Erosion'S. 
D Lichen planus-like features 
D Fissures 
D Lichen sclerosis-like features 
D Ulcers 
D Vaginal scarring (female) 
D Phimosi; (male) 
D Clitoral/labial agglutination (female) 
D Urethralme.ants scarring/ stenosis (male) 
D Labial re.:;orption (bm.'lle) 
D Abnormalily present but NOT thought to represent GI'HD (specify cause): 
D Abnormalily thought to represetlt GVHD PLUS other causes(specify cause): 
• Gem tal symptoms are ~tot specific to cGVHD and can represent premaiurt gonadal fOllure or genital tract mfecflon. 
If a gyne('ologist is un~,·aiJable, external examination may be performed to de-te.mline ~'discomfort on exam" as follows: 
a) Spread the labia lllJljora to inspe.ct the. vulva for the above signs. Touch the vestibular gland openings (Skene's and 
Bartholin's), labia minora and majora gently with a qtip. Vulvar pain elicited by the gentle touch of a qrip is 
classified as discoofort on examination. Palpate. the vaginal walls with a single. digit to detect bauds, shortening, 
narrowing or other signs of vaginal scarring. 
b) If the woman is sexually active, detenniue whether qtip palpation or gentle palpation of scarred ridges elicits pain 
similar to that which the woman experiences during intercourse . 
Female g-enitalia: Severity of signs: 
I) Mild (any of the following); erythe.ma on vulvar mucosal surfaces, vulva: lichen-planus or""'"' lichen-sclerosis. 
2) Moderate-(any of the following)~ erosive intlammatOI)' changes of the. \<1llvar mucosa, fissures in vulvar folds 
3) Severe (any of the following); labial fttsion, clitoral hood agglutinatio11, fibrinous vaginal adhesions, circumferential 
fibrous vaginal bandmg, vaginal shorte-ning, synechi~ dense sclerotic dwtges. and complete vaginal stenosis. 
~{ale gtnitalia: Diagn()stic features include lichen planus-like or lichen sclerosis-like feat\lres and phymosis or urethral 
scarring or stenosis. Se\'e-rity of sigru: 
I) .Mild: lichen planus-like featme.; 
2) Moderate: lichen sclerosus-like feature or moderate erythema; 
3) Severe: phimosis or urethraVmeataJ scarring. 
Bi-op-~' obtained: D Ye.~ D !\o 
Site biop.;ied: _____ G\"BD C'onfirmed by hi<i-tology: D Yes 
D No 
Change from prniou<> e'l':tlu:ttion: D No prior or <'Urnnl CYHD D lmprond D St~ble 
D \Yom D 'S/A (b . ...W.t) 
Completed b;- (pl'int n.1me): 
Date fol'm ('Ompleftd: 


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Amendment 3.0 Global
CONFIDENTIAL
Page 87
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Appendix 4.
For Baseline + Subsequent Visits: 
Response Determination for the NIH cGVHD Activity Assessment (NCAA) {Lee et al 2015}
Organ 
Complete Response 
Parlial Response 
Progression 
Skin 
NIH Skin Score 0 after 
Decrease in NIH Skin Score 
Increase in NIH Skin Score by 1 or 
previous involvement 
by 1 OJ' more points 
more points, except 0 to 1 
Eyes 
NIH Eye Score 0 after 
Decrease in NIH Eye Score 
Increase in NIH Eye Score by 1 or 
previous iovolvemem 
by 1 or more points 
more points, except 0 to 1 
Mouth 
NIH Modified OMRS 0 after 
Decrease in NIH Modified OMRS 
Increase in NIH Modified OMRS 
previous involvement 
of 2 or more points 
of 2 or more points 
Esophagus 
NIH Esophagus Score 0 after 
Decrease in NIH Esophagus 
Increase in NIH Esophagus Score 
previous involvement 
Score by 1 or more points 
by 1 or more points. except 0 to I 
Upper Gl 
NIH Upper Gl Score 0 after 
Decrease in NIH Upper Gl 
Increase in NIH Upper Gl Score 
previous involvement 
Score by 1 or more points 
by 1 or more points, except 0 to 1 
!.ower Gl 
NIH tower Gl Score 0 after 
Decrease in NIH tower Gl 
Increase in NIH tower Gl Score by 1 
previous involvement 
Score by 1 or more point~ 
or more points, except from 0 to 1 
Uver 
Normal AL T, alkaline 
Decrease by 50% 
Increase by 2 x ULN 
phosphatase, and Total 
bilirubin after previous 
elevation of 1 or more 
Lungs 
- Normal J FEVl after 
Increase by 1 0% predicted 
- DeCI'ease by 10% pr·edicted 
previous involvement 
absolute value of JFEV1 
absolute value of JFEV1 
- If PFTs nor available, NIH 
• If PFTs nor available, decrease 
• If PFTs not available, increase in 
Lung Symptom Score 0 
in NIH Lung Symptom Score 
NIH Lung Symptom Score by 1 
after previous involvement 
by 1 or more points 
or more points, except 0 to 1 
Joints and fascia 
Both NIH Joint and Fascia 
Decrease in NIH Joint and Fascia 
Increase in NIH joint and Fascia 
Score 0 and P-ROM score 
Score by 1 or more points or 
Score by 1 or more points or 
25 after previous involvement 
increase in P-ROM score by 1 
decrease in P-ROM score by 1 
by at least 1 measure 
point for any site 
point for any site 
Global 
Clinician overall severity score 0 
Clinician overall severily score 
Clinidan overall severily score 
decreases by 2 or more points 
increases by 2 or more points 
on a 0·10 scale 
on a 0-10 scale 
ULN indicates upper limit of normal. 


Entospletinib 
Protocol GS-US-406-1840 
Gilead Sciences, Inc. 
Final 
Amendment 3.0 Global 
Appendix 5. 
I FORMA I 
For Baseline+ Subsequent Visits: Chronic GVHD Activity Assessment- Clinician {Lee et al 2015} 
Cu rrent Patient Weight: ____ _ 
Today's Date: _____ MR#/Name: ---------
CHRONIC GVHD ACTIVITY ASSESSMENT- CLINICIAN 
Health Care Provider 
Since the last assessment would you say that this 
Global Ratings: 
Where would you rate the severity of this patient's chronic GvHD symptoms on 
patient's cGvHD is 
the following scale, where 0 is cGVHD symptoms that are not at all severe and 10 
+3= Very much better 
O=none 
is the most severe cGVHD symptoms possible: 
+ 2= Moderately better 
1= mild 
+ 1 = A little better 
2=moderate 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
0= About the same 
3=severe 
10 
-1 =A little worse 
cGvHD symptoms 
Most 
-2=Moderately worse 
severe cGvHD 
-3=Very much worse 
not at all severe 
svm~toms possible 
Erythema 
None 
0 
Mild erythema or 
1 
Moderate (<:25%) or 
2 
Severe erythema 
Mouth 
moderate erythema 
Severe erythema 
(2:25%) 
(<25%) 
(<25%) 
Lichenoid 
None 
0 
Lichen-like changes 
1 
Lichen-like changes 
2 
Lichen-like changes 
(<25%) 
(25-50%) 
(>50%) 
Ulcers 
None 
0 
Ulcers involving 
3 
Severe ulcerations 
(520%) 
(>20%) 
Total score for all mucosal changes 
Gastrointestinal-Esophageal 
0= no esophageal symptoms 
• 
Dysphagia 
OR 
1=0ccasional dysphagia or odynophagia with solid food or pills during the past week 
Odynophagia 
2=1ntermittent dysphagia or odynophagia with solid foods or pills, but not for liquids or soft foods, during the past week 
3=Dysphagia or odynophagia for almost a{{ oral intake, on almost everv dav of the oast week 
Gastrointestinal-Upper Gl 
0= no symptoms 
• 
Early satiety OR 
1=mild, occasional symptoms, with little reduction in oral intake during the past week 
• 
Anorexia 
OR 
2=moderate, intermittent symptoms, with some reduction in oral intake during the past week 
3 
3 
6 
• 
Nausea & Vomiting 
3=more severe or persistent symptoms throughout the day, with marked reduction in oral intake, on almost everv day of the past 
week 
Gastrointestinal-Lower Gl 
0= no loose or liquid stools during the past week 
• 
Diarrhea 
1= occasional loose or liquid stools, on some days during the past week 
2=intermittent loose or liquid stools throughout the day, on almost every day of the past week. without requiring intervention to 
prevent or correct volume depletion 
3=voluminous diarrhea on almost every dav of the oast week reauirina intervention to orevent or correct volume deoletion 
CONFIDENTIAL 
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Entospletinib 
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Gilead Sciences, Inc. 
Amendment 3.0 Global
CONFIDENTIAL
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Lungs (Liters and % 
predicted)

Bronchiolitis Obliterans
FEV1
FVC
Single Breath DLCO (adjusted for 
hemoglobin)
TLC
RV
Liver Values
Total serum bilirubin
                            
mg/dL
ULN
                           
                     mg/dL
ALT
                          
U/L
   ULN                   
                                 
U/L
A kaline Phosphatase
                                  
U/L
ULN
                       
                              U/L
Baseline Values
Total Distance Walked in 2 or 6 Mins: 
                                                 2 min        
6 min
Karnofsky or 
Lansky 
Platelet Count              
                                    
K/uL
Total WBC                      
                                      
K/uL
Eosinophils
                           
                            %        
 Abnormality present but explained entirely by non-GVHD documented cause (specify site/alternate 
cause):_______________________________
 Abnormality present but explained entirely by non-GVHD documented cause (specify site/alternate 
cause):_______________________________
 Abnormality present but explained entirely by non-GVHD documented cause (specify site/alternate 
cause):_______________________________


Entospletinib 
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Final
Gilead Sciences, Inc. 
Amendment 3.0 Global
CONFIDENTIAL
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CHRONIC GVHD ACTIVITY ASSESSMENT- CLINICIAN (FORM A)
SCORE 0
SCORE 1
SCORE 2
SCORE 3
SKIN
GVHD features to be scored     
by BSA:
Check all that apply:
 Maculopapular rash / erythema
 Lichen planus-like features 
 Sclerotic features
 Papulosquamous lesions or
    ichthyosis
 Keratosis pilaris-like
  No BSA   involved
  1-18% BSA 
  19-50% BSA  
  >50% BSA
 Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________
SKIN FEATURES 
SCORE:
 No sclerotic 
features
 Superficial 
   sclerotic features “not 
hidebound” (able to pinch)
Check all that apply:
 Deep sclerotic                         
features 
 “Hidebound”                          
(unable to pinch) 
 Impaired mobility 
 Ulceration
If skin features score = 3, BSA% of non-moveable sclerosis/fasciitis  ___________
How would you rate the severity of this patient’s skin and/or joint tightening on the following scale, where 0 is not at all severe and 10 is the most severe 
symptoms possible:
             0       1         2         3         4         5         6         7         8          9         10
Symptoms
                                                                                                  Most severe
not at all severe                                                                                             symptoms possible


Entospletinib 
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Final
Gilead Sciences, Inc. 
Amendment 3.0 Global
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EYES
  No symptoms 
     symptoms 
  Mild dry eye symptoms 
not affecting ADL 
(requirement of 
lubricant eye drops < 3 
x per day) 
  Moderate dry eye symptoms 
partially affecting ADL 
(requiring lubricant eye drops 
> 3 x per day or punctal 
plugs), WITHOUT new 
vision impairment due to KCS
  Severe dry eye symptoms 
significantly affecting 
ADL (special eyeware to 
relieve pain) OR unable to
work because of ocular 
symptoms OR loss of 
vision due to KCS
 Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________
LUNGS
 No symptoms
  Mild symptoms 
(shortness of breath 
after climbing one 
flight of steps)
  Moderate symptoms 
(shortness of breath after 
walking on flat ground)
  Severe symptoms 
(shortness of breath  at rest; 
requiring 02)
 Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________
JOINTS AND FASCIA
  No symptoms
  Mild tightness of arms or 
legs, normal or mild 
decreased range of motion 
(ROM) AND not affecting 
ADL
  Tightness of arms or legs OR 
joint contractures, erythema 
thought due to fasciitis, moderate 
decrease ROM AND mild to 
moderate limitation of ADL
  Contractures WITH 
significant decrease of ROM 
AND significant limitation of 
ADL (unable to tie shoes, 
button shirts, dress self etc.) 
 Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________


Entospletinib 
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Final
Gilead Sciences, Inc. 
Amendment 3.0 Global
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. Abnormality present but explained entirely by non-GVHD documented cause (specify):_______________________
Not done
Not done
Not done
Not done


Entospletinib 
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Final
Gilead Sciences, Inc. 
Amendment 3.0 Global
CONFIDENTIAL
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                        Today’s Date: ________________________
MR#/Name: ________________________
CHRONIC GVHD ACTIVITY ASSESSMENT-PATIENT SELF REPORT
Symptoms
Not                                                                                                                                           As Bad As You
Present                                                                                                                                     Can Imagine
   
 0           1        2         3          4         5         6         7         8          9         10
Please rate how severe the following symptoms 
have been in the last seven days.  Please fill in the 
circle below from 0 (symptom has not been 
present) to 10 (the symptom was as bad as you 
can imagine it could be) for each item.
Your skin itching at its WORST?
O
O
O
O
O
O
O
O
O
O
O
Your skin and/or joint tightening at their 
WORST?
O
O
O
O
O
O
O
O
O
O
O
Your mouth sensitivity at its WORST?
O
O
O
O
O
O
O
O
O
O
O
Your genital discomfort at its WORST?
(Women – vagina, vulva, or labia)
(Men – penis)
O
O
O
O
O
O
O
O
O
O
O
Eyes
What is your main complaint with regard to your eyes?
Please rate how severe this symptom is, from 0 (not at all 
severe) to 10 (most severe):
0    1     2     3     4     5     6     7     8      9    10
FORM B


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Patient Global Ratings:
1. Overall, do you think that your chronic graft versus host disease is mild, moderate or severe?
1= mild
2=moderate
3=severe
2. Please circle the number indicating how severe your chronic graft versus host disease symptoms are, where 0 is cGvHD symptoms that are not at all 
severe and 10 is the most severe chronic GvHD symptoms possible.
          0         1           2           3           4           5          6           7           8            9           10
cGvHD symptoms                                                                                                                                       Most severe cGvHD                                                                                                                                           
not at all severe                                                                                                                                           symptoms  possible
                                                                                                                                                                           
3. Compared to a month ago, overall would you say that your cGvHD symptoms are:
+3= Very much better
+2= Moderately better
+1=A little better
0= About the same
-1=A little worse
-2=Moderately worse
-3=Very much worse


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Appendix 6.
For Baseline + Subsequent Visits: Lee Symptom Scale {Lee et al 2002}
By circling one (1) number per line, please indicate how much you have been bothered by the 
following problems in the past 7 days: 
SKIN: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
1. 
Abnormal skin color. ................... 
0 
2 
3 
4 
2. 
Rashes .................. ···············-·· 
0 
2 
3 
4 
3. 
Thickened skin ........ ... ............ 
0 
2 
3 
4 
4. 
Sores on ski11.. ..........•... ·····- ····· 
0 
2 
3 
4 
5. 
Itchy skin ...... .............. .......... 
0 
2 
3 
4 
EYES AND MOUTH: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
6. 
Dry eyes ....•............................. 
0 
2 
3 
4 
7. 
Need to use eye drops frequently .. 
0 
2 
3 
4 
8. 
Difficulty seeing cleal'fy ........... , ... 
0 
2 
3 
4 
9. 
Need to avoid certain foods due to 
0 
2 
3 
4 
mouth pain .•........ 
. ............ 
10. Ulc.ers in mouth ......................... 
0 
2 
3 
4 
1"1. Receiving nutrition from an 
intravenous line or feeding tube .... 
0 
2 
3 
4 
BREATHING: 
rJot at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
12. 
Frequent coogh .......•... , ......•...... 
0 
2 
3 
4 
13. Colored sputum ......................... 
0 
2 
3 
4 
14. Shortness of breath with exereise .. 
0 
2 
3 
4 
15. Shortness of breath at rest. ........ 
0 
2 
3 
4 
16. Need to use oxygen ................. 
0 
2 
3 
4 


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EATING AND DIGESTION: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
17. Difficulty swallo"'ing solid foods .... 
0 
1 
2 
3 
4 
18. Difficulty swallowing liquids ......... 
0 
2 
3 
4 
19. Vomiting ............................ 
0 
1 
2 
3 
4 
20. Weight loss .........•... 
0 
2 
3 
4 
MUSCLES AND JOINTS: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
21. Joint and muscle aches ........... 
~. ~ 
0 
1 
2 
3 
4 
22. 
Lim~ed joint movement ............. 
0 
2 
3 
4 
23. Muscle cramps ................. 
0 
2 
3 
4 
24. Weak muscles ... ....... 
·· ~ ........ 
0 
2 
3 
4 
ENERGY: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
25. 
Loss of energy ....................•.... 
0 
1 
2 
3 
4 
26. 
Need to sleep more/take naps ..... 
0 
1 
2 
3 
4 
27. 
Fevers ........................ ........... 
0 
1 
2 
3 
4 
MENTAL AND EMOTIONAL: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
28. 
Depression ........• .................... 
0 
1 
2 
3 
4 
29. 
Anxiety .............. ..................... 
0 
2 
3 
4 
30. 
Difficulty sleeping .. ................... 
0 
1 
2 
3 
4 


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Summary of the Lee Symptom Scale
Which 2 of the following organs/systems have you found to affect you the most in the last seven 
days:
1) Skin
2) Eyes 
3) Mouth
4) Breathing
5) Eating and Digestion
6) Muscles and Joints
7) Energy
8) Mental and Emotional


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Appendix 7.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated 
Grade 2
Moderate
Local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL 
Grade 3
Severe
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADL  
Grade 4
Life-threatening
Urgent intervention indicated 
Grade 5
Death 
Death related AE 
*
Activities of Daily Living (ADL) Instrumental ADL refer to opening preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden


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Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
ENTO is contraindicated in pregnancy as animal studies in rats and rabbits have shown that 
study drug is teratogenic. Pregnancy must be excluded before the start of treatment with study 
drug and prevented thereafter by reliable contraceptive methods. Pregnancy tests will be 
performed regularly throughout this study per Table 6-1. Please refer to the latest version of the 
investigator’s brochure for additional information.
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 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
ENTO is contraindicated in pregnancy as there is a strong suspicion of human 
teratogenicity/fetotoxicity in early pregnancy based on non-clinical data. In addition, ENTO has 
insufficient data 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. 
Please refer to the latest version of the investigator’s brochure for additional information.
b) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must also not rely on hormone-containing contraceptives as a 
form of birth control during the study.  They must have a negative serum pregnancy test at


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screening and a negative pregnancy test on the Baseline/Day 1 Visit.  Pregnancy tests will be 
performed on the protocol-specified schedule thereafter.  Female subjects must agree to one of 
the following methods to avoid pregnancy from Screening until 30 days from the last dose of 
ENTO:

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.
a) Intrauterine device (IUD) with a failure rate of <1% per year
b) Tubal sterilization
c) Essure micro-insert system (provided confirmation of success 3 months after procedure)
d) 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 from the last dose of ENTO.
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 from the 
last dose of ENTO.  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 
from the last dose of ENTO.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose.  Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator.  Instructions for reporting pregnancy, partner pregnancy, and pregnancy 
outcome are outlined in Section 7.6.


PPD 
Entospletinib 
Protocol GS-US-406-1840 
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Prot_001.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Clinical Program 
Manager: 
Gilead Medical 
Monitor: 
Protocol Version/Date: 
(!') GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Efficacy and Tolerability ofEntospletinib, a Selective 
SYK Inhibitor, in Combination with Systemic Corticosteroids as 
First-Line Therapy in Subjects with Chronic Graft Versus Host 
Disease ( cGVHD) 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
116416 
2015-004572-30 
TBD 
Chronic Graft. Versus Host Disease ( cGVHD) 
GS-US-406-1840 
Name: 
Telephone: 
Fax: 
Name: 
Telephone: 
Fax: 
Mobile: 
Original 
PPD 
PPD 
PPD 
Mario Marcondes, MD, PhD 
-PD 
PPD 
PPD 
11 November 2015 
CONFIDENTIALITY STATEMENT 
The infonnation contained in this document, particularly lmpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaty to obtain infmm ed consent from those 
persons to whom the dmg may be administered. 


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Original
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................13
1.
INTRODUCTION ..............................................................................................................................................17
1.1.
Background ............................................................................................................................................17
1.1.1.
Background on Chronic Graft Versus Host Disease ............................................................17
1.2.
Entospletinib (ENTO)............................................................................................................................20
1.2.1.
Preclinical Pharmacology and Toxicology...........................................................................21
1.2.2.
Clinical Trials of Entospletinib (ENTO) ..............................................................................22
1.3.
Rationale for This Study ........................................................................................................................23
1.4.
Rationale for Dose Selection..................................................................................................................23
1.5.
Risk/Benefit Assessment for the Study..................................................................................................24
1.6.
Compliance ............................................................................................................................................24
2.
OBJECTIVES.....................................................................................................................................................25
3.
STUDY DESIGN................................................................................................................................................26
3.1.
Endpoints ...............................................................................................................................................26
3.2.
Study Design..........................................................................................................................................27
3.3.
Study Treatments ...................................................................................................................................27
3.4.
Discontinuation Criteria.........................................................................................................................29
3.5.
Biomarker Testing..................................................................................................................................29
3.5.1.
Biomarker Samples to Address the Study Objectives:.........................................................29
3.5.2.
Optional Future Research.....................................................................................................30
3.5.3.
Optional Cellular Turnover Substudy {37403}, {37404}, {37405} ....................................30
4.
SUBJECT POPULATION..................................................................................................................................31
4.1.
Number of Subjects and Subject Selection ............................................................................................31
4.2.
Inclusion Criteria....................................................................................................................................31
4.3.
Exclusion Criteria...................................................................................................................................32
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................34
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................34
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................34
5.2.
Description and Handling of Study Drug...............................................................................................35
5.2.1.
Formulation..........................................................................................................................35
5.2.2.
Packaging and Labeling .......................................................................................................35
5.2.3.
Storage and Handling...........................................................................................................35
5.3.
Dosage and Administration....................................................................................................................36
5.4.
Prior and Concomitant Medications.......................................................................................................36
5.5.
Accountability for Investigational Medicinal Product ...........................................................................39
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................39
6.
STUDY PROCEDURES ....................................................................................................................................40
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................40
6.2.
Study Assessments.................................................................................................................................40
6.2.1.
Screening Visit .....................................................................................................................44


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6.3.
Baseline/Day 1 Visit ..............................................................................................................................44
6.4.
Treatment Assessments (Weeks 2-48 and OLE)....................................................................................45
6.5.
Post-treatment Assessments ...................................................................................................................46
6.5.1.
Unscheduled Visit ................................................................................................................46
6.5.2.
Early Study Drug Discontinuation (ESDD) .........................................................................46
6.6.
30 Day Follow-Up Visit.........................................................................................................................47
6.7.
Vital Signs..............................................................................................................................................47
6.8.
Biomarker Sample Collection ................................................................................................................47
6.8.1.
Clinical Laboratory Tests/Assessments................................................................................47
6.9.
Criteria for Discontinuation of Study Treatment....................................................................................48
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................50
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................50
7.1.1.
Adverse Events.....................................................................................................................50
7.1.2.
Serious Adverse Events........................................................................................................50
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................51
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................51
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................51
7.2.2.
Assessment of Severity ........................................................................................................52
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................53
7.4.
Gilead Reporting Requirements.............................................................................................................55
7.4.1.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events Toxicity Management .....................................55
7.4.2.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................56
7.4.3.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................56
7.4.4.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................56
7.5.
Toxicity Management ............................................................................................................................56
7.6.
Special Situations Reports......................................................................................................................57
7.6.1.
Definitions of Special Situations..........................................................................................57
7.6.2.
Instructions for Reporting Special Situations.......................................................................57
8.
STATISTICAL CONSIDERATIONS................................................................................................................60
8.1.
Analysis Objectives and Endpoints........................................................................................................60
8.1.1.
Analysis Objectives..............................................................................................................60
8.1.2.
Primary Endpoint .................................................................................................................61
8.1.3.
Secondary Endpoint .............................................................................................................61
8.1.4.
Other Endpoints of Interest ..................................................................................................62
8.2.
Analysis Conventions.............................................................................................................................62
8.2.1.
Analysis Sets ........................................................................................................................63
8.3.
Data Handling Conventions ...................................................................................................................63
8.4.
Demographic Data and Baseline Characteristics ...................................................................................65
8.5.
Efficacy Analysis ...................................................................................................................................65
8.5.1.
Primary Analysis..................................................................................................................65
8.5.2.
Secondary Analyses .............................................................................................................65
8.5.3.
Exploratory Analyses ...........................................................................................................66
8.5.4.
Interim Analysis ...................................................................................................................66
8.5.5.
Final Analysis.......................................................................................................................66
8.6.
Safety Analysis.......................................................................................................................................67
8.6.1.
Extent of Exposure...............................................................................................................67
8.6.2.
Adverse Events.....................................................................................................................67
8.6.3.
Laboratory Evaluations ........................................................................................................67
8.6.4.
Other Safety Evaluations......................................................................................................67


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8.7.
Pharmacokinetic Analysis......................................................................................................................68
8.8.
Biomarker Analysis................................................................................................................................68
8.9.
Sample Size............................................................................................................................................68
8.10.
Data Monitoring Committee ..................................................................................................................68
9.
RESPONSIBILITIES..........................................................................................................................................70
9.1.
Investigator Responsibilities ..................................................................................................................70
9.1.1.
Good Clinical Practice..........................................................................................................70
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................70
9.1.3.
Informed Consent.................................................................................................................70
9.1.4.
Confidentiality......................................................................................................................71
9.1.5.
Study Files and Retention of Records ..................................................................................71
9.1.6.
Case Report Forms...............................................................................................................72
9.1.7.
Inspections............................................................................................................................73
9.1.8.
Protocol Compliance............................................................................................................73
9.2.
Sponsor Responsibilities ........................................................................................................................73
9.2.1.
Protocol Modifications.........................................................................................................73
9.2.2.
Study Report and Publications .............................................................................................74
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................74
9.3.1.
Payment Reporting...............................................................................................................74
9.3.2.
Access to Information for Monitoring..................................................................................74
9.3.3.
Access to Information for Auditing or Inspections ..............................................................75
9.3.4.
Study Discontinuation..........................................................................................................75
10.
REFERENCES ...................................................................................................................................................76
11.
APPENDICES ....................................................................................................................................................79
Appendix 1.
Investigator Signature Page....................................................................................................80
Appendix 2.
For Screening: NIH cGVHD Diagnosis and Staging Criteria, Global Severity Score 
{34157}..................................................................................................................................81
Appendix 3.
For Screening: NIH cGVHD Diagnosis and Staging Criteria (NCDSC) Form 
{34157}..................................................................................................................................82
Appendix 4.
For Baseline + Subsequent Visits:  Response Determination for the NIH cGVHD 
Activity Assessment (NCAA) {34478} .................................................................................86
Appendix 5.
For Baseline + Subsequent Visits: Chronic GVHD Activity Assessment- Clinician.............87
Appendix 6.
For Baseline + Subsequent Visits: Lee Symptom Scale {34211}..........................................92
Appendix 7.
Grading of Adverse Event Severity........................................................................................94
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................95
Appendix 9.
Schedule of Assessments for the Optional Cellular Turnover Substudy...............................98
LIST OF IN-TEXT TABLES
Table 5-1.
Tapering of Prednisone after reaching PR/CR .......................................................................37
Table 5-2.
Examples of Prohibited Agents ..............................................................................................38
Table 5-3.
List of Sensitive Substrates of UGT1A1, OATP1B1, OATP1B3, P-gp and BCRP...............38
Table 6-1.
Schedule of Assessments........................................................................................................41
Table 7-1.
Grading of Adverse Event Severity........................................................................................52
Table 7-2.
Grading of Adverse Event Severity: Upper Respiratory ........................................................53
Table 8-1.
Criteria for time point response determination.......................................................................61


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LIST OF IN-TEXT FIGURES
Figure 1-1.
cGVHD prophylaxis with rituximab.  (A) Cumulative incidence of cGVHD. 
(B) Non-relapse mortality & GVHD recurrence. (C) Overall survival ..................................18
Figure 1-2.
Entospletinib Induces Apoptosis in B Cells from cGVHD Patients.......................................20
Figure 3-1.
Study Schema.........................................................................................................................28


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Protocol GS–US-406-1840
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Gilead Sciences, Inc. 
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Efficacy and Tolerability of Entospletinib, a Selective 
SYK Inhibitor, in Combination with Systemic Corticosteroids as 
First-Line Therapy in Subjects with Chronic Graft Versus Host 
Disease (cGVHD)
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
116416
2015-004572-30
TBD 
Study Centers 
Planned:
Approximately 30 centers in the North America, Europe, Asia and 
Australia 
Objectives:
The primary objective is:
To evaluate the effect of ENTO on the best overall response rate 
(BORR) as assessed by the NIH cGVDH Activity Assessment 
(NCAA) {34478} by 24 weeks in the setting of add-on to systemic 
corticosteroids as part of first-line therapy for cGVHD
The key secondary objectives are:

To evaluate the effect of ENTO on the skin domain of the Lee 
Symptom Scale (LSS)  (Appendix 6) at 24 weeks

To evaluate the effect of ENTO on the mouth domain of the LSS
at 24 weeks

To evaluate the effect of ENTO on the eyes domain of the LSS at
24 weeks

To evaluate the effect of ENTO on the total score of the LSS at 
24 weeks
Additional secondary objectives include:

To evaluate the effect of ENTO on duration of response (DOR)

To evaluate the effect of ENTO on dose reduction of 
corticosteroids


Entospletinib 
Protocol GS-US-406-1840 
Final 
Gilead Sciences, Inc. 
Original 
Study Design: 
Nmnber of Subjects 
Planned: 
Target Population: 
CONFIDENTIAL 
• 
To evaluate the effect ofENTO on initiation of second-line 
therapy for cGVHD 
• 
To evaluate the effect ofENTO on progression of cGVHD 
• 
To evaluate the safety and tolerability ofENTO 
Exploratmy objectives include: 
D 
I 
I 
Randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the efficacy and safety ofENTO (Treatment Aim 1) vs. 
placebo (Treatment Aim 2) in combination with systemic 
cmticosteroids for subjects with cGVHD. 
An interim analysis for futility is planned when approximately 50% of 
subjects have been on study for 24 weeks. The primaty endpoint will 
be evaluated when all subjects complete 24 weeks of treatment. 
Dmation and quality of response will be evaluated up to 48 weeks of 
blinded treatment. 
After 48 weeks, all subjects will have the option to receive open-label 
extension (OLE) with ENTO and attend visits per the schedule of 
assessments (Table 6-1) for an additional 96 weeks. 
Subjects who complete the study tlrrough week 48 and do not wish to 
patticipate in the OLE will be required to retum to the clinic after 
completion of study drug for a 30-Day Follow-up Visit. 
Approximately 100 subjects. Randomization will be stratified by 
1) calcinemin inhibitor or mycophenolate mofetil (MMF) use 
(no vs. yes) and 2) moderate vs. severe cGVHD as detetmined by the 
NIH cGVHD Diagnosis and Staging Criteria (NCDSC) at the 
Screening visit. 
Adult males or non-pregnant, non-lactating, female subjects with 
c.GVHD 
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Duration of 
Treatment:
48 weeks in the double-blind, placebo-controlled period.  After 
48 weeks all subjects will have the option to receive OLE with ENTO
and attend visits per the schedule of assessments (Table 6-1) for an 
additional 96 weeks.
Diagnosis and Main 
Eligibility Criteria:
The following are a summary of the key criteria: 
Key Inclusion Criteria: 

Male or non-pregnant, non-lactating, female subjects 

18-75 years of age, inclusive at Screening

Newly diagnosed cGVHD defined by:
a) At least 100 days after receiving any allogeneic hematopoietic 
stem cell transplant 
AND 
b) Receiving new course of systemic corticosteroids 
(1.0 mg/kg/day or prednisone equivalent) as first-line therapy 
for cGVHD within 10 days of screening 
AND
c) Moderate to severe cGVHD as assessed by NCDSC with at 
least three organ systems involved OR one organ system with 
a score of 2 OR lung organ score = 1 (Appendix 2) 

Subjects who have undergone transplant for hematologic 
malignancy are required to be in complete remission. 

Have either a normal ECG or one with abnormalities that are 
considered clinically insignificant by the investigator in 
consultation with the Sponsor
Key Exclusion Criteria:

Uncontrolled infection within 4 weeks of Screening

History of the following therapies in the post-transplant period:
B cell depleting biologic agents 
CD19 CAR-T cells based therapies 
BTK/SYK/JAK/PI3K inhibitors
Phototherapy-unless administered for acute GVHD 


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
Treatment of cGVHD with anti-thymocyte globulins (ATG), or 
campath within 60 days of Screening visit unless used for  
treatment of acute GVHD

Severe organ dysfunction manifested during Screening period: 
Requiring supplemental oxygen at more than 2 L/min
Uncontrolled arrhythmia or heart failure
Study Procedures/
Frequency:
Eligible subjects will be randomized 1:1 to Treatment Arm 1 or 
Treatment Arm 2 to receive study drug for 48 weeks.  Following 
Screening and Baseline/Day 1 Visits, subjects will return for study 
visits at Weeks: 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48.  Subjects 
that participate in the OLE will return for visits at weeks: 50, 52, 56, 
60, 64, 72 and visits every 12 weeks thereafter. Subjects who do not 
wish to participate in the OLE will have a 30-day Follow-Up visit 
after their week 48 visit. 
NOTE for subjects receiving tacrolimus, cyclosporine or MMF:
For subjects receiving these medicines at enrolment and are
continuing on these medicines, the blood levels of tacrolimus, 
cyclosporine or the active metabolite of MMF (MPA) will be 
monitored at Baseline/Day 1 (prior to starting ENTO or placebo-to-
match (PTM))), on Day 2 or Day 3 and Day 6 or Day 7 after initiating 
ENTO or PTM, and at the end of week 2 study visit. Beyond these 
time points, concentration monitoring for tacrolimus, and 
cyclosporine should follow the treating institution’s protocol and 
therapeutic range for monitoring these medicines. For subjects who 
initiate these medicines while already receiving ENTO, concentration 
monitoring for tacrolimus, cyclosporine and MPA should follow the 
treating institution’s protocol and therapeutic range for monitoring 
these medicines. When a concentration sample is taken at a local lab
in accordance with the treating institution’s protocol for monitoring 
these medications, a sample may also be requested for central lab 
analysis.
At Screening the NIH cGVHD Diagnosis and Staging Criteria 
(NCDSC) (Appendix 3) will be administered. At Baseline/Day1 and 
Weeks 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, 56, 60, 64, 72, 96 and Early 
Study Drug Discontinuation (ESDD) the NCAA (Appendix 5), and 
the LSS (Appendix 6) will be administered. Serological screening for 
HIV antibody (Ab), hepatitis B antigen, hepatitis C Antibody will be 
collected at the Screening visit.  For subjects with hematologic
malignancy, assessments of residual disease will be followed per the 
institutional guidelines.  


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Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
CONFIDENTIAL 
Final 
Original 
Blood and urine will be collected at all study visits per the schedule of 
assessments (Table 6-1). 
Blood for selected biomarkers will be collected at Screening, predose 
and at Weeks: 2, 4, 8, 12, 20, 24, 42, 48, ESDD, and/or OLE Weeks 
60, 64 and 72. 
PPD 
Treatment Atm 1: ENTO 400 mg twice daily: 2 X 200 mg tablets 
twice daily, for subjects clmently on proton pump inhibitors (PPI)* 
Treatment Atm 2: Placebo-to-match (PTM) twice daily 
Both treatment anns will be administered orally without food (in a 
fasted state) for 48 weeks. 
*For subjects NOT cmTently taking a PPI, the dose will be adjusted to 
ENTO 200 mg twice daily: 1 X 200 mg tablet orally twice daily 
without food (in a fasted state) for 48 weeks. 
Systemic c01ticosteroids at a dose and route consistent with fn·st-line 
therapy for newly diagnosed cGVHD. 
Systemic corticosteroids will be administered per provided treatment 
schema. 
Safety evaluations include documentation of AEs, physical 
examination, vital signs, ECGs, and clinical laboratory evaluations. 
The primmy endpoint is BORR by 24 weeks, as assessed by the 
NCAA{34478}, in the setting of add-on therapy to systemic 
corticosteroids as part of first-line therapy for cGVHD. 
The key secondmy endpoints are: 
• 
Change from Baseline in the skin domain of the LSS at 24 weeks 
• 
Change from Baseline in the mouth domain of the LSS at 
24 weeks 
• 
Change from Baseline in the eyes domain of LSS at 24 weeks 
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Phmmacokinetics: 
Statistical Methods: 
CONFIDENTIAL 
Change from Baseline in the total score of the LSS at 24 weeks 
Other secondmy endpoints include: 
• 
DOR 
Final 
Original 
• 
Prop011ion of subjects who achieve at least 50% reduction in 
systemic c011icosteroid dose relative to baseline 
• 
Prop011ion of subjects who initiate second-line therapy for 
cGVHD 
• 
Failure-free-smvival (FFS) 
• 
Safety and tolerability ofENTO 
Explorat01y endpoints of this study include: 
D 
I 
I 
I 
PK blood sampling will occur at Weeks 2 through Week 48 and then 
eve1y 12 weeks thereafter. 
The prima1y endpoint ofBORR by 24 weeks is defmed as the 
prop011ion of subjects who achieve a complete or pmtial response 
(CR or PR) within 24 weeks, as assessed by the NCAA. A CR is 
achieved when all signs and symptoms of cGVHD have resolved. A 
PR is achieved when an objective response is observed in any organ 
system without progression in another organ system, and no 
additional systemic therapy is needed. 
The prima1y analysis for BORR will be perf01med in the 
intent-to-treat (ITT) Analysis Set, which includes all subjects who 
were randomized. Response rate will be summarized by count and 
percent of subjects with each ordinal response (CR, PR, and 
CR + PR). A stratified Cochran-Mantel-Haenszel (CMH) Chi-squm·e 
test will be performed to compare BORR between ENTO and PTM by 
24 weeks. The difference in response rates between treatment groups 
and the conesponding 95% Cis will be presented. 
Change from Baseline in the LSS scores will be analyzed using a 
mixed model repeated measures (MMRM) model. Duration of 
response (DOR) will be analyzed using the Kaplan-Meier method. 
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A sequential testing strategy will be implemented to preserve the 
overall type I error rate across the primary and key secondary 
endpoints of the study at a 2-sided significance level of 0.05.  If the 
primary hypothesis is rejected, the key secondary endpoints will be 
sequentially tested at the 2-sided 0.05 significance level in the
following order: (1) change from Baseline in the skin domain of the 
LSS, (2) change from Baseline in the mouth domain of the LSS, 
(3) change from Baseline in the eyes domain of the LSS, and 
(4) change from Baseline in the total score of the LSS.  If a null 
hypothesis is not rejected, formal sequential testing will stop and only 
nominal significance will be cited for the remaining endpoints.
With 40 subjects per treatment group, there is 75% power to detect a 
30% improvement in response rate at the 2-sided 0.05 significance
level using a Fisher’s exact test, assuming a placebo response rate of 
50%. A total of 100 subjects (50 per treatment group) will be enrolled 
assuming a 20% dropout rate.  
Safety data will be listed by subject and summarized by treatment and 
frequency of event/abnormality or descriptive statistical summaries, 
as appropriate. The endpoints to be evaluated will include AEs, 
physical examination, clinical laboratory test findings, ECG 
abnormalities and interval measurements, and vital signs 
measurements.
An external multidisciplinary data monitoring committee (DMC) will 
review the progress of the study, perform interim reviews of safety 
data at regular intervals approximately every 3 months, and perform 
an interim review of efficacy data for futility when approximately 
50% of subjects have been on study for 24 weeks, as described in the 
DMC Charter.  The DMC will provide recommendations to Gilead as 
to whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the 
study in the best interests of the participants, whether the study should 
continue as planned, or the study should continue with modifications.
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
aGVHD
Acute Graph Versus Host Disease 
ADL
Activities of daily living 
AKT
Protein kinase B
ALT
alanine aminotransferase
AML
acute myeloid leukemia 
APC
antigen presenting cell 
AST
aspartate aminotransferase
ATG
anti-thymocyte globulins
AUC
area under curve versus time
BAFF
B cell Activating Factor
BCMA
B cell maturation antigen
BCR
B cell receptor
BCRP
breast cancer resistance protein
BLNK
B cell linker protein
BLQ
below limit of quantitation
BTK
Bruton’s tyrosine kinase
BORR
best overall response rate
cGMP
Current Good Manufacturing Practice
CI
confidence interval
cGVHD
Chronic Graft Versus Host Disease
Clast
last observed quantifiable concentration
CL
systemic clearance following IV administration
CLL 
chronic lymphocytic leukemia
Cmax
maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
concentration at the end of the dosing interval
CONMED
concomitant medication
CPK
creatine phosphokinase
CR
complete response
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
DSPH
Drug Safety and Public Health
DMC
Data Monitoring Committee
DOR
duration of response
E2
Estradiol
ECG
Electrocardiogram
eCRF
electronic case report form(s)


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ENTO
Entospletinib 
ENTO BIS-MSA
Entospletinib bismesylate monohydrate
ENTO MSA
Entospletinib methanesulfonate
ENTO SSD
Entospletinib spray-dried dispersion tablet
ERK
Extracellular signal regulated kinase
ESR
erythrocyte sedimentation rate
ET
early termination
FDA
(United States) Food and Drug Administration
FFS
failure-free survival
FSH
follicle-stimulating hormone
cGVHD
Chronic Graph Versus Host Disease 
GCP
Good Clinical Practice (Guidelines)
GGT
Gamma-glutamyl transferase
GVHD
Graph Versus Host Disease 
GSI
Gilead Sciences, Inc.
Hb
Hemoglobin
HBV
Hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDPE
high-density polyethylene
hERG
human-ether-a-go-go related gene
HIV
Human immunodeficiency virus
HSCT
hematopoietic stem cell transplant
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IgG
immunoglobulin G
IgM
immunoglobulin M
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
IRB
institutional review board
ITT
intent-to-treat 
IUD
intrauterine device
IV
Intravenous
IxRS
interactive voice/web response system
JAK
janus kinase
LDL
low-density lipoprotein
LLN
lower limit of the normal range


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LLOQ
lower limit of quantitation
LOCF
last observation carried forward
LOEL
lowest observed effect level
LOQ
limit of quantitation
LSS
Lee Symptom Scale 
MAD
multiple ascending dose
MAP
mitogen-activated protein
MedDRA
Medical Dictionary for Regulatory Activities
MK2
MAP kinase activated protein kinase-2
MMF
mycophenolate mofetil
MMP9
Matrix metallopeptidase-9
MMRM
mixed model repeated measures
µm
Micro millimeter
NDA
New Drug Application
NCAA
NIH cGVHD Activity Assessment
NCDSA
NIH cGVHD Diagnosis and Staging Criteria
NIH
National Institute of Health
NOAEL
no observable adverse effect level
NRI
non-responder imputation
PE
physical examination
PFT 
pulmonary function tests 
PI3K
phosphatidylinositol-4,5-bisphosphate 3-kinase
PK
Pharmacokinetic
PP
per-protocol
PR
PPI
pulse rate
proton pump inhibitor 
PTM
placebo-to-match
Q1
first quartile
Q3
third quartile
QTcF
Quantum Tunnelling Composite Fridericia
RA
rheumatoid arthritis
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SEM
standard error of measure
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
SYK
Spleen tyrosine kinase


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TACI
Transmembrane activator and CAML interactor
TLC
total lung capacity
tmax
the time (observed time point) of Cmax
t½
an estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant 
(λz)
UGT1A1
uridine disphosphate glucuronosyltransferase 1A1
ULN
upper limit of the normal range
US
United States
Vz
apparent volume of distribution following IV administration
WBC
White blood cell
WHO
World Health Organization
λz 
terminal phase rate constant


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1.
INTRODUCTION
1.1.
Background
1.1.1.
Background on Chronic Graft Versus Host Disease
Chronic Graft Versus Host Disease (cGVHD) is a disease observed in recipients of allogeneic 
hematopoietic stem cells, where the new immune system is reconstituted without complete 
tolerance to the host and begins to attack multiple organ systems including eyes, skin, mucosa, 
lungs, gut, and liver. Classic acute GVHD (aGVHD) occurs in episodes with donor cell 
engraftment before 100 days post-transplant and is thought to be mediated by donor T cells. 
Acute GVHD is observed in 35-50% of patients receiving hematopoietic stem cell transplant 
(HCT) {34291}. Acute GVHD is a risk factor for developing cGVHD, but cGVHD can develop 
without history of aGVHD. Chronic GVHD occurs in 35-70% of patients receiving allogeneic 
transplants. In the U.S., the incidence of cGVHD is estimated at ~3000-5000 patients per year, 
with prevalence at approximately 10,000 {34214}. Initial therapy for cGVHD consists of high 
dose systemic corticosteroids, however 50 to 60% of patients fail to have a complete response to 
this line of therapy. 
No agents are currently approved for cGVHD. A combination of calcineurin inhibitors, mTOR 
inhibitors and mycophenolate mofetil (MMF) are frequently added as second-line therapy with 
an initial response rate of 20-70% {34212}. The majority of responses are not durable, and 
cGVHD is associated with a 5-year mortality of 30-50% {34292}. Current immunosuppressive 
treatments also increase the rate of life-threatening infections and cancer relapse due to 
presumably the loss of graft versus tumor effect. The absence of effective therapies is attributed 
to the limited understanding of disease pathophysiology and limited directed development by 
industry.  
1.1.1.1.
Role of SYK in cGVHD
Unlike aGVHD which is believed to be mediated by allo-reactive T cells; the current biological
and clinical evidence implicates that dysregulated B cell homeostasis is involved in 
establishment of the chronic phase of GVHD.  B cell depletion in the peri-HSCT period is 
correlated with a reduction in the incidence of cGVHD.  In addition, antibodies against minor 
histocompatibility antigens have been associated with the occurrence of cGVHD.  In murine 
models of cGVHD, donor B cell alloantibodies have been shown to be responsible for the 
pathogenesis of the disease.   A single open label study with the CD20 B cell depleting 
agent -rituximab- evaluated the potential of prophylactic therapy for development of cGVHD 
post-transplant period {34102}  . This study demonstrated clinically relevant differences in the 
cumulative incidence of cGVHD and overall survival (Figure 1-1).


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Figure 1-1.
cGVHD prophylaxis with rituximab. 
(A) Cumulative incidence of cGVHD.
(B) Non-relapse mortality & GVHD recurrence.
(C) Overall survival
In a subsequent study, subjects with steroid-refractory cGVHD received open-label rituximab 
{34101} and an overall response rate of 70% was observed. This is in comparison to an expected 
response rate of ~50% for those receiving standard of care alone {34102} {34153}. These efficacy 
data with rituximab in cGVHD represent clinical validation that therapy targeting B cells in this 
disease indication is effective. However, treatment of cGVHD with rituximab is suboptimal. The 
treatment effect is not durable as altered B cell populations recover {34104}, and non-selective 
depletion of B cells results in complications such as hypogammaglobulinemia {34102}. Targeting 
the pathogenic B cell subpopulation that drives cGVHD may therefore yield enhanced efficacy 
and safety.
Emerging data also indicates that alterations in B cell homeostasis play a pathogenic role in 
cGVHD {34098}. In healthy individuals, newly generated B cells emerge from the bone marrow 
as transitional B cells and must complete maturation and selection in the periphery {35386}. 
About 40% of these newly emerged B cells are auto reactive. Transitional B cells are dependent 
upon both BAFF (B cell Activating Factor) and BCR signaling for their differentiation/maturation
and survival.  Low BAFF levels facilitate deletion of autoreactive B cells.  Following HSCT, 


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donor B cell reconstitution occurs in the presence of a high foreign antigen load and high BAFF 
levels. This unique setting promotes the survival of activated, potentially allo- and auto-reactive 
B cells that would normally undergo negative selection.   These donor-derived B cells can react 
with recipient tissue, facilitate tissue damage, produce inflammatory cytokines and serve as 
antigen presenting cell (APCs).   Importantly, patients with cGVHD treated with anti-CD20 who 
have persistent B cell lymphopenia after treatment experience worsening symptoms, suggesting 
that both high BAFF levels and limited capacity to generate sufficient native and transitional 
B cells contribute to the abnormal B cell homeostasis that underlies the disease pathology.  High 
numbers of native and transitional B cells protect from cGVHD development, possibly by
binding and decreasing BAFF levels.  These results further support the hypothesis that normal 
B cell homeostasis is required for protection from cGVHD.  
As described, BAFF and B cell receptor (BCR) signaling play critical roles in the establishment 
of B cell homeostasis by regulating the auto-reactive B cell population.  Patients with cGVHD 
have significantly increased BAFF levels versus B cell numbers {34104}.  Circulating CD27+ 
B cell subsets are increased and have high expression levels of the BAFF receptors.  These cells 
are present in patients with autoimmune disease, but are absent in healthy individuals.  These
CD27+ cells are able to constitutively produce IgG and potentially mediate anti-recipient tissue 
responses.  In the cGVHD murine model, elevated BAFF was shown to maintain B cells in a 
state of heightened sensitivity to antigen stimulation following BCR stimulation. This 
observation led to the hypothesis that B cells of cGVHD patients become more sensitive to 
antigen stimulation via BCR stimulation, resulting in loss of peripheral tolerance and survival of 
autoreactive B cell clones.  In vitro studies in human B cells from cGVHD patients vs. those 
without cGVHD, revealed that cGVHD B cells have increased proliferative responses to BCR 
stimulation and reduced apoptosis {34099}.   
A mechanistic understanding of BAFF and BCR signaling in cGVHD is currently being 
investigated and highlights that therapeutic kinase inhibition may benefit cGVHD patients with 
altered B cell homeostasis.  The aberrant B cell survival in cGVHD patients is postulated to 
involve BAFF signaling via a SYK-AKT-ERK axis {34099}.  Following HSCT, peripheral 
B cells isolated from cGVHD patients signal through protein kinase B and ERK and have 
decreased expression of the proapoptotic molecule, BIM, resulting in heightened metabolism and 
resistance to apoptosis {34099}.  Importantly, B cells from cGVHD patients also have increased 
proliferative responses to BCR stimulation, with concomitant elevations in B cell linker protein 
(BLNK) and SYK phosphorylation compared to patients without cGVHD {34100}.  
Pharmacologically blocking SYK kinase activity with fostamatinib in vitro in cGVHD donor 
B cells, prevented BCR hyper-responsiveness of B cells to BCR stimulation with anti-IgM 
{34100}.  Inhibition of Burton’s tyrosine kinase (BTK) activity by ibrutinib blocked 
PLC- gamma 2 activation in cGVHD patient B cells; impacting survival of cGVHD B cells in a 
BTK dependent manner {36995}, {36996}. These data suggest that BAFF and BCR cooperate to 
prime cGVHD B cells for survival and antigen responsiveness by lowering the threshold for 
BCR activation in cGVHD.  Blockade of BCR signaling, therefore, could be of therapeutic 
benefit by reestablishing normal B cell homeostasis. Therefore, both SYK and BTK inhibition 
have potential to modulate aberrant B cell function in cGVHD. In contrast to SYK, there are no 
published data to indicate that BTK is activated in cGVHD patient samples. Preliminary


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unpublished data from the Sarantopoulos Lab at Duke University with ENTO in the same assay 
with active cGVHD patient samples demonstrates a dose-dependent effect of ENTO to induce 
apoptosis of B cells vs. in samples from patients without active cGVHD (Figure 1-2).
Figure 1-2.
Entospletinib Induces Apoptosis in B Cells from cGVHD Patients
In summary, failed induction of B cell tolerance after HSCT is postulated to underlie the 
pathophysiology of human cGVHD.  Factors contributing to impaired tolerance induction 
include post-HSCT lymphopenia, persistent allo-antigen stimulation, and high BAFF levels, all 
of which contribute to hyper-responsive BCR pathways. SYK inhibition of cGVHD B cells
subsets could antagonize the pro-survival signaling and result in pathogenic B cell deletion that 
could help reestablish B cell homeostasis.
1.2.
Entospletinib (ENTO)
For further information refer to Entospletinib Investigator’s Brochure (IB).


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1.2.1.
Preclinical Pharmacology and Toxicology
Entospletinib (ENTO) was evaluated in a standard battery of safety pharmacology studies to 
assess potential effects on central nervous, cardiovascular, and respiratory systems. ENTO had 
no effect on central nervous and respiratory system parameters evaluated in rats. In a 
cardiovascular safety pharmacology study in dogs, small increases in heart rate (up to a 
25% increase) were observed in male dogs given ENTO at 15, 50, or 150 mg/kg. While the 
higher heart rates were considered ENTO related, the relevance of these changes to humans is 
not known. Due to the observed increases in heart rate, a no observed effect level (NOEL) was 
not identified and the lowest observed effect level was 15-mg/kg. ENTO had no effect on ECGs 
or arterial blood pressure values at oral doses up to 150 mg/kg, the highest dose tested. 
Consistent with the lack of effect on ECG parameters, ENTO has no meaningful effect on the 
human-ether-a-go-go related gene (hERG), indicating that ENTO would not be expected to 
induce clinical QT prolongation. 
The toxicity of ENTO has been characterized in animal genotoxicity, embryo-fetal reproductive 
toxicity, and phototoxicity studies. Recently published data demonstrated that species-specific GI 
toxicity and lymphoid changes, similar to that which was observed following ENTO
administration to dogs, can occur in dogs but not rats, cynomolgus monkeys, or humans treated 
with p38 map kinase and mitogen-activated protein (MAP) kinase activated protein kinase-2 (MK2)
small molecule kinase inhibitors that inhibit pathways that overlap with SYK signaling pathways 
{17647}. Oral administration of ENTO to rats for up to 26 weeks or cynomolgus monkeys for up 
to 39 weeks showed no evidence of GI toxicity or lymphoid changes at exposures which 
overlapped with or exceeded those that resulted in acute toxicity in dogs. Furthermore, ENTO
(administered as Entospletinib methanesulfonate (ENTO MSA)) has been previously 
investigated in healthy human subjects at doses up to 1200 mg twice a day for 7 days and in 
subjects with rheumatoid arthritis (RA) at doses up to 900 mg twice a day for 26 days and no 
evidence of GI or lymphoid toxicity was observed in these clinical studies. Therefore, the 
relevance of these findings to humans is not known.
ENTO inhibits uridine disphosphate glucuronosyltransferase 1A1 (UGT1A1) with an IC50 of 
2 μM. This enzyme is involved in glucuronidation of bilirubin, and inhibitors of UGT1A1 have 
the potential to produce increased levels of total and indirect (unconjugated) bilirubin in the 
circulation {8443}. 
ENTO is considered non-genotoxic and administration of ENTO did not result in skin reactions 
indicative of phototoxicity in mice.
Administration of ENTO to pregnant female rats and rabbits from implantation to the closure of 
the hard palate (International Conference on Harmonisation [ICH] Harmonised Tripartite 
Guideline stages C to D) resulted in dose-dependent developmental findings including increased 
incidence of early and late fetal resorptions and reduced fetal weights, and delays in ossification 
of the forelimb phalanges (rats and rabbits) and metacarpals (rabbits only). These fetal findings 
occurred at ENTO doses that caused maternal toxicity as demonstrated in both studies by 
dose-dependent decreases in body weight gain and/or body weight loss and decreased food 
consumption of the dams. Maternal toxicity was also demonstrated in these studies at doses that 
did not result in developmental findings.


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1.2.1.1.
Non Clinical Pharmacology
For further information refer to ENTO Investigator’s Brochure (IB).
1.2.1.2.
Toxicology
In vitro and in vivo nonclinical studies were conducted to examine the potential toxicity of 
ENTO. In vivo studies were conducted in rats and dogs. Oral administration is proposed for the 
initial clinical trials; therefore, multiple-dose studies with ENTO were conducted via the oral 
route (gavage). 
Based on the totality of the data from the standard battery of in vitro and in vivo genotoxicity 
studies, ENTO is considered non-genotoxic. 
Further details can be found in the ENTO IB.
1.2.2.
Clinical Trials of Entospletinib (ENTO) 
To date, 11 clinical studies have been initiated with ENTO including a total of 566 subjects 
(including 328 healthy subjects, 7 subjects with RA, 76 subjects with CLL, 155 subjects with 
NHL; 26 subjects receiving placebo in Phase 1 and Phase 2 clinical studies. Of the 566 subjects 
receiving ENTO in these studies, ENTO has generally been well tolerated.
Positive results have been reported from a Phase 2 clinical trial with the putative SYK inhibitor 
fostamatinib showing objective anti-tumor responses in chronic lymphocytic leukemia (CLL)
and Non-Hodgkin’s lymphoma (NHL) subjects {22804}. These responses occurred despite off 
target toxicities that limited drug exposure. ENTO is a highly selective inhibitor of SYK and 
hence has the potential for an improved efficacy and tolerability profile in subjects with 
hematologic malignancies. 
ENTO is being evaluated in an ongoing Phase 2 clinical trial in subjects with relapsed or 
refractory CLL/NHL. A Phase 1b/2 clinical trial is being conducted for subjects with ENTO 
monotherapy and in combination with chemotherapy in subjects with acute myeloid leukemia 
(AML) and acute lymphocytic leukemia (ALL).
ENTO has been studied in single and multiple ascending dose studies in 304 healthy subjects, 
7 subjects with rheumatoid arthritis who were on stable doses of methotrexate, 80 subjects with 
CLL and 95 subjects with NHL.  Of these subjects, 460 received ENTO and 26 received placebo.  
In Pharmacokinetic (PK) studies at steady state in healthy subjects, ENTO was well tolerated 
when given in a fasted state for 7 days at doses of 25, 75, 200, 600, 900, and 1200 mg twice daily
(GS-US-245-0101) and when given in a fed state for 6 days at doses of 100 and 900 mg 
twice daily (GS-US-245-0106), for 4 days at doses of 200 and 600 mg twice daily 
(GS-US-339-0101), and at 1200 mg twice daily for 5 days (GS-US-339-0109).Exposure, as 
measured by AUC and maximum concentration Cmax, did not increase appreciably at doses 
above 600 mg under fasted condition.


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To provide a margin for inter-patient variability, a dose of 900 mg twice daily was chosen for the 
study of subjects with rheumatoid arthritis receiving stable doses of methotrexate in Study 
GS-US-245-0101.  A dose of 900 mg ENTO twice daily was given in a fasted state for 26 days 
in 7 subjects.  The median AUCtau in these subjects was similar to that of the healthy subjects.  In 
general, this dose was well tolerated.   One subject developed reversible, Grade 2 alkaline 
phosphatase and transaminase elevations starting 7 days after her last dose of ENTO, concurrent 
with new onset of a bronchopneumonia.  One other subject reported not feeling well and 
experienced hot flashes, fever, shivers, rash, headache, dizziness, and fainting 1 day after her last 
dose of ENTO with reversible Grade 1 alkaline phosphatase and Grade 3 transaminase elevations 
which peaked 1 week later.  While these events are potentially confounded by concurrent 
illnesses, hepatic enzymes will be closely monitored during this study.
Consistent with the known inhibition of UGT1A1 by ENTO, 8 of the 178 healthy subjects 
developed asymptomatic indirect bilirubin elevations (6 Grade 1, 1 Grade 2 and 1 Grade 3) that 
resolved following discontinuation of the drug.  Three of the 7 subjects with rheumatoid arthritis
who received ENTO for 26 days developed asymptomatic indirect bilirubin elevations 
(2 Grade 1, 1 Grade 3) which improved despite continued dosing.
Common AEs from an on-going Phase 2 study evaluating chronic administration of ENTO
monotherapy in 186 subjects with hematologic malignancies are fatigue (53.2%), 
nausea (45.2%), diarrhea (38.7%), decreased appetite (24.7%), constipation (23.7%), 
cough (21.0%), and headache (21.0%) as of 21 November 2014. One out of a total of 
201 subjects (0.5%) experienced pneumonitis in this monotherapy study as of 11 March 2015.
1.3.
Rationale for This Study
Given the emerging role of B cells in cGVHD (abnormal response to BAFF, errors in B cell 
reconstitution/differentiation, BCR signaling via SYK or BTK, failed induction of B cell 
tolerance), ENTO, in a dose responsive manner, induces ex vivo apoptosis of a population of 
B cells present only in patients with active cGVHD, and the proof-of-concept studies with 
rituximab demonstrating that B cell targeted therapy shows benefit in cGVHD (see 
Section 1.1.1.1), Gilead is pursuing an investigation into whether ENTO is an effective treatment 
for cGVHD. Study GS-US-406-1840 is designed to evaluate the efficacy and tolerability of 
ENTO in addition to systemic corticosteroids in subjects at the time of initial diagnosis of 
cGVHD requiring treatment. Safety reviews will be performed in real time and will include 
evaluations of clinical laboratory abnormalities, relapse of primary malignancy, physical 
examinations, vital signs and AE reporting.
1.4.
Rationale for Dose Selection 
Since the target coverage necessary to achieve efficacy in subjects cannot be established in 
ex vivo experiments or animal models, the objective for dose selection is to achieve >50% target 
inhibition (% inhibition in stimulated CD63+ basophils) at trough. At 200 mg twice daily of 
ENTO BIS-MSA, the degree of inhibition of CD63+ cells is ~50% at steady state Ctrough. 
However, the majority of cGVHD subjects are administered proton pump inhibitors (PPIs),
which would be expected to decrease target inhibition below 50% at this dose. At an ENTO


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BIS-MSA dose of 400 mg twice daily in the presence of a PPI, target inhibition at Ctrough is 
~50%. Thus, the selected dose in cGVHD is 400 mg twice daily of ENTO in patients currently 
taking a PPI, and 200 mg twice daily of ENTO in patients not currently taking a PPI.
Furthermore, ENTO has a safety profile that is acceptable for subjects receiving treatment for 
malignancy (including cGVHD subjects). In studies with ENTO, the rate of Grade 3 or 4 
AST/ALT elevations is between 10-14%, and these events are reversible with interruption of 
dosing. Reversible episodes of elevated indirect bilirubin (≥ Grade 1) occur in ~11% of subjects.
1.5.
Risk/Benefit Assessment for the Study
Chronic GVHD remains a highly morbid disease with a high mortality rate, and given the 
cumulative safety data in healthy volunteers and patients with hematologic malignancies, the 
safety profile of ENTO is expected to be similar in cGVHD patients. ENTO is 
immunomodulatory, and even though ENTO has not been associated with an increased rate of 
infections in clinical studies in hematologic malignancy, serious infections are events of interest 
in this population as patients with cGVHD have a high rate of infections. Any 
immunomodulatory agent has a theoretical risk of decreasing the graft versus tumor effect, and 
malignancy relapse is also an event of interest in this study. However, as SYK inhibition affects 
primarily B cell function and not T-cell function, loss of the graft versus tumor effect is not 
expected as a result of treatment with ENTO. ENTO is associated with transaminase elevations 
and bilirubin increases, but these episodes have been reversible. The evaluation of safety of 
ENTO administration in the cGVHD population is facilitated in this study with the inclusion of a 
placebo control group.
Refer to the IB for full details of prior and ongoing pre-clinical and clinical studies including 
summary safety and efficacy data. 
1.6.
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 primaty objective is: 
Final 
Original 
To evaluate the effect ofENTO on the best overall response rate (BORR) as assessed by the 
cGVHD Activity Assessment (NCAA) {34478} by 24 weeks in the setting of add-on to systemic 
cotiicosteroids as patt of first-line therapy for cGVHD 
The key secondaty objectives aTe: 
• 
To evaluate the effect of ENTO on the skin domain of the Lee Symptom Scale (LSS) 
(Appendix 6) at 24 weeks 
• 
To evaluate the effect of ENTO on the mouth domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the eyes domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the total score of the LSS at 24 weeks 
Additional secondmy objectives include: 
• 
To evaluate the effect ofENTO on dmation of response (DOR) 
• 
To evaluate the effect ofENTO on dose reduction of corticosteroids 
• 
To evaluate the effect of ENTO on initiation of second-line therapy for cGVHD 
• 
To evaluate the effect of ENTO on progression of cGVHD 
• 
To evaluate the safety and tolerability of ENTO 
Exploratmy objectives include: 
I 
I 
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3. 
STUDY DESIGN 
3.1. 
Endpoints 
The primary endpoint of this study is: 
Final 
Original 
• 
The primary endpoint is BORR as assessed by the NCAA by 24 weeks in the setting of add-
on to systemic corticosteroids as part of first-line therapy for cGVHD 
The key secondary endpoints are: 
• 
Change from Baseline in the skin domain of the LSS at 24 weeks 
• 
Change from Baseline in the mouth domain ofthe LSS at 24 weeks 
• 
Change from Baseline in the eyes domain ofthe LSS at 24 weeks 
• 
Change from Baseline in the total score ofthe LSS at 24 weeks 
Other secondary endpoints include: 
• 
DOR 
• 
Proportion of subjects who achieve at least 50% reduction in systemic corticosteroid dose 
relative to baseline 
• 
Proportion of subjects who initiate second-line therapy for cGVHD 
• 
Failure-free survival (FFS) 
• 
Safety and tolerability of ENTO 
Exploratory endpoints ofthis study include: 
I 
I 
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3.2.
Study Design
This protocol describes a randomized, double-blind, placebo-controlled multicenter study to 
evaluate the efficacy and safety of ENTO (Treatment Arm 1) vs. placebo (Treatment Arm 2) in 
combination with systemic corticosteroids for subjects with cGVHD.  
A total of 100 eligible subjects will be randomized in a 1:1 manner to ENTO (Treatment Arm 1)
or placebo-to-match (PTM) (Treatment Arm 2), and treated for 48 weeks during the blinded 
phase. Randomization will be stratified by the following 2 factors at the Baseline/Day 1Visit:
Stratification Factor
Stratification Levels
Calcineurin inhibitor or MMF use
Yes vs. No
Disease severity as determined by the 2014 NIH 
Consensus cGVHD criteria
Moderate cGVHD:

≥ 1 organ with score = 2, or

≥ 3 organs with score = 1, or

lung score = 1
Severe cGVHD:

any organ score = 3 or

lung score ≥ 2
The final analysis for BORR is planned when all subjects have been on study for 24 weeks.  All 
subjects will be followed up to 48 weeks for DOR evaluation.  At the week 48 visit, all subjects 
will have the option to receive open-label extension (OLE) with ENTO.
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study, perform interim reviews of safety data at regular intervals approximately every 3 months, 
and perform an interim review of efficacy data for futility when approximately 50% of subjects 
have been on study for 24 weeks, as described in the DMC Charter.  The first DMC meeting will 
be conducted after the 20th subject has been on study for 4 weeks.  The DMC will provide 
recommendations to Gilead as to whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the study in the best interests of 
the participants, whether the study should continue as planned, or the study should continue with 
modifications. 
3.3.
Study Treatments
After 48 weeks of blinded treatment, all subjects will have the option to receive open-label 
extension (OLE) with ENTO and attend visits per the schedule of assessments (Table 6-1) for an 
additional 96 weeks.
Subjects who provide written informed consent and meet all eligibility criteria will be 
randomized in a 1:1 fashion to either Treatment Arm 1 or Treatment Arm 2.  


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Subjects will retum for study visits at weeks: 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48. At the 
week 48 visits all subjects will have the option to patticipate in the OLE. If subjects elect not to 
enroll in the OLE phase of the trial, they will retmn for a 30-day follow-up visit. 
Subjects that will continue in the OLE phase of the trial will retum for the following study visits 
at weeks: 50, 52, 56, 60, 64, 72 and visits evety 12 weeks thereafter. NOTE for subjects 
receiving tacrolimus, cyclosporine or MMF: For subjects receiving these medicines at 
enrolment and are continuing on these medicines, the blood levels of tacrolimus, cyclosporine or 
the active metabolite ofMMF (MPA) will be monitored at baseline/Day 1 (prior to stru1ing 
ENTO or PTM), on Day 2 or Day 3 and Day 6 or Day 7 after initiating ENTO or PTM, and at 
the end of Week 2 study visit. Beyond these time points, concentration monitoring for 
tacrolimus, cyclosporine and MPA should follow the treating institution's protocol and 
therapeutic range for monitoring these medicines. For subjects who initiate these medicines 
while ah'eady receiving ENTO or PTM, concentration monitoring for tacrolimus, cyclosporine 
and MPA should follow the treating institution's protocol and therapeutic range for monitoring 
these medicines. When a concentration sample is taken at a local lab in accordance with the 
treating institution's protocol for monitoring these medications, a sample may also be requested 
for central lab analysis. 
PD 
Figure 3-1. 
Screening 
prior 
to Baseline 
Study Schema 
Baseline 
(Day I)" 
Treatment Arm 1: Entospletinib+SystemicoorticoidS' 
for 48 weeks (n=50)' 
TrurmentArm 2: Plaeebo + Systemic oorticoids 
for 48 weeks (n=50)I> 
30 Day 
Open-Label Extension 
FlU 
I.ntospletinibd 
a 
Following the Baseline/ Day 1 visit subjects willrettu11 to the clinic for visits at weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48. 
b 
For subjects receiving tacrolimus, cyclosporine or MMF the blood levels of tacrolimus, cyclosporine or dte active metabolite 
ofMMF (MPA) will be monitored at baseline/Day 1 (prior to starting ENTO or PTM), on day 2 or day 3 and day 6 or day 7 
after initiating ENTO or PTM, and at the end of week 2 study visit. Beyond these time points, concentration monitoring for 
tacrolimus, cyclosporine and MP A should follow the treating institutions protocol and ilierapeutic range for monitoring 
these medicines 
c 
Subje.cts who complete ilie study du·ough week 48 and do not wish to continue to participate in the OLE phase of ilie trial 
will be requu·ed to ret1u11 to dte clinic 30 days after the completion of stltdy dmg for a 30-Day Follow-up visit 
d 
After Week 48, all subjects will have the option to receive OLE for an additional96 weeks. Subjects will attend visits at 
Weeks: 50, 52, 56, 60, 64, 72 and evety 12 weeks thereafter. 
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3.4.
Discontinuation Criteria
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

Unacceptable toxicity, 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

Relapse of primary disease  

Severity of cGVHD requiring therapy that is not allowed as concomitant therapy on study
(for example JAK inhibitor/BTK inhibitor /mTOR inhibitors/ any cell depletion agent/ 
phototherapy)

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 8

Discontinuation of the study at the request of Gilead, a regulatory agency or an 
Institutional Review Board or Independent Ethics Committee (IRB/IEC)
3.5.
Biomarker Testing
3.5.1.
Biomarker Samples to Address the Study Objectives:
Blood will be collected in this study and will be used to evaluate the effect of ENTO on markers 
relevant to cGVHD and/or the SYK pathway. The specific markers may include, but are not
limited to the following:  cytokines, leukocyte subsets, SYK pathway markers, immunoglobulin 
levels, and/or antigen-specific B cell responses.
Because biomarker science is a rapidly evolving area of investigation, and adverse events in 
particular are difficult to predict, 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 art knowledge. 
The samples obtained for the study may be stored for 15 years after the end of the study.


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3.5.2. 
Optional Future Research 
PD 
3.5.3. 
Optional Cellular Turnover Substudy {37403}, {37404}, {37405} 
p 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 subjects who meet the inclusion/exclusion criteria will be enrolled. 
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) The ability to understand and sign a written informed consent form, which must be obtained 
prior to initiation of study procedures
2) 18-75 years of age, inclusive at Screening
3) Newly diagnosed cGVHD defined by: 
a) At least 100 days after receiving any allogeneic hematopoietic stem cell transplant 
AND 
b) Receiving new course of systemic corticosteroids (1.0 mg/kg/day or prednisone 
equivalent) as first-line therapy for cGVHD within 10 days of screening 
AND
c) Moderate to severe cGVHD as assessed by NCDSC with at least three organ systems 
involved OR one organ system with a score of 2 OR lung organ score = 1 (Appendix 2)
4)
Subjects who have undergone transplantation for benign indications are eligible for the 
study. Complete remission is required for subjects who have undergone transplantations for 
hematologic malignancies. 
5) Have either a normal ECG or one with abnormalities that are considered clinically 
insignificant by the investigator in consultation with the Sponsor
6) A negative serum pregnancy test is required for female subjects (unless permanently sterile 
or greater than two years post-menopausal) 
7) A female subject is eligible to enter the study if it is confirmed that she is: 
a) Not pregnant or nursing
b) Of non-childbearing potential (i.e., women who have had a hysterectomy, have had both 
ovaries removed or medically documented ovarian failure, or are postmenopausal women 
> 54 years of age with cessation (for 12 months) of previously occurring menses), or


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c) Of childbearing potential (as defined in Appendix 8) and agrees to utilize a highly 
effective protocol-specified contraceptive method or be non-heterosexually active or 
practice sexual abstinence from Screening throughout the duration of study treatment and 
for 30 days following the last study drug dose
d) Female subjects who utilize a hormonal contraceptive as one of their birth control 
methods must have used the same method for at least three months prior to study dosing
8) Male subjects of childbearing potential who engage in heterosexual intercourse must agree to 
use protocol specified method(s) of contraception as described in Appendix 8.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Uncontrolled infection within 4 weeks of Screening
2) History of the following therapies in the post-transplant period:
a) B cell depleting biologic agents
b) CD19 CAR-T cells based therapies 
c) BTK/SYK/JAK/PI3K inhibitors
d) Phototherapy-unless administered for aGVHD 
3) Treatment of cGVHD with anti-thymocyte globulins (ATG), or campath within 60 days of 
Screening visit unless used for  treatment of acute GVHD
4) Severe organ dysfunction manifest during Screening period: 
a) Requiring supplemental oxygen at more than 2L/min
b) Uncontrolled arrhythmia or heart failure
c) Creatinine clearance (Cockroft-Gault) < 30 mL/min
5) Known hypersensitivity to the Investigational Medicinal Product (IMP), the metabolites, or 
formulation excipient.
6) Laboratory abnormalities including: 
a) Human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen or hepatitis 
C antibody positive (Subjects with positive HCV antibody and without detectable HCV 
RNA are permitted to enroll) 


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b) Aspartate aminotrasferase (AST)/Alanine aminotransferase (ALT) ≥ 2 X upper limit of 
normal (ULN) unless deemed to be secondary to Liver GVHD
c) Total bilirubin ≥2 X ULN unless deemed to be secondary to Liver GVHD
7) Positive serum pregnancy test (for female subjects) 
8) Any other clinical condition or prior therapy that, in the opinion of the investigator, would 
make the subject unsuitable for the study or unable to comply with dosing requirements 
9) Participation in any other clinical trial without prior approval from the sponsor is prohibited 
while participating in this trial 
10) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance or subject safety
11) Subjects receiving ongoing therapy with any of the following medications in the Table 5-2.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
Subjects will be assigned a screening number at the time of consent.  The Randomization and 
Baseline/Day 1 visit cannot occur until the Investigator has received the results of the Screening 
tests and subject eligibility has been confirmed. 
Once eligibility has been confirmed, each subject will be assigned a unique subject number. 
Once a subject number has been assigned to a subject, it will not be reassigned to any other 
subject. Prior to or during the Baseline/Day 1 visit, the investigator or designee will randomize 
the subject using an Interactive Web Response System (IWRS).  Subjects will be randomized in 
a 1:1 ratio to Treatment Arm 1 or Treatment Arm 2. The IWRS will assign blinded study drug 
bottle numbers at each study visit (except weeks 2, 30 and 42).  Study drug will be dispensed to 
the subject in a blinded fashion until week 48.  Randomization will be stratified by the following 
2 factors at the Screening and Baseline/Day1 Visit:
Stratification Factor
Stratification Levels
Calcineurin inhibitor or MMF use
Yes vs. No
Disease severity as determined at 
Screening by the NIH cGVHD 
Staging and Diagnosis Criteria 
(NCSDC) Global Severity Score
Moderate cGVHD:

≥ 1 organ with score = 2, or

≥ 3 organs with score = 1, or

lung score = 1
Severe cGVHD:

any organ score = 3 or

lung score ≥ 2
All Baseline/Day1 tests and procedures must be completed prior the administration of the 
first dose of the study drug. The subject must complete the Baseline procedures prior to 
randomization and drug dispensation.  Initiation of treatment with the study drug must 
take place within 24 hours after the Baseline/Day 1 visit.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IXRS system 
for that subject. Gilead recommends but does not require that the investigator contact the 
Gilead medical monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the case report form/ 
electronic case report form (eCRF), along with the date on which the treatment assignment was 
obtained. The investigator is requested to contact the Gilead medical monitor promptly in case of 


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any treatment unblinding. Blinding of study treatment is critical to the integrity of this clinical 
trial and therefore, if a subject’s treatment assignment is disclosed to the investigator, the subject 
will have study treatment discontinued. All subjects will be followed until study completion 
unless consent to do so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.2.
Description and Handling of Study Drug
5.2.1.
Formulation
ENTO is available as 200-mg strength tablets. ENTO 200 mg tablets are blue, plain-faced, 
capsule-shaped, film-coated tablets. Each tablet contains the equivalent of 200 mg Entospletinib
free base in the form of Entospletinib bismesylate monohydrate (ENTO BIS-MSA). In addition 
to the active ingredient, ENTO tablets contain the following inactive ingredients:
methanesulfonic acid, hydroxypropyl methylcellulose, mannitol, microcrystalline cellulose, 
crospovidone, poloxamer 188, silicon dioxide, magnesium stearate, polyethylene glycol, 
polyvinyl alcohol, talc, titanium dioxide, and FD&C blue #2 aluminum lake.
Placebo-to-match (PTM) tablets 200 mg are blue, plain-faced, capsule-shaped, film-coated 
tablets. Each tablet contains the following inactive ingredients: lactose monohydrate, 
microcrystalline cellulose, crospovidone, magnesium stearate, polyethylene glycol, polyvinyl 
alcohol, talc, titanium dioxide, and FD&C blue #2 aluminum lake.
5.2.2.
Packaging and Labeling
ENTO (GS-9973) 200-mg and PTM tablets are packaged in white, high-density polyethylene 
(HDPE) bottles. Each bottle contains 60 tablets, silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant polypropylene 
screw cap with an induction-sealed and aluminum-faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
5.2.3.
Storage and Handling
Study drug (ENTO and PTM) 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. 


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Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure through inhalation when handling.
5.3.
Dosage and Administration 
ENTO and PTM tablets will be provided by Gilead Sciences.  
ENTO or PTM should be taken under fasted conditions. Fasting is defined as no food or liquids 
other than water for 2 hours pre- and 1 hour post-dose. Subjects unable to swallow tablets should 
contact Gilead Medical Monitor for guidance. If vomiting occurs within 30 minutes after IMP 
administration and undissolved tablets are present in the vomitus, the subject should take another 
dose.
Study medication will be adjusted for whether the subject is taking a proton pump inhibitor (PPI) 
per the following table, both at study entry and throughout the study.
PPI status
ENTO or PTM dose
Subject is taking PPI
400 mg (2 x 200 mg tablet) twice daily 
Subject is NOT taking PPI
200 mg (1 x 200 mg tablet) twice daily 
5.4.
Prior and Concomitant Medications 
Systemic corticosteroids are required at study entry. Administration and taper recommendations 
are below:

Prednisone: administered initially as a single early morning dose of 1.0 mg/kg/day 
[or equivalent (Adults: maximum dose 100 mg)]. 

Prednisone therapy continues at the initial dose until there is objective evidence of 
improvement in manifestations of cGVHD (ie, a PR or better), minimum of 14 days. 

The initial taper of prednisone from the starting dose of 1.0 mg/kg/day (or equivalent) is 
attempted within 2 weeks after the first evidence of improvement in cGVHD

If exacerbation or recurrence of cGVHD is evident at any step of the taper, the dose of 
prednisone should be increased promptly by 2 levels, with daily administration for 2 to 
4 weeks, followed by resumption of alternate-day administration. Please see Table 5-1 for 
tapering. 


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Table 5-1.
Tapering of Prednisone after reaching PR/CR
Week 
Dose, mg/kg body weight (example for 80kg patient in mg)
0
1.0 qday (80)
1-3
1.0/0.5 (to begin within 1 week after objective improvement, 
alternating days) (80/40/80)
4-5
0.5 qday (40)
6-7
0.5  every other day (40/0/40)
8-9
0.25 every other day  (20/0/20)
10
0.1 every other day (10/0/10)

Inhaled and topical steroids (eg, Budesonide/ Beclomethasone) are not considered second-
line therapy and are permitted throughout the duration of the study. Addition of the 
aforementioned agents will be recorded in the eCRF for posterior analysis.   

Local organ-specific treatment (eg, eye drops) will be recorded in the eCRF and assessment 
of response after local organ-specific treatment will be based on the NCAA.
Disallowed Medications: 
In vivo and in vitro data indicates that ENTO is a substrate of CYP2C9 and CYP3A. 
Co-administration of CYP2C9 inhibitors or inducers may increase or decrease ENTO exposure, 
respectively. As such, co-administration of moderate and strong CYP3A and CYP2C9 inducers
and strong CYP2C9 inhibitors are prohibited in this study. Caution should be exercised when co-
administering drugs that are moderate inhibitors of CYP2C9 (eg fluconazole, voriconazole or 
amiodarone) as they may increase ENTO exposure. Administration of strong and moderate 
CYP3A and CYP2C9 inducers, and strong CYP2C9 inhibitors, is also prohibited for 2 weeks 
prior to study drug administration. Examples of strong CYP2C9 inhibitors and moderate/strong 
CYP3A and CYP2C9 inducers, and other medications that are prohibited in this study are 
provided in Table 5-2


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Table 5-2.
Examples of Prohibited Agents
Drug Class
Examples of Prohibited Agents (but not limited to)
mTOR inhibitor
Everolimus, sirolimus
Any cell depleting antibody
Rituxan®
Phototherapy
Phototherapy
BTK agents
Ibrutinib
JAK inhibitors
Tofacitinib, ruxolitinib
Moderate CYP3A/2C9 inducers
Bosentan, modafinil, nafcillin, ritonavir, efavirenz, thioridazine, lopinavir, 
etravirine, lersivirine, talviraline, tipranavir/ritonavir, semagacestat 
Strong CYP3A/2C9 inducers
Rifampin, mitotane, avasimibe, phenytoin, carbamazepine, enzalutamide, St 
John’s Wort, rifabutin, phenobarbital
Strong CYP2C9 inhibitors
Miconazole (systemic)
Herbal/Natural Supplements 
St. John’s Wort 
Use with Caution: 
In vitro data indicates that Entospletinib has the potential to inhibit several transporters and the 
metabolizing enzyme UGT1A1, which may affect the plasma concentrations of substrates of 
these transporters and/or enzyme. Caution should be exercised when 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. A list of sensitive substrates of this enzyme and/or transporters 
is provided below; any use of these medicines should be discussed with the medical monitor.
Table 5-3.
List of Sensitive Substrates of UGT1A1, OATP1B1, OATP1B3, P-gp 
and BCRP
Transporter
Substrate
P-gp
Aliskiren, aldosterone, ambrisentan, colchicine, dasatinib, dabigatran etexilate, 
dexamethasone, digoxin, diltiazem, domperidone, etoposide, fexofenadine, imatinib, 
itraconazole, ivermectin, loperamide, lapatinib, maraviroc, methylprednisolone, 
nilotinib, posaconazole, quinidine, ranolazine, saxagliptin, sitagliptin, sparfloxacin, 
talinolol, tolvaptan, topotecan, vinblastine
BCRP
Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, 
sulfasalazine, topotecan
OATP1B1
Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, SN-38 (active metabolite 
of irinotecan), rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide,  
valsartan, olmesartan
OAPT1B3
Atorvastatin, rosuvastatin, pitavastatin, telmisartan, valsartan, olmesartan
UGT1A1
Acetaminophen, atorvastatin, bropirimine, carvedilol, clofibrate, ezetimibe, 
flavopiridol, gemfibrozil, genistein, nalorphine, naltrexone, naringenin, raloxifene, 
SN-38, simvastatin, telmisartan, troglitazone


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In a study in healthy volunteers, Entospletinib 400 mg twice daily increased rosuvastatin 
exposure by approximately 3-4-fold, which may theoretically increase the risk of 
rhabdomyolysis. In reviewing the safety of subjects whom have received a statin with 
Entospletinib there have been no reports of rhabdomyolysis nor a different adverse events 
profile, but in the interest of caution, the following restrictions apply to the use of HMG-CoA 
reductase inhibitors with Entospletinib:
HMG-CoA reductase inhibitor
Dose Adjustment Required
Atorvastatin
Maximum dose 20 mg QD
Rosuvastatin
Maximum dose 10 mg QD
Pravastatin
Maximum dose 20 mg QD
Simvastatin
Maximum dose 20 mg QD
Lovastatin
Maximum dose 20 mg QD
Fluvastatin
Maximum dose 20 mg QD
5.5.
Accountability for Investigational Medicinal Product 
The investigator is responsible for ensuring adequate accountability of all used and unused IMP.
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
Study drug accountability records will be provided by Gilead Sciences (or equivalent 
documentation maintained by the study site) to:

Record the date received and quantity of IMP bottles

Record the date, subject number, subject initials, the IMP bottle number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
IMP return and disposal will be performed as outlined in Section 9.1.6.


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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 the schedule of assessment 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).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that each subject is eligible for the study 
before enrollment in the study.  Please refer to Section 5.1 for details about randomization and 
treatment assignment.  
6.2.
Study Assessments 
Study procedures are outlined in Table 6-1.


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Table 6-1.
Schedule of Assessments 
Visit
Screeninga
Baseline/
Day1c
END OF WEEK b
Every 12 
Weeks
30 Day 
Follow
-up
2
4
8
12
16
20
24
30
36
42
48/
ESDDd
50
52
56
60
64
72
Visit Window
-30 days
0
3
3
3
3
3
3
5
5
5
5
5
3
3
3
3
3
5
5
Written Informed 
Consent
X
Medical History 
X
Complete 
Physical Exam
X
X
X
X
X
Symptom-
Directed Physical 
Exame
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
Testf
X
Urine Pregnancy 
testf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum FSHf
X
NIH cGVHD 
Diagnosis and 
Staging Criteria
X
NIH cGVHD 
Activity 
Assessment
(NCAA) Form  
Ag
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NIH cGVHD 
Activity 
Assessment
(NCAA) Form Bh  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lee Symptom 
Scale (LSS)h 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Visit
Screeninga
Baseline/
Day1c
END OF WEEK b
Every 12 
Weeks
30 Day 
Follow
-up
2
4
8
12
16
20
24
30
36
42
48/
ESDDd
50
52
56
60
64
72
Visit Window
-30 days
0
3
3
3
3
3
3
5
5
5
5
5
3
3
3
3
3
5
5
Primary disease 
assessment per 
institutional 
guidelines 
X
X
X
X
Height 
X
Vital Signs & 
Weighti
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematologyj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistryk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Analysisl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Metabolic Panel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1, HBV, & 
HCV Serologym 
X
12 lead ECG-
performed supine 
X
X
X
PKn
X
X
X
X
X
X
X
X
X
X
X
X
X
Monitoring of 
calcineurin 
inhibitors and 
MPA o
X
X
X
Biomarkersp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PFTs
X
X
X
Randomize 
X
Drug Dispensingq
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Visit
Screeninga
Baseline/
Day1c
END OF WEEK b
Every 12 
Weeks
30 Day 
Follow
-up
2
4
8
12
16
20
24
30
36
42
48/
ESDDd
50
52
56
60
64
72
Visit Window
-30 days
0
3
3
3
3
3
3
5
5
5
5
5
3
3
3
3
3
5
5
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medicationsr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Evaluations to be completed within 30 days prior to Day 1. 
b
All study visits are to be scheduled relative to the Day 1 visit date. 
c
Initiation of treatment with the study drug must take place within 24 hours after the Baseline/Day 1 Visit
d
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug 
e
Symptom-directed physical exam as needed 
f
FSH: For female subject post-menopausal for less than two years, if FSH 40 mIU/ mL a serum pregnancy test will be required.  Women determined to be of child bearing 
potential will have a serum pregnancy test performed at screening.  All subsequent visits will have a urine test, and positive urine pregnancy tests will be confirmed with a 
serum test. 
g
NCAA Form A (Appendix 5) with spirometry measures will be completed by the Investigator or Sub-I. In the OLE this will be assessed at weeks 56, 60, 64, 72 and 96. 
NCAA should also be performed at the time of initiation of second-line therapy.
h
LSS (Appendix 6) and the NCAA Form B (Appendix 5) is to be completed by the subject. The subject is to read the questionnaire by himself/herself and write/mark answers 
directly onto the questionnaire. In the OLE this will be assessed at Weeks 56, 60, 64, 72 and 96. The LSS and the NCAA Form B should also be administered at the time of 
initiation of second-line therapy.
i
Vital sign measurements include blood pressure, pulse, respiration rate, weight and temperature
j
Complete blood count (CBC) with differential platelet count 
k
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorous, magnesium, potassium, sodium, uric acid, and amylase and (reflex lipase testing is performed in subjects with total amylase 
> 1.5 ULN) 
l
Urine collection for urinalysis and urine pregnancy test (if applicable) 
m
Subjects with positive HCV antibody and without detectable HCV RNA are permitted to enroll 
n
Randomly timed PK sampling. Sites should enter the time of the last dose of study medication in the eCRF for sample reconciliation. PK samples will be drawn at Week 60 
and every 12 weeks in the OLE. 
o
For subjects receiving tacrolimus, cyclosporine or MMF the blood levels of tacrolimus, cyclosporine or the active metabolite of MMF (MPA) will be monitored at 
baseline/Day 1 (prior to starting ENTO or PTM), on day 2 or day 3 and day 6 or day 7 after initiating ENTO or PTM, and at the end of week 2 study visit. Beyond these time 
points, concentration monitoring for tacrolimus, cyclosporine and MPA should follow the treating institutions protocol and therapeutic range for monitoring these medicines 
p
Assessments may include but are not limited to: cytokines, cell subset analysis, pathway markers, and/or other leukocyte markers, immunoglobulin levels, and/or 
antigen-specific B cell response.  Timepoints may differ depending on the specific biomarker and will be outlined in the biomarker Lab Manual.  
q
At visit 2, 30,  42 and (OLE visit 50) drug accountability only, study drug will not be dispensed at these visits 
r
Will include the following: systemic corticosteroid dose, other immunosuppressive, antimicrobials, PPI 
s
PFTs will include spirometry with bronchodilator, and diffusing capacity of the lungs for carbon monoxide (DLCO). PFTs will be done at ESDD, if ESDD visit greater than 
12 weeks from Baseline. 


Entospletinib 
Protocol GS-US-406-1840 
Gilead Sciences, Inc. 
6.2.1. 
Screening Visit 
Final 
Original 
Written inf01med consent must be obtained from each subject before initiation of any visit 
procedures. After a subject has provided inf01med consent, the investigator and other study 
personnel (listed on the F01m FDA 1572) will detetmine if the subject is eligible for pruticipation 
in the study. Subjects will be screened within 30 days before the Baseline/Day 1 visit to 
detetmine eligibility for the patiicipation in the study. This assessment will include review of the 
Inclusion/Exclusion criteria and completion of all Screening visits procedures as outlined in 
Table 6-1. 
Screening visit procedures will include the following for all subjects that provide infonned 
consent: vital signs (including height and weight), medical hist01y, complete physical 
examination, 12-lead ECG (perf01med supine), concomitant medications, serum pregnancy test 
(for women of child beaTing potential), serum FSH (if applicable), primruy malignancy 
assessment (if applicable), complete the NCDSC, blood draws for the following tests: 
hematology, chemistly, metabolic panel, HN -1, HBV, and HCV serology unless specified 
othetwise. Urine will be collected for urinalysis. 
Pulmonruy function tests (PFTs) will be required at Screening: spirometry with bronchodilator 
and diffusing capacity of the lungs for cru·bon monoxide (DLCO). Investigators will be required 
to perform PFTs, seek specialist examination for ocular and gynecological involvement, and 
other items as described in the NCDSC. 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will retum to the 
clinic within 30 days from the Screening visit for randomization into the study. 
From the time of obtaining informed consent through the first administr·ation of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report f01m (eCRF). All 
other tmtowru·d medical occmTences observed during the screening period, including 
exacerbation or changes in medical histoty ru·e to be captured on the medical histoty eCRF. 
See Section 7. for additional details. 
6.3. 
Baseline/Day 1 Visit 
The following evaluations ru·e to be completed at the Baseline/Day 1 visit. The Investigator must 
confum subject eligibility prior to randomization. Initiation of tr·eatrnent with the study dmg 
must take place within 24 hours after the Baseline/Day 1 visit. 
Baseline/Day 1 visit procedures will include the following: review of adverse events and 
concomitant medication use. Sites will obtain: vital signs (including weight), complete physical 
exam, primruy malignancy assessment (if applicable), NCAA and LSS. Blood will be collected 
for the following tests: hematology, chemistry, metabolic panel, Blood specimens for selected 
biomru·kers will be collected at Baseline, and urine for urine regnancy test (if applicable and 
urine anal sis. PO 
CONFIDENTIAL 
Page44 
11 November 2015 


Entospletinib 
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Gilead Sciences, Inc. 
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NCAA Form A with spirometry should be completed by the Investigator or Sub-Investigator. 
The NCAA Form Band the LSS should be completed by the subject. Subject is to read 
questionnaire by himself/herself and write/mark answers directly on the questionnaire. 
Eligible subjects will be randomized in the IXRS to obtain the subject number. Study drug will 
be dispensed in a blinded fashion. Subjects should initiate dosing of study drug within 24 hours 
ofthe Baseline/Day 1 visit. 
ENTO or PTM should be taken under fasted conditions. Fasting is defined as no food or liquids 
other than water for 2 hours pre- and 1 hour post-dose. Subjects should be instructed not to bite 
or chew the tablets. In case of breakage of the tablets in the oral cavity, additional water should 
be taken as a rinse. Subject should be counseled on the importance of taking study medication 
daily and to return study medication bottles to each visit. 
6.4. 
Treatment Assessments (Weeks 2-48 and OLE) 
Evaluations listed in Table 6-1 are to be completed at the end of weeks: 2, 4, 8, 12, 16, 20, 24, 30 
36, 42 and 48 in blinded fashion. For subjects continuing in the OLE the evaluations listed in 
Table 6-1 are to be completed at the end ofweeks: 50, 52, 56, 60, 64, and every 12 weeks post 
week 72 up to week 96 or, until unacceptable toxicity, withdrawal of consent by subject or 
withdrawal from study by investigator, or until ENTO becomes commercially available. 
Study visits are to be completed within ±3 days ofthe Baseline/Day 1 visit for Weeks 2-20; 
50-64 and ±5 days for weeks 24-48. NOTE for subjects receiving tacrolimus, cyclosporine or 
MMF: For subjects receiving these medicines at enrolment and are continuing on these 
medicines, the blood levels oftacrolimus, cyclosporine or the active metabolite of MMF (MP A) 
will be monitored at baseline/Day 1 (prior to starting ENTO or PTM), on Day 2 or Day 3 and 
Day 6 or Day 7 after initiating ENTO or placebo-to-match (PTM), and at the end of week 2 
study visit. Beyond these time points, concentration monitoring for tacrolimus, cyclosporine and 
MPA should follow the treating institution's protocol and therapeutic range for monitoring these 
medicines. For subjects who initiate these medicines while already receiving ENTO, 
concentration monitoring for tacrolimus, cyclosporine and MP A should follow the treating 
institution's protocol and therapeutic range for monitoring these medicines. When a 
concentration sample is taken at a local lab in accordance with the treating institution's protocol 
for monitoring these medications, a sample may also be requested for central lab analysis. 
At all visits the following will occur: review of adverse events (AEs) and changes in concomitant 
medications, vital signs (including weight), primary malignancy assessment (if applicable), 
blood for hematology, chemistry, metabolic anel, and urine for: regnancy test if applicable), 
and urinalysis. PPD 
PFTs will be required at on treatment Weeks 24 and 48 only: spirometry with bronchodilator 
and diffusing capacity of the lungs for carbon monoxide (DLCO) 
ECG will be performed at on treatment Weeks 24 and 48 only. 
CONFIDENTIAL 
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Blood specimens for selected biomarkers will be collected at Screening, predose and at Weeks:
2, 4, 8, 12, 20, 24, 42, 48, ESDD, and/or OLE Weeks 60, 64 and 72. The timeponts may differ 
depending on the specific biomarker and will be outlined in the biomarker manual. 
PK blood draws will be collected at Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42 and 48 and Week 60 
and every 12 weeks in the OLE. 
Complete physical exam will be performed at Weeks 12, 24 and 48, symptom directed physical 
exam will be completed as needed at all other visits.
NCAA Form A with spirometry should be completed by the Investigator or Sub-Investigator at 
all study visits (except Week 2) and during the OLE at Weeks 56, 60, 64, 72 and 96. The NCAA 
Form A should also be performed at the time of initiation of second-line therapy. Situations 
where subjects have comorbid or irreversible conditions that may interfere with response 
assessment, the check box on the NCAA indicating that the abnormality is entirely explained by 
a non-GVHD documented cause should be marked. Organ-specific response measures may be 
delayed until the following visit to allow for resolution of a non-GVHD issue. All other organs 
should still be scored.
LSS and NCAA Form B should be completed by the subject.  The Subject is to read the 
questionnaire by himself/herself and write/mark answers directly on the questionnaire. The PROs 
will be completed at all study visits (except Week 2) and during the OLE will be assessed at 
weeks 56, 60, 64, 72 and 96. One question has been added to the LSS which asks which 
two domains are most impactful to the subject.
Document study drug dispensation and accountability for all study drugs dispensed. No study
drug will be dispensed at the weeks 2, 30, 42 and 50 visits, only drug accountability will be done 
at those visits. 
6.5.
Post-treatment Assessments
6.5.1.
Unscheduled Visit 
A subject should attend an unscheduled visit if requested by the Sponsor or the investigator. The
assessments performed are at the investigator’s discretion.  
For subjects that initiate second line therapy during the study, every attempt should be made to 
collect the NCAA and LSS at an unscheduled visit and to keep the subject in the study and study 
related follow-up procedures should be continued. 
6.5.2.
Early Study Drug Discontinuation (ESDD) 
If the subject discontinues study drug prior to the end of study, the subject will be asked to return 
to the clinic within 72 hours of stopping study drug for the Early Study Drug Discontinuation 
Visit.  The subject will be asked to continue attending the schedule study visits through week 48. 
Subjects who ESDD will not be eligible for the OLE phase of the study. 


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At the ESDD visit, any evaluations showing abnormal results indicating that there is a possible 
or probable causal relationship with the study drug, should be repeated weekly (or as often as 
deemed prudent by the investigator) until the abnormality is resolved, returns to baseline, or is 
otherwise explained. 
Evaluation listed in Table 6-1 will be completed at the ESDD visit.  
The following will be conducted at the ESDD: review of adverse events (AEs) and changes in 
concomitant medications, vital signs (including weight), complete physical exam, primary 
malignancy assessment (if applicable), blood for hematology, chemistry, metabolic panel, 
selected biomarkers and urine for: pregnancy test (if applicable), and urinalysis. The NCAA and 
LSS will be assessed.
PFTs will be required at ESDD: spirometry with bronchodilator and diffusing capacity of the 
lungs for carbon monoxide (DLCO).
6.6.
30 Day Follow-Up Visit 
Subjects who complete through Week 48 visit and who do not wish to participate in the OLE
phase of the study will return to the clinic 30 days after the completion of study drug for the 
30-Day follow-up visit. 
Subjects who permanently discontinue study drug during the blinded phase and refuse to 
continue in the study through the week 48 visit will be asked to return to the clinic 30 days after 
the completion of the ESDD visit for the 30-Day follow-up visit. 
For the purpose of scheduling a 30-Day follow-up visit, a ± 5 days window may be used. 
Table 6-1 lists all procedures to be completed at the 30-Day Follow-up visit. 
6.7.
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiration rate, weight and temperature. 
Height will be measured at the Screening visit only. 
6.8.
Biomarker Sample Collection 
Blood for selected biomarkers may include, but not limited to, cytokines, leukocyte subsets, 
SYK pathway markers, immunoglobulin levels, and/or antigen-specific B cell responses. Please 
refer to Table 6-1 for collection timepoints.
6.8.1.
Clinical Laboratory Tests/Assessments
Blood and urine samples will be collected as outlined in Table 6-1.  

Hematology profile: completed blood count (CBC) with differential and platelet count 


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
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, uric acid

Metabolic assessments: lipid panel (total cholesterol, HDL, direct LDL, and triglycerides).  

Immunoglobulin levels: Immunoglobulin A-E  

Serum and biomarker storage sample for possible additional clinical testing (if subject 
agrees) 

Urine pregnancy test (females of child bearing potential only); positive urine pregnancy tests 
will be confirmed with a serum test. 

Urinalysis 
6.9.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

Unacceptable toxicity, 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

Relapse of primary disease  

Severity of cGVHD requiring therapy that is not allowed as concomitant therapy on study

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 8

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)
If the investigator considers discontinuing study medication for any reason other than those listed 
above, such as sustained complete remission of cGVHD for more than 3 months, then tapering to 
discontinue ENTO can be considered and should follow the schedule listed below:


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Starting Dose
Action
400 mg twice daily
200 mg, twice daily, for 2 weeks
200 mg once daily for 2 weeks
200 mg, once daily, every other day for 2 weeks
Stop Study Medication
200 mg twice daily
200 mg once daily for 2 weeks
200 mg, once daily, every other day for 2 weeks
Stop Study Medication


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Pre-existing 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 (see Section 7.6.2.2)

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

Relapse of primary disease 

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.)


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
In-patient hospitalization or prolongation of existing hospitalization

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 (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.4.1.
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 (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).


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
Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the modified CTCAE, version 4.03.  For each episode, 
the highest grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening) or 
Grade 5 (fatal) to describe the maximum intensity of the adverse event.  For purposes of 
consistency with the CTCAE, these intensity grades are defined in Table 7-1 and Appendix 7.
Table 7-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2
Moderate
Local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL 
Grade 3
Severe
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL  
Grade 4
Life-threatening
Urgent intervention indicated 
Grade 5
Death 
Death related AE 
*
Activities of Daily Living (ADL) Instrumental ADL refer to opening preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden


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Table 7-2.
Grading of Adverse Event Severity: Upper Respiratory 
The only modification to the CTCAE criteria has been the addition of a Grade 1 upper 
respiratory infection as follows:
CTCAE 
v4.0 Term
Grade 1*
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.03 
AE Term 
Definition
Upper 
respiratory 
infection
Mild 
symptoms; 
symptomatic 
relief (cough 
suppressant, 
decongestant, 
etc.)
Moderate 
symptoms; oral 
intervention 
indicated 
(e.g., antibiotic, 
antifungal, 
antiviral)
IV antibiotic, 
antifungal, or 
antiviral 
intervention 
indicated; 
radiologic, 
endoscopic, or 
operative 
intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder 
characterized by 
an infectious 
process involving 
the upper 
respiratory tract 
(nose, paranasal 
sinuses, pharynx, 
larynx, or 
trachea).
The distinction between the seriousness and the severity of an adverse event 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 one 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 case report form (eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 


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eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur within 30-days of the last dose of study IMP, regardless of 
causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing
or emailing the report form within 24 hours of the investigator’s knowledge of the event to 
the attention of Gilead DSPH or to the designated CRO.
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 DSPH 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 as described above.

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.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 

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.


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
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 IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.4.1.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events Toxicity Management 

All clinical events and clinically significant laboratory toxicities will be managed according 
to uniform guidelines detailed in Appendix 7.

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for Modified CTCAE 4.03 for Severity of Adverse Events and Laboratory 
Abnormalities. 

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose or modified dose that is 
dependent upon discussion with the Gilead Sciences Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.


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
Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
7.4.2.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue investigational medicinal product at the discretion of the investigator.
7.4.3.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to Grade 2.

If a laboratory abnormality recurs to Grade 3 following rechallenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.
7.4.4.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. The subject should be followed as clinically indicated 
until the laboratory abnormality returns to baseline or is otherwise explained, whichever 
occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade.
Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (e.g., Grade 4 CK after strenuous exercise or 
triglyceride elevation that is nonfasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product.
7.5.
Toxicity Management 
Concentration Monitoring of Calcineurin Inhibitors and Mycophenolate Mofetil
ENTO has been shown in vitro to inhibit the drug transporters organic anion transporting 
polypeptides 1B1 and 1B3 (OATP1B1 / OATP1B3), P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP), as well as the drug metabolizing enzyme glucuronosyltransferase
UGT1A1. Due to the involvement of these pathways in the disposition of the calcineurin 


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inhibitors tacrolimus and cyclosporine, and the active (mycophenolic acid [MPA]) and inactive 
metabolites of mycophenolate mofetil, Entospletinib may potentially affect the exposure of these 
medicines.
For subjects receiving these medicines, the blood levels of tacrolimus, cyclosporine or the active 
metabolite of MMF (MPA) will be monitored at baseline/Day 1 (prior to starting ENTO), on day 
2 or day 3 and day 6 or day 7 after initiating ENTO or PTM, and at the end of week 2 study visit. 
Beyond these time points, concentration monitoring for tacrolimus, cyclosporine and MPA 
should follow the treating institution’s protocol and therapeutic range for monitoring these 
medicines. When a concentration sample is taken at local lab, in accordance with the treating 
institution’s protocol for monitoring these medications, a sample may also be requested for 
central lab analysis. 
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 DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.


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Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH 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 DSPH, 
fax number +1 650 522-5477 or email Safety_FC@gilead.com. 
Refer to Appendix 8 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 Gilead DSPH 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 Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism
of special situations reporting.


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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.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primaty objective is: 
Final 
Original 
To evaluate the effect ofENTO on BORRas assessed by the NCAA {34478} by 24 weeks in the 
setting of add-on to systemic corticosteroids as part of first-line therapy for cGVHD 
The key secondaty objectives are: 
• 
To evaluate the effect ofENTO on the skin domain of the LSS at 24 weeks 
• 
To evaluate the effect of ENTO on the mouth domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the eyes domain of the LSS at 24 weeks 
• 
To evaluate the effect ofENTO on the total score of the LSS at 24 weeks 
Additional secondary objectives include: 
• 
To evaluate the effect ofENTO on DOR 
• 
To evaluate the effect ofENTO on dose reduction of cmiicosteroids 
• 
To evaluate the effect of ENTO on initiation of second-line therapy for cGVHD 
• 
To evaluate the effect of ENTO on progression of cGVHD 
• 
To evaluate the safety and tolerability ofENTO 
• 
Exploratmy objectives include: 
I 
I 
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8.1.2.
Primary Endpoint
The primary endpoint is BORR by 24 weeks, defined as the proportion of subjects who achieve a 
complete or partial overall response (CR or PR) as assessed by the NCAA {34478} within 24 
weeks, in the setting of add-on therapy to systemic corticosteroids as part of first-line therapy for 
cGVHD. 
At each assessment time point, organ-specific responses will be determined according to 
Appendix 4.  An overall time point response across all involved organs will then be determined 
according to Table 8-1.  The best overall response across all time points up to 24 weeks will be 
used to calculate BORR by 24 weeks. 
Table 8-1.
Criteria for time point response determination
Response Category
Response Criteria
Complete response (CR)
Resolution of all cGVHD manifestations in each organ or site as described in the 
NCAA organ response determination table
Partial response (PR)
Improvement of at least 1 organ or site, without progression in any other organ or 
site as described in the NCAA organ response determination table.
Stable disease (SD)
Neither sufficient improvement to qualify for a PR nor sufficient decline to qualify 
for a PD
Progressive disease (PD)

Worsening of signs and symptoms in any organ or site as described in the 
NCAA organ response determination table, taking the current best overall 
response as reference that is not a flare. A flare is defined as acute 
worsening of signs and symptoms in any organ or site that occurs at least 4 
weeks after PR/CR is achieved, which lasts ≤ 4 weeks. 
OR

Increase in systemic corticosteroid dose to ≥ baseline dose (1 mg/kg/day)
OR

Initiation of systemic immunosuppressive therapy other than systemic 
corticosteroids
8.1.3.
Secondary Endpoint
The key secondary endpoints are:

Change from baseline in the skin domain of the LSS at 24 weeks

Change from baseline in the mouth domain of the LSS at 24 weeks

Change from baseline in the eyes domain of the LSS at 24 weeks

Change from baseline in the total score of the LSS at 24 Weeks 


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Other secondaty endpoints include: 
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• 
DOR, defmed as the time from the documentation ofBORR to the documentation ofPD as 
defmed in Table 8-1 . Note that a flare does not constitute an end to response. 
• 
Prop01tion of subjects who achieve at least 50% reduction in systemic cotiicosteroid dose 
relative to baseline, where % reduction is calculated as (systemic c01ticosteroid dose at 
24 weeks - baseline systemic c01ticosteroid dose) I baseline systemic c01ticosteroid dose 
• 
Prop01tion of subjects who initiate second-line therapy for cGVHD, defmed as receiving any 
therapy besides systemic c01ticosteroids or study drug for the treatment of cGVHD. Inhaled 
and topical steroids are not considered second-line therapy. 
• 
Failure-free smvival (FFS), defined as the time from randomization to the earliest of first 
documentation of systemic therapy change, nonrelapse mo1tality, or recurrent malignancy 
• 
Safety and tolerability of ENTO 
8.1.4. 
Other Endpoints of Interest 
Explorato1y endpoints include: 
0 
I 
I 
I 
I 
8.2. 
Analysis Conventions 
All individual subject data will be listed as measured. All statistical summaries and analyses will be 
perfo1med using SAS® software (SAS Institt1te, Cary, N01th Car·olina, USA). 
In general, data will be described and summarized by relevant treatment ann, analysis set, and 
time point. As appropriate, changes from baseline to each subsequent time point will be 
described and summarized by treatment arm. Graphical teclmiques ( eg, Kaplan-Meier cmves, 
waterfall plots, etc.) may be used when such methods are appropriate and inf01mative. 
Summary tables for continuous var·iables will contain the following statistics: N (number in 
analysis set), n (number with data), mean, standard deviation (SD), 95% confidence inte1vals 
(Cis) on the mean, median, minimum, first quatiile (Ql), third qumtile (Q3), and maximum. 
Summaty tables for categorical variables will include: N, n, percentage, and 95% Cis on the 
percentage. 
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Subjects with discrepancies between the stratification factor values at randomization and the
actual values as documented on data review will be categorized in the analyses according to the
actual values.
Unless otherwise specified, all statistical tests will be 2-sided.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analyses will be the Intent-to-Treat (ITT), which includes 
data from all randomized subjects, with treatment assignments designated according to 
randomization. 
Selected efficacy endpoints may also be evaluated using the Per-Protocol (PP) analysis set,
which includes all randomized subjects who received at least one dose of study drug, did not 
violate any major entry criteria, and did not have any major protocol deviations.
8.2.1.2.
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set, which includes data 
from all subjects who received at least one dose of study drug, with treatment assignments 
designated according to actual treatment received. All data collected up to the last dose of study 
drug plus 30 days will be included in the safety summaries. 
8.2.1.3.
Pharmacokinetics (PK)
The PK Analysis Set will include data from subjects in the Safety Analysis Set who have the 
necessary baseline and on-study measurements to provide interpretable results for the specific 
parameters of interest. 
8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial results. In general, values for 
missing data will not be imputed unless methods for handling missing data are specified.
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. 

If a subject received study drug, the subject will be included in the summary of AEs 
according to the treatment received; otherwise, if the subject is not dosed then they will be 
excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject
will be excluded from the calculation of summary statistics for that time point. If the subject
is missing a pre-dose value, then the subject will be excluded from the calculation of
summary statistics for the pre-dose value and the change from pre-dose values.


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Values for missing safety laboratory data will not be imputed; however, a missing Baseline/Day 1
result will be replaced with a screening result, if available. If no pre-treatment safety laboratory 
value is available, the Baseline/Day 1 value will be assumed to be normal (ie, no grade 
[Grade 0]) in the summary of graded laboratory abnormalities. Values for missing vital signs 
data will not be imputed; however, a missing Baseline/Day 1 result will be replaced with a 
screening result, if available.
Laboratory data that are continuous in nature but are less than the lower limit of quantitation 
(LOQ) or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used for calculation of descriptive statistics if 
the data is reported in the form of “<x” (x is considered the LOQ). For example, if the values 
are reported as <50 and <5.0, then values of 49 and 4.9 will be used for calculation of 
summary statistics, respectively. 

A value that is 1 unit above the LOQ will be used for calculation of descriptive statistics if 
the data is reported in the form of “>x” (x is considered the LOQ). For example, if the values 
are reported as >50 and >5.0, then values of 51 and 5.1 will be used for calculation of 
summary statistics, respectively.

The LOQ will be used for calculation of descriptive statistics if the data is reported in the 
form of “≤ x” or “≥ x” (x is considered as the LOQ).
PK concentration values that are below the limit of quantitation (BLQ) will be presented as 
“BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 at pre-dose time 
points, and one-half the value of the lower limit of quantitation (LLOQ) at post-baseline time 
points, where LLOQ is corrected for the dilution factor (ie, reported LLOQ/dilution factor) for 
determination of summary and order statistics.
The following conventions will be used for the presentation of summary and order statistics:

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ”

If more than 25% of the subjects have a concentration value of BLQ for a given time point, 
the minimum and Q1 values will be displayed as “BLQ” 

If more than 50% of the subjects have a concentration value of BLQ for a given time point, 
the minimum, Q1, and median values will be displayed as “BLQ” 

If more than 75% of the subjects have a concentration value of BLQ for a given time point, 
the minimum, Q1, median, and Q3 values will be displayed as “BLQ” 

If all subjects have concentration values of BLQ for a given time point, all order statistics 
(minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ”


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PK parameters that are BLQ will be imputed as one-half LLOQ before log transformation or 
statistical model fitting.
8.4.
Demographic Data and Baseline Characteristics
Demographic data and baseline characteristics will be summarized by treatment group and 
overall using standard descriptive statistics for the ITT Analysis Set.
Demographic data will include: age, gender, race, and ethnicity.
Baseline characteristics will include: body weight, height, body mass index, and other covariates 
as necessary.
The number (proportion of subjects) in each stratum will also be summarized.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary endpoint is BORR by 24 weeks in the setting of add-on therapy to systemic 
corticosteroids as part of first-line therapy for cGVHD. The primary analysis will test the null 
hypothesis that there is no difference in response rate between ENTO + systemic corticosteroids 
and placebo + systemic corticosteroids versus the alternative hypothesis that there is a difference.  
Response rate will be summarized by count and percent of subjects with each ordinal response
(CR, PR, and CR + PR).  A stratified Cochran-Mantel-Haenszel (CMH) Chi-square test for 
association will be performed to compare BORR between ENTO and PTM by 24 weeks.  The 
difference in response rates between treatment groups and the corresponding 95% CIs will be 
presented.
8.5.2.
Secondary Analyses
A sequential testing strategy will be implemented to preserve the overall type I error rate across 
the primary and key secondary endpoints of the study at a 2-sided significance level of 0.05.  The 
primary endpoint analysis will serve as the gatekeeper for the key secondary endpoint analyses,
ie, the primary efficacy endpoint must be met before the key secondary efficacy endpoints can be
tested. The key secondary endpoints included in this sequential testing approach are (1) change 
from baseline in the skin domain of the LSS at 24 weeks, (2) change from baseline in the mouth
domain of the LSS at 24 weeks, (3) change from baseline in the eyes domain of LSS at 
24 weeks, and (4) change from baseline in the total score of the LSS at 24 weeks.
If the primary hypothesis is rejected, the key secondary endpoints will be sequentially tested at 
the 2-sided 0.05 significance level in the order listed above. If a null hypothesis is not rejected, 
formal sequential testing will stop and only nominal significance will be cited for the remaining 
endpoints. 


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The key secondaty endpoints will be analyzed using a MMRM model that includes all available 
data at baseline and all post-baseline visits. The model will include temlS for baseline value, 
stratification factor, treatment, visit, and treatment-by-visit interaction. The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom and adjust standard 
enors. Treatment comparisons will be generated within the MMRM model based on the linear 
contrast of the least square means at all-time points. Adjusted means and 95% Cis will be 
presented by treatment group. Plots of mean (±SE) change from baseline over time will be 
provided by treatment group. Additional sensitivity analyses to fmther evaluate the impact of 
missing data may be perf01med and will be specified in the statistical analysis plan (SAP). 
Other secondaty endpoints will be analyzed as follows: 
DOR and FFS will be analyzed using the Kaplan-Meier (KM) method and stratified logrank test. 
Kaplan-Meier summaty statistics (median, 95% CI for median, and 25th, 75th percentiles) and 
number and percentage of events will be presented by treatment group. A stratified Cox 
prop01iional hazards model will be used to estimate the hazard ratio and conesponding 95% CI. 
A KM survival plot will also be provided. Data for subjects who do not experience an event will 
be censored at the date of last visit. 
Prop01iion of subjects with at least 50% reduction in systemic corticosteroid dose relative to 
baseline and prop01tion of subjects who initiated second-line therapy for cGVHD will be 
analyzed similarly to the primaty endpoint. 
8.5.3. 
Exploratory Analyses 
8.5.4. 
Interim Analysis 
An interim analysis for futility is planned when approximately 50% of subjects have been on 
study for 24 weeks. The futility analysis will be perf01med on BORR by 24 weeks in the ITT 
Analysis Set. A non-binding futility mle will be implemented. Based upon the analysis results, 
the DMC may recommend tetminating the study for lack of efficacy if the predictive power of 
obtaining a statistically significant result at the final analysis given the observed interim data is 
5%. A 2-sided alpha ofO.OOl will be allocated to this futility interim; following the 
Haybittle-Peto approach {1981}, {9845}, the final analysis alpha level is 0.05 (2-sided). 
8.5.5. 
Final Analysis 
The fmal analysis for BORRis platmed when all subjects have been on study for 24 weeks. 
Duration and quality of response will continue to be assessed up to 48 weeks. 
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8.6.
Safety Analysis
All safety data collected on or after the date that ENTO/PTM was first administered up to the 
date of last dose of ENTO/PTM plus 30 days will be summarized by treatment group 
(according to the treatment received). Data for the pre-treatment period will be included in 
data listings. 
8.6.1.
Extent of Exposure
A subject’s extent of exposure to ENTO will be generated from the study drug administration 
eCRF page. Exposure data will be summarized by treatment group. 
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event is defined as any adverse event with onset date on or after the date of first dose of 
study drug up to 30 days after permanent study drug discontinuation, or any adverse events 
leading to premature study drug discontinuation.  Summaries (number and percentage of 
subjects) of treatment-emergent adverse events (by SOC and PT) will be provided by treatment 
group. 
8.6.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using modified CTCAE 4.03.  Maximum
post-baseline grade will be summarized by count and percentage of subjects with each grade.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least
one toxicity grade from baseline at any time post-baseline, will be summarized by treatment
group. If baseline data are missing, then any graded abnormality (ie, at least a Grade 1) will be
considered treatment-emergent.
Laboratory abnormalities that occur before the first dose of study drug or after the subject has 
been discontinued from treatment for at least 30 days will be included in data listings.
8.6.4.
Other Safety Evaluations
Individual data for 12-lead ECG, vital signs measurements will be listed by subject and 
summarized by treatment group by incidence of events/abnormalities or descriptive statistical 
summaries (n, mean, SD, median, Q1, Q3, minimum, and maximum), as appropriate. In 


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comparison to pre-treatment (either Screening or pre-dose on Day 1) values, vital signs 
measurements and ECG findings will additionally be summarized using predetennined, 
clinically relevant thresholds. 
8.7. 
Pharmacokinetic Analysis 
Final 
Original 
Plasma concentrations ofENTO (and metabolite, if applicable) will be displayed as individual 
concentration vs. time using scheduled sampling times, as appropriate. Concentrations will be 
listed by subject and summarized using descriptive statistics ( eg, n, arithmetic mean, geometric 
mean, % coefficient of variation [CV], SD, median, Ql, Q3, minimum, and maximum). Plasma 
concentration vs. time cmves may also be plotted in semi-logarithmic and linear f01mats as mean 
(± SD) and median (Ql , Q3). Available PK parameters will be listed and smnmarized for GS-
9973 using descriptive statistics. 
8.8. 
Biomarker Analysis 
Descriptive statistics of baseline and change in biomarkers will be provided at each sampling 
time for all subjects and by treatment. 
8.9. 
Sample Size 
With 40 subjects per treatment group, there is 75% power to detect a 30% improvement in 
response rate at a 2-sided 0.05 significance level using Fisher's exact test, assuming a placebo 
response rate of 50%. A total of 100 subjects (50 per treatment group) will be emolled assmning 
a 20% dropout rate. 
8.10. 
Data Monitoring Committee 
An extemal multidisciplinmy data monitoring committee (DMC) will review the progress of the 
study, perform interim reviews of safety data at regular inte1vals approximately eve1y 3 months, 
and perform an interim review of efficacy data for futility when approximately 50% of subjects 
have been on study for 24 weeks, as described in the DMC Chmier. The DMC will provide 
recommendations to Gilead as to the whether the nature, frequency, and severity of adverse 
effects associated with study treatment wanant the early te1mination of the study in the best 
interests of the pmticipants, whether the study should continue as planned, or the study should 
continue with modifications. 
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The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable 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.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an . The investigator will not begin any study subject activities until 
approval from the IRB/EC has been documented and provided as a letter to the investigator.
Before implementation, the Investigator will submit to and receive documented approval from 
the IRB/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/EC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/EC approved consent form for documenting 


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written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by the IRB/EC. 
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,., 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 instruction.  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, 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. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 


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as described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (e.g. data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5. 
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.
9.1.7.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/EC, or to regulatory authority or health authority 
inspectors.
9.1.8.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/EC in 
accordance with local requirements and receive documented IRB/EC approval before 
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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies. Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.


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


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10.
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Sarantopoulos S, Stevenson KE, Kim HT, Washel WS, Bhuiya NS, Cutler CS, et 
al. Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host 
disease. Blood 2011;117 (7):2275-83.
34153
Inamoto Y, Flowers ME, Sandmaier BM, Aki SZ, Carpenter PA, Lee SJ, et al. 
Failure-free survival after initial systemic treatment of chronic graft-versus-host 
disease. Blood 2014;124 (8):1363-71.
34157
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. 
National Institutes of Health Consensus Development Project on Criteria for 
Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and 
Staging Working Group Report. Biol Blood Marrow Transplant 2015;21 (3):389-
401 e1.
34211
Lee S, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to 
measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow 
Transplant 2002;8 (8):444-52.
34212
Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood 
2015;125 (4):606-15.
34214
Vigorito AC, Campregher PV, Storer BE, Carpenter PA, Moravec CK, Kiem HP, 
et al. Evaluation of NIH consensus criteria for classification of late acute and 
chronic GVHD. Blood 2009;114 (3):702-8.
34291
Jacobsohn DA, Vogelsang GB. Acute graft versus host disease. Orphanet J Rare 
Dis 2007;2:35.
34292
Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology 
and therapy. Nature reviews 2012;12 (6):443-58.
34478
Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, et al. Measuring 
Therapeutic Response In Chronic Graft-Versus-Host Disease. Biol Blood Marrow 
Transplant 2015.
34778
Herskowitz A, Willoughby SB, Baughman KL, Schulman SP, Bartlett JD. 
Cardiomyopathy associated with antiretroviral therapy in patients with HIV 
infection: a report of six cases. Ann Intern Med 1992;116 (4):311-3.
35386
Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. 
Predominant autoantibody production by early human B cell precursors. Science 
2003;301 (5638):1374-7.
36995
Dubovsky JA, Flynn R, Du J, Harrington BK, Zhong Y, Kaffenberger B, et al. 
Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin 
Invest 2014;124 (11):4867-76.


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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36996
Miklos DB, Arora M, Cutler CS, Nakamura R, Juretic M, Li Y, et al. A 
multicenter open-label phase 1b/2 study of ibrutinib in steroid dependent or 
refractory chronic graft versus host disease (cGVHD) [Abstract 7024]. American 
Society of Clinical Oncology (ASCO) Annual Meeting; 2015 29 May - 02 June; 
Chicago, IL. 
37403
Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesar D, et al. In 
vivo measurements document the dynamic cellular kinetics of chronic 
lymphocytic leukemia B cells. J Clin Invest 2005;115 (3):755-64.
37404
Ladell K, Hellerstein MK, Cesar D, Busch R, Boban D, McCune JM. Central 
memory CD8+ T cells appear to have a shorter lifespan and reduced abundance as 
a function of HIV disease progression. J Immunol 2008;180 (12):7907-18.
37405
Emson CL, Fitzmaurice S, Lindwall G, Li KW, Hellerstein MK, Maibach HI, et 
al. A pilot study demonstrating a non-invasive method for the measurement of 
protein turnover in skin disorders: application to psoriasis. Clinical and 
translational medicine 2013;2:12.


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 79
11 November 2015
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
For Screening: NIH cGVHD Diagnosis and Staging Criteria, Global Severity Score 
{34157}
Appendix 3.
For Screening: NIH cGVHD Diagnosis and Staging Criteria (NCDSC) Form 
{34157}
Appendix 4.
For Baseline + Subsequent Visits:  Response Determination for the NIH cGVHD 
Activity Assessment (NCAA) {34478}
Appendix 5.
For Baseline + Subsequent Visits: Chronic GVHD Activity Assessment- Clinician
Appendix 6.
For Baseline + Subsequent Visits: Lee Symptom Scale {34211}
Appendix 7.
Grading of Adverse Event Severity
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 9.
Schedule of Assessments for the Optional Cellular Turnover Substudy


Entospletinib 
Protocol GS-US-406-1840 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Fioa.l 
Original 
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO 
ASSESS THE EFFICACY AND TOLERABILITY OF ENTOSPLETINffi, A 
SELECTIVE SYK INHIBITOR, IN COMlUNATION WITH SYSTEMIC 
CORTICOSTEROIDS AS FIRST-LINE THERAPY IN SUBJECTS WITH CHRONIC 
GRAFT VERSUS HOST DISEASE (CGVHD) 
GS-US-406-1840 Protocol Original ll November 2015 
This protocol has been approved by Gilead Sciences, Inc. The fo11owing signature documents 
this approval. 
PD 
11 · n!+Kio 
HAlleo/1/Po 
Name (Printed) Mario Marcondes, MD, 
PhD 
II 
Date 
1 
l have read the protocol, including all appendices, and 1 agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
Twill provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Jnc. I will discuss this material with them to ensure 
lhat they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Sile Number 
CONFIDENTIAL 
Page 80 
I l November 2015 


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CONFIDENTIAL
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Appendix 2.
For Screening: NIH cGVHD Diagnosis and Staging Criteria, Global Severity Score {34157}
Mild chronic GVHD
1 or 2 Organs involved with no more than score 1
plus
Lung score 0
Moderate chronic GVHD
3 or More organs involved with no more than score 1
OR
At least 1 organ (not lung) with a score of 2
OR
Lung score 1
Severe chronic GVHD
At least 1 organ with a score of 3
OR
Lung score of 2 or 3
Key points:
In skin: higher of the 2 scores to be used for calculating global severity.
In lung: FEV1 is used instead of clinical score for calculating global severity.
If the entire abnormality in an organ is noted to be unequivocally explained by a non-GVHD documented cause, that organ is not included for 
calculation of the global severity.
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes) the scored organ will be used for calculation of the 
global severity regardless of the contributing causes (no downgrading of organ severity score).


Entospletinib 
Protocol GS-US-406-1840 
Final 
Gilead Sciences, Inc. 
Original 
Appendix 3. 
For Screening: NIH cGVHD Diagnosis and Staging Criteria (NCDSC) 
Form 
{34157} 
SCOREO 
SCOREJ 
SCORE2 
PKRFOJntA="Ct: 
0 Asymptomatic and 
0 Symptomatic, 
0 Symptomatic, 
0 Symptomatic, 
SCORE: 
fully active (ECOG 
I 
fully ambulatory, 
ambulatory, capabl• 
Limited self-care, 
0: KPS or LJ>S 
restricted only in 
of self-care. >50% 
>50% ofv."llking 
KPS ECOC LPS 
100%) 
physically 
of waking hours ou 
bours in bed (ECOG 
SKfNt 
SCORE"'o USA D 
G Vi !D features to be scored 
0 No BSA 
involve-d 
Ch«k all that apply: 
0 Maculopapula.r raslllerylhema 
0 Lichen planus-like features 
0 Sclerotic fea11u es 
0 Papulosquamous lesions or 
icblbyosis 
0 Keratosis pilaris-like GVHD 
SKIN Ff'.A TI;R.F;S 
SCOR£: 
0 No sclerotic 
features 
Odrer .ykju GVliD &atrrre• fNOT •corM kv 8.\"4) 
Check all that apply: 
0 IlyperpJgmenunion 
0 Hypopigmcnlation 
0 Polkilodcnna 
0 Severe or generalized pruritus 
0 Hair 
0 Nail involvcmenl 
strenuous activil)l 
(ECOG I. KPS 
or LPS 80-90%) 
0 1-J S% BSA 
oflwd (ECOG 2, 
KPS or LI'S 60-
70%) 
0 19-50% BSA 
0 SupcrCicial 
sclerotic features 
"not hidebound" 
(able to pinch) 
0 Abnormali1y presem blll explained emirely by non-C VHD tfocumemed cause (specify): 
Moun1 
0 No symptoms 
0 Mild symptoms 
0 Mo<kratc 
Uchen pl011us-like 
with disease signs 
symptoms with 
features present: 
but not limitmg 
disease signs with 
0 Yes 
oral intake 
partial limitation 
0 
o 
significantly 
of oral intake 
0 Ab11ormality pre.sem bur explained emire/y by no!I·CV/iD documemed <:OIISe (sped.fyj; 
3-4. KPS or LPS 
<60%) 
0 >50% BSA 
Cbssk all that apply: 
0 Deep sclerotic 
features 
0 "tlidcbound" 
(unable to piurh) 
0 lmpitir<Jd mobllity 
0 {)lceration 
0 Severe symptoms with 
disease signs oo 
examination with major 
limitation of oral intake 
I. Organ sc:o m g a r cluulic CVHO. ECOC i nd1Cilld 
Cool"'rat..., Onc:ology Croup; KJ>S. t<.trno&ky 11! 
StalllS; I.PS. Lansky 
BSA. body surf.our area: AOl. ao:ivltoes or da1ly hvmg: l.Fl's. hver funcoon ""ts; AP. 
AI.T. alan ine anunottansfrra.se; ULN. rr>rmal upprr 
"WeJgln lass WJtbm 3 rnondu.ISlcin SCOJingsttould u.sr both pt•;ru'Tir.ageorBSA o:tV<llved by 
signs and theCUl.dnrous rurures sc.tles. When a d.screp.mcy exlsts 
the pcrct'lltage of liltat body 
(BSA) 
.md 
sldn 
scote. OR if s uperlicl.d scll!rotic 
.cre present 
but there is 
mobiluy or 
(Score 3). the hJgher 
should be used for the liuaJ skin scoring. lio be 
by spcc1alist ot tr.lmt'd 
kal 
S..pprnrruJ ltJ:tn). - LlDlJ: sc:omg should be perfomr d using both lhe symptoolS and fEVl srores 
posstblt. f£Vl should be 
10 the final lung 
where there is dJSCrep.lrcy bet"""'" symptoms and fi:VI srord. 
CONFIDENTIAL 
Page 82 
11 November 2015 


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SCOREO 
0 No symptoms 
Ke.ratoconjrmctivitis 
sicca (KCS) confinned 
by ophthalmologist: 
0 Yes 
0 No 
0 Not examined 
SCORE I 
0 Mild dry eye 
symptorus not 
affecting ADL 
(requirement of 
lubricant eye 
drops .::, 3 x per 
day) 
SCORE2 
0 Moderate dry eye 
symptoms partially 
affecting ADL 
(requiring lublicant 
eye drops > 3 x per 
day or puncta) 
plugs), 
WITHOUT new 
vision impairment 
dueto KCS 
0 Abnormality present bwt explained entirely by non-GVHD documented cause (soecifl'): 
Gl Tract 
Check all that apply: 
0 Esophageal web/ 
proximal stricture 
or ring 
0 Dysphagia 
OAnorexia 
0 Nausea 
0 Vomiting 
0 Diarrhea 
0 Weight lo.s 2:_S%* 
0 Failure to thrive 
0 No s}mptoms 
0 Symptoms 
without 
significant weight 
loss• (<5%) 
0 Symptoms 
associated with 
mild to moderate 
weigbl loss• 
(5- 15%) OR 
modcntc diarrhea 
without 
interference with 
daily living 
0 Abnormality presentlwt explained entirely by non-G VHD documented cause [.\pec{/YL-
0 NonnaJ tota I 
bilirobin and 
ALTorAP 
< 3xULN 
0 Not·roaJ total 
bilirubin with ALT 
:::;3 to5 x ULN or 
AP2:_3x ULN 
0 Elevated total 
bilirubin but 
.::,3 mgfdL or 
ALT>5 ULN 
0 Ab,tormulity present but explained entire!)' by non-GVHD documented cause (soecify): 
LUNGS .. 
score; 
Lung score: 
%FBVJD 
Pulmonary j imction tests 
0 Not perfonned 
0 No symptoms 
0 f'EV1<:80% 
0 Mild symptoms 
(shortness of 
bn:ath at\er 
climbing one Oight 
of steps) 
O FEVI 60..79% 
0 Mode.mte 
symptoms 
(shortrtCSS ofbn:alh 
after ·walking on 
flat grow1d) 
0 FEVJ 40-59% 
SCORE 3 
0 Severe dry eye 
symptoms significantly 
affecting ADL (special 
eyeware to relieve pain) 
OR unable to work 
because of ocular 
symptoms OR Joss of 
vision due to KCS 
0 Symptoms associated 
with significant weight 
loss• > 15%. requires 
nutritional 
fOr 
most calorie needs OR 
esophageal dilation OR 
severe dian·hca with 
significant interference-
with daily living 
0 Elevated total 
bilintbin > 3 rog/dL 
0 Severe syroptoms 
(shortness of breath at 
rcs1; requirin.g Oz) 
0 FEV199% 
0 Abnormality present bwt explained entirely by nou-OVf{f) d<)CUmellled cause 
f'.gure 1. {oondrrued). 


Entospletinib 
Protocol GS-US-406-1840 
Gilead Sciences, Inc. 
JOIXrS Al\"D FASCIA 
P-ROM score 
(su below) 
Shoulder (1-7):_ 
F.lbow( l-7): _ 
WrisTlnnger (1-7):_ 
Ankle (1 -4) :_ 
SCOREO 
0 No 
symptoms 
SCORE 1 
0 :'vlild 
of 
arms or legs, 
nonnaJ or mild 
decreased range of 
motion (ROM) 
AND not affecting 
ADL 
SCORE2 
0 Tightness of arms or 
legs OR joint 
contrucrun:s. 
<:rythcma thought 
due to fasciitis, 
moderate decrease 
ROM AND mild to 
moderate limitation 
ofADL 
Final 
Original 
SCORE 3 
0 Conn·acturcs WITH 
significant decrease of 
ROM AND significant 
limitation of ADL 
(unable to tie shoes, 
button 
self 
etc.) 
0 Abnonnality presenr bu1 l"xplained entirl"ly by non-GVHD documl"nted c.fiJJSl" (specify): __________ __ . 
GENI1'AL TRACJ' 
0 No signs 
0 Mild signs1 and 
0 Moderate signsl and 
(Srr Sunplrmen(al figure' ) 
t'emales with or 
may have 
0 Not examined 
wilbout discomfort 
symptoms with 
Currently sexually aclivt> 
on exam 
discomfo1t on exam 
D Yes 
0 No 
0 Abnonnaliry present bur &p!ained entirely bv non-GVHD documl'nted cause (specify): 
0 Severe signs1 Yooilh 
or wilbouL 
symptoms 
Other indi<:ators, slinicnl fsatnr£f gr sonrglka!fons related to chronic CVllp Cshsck all thai apply and ay,jgn. a 
.score IO seyeriry m, :ll hued on functional Impact 
anplicallle nons- 0 mild ·I moderate - 2 
3) 
0 Ascites. (serositis)_ 
0 Pericar>dial Effusion_ 
0 Pleural Effu,ion(s)_ 
CONFIDENTIAL 
0 Myastbenia Gravis_ 
0 Peripheral Neuropalby_ 
0 Polymyositis_ 
0 Wei lloss>S%• w iliJOI.Il Gl s 
[J NoGVUD 
[J MUd 
Wrtfit,'f'inttr 
Figure J_ (a>n OnUt'd). 
Page 84 
0 Eosinophilia > 500/JII_ 
0 Platelets <100,000/J!I _ 
0 
[J 1\todu atc 
[J Severe 
11 November 2015 


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Supplemenr f igure - Genital Tract Chronic Graft-,·er:.5us-Hosr Assessment and Scoring f orm 
:"'Jame· 
. . 
Date of binb· 
Assessment date· 
" 
. 
SCORE O 
SCORE I 
SCORE 2 
SGORE3 
GE!'<TI.U TR'I.CT 
D No signs 
D Mild signs and 
D Moderate signs 
D Severt signs with 
Check: 
females may have 
and may have 
or without 
symptoms" WITH 
symptoms* with 
symptoms* 
D Male DFema!e 
di3comfort ou exam 
discomfort on cxnm 
Cul'renrh· sexuallY actin: 
D Yes 0
No 
oll 
tl1af Dfl2.ll': 
D Erosion'S. 
D Lichen planus-like features 
D Fissures 
D Lichen sclerosis-like features 
D Ulcers 
D Vaginal scarring (female) 
D Phimosi; (male) 
D Clitoral/labial agglutination (female) 
D Urethralme.ants scarring/ stenosis (male) 
D Labial re.:;orption (bm.'lle) 
D Abnormalily present but NOT thought to represent GI'HD (specify cause): 
D Abnormalily thought to represetlt GVHD PLUS other causes(specify cause): 
• Gem tal symptoms are 
specific to cGVHD and can represent premaiurt gonadal fOllure or genital tract mfecflon. 
If a gyne('ologist is 
external examination may be performed to de-te.mline 
on exam" as follows: 
a) Spread the labia lllJljora to inspe.ct the. vulva for the above signs. Touch the vestibular gland openings (Skene's and 
Bartholin's), labia minora and majora gently with a qtip. Vulvar pain elicited by the gentle touch of a qrip is 
classified as discoofort on examination. Palpate. the vaginal walls with a single. digit to detect bauds, shortening, 
narrowing or other signs of vaginal scarring. 
b) If the woman is sexually active, detenniue whether qtip palpation or gentle palpation of scarred ridges elicits pain 
similar to that which the woman experiences during intercourse . 
Female g-enitalia: Severity of signs: 
I) Mild (any of the following); erythe.ma on vulvar mucosal surfaces, vulva: lichen-planus or""'"' lichen-sclerosis. 
2) Moderate-(any of the 
erosive intlammatOI)' changes of the. \<1llvar mucosa, fissures in vulvar folds 
3) Severe (any of the following); labial fttsion, clitoral hood agglutinatio11, fibrinous vaginal adhesions, circumferential 
fibrous vaginal bandmg, vaginal shorte-ning, 
dense sclerotic dwtges. and complete vaginal stenosis. 
gtnitalia: Diagn()stic features include lichen planus-like or lichen sclerosis-like feat\lres and phymosis or urethral 
scarring or stenosis. Se\'e-rity of sigru: 
I) .Mild: lichen planus-like featme.; 
2) Moderate: lichen sclerosus-like feature or moderate erythema; 
3) Severe: phimosis or urethraVmeataJ scarring. 
obtained: 
D !\o 
Site biop.;ied: _____ G\"BD C'onfirmed by hi<i-tology: D Yes 
D No 
Change from prniou<> e'l':tlu:ttion: D No prior or <'Urnnl CYHD D lmprond D 
D \Yom D 'S/A (b . ...W.t) 
Completed b;- (pl'int n.1me): 
Date fol'm ('Ompleftd: 


Entospletinib 
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CONFIDENTIAL
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Appendix 4.
For Baseline + Subsequent Visits: 
Response Determination for the NIH cGVHD Activity Assessment (NCAA) {34478}
Organ 
Complete Response 
Parlial Response 
Progression 
Skin 
NIH Skin Score 0 after 
Decrease in NIH Skin Score 
Increase in NIH Skin Score by 1 or 
previous involvement 
by 1 OJ' more points 
more points, except 0 to 1 
Eyes 
NIH Eye Score 0 after 
Decrease in NIH Eye Score 
Increase in NIH Eye Score by 1 or 
previous iovolvemem 
by 1 or more points 
more points, except 0 to 1 
Mouth 
NIH Modified OMRS 0 after 
Decrease in NIH Modified OMRS 
Increase in NIH Modified OMRS 
previous involvement 
of 2 or more points 
of 2 or more points 
Esophagus 
NIH Esophagus Score 0 after 
Decrease in NIH Esophagus 
Increase in NIH Esophagus Score 
previous involvement 
Score by 1 or more points 
by 1 or more points. except 0 to I 
Upper Gl 
NIH Upper Gl Score 0 after 
Decrease in NIH Upper Gl 
Increase in NIH Upper Gl Score 
previous involvement 
Score by 1 or more points 
by 1 or more points, except 0 to 1 
!.ower Gl 
NIH tower Gl Score 0 after 
Decrease in NIH tower Gl 
Increase in NIH tower Gl Score by 1 
previous involvement 
Score by 1 or more 
or more points, except from 0 to 1 
Uver 
Normal AL T, alkaline 
Decrease by 50% 
Increase by 2 x ULN 
phosphatase, and Total 
bilirubin after previous 
elevation of 1 or more 
Lungs 
- Normal J FEVl after 
Increase by 1 0% predicted 
- DeCI'ease by 10% pr·edicted 
previous involvement 
absolute value of JFEV1 
absolute value of JFEV1 
- If PFTs nor available, NIH 
• If PFTs nor available, decrease 
• If PFTs not available, increase in 
Lung Symptom Score 0 
in NIH Lung Symptom Score 
NIH Lung Symptom Score by 1 
after previous involvement 
by 1 or more points 
or more points, except 0 to 1 
Joints and fascia 
Both NIH Joint and Fascia 
Decrease in NIH Joint and Fascia 
Increase in NIH joint and Fascia 
Score 0 and P-ROM score 
Score by 1 or more points or 
Score by 1 or more points or 
25 after previous involvement 
increase in P-ROM score by 1 
decrease in P-ROM score by 1 
by at least 1 measure 
point for any site 
point for any site 
Global 
Clinician overall severity score 0 
Clinician overall severily score 
Clinidan overall severily score 
decreases by 2 or more points 
increases by 2 or more points 
on a 0·10 scale 
on a 0-10 scale 
ULN indicates upper limit of normal. 


Entospletinib 
Protocol GS- US-406-1840 
Gilead Sciences, Inc. 
Final 
Original 
Appendix 5. 
I FORMA 
For Baseline + Subsequent Visits: Chronic GVHD Activity 
Assessment- Clinician 
Current Patient Weight: ____ _ 
Today's Date: _____ MR#/Name: ---------
CHRONIC GVHD ACTIVITY ASSESSMENT- CLINICIAN 
Health Care 
Since the last assessment would you 
Provider 
Where would you rate the severity of this patient's chronic 
say that this patient's cGvHD is 
Global 
GvHD symptoms on the following scale, where 0 is cGVHD 
+3= Very much better 
Ratings: 
symptoms that are not at all severe and 10 is the most 
+2= Moderately better 
severe cGVHD symptoms possible: 
+1= A little better 
O=none 
0= About the same 
1=mild 
0 
1 
2 
3 
4 
5 
6 
7 
-1 =A little worse 
2=moderate 
8 
9 
10 
-2=Moderately worse 
3=severe 
cGvHD symptoms 
-3=Very much worse 
Most severe cGvHD 
not at all severe 
symptoms ossible 
Erythem 
No 
0 
Mild erythema 
1 
Moderate 
2 
Severe 
3 
Mouth 
a 
ne 
or moderate 
or 
erythema 
erythema 
Severe 
(<25%) 
erythema 
(<25%) 
Lichenoi 
No 
0 
Lichen-like 
1 
Lichen-like 
2 
Lichen-like 
3 
d 
ne 
changes 
changes (25-
changes 
(<25%) 
50%) 
(>50%) 
Ulcers 
No 
0 
Ulcers 
3 
Severe 
6 
ne 
involving 
ulcerations 
(>20%) 
Total score for all mucosal changes 
Gastrointestinal-
0= no esophageal symptoms 
Esophageal 
1=0ccasional dysphagia or odynophagia with solid food or pills during the past week 
• 
Dysphagia 
2=1ntermittent dysphagia or odynophagia with solid foods or pills, but not for liquids or soft 
OR 
foods, during the e.ast week 
Odynophagia 
3=Dysphagia or odynophagia for almost all oral intake, on almost everv dav of the past 
week 
Gastrointestinal-
0= no symptoms 
UpperGI 
1=mild, occasional symptoms, with little reduction in oral intake during the past week 
• 
Early satiety 
2=moderate, intermittent symptoms, with some reduction in oral intake during the past week 
OR 
3=more severe or persistent symptoms throughout the day, with marked reduction in oral 
• 
Anorexia 
intake, on almost every dav of the e.ast week 
OR 
• 
Nausea & 
Vomiting 
Gastrointestinal-
0= no loose or liquid stools during the e.ast week 
Lower Gl 
1= occasional loose or liquid stools, on some days during the past week 
• 
Diarrtlea 
2=intermittent loose or liquid stools throughout the day, on almost every day of the past 
week. without requiring intervention to prevent or correct volume depletion 
3=voluminous diarrhea on almost every da-r. of the e.ast week, requiring intervention to 
orevent or correct volume deoletion 
Lungs (Liters and % 
FEV1 
FVC 
Single Breath DLCO (adjusted 
TLC 
RV 
predicted) 
for hemoglobin) 
• 
Bronchiolitis 
Obliterans 
CONFIDENTIAL 
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Liver Values
Total serum 
bilirubin
                          
mg/dL
ULN
                          
                     
mg/dL
ALT
                      
U/L
  ULN                
                          
U/L
A kaline 
Phosphatase
                            
U/L
ULN
                       
                       
U/L
Baseline Values
Total Distance Walked in 2 or 6
Mins: 
                                                 
2 min        6 min
Karnofsky or 
Lansky 
Platelet Count    
                          
K/uL
Total WBC           
                            
K/uL
Eosinophils
                        
                        
%               
. Abnormality present but explained entirely by non-GVHD documented cause (specify site/alternate 
cause):_______________________________
 Abnormality present but explained entirely by non-GVHD documented cause (specify site/alternate 
cause):_______________________________
 Abnormality present but explained entirely by non-GVHD documented cause (specify site/alternate 
cause):_______________________________


Entospletinib 
Protocol GS- US-406-1840 
Gilead Sciences, Inc. 
Final 
Original 
CHRONIC GVHD ACTIVITY ASSESSMENT- CLINICIAN (FORM A) 
SCOREO 
SCORE 1 
SCORE2 
SCORE3 
SKii'\T 
0 NoBSA 
0 1-18%BSA 
0 19-50%BSA 
0 >50%BSA 
involved 
GVHD (§atures to be 
scored 
bvBSA: 
Check all that aJ!J!lv: 
0 Maculopapular rash I 
erythema 
0 Lichen planus-like 
features 
0 Sclerotic features 
0 Papulosquamous lesions 
or 
ichthyosis 
0 Keratosis pilaris-like 
D Abnotmality present but explained entirely by non-GVHD documented cause 
(specify): 
r'h('ck all that aJ)_nfy: 
SKIN FEATURES 
0 No sclerotic 
0 Superficial 
0 Deep sclerotic 
SCORE: 
featmes 
sclerotic features "not 
features 
hidebotmd" (able to 
0 "Hidebound" 
pinch) 
(tmable to pinch) 
0 Impaired mobility 
0 Ulceration 
If skin features score = 3, BSA% of non-moveable sclerosis/fasciitis 
How would you rate the severity of this patient's skin and/or joint tightening on the following scale, where 0 is 
not at all severe and 10 is the most severe symptoms possible: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Symptoms 
Most severe 
not at all severe 
symptoms possible 
EYES 
0 No 
0 Mild dty eye 
0 Moderate dty eye 
0 Severe dty eye 
symptoms 
symptoms not 
symptoms partially 
symptoms 
symptoms 
affecting ADL 
affecting ADL 
significantly 
(requirement of 
(requiring lubricant 
affecting ADL 
lubricant eye 
eye dt·ops > 3 x per 
(special eyeware 
drops .:::: 3 x per 
day or ptmctal 
to relieve pain) 
day) 
plugs), WITHOUT 
OR unable to 
new vtston 
work because of 
impairment due to 
ocular symptoms 
KCS 
OR loss of vision 
duetoKCS 
D Abnmmality present but explained entirely by non-GVHD documented cause 
(specify): 
CONFIDENTIAL 
Page 89 
11 November 2015 


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 90
11 November 2015
SCORE 0
SCORE 1
SCORE 2
SCORE 3
LUNGS
 No symptoms
  Mild symptoms 
(shortness of 
breath after 
climbing one 
flight of steps)
  Moderate symptoms 
(shortness of breath 
after walking on flat 
ground)
  Severe symptoms 
(shortness of 
breath  at rest; 
requiring 02)
 Abnormality present but explained entirely by non-GVHD documented cause
(specify):
JOINTS AND FASCIA
  No symptoms   Mild tightness of 
arms or legs, normal 
or mild decreased 
range of motion 
(ROM) AND not 
affecting ADL
  Tightness of arms or 
legs OR joint 
contractures, erythema 
thought due to fasciitis, 
moderate decrease ROM 
AND mild to moderate 
limitation of ADL
  Contractures WITH
significant decrease of 
ROM AND 
significant limitation 
of ADL (unable to tie 
shoes, button shirts, 
dress self etc.) 
 Abnormality present but explained entirely by non-GVHD documented cause
(specify):_______________________
Not done
Not done
Not done
Not done


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 91
11 November 2015
                        Today’s Date: ________________________
MR#/Name: ________________________
CHRONIC GVHD ACTIVITY ASSESSMENT-PATIENT SELF REPORT
Symptoms
Not                                                                                                                                           
As Bad As You
Present                                                                                                                                    
Can Imagine
   
 0           1         2         3          4         5         6         7         8          9         10
Please rate how severe the 
following symptoms have been in 
the last seven days.  Please fill in 
the circle below from 0 (symptom 
has not been present) to 10 (the 
symptom was as bad as you can 
imagine it could be) for each item.
Your skin itching at its WORST?
O
O
O
O
O
O
O
O
O
O
O
Your skin and/or joint tightening
at their WORST?
O
O
O
O
O
O
O
O
O
O
O
Your mouth sensitivity at its 
WORST?
O
O
O
O
O
O
O
O
O
O
O
Your genital discomfort at its 
WORST?
(Women – vagina, vulva, or labia)
(Men – penis)
O
O
O
O
O
O
O
O
O
O
O
Eyes
What is your main complaint with regard to your eyes?
Please rate how severe this symptom is, 
from 0 (not at all severe) to 10 (most 
severe):
0    1     2     3     4     5     6     7     8      9    10
Patient Global Ratings:
1. Overall, do you think that your chronic graft versus host disease is mild, moderate or severe?
1= mild
2=moderate
3=severe
2. Please circle the number indicating how severe your chronic graft versus host disease symptoms are, 
where 0 is cGvHD symptoms that are not at all severe and 10 is the most severe chronic GvHD symptoms 
possible.
          0         1           2           3           4           5           6           7           8            9           10
cGvHD symptoms                                                                                                                                       Most severe cGvHD                                                
not at all severe                                                                                                                                           symptoms  possible
                                                                                                                                                                           
3. Compared to a month ago, overall would you say that your cGvHD symptoms are:
+3= Very much better
+2= Moderately better
+1=A little better
0= About the same
-1=A little worse
-2=Moderately worse
-3=Very much worse
FORM B


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 92
11 November 2015
Appendix 6.
For Baseline + Subsequent Visits: Lee Symptom Scale {34211}
By circling one (1) number per line, please indicate how much you have been bothered by the 
following problems in the past 7 days: 
SKIN: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
1. 
Abnormal skin color. ................... 
0 
2 
3 
4 
2. 
Rashes .................. ···············-·· 
0 
2 
3 
4 
3. 
Thickened skin ........ ... ............ 
0 
2 
3 
4 
4. 
Sores on ski11.. ..........•... ·····- ····· 
0 
2 
3 
4 
5. 
Itchy skin ...... .............. .......... 
0 
2 
3 
4 
EYES AND MOUTH: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
6. 
Dry eyes ....•............................. 
0 
2 
3 
4 
7. 
Need to use eye drops frequently .. 
0 
2 
3 
4 
8. 
Difficulty seeing cleal'fy ........... , ... 
0 
2 
3 
4 
9. 
Need to avoid certain foods due to 
0 
2 
3 
4 
mouth pain .•........ 
. ............ 
10. Ulc.ers in mouth ......................... 
0 
2 
3 
4 
11 . Receiving 
from an 
intravenous line or feeding tube .... 
0 
2 
3 
4 
BREATHING: 
Not at 
Slightly 
Moderately 
Quite a 
Extremely 
all 
bit 
12. Frequent cough ......................... 
0 
2 
3 
4 
13. Colored sputum ......................... 
0 
2 
3 
4 
14. Shortness of bteath with exercise .. 
0 
2 
3 
4 
15. Shortness of breath at rest. ........ 
0 
2 
3 
4 
16. Need to use oxygen ................. 
0 
2 
3 
4 


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 93
11 November 2015
Which of the following 2 have you found to affect you the most in the last seven days:
1. Skin
2. Eyes and Mouth
3. Breathing
4. Eating and Digestion
5. Muscles and Joints
6. Energy 


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 94
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Appendix 7.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2
Moderate
Local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL 
Grade 3
Severe
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL  
Grade 4
Life-threatening
Urgent intervention indicated 
Grade 5
Death 
Death related AE 
*
Activities of Daily Living (ADL) Instrumental ADL refer to opening preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 95
11 November 2015
Appendix 8.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
ENTO is contraindicated in pregnancy as animal studies in rats and rabbits have shown that 
study drug is teratogenic. Pregnancy must be excluded before the start of treatment with study 
drug and prevented thereafter by reliable contraceptive methods. Pregnancy tests will be 
performed regularly throughout this study per Table 6-1. Please refer to the latest version of the 
investigator’s brochure for additional information.
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 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
ENTO is contraindicated in pregnancy as there is a strong suspicion of human 
teratogenicity/fetotoxicity in early pregnancy based on non-clinical data. In addition, ENTO has 
insufficient data 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. 
Please refer to the latest version of the investigator’s brochure for additional information.
b) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must also not rely on hormone-containing contraceptives as a 
form of birth control during the study.  They must have a negative serum pregnancy test at


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 96
11 November 2015
screening and a negative pregnancy test on the Baseline/Day 1 Visit.  Pregnancy tests will be 
performed on the protocol-specified schedule thereafter.  Female subjects must agree to one of 
the following methods to avoid pregnancy from Screening until 30 days from the last dose of 
ENTO:

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.
a) Intrauterine device (IUD) with a failure rate of <1% per year
b) Tubal sterilization
c) Essure micro-insert system (provided confirmation of success 3 months after procedure)
d) 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 from the last dose of ENTO.
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 from the 
last dose of ENTO.  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 
from the last dose of ENTO.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.


Entospletinib 
Protocol GS–US-406-1840
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 97
11 November 2015
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose.  Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator.  Instructions for reporting pregnancy, partner pregnancy, and pregnancy 
outcome are outlined in Section 7.6.


PPD 
Entospletinib 
Protocol GS-US-406-1840 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Page 98 
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Original 
11 November 2015 

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