Clinical trial NCT02343939
Conditions: Acute Myeloid Leukemia
Sponsor: Gilead Sciences
Start date: 2015-07-01; Completion date: 2019-02-21
Enrollment: 148 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will evaluate the efficacy, safety, and tolerability of entospletinib when administered as monotherapy or in combination with chemotherapy in adults with acute myeloid leukemia (AML).

Detailed description:

Arms: arm 1: Dose Escalation: Entospletinib up to 400 mg for 14 days and then entospletinib up to 400 mg in combination with daunorubicin and cytarabine for up to two 14-day cycles.

Dose Expansion: Entospletinib 400 mg for 14 days and then entospletinib 400 mg in combination with daunorubicin and cytarabine for up to two 14-day cycles. Some participants will have the option to receive post-induction therapy with entospletinib 400 mg in combination with cytarabine/cytosine arabinoside (ARA-C). Participants may receive maintenance therapy with 28-day cycles of entospletinib 400 mg for up to twelve 28-day cycles, if the participant is not eligible for stem cell transplant. arm 2: Dose Escalation: Entospletinib 400 mg for 14 days and then entospletinib 400 mg in combination with decitabine for 10 days beginning on Day 1 of every 28-day cycle (at least 2 cycles of induction therapy but no more than 4 cycles). Participants who are intolerant of decitabine may switch to entospletinib monotherapy maintenance at any time after completing the first 2 cycles.

Dose Expansion: Entospletinib 400 mg for 14 days for the safety run-in participants or Entospletinib 400 mg for 5 days for the randomization participants. Then entospletinib 400 mg in combination with decitabine or azacitidine (at least 2 cycles of induction therapy but no more than 4 cycles). Some participants will have the option to receive maintenance therapy with entospletinib in combination with decitabine or azacitidine. Participants who are intolerant of decitabine or azacitidine may switch to entospletinib monotherapy maintenance at any time after completing the first 2 cycles. arm 3: Dose Escalation: Entospletinib up to 800 mg for 28-day cycles until the participant meets criteria for study treatment discontinuation per the study protocol.

Dose Expansion: Entospletinib 400 mg for 28-day cycles until the participant meets criteria for study treatment discontinuation per the protocol.
Interventions: intervention 1: Entospletinib intervention 2: Daunorubicin intervention 3: Cytarabine intervention 4: Decitabine intervention 5: Azacitidine
Intervention descriptions: intervention 1: Tablet(s) administered orally every 12 hours intervention 2: 60 mg/m\^2 administered intravenously daily on Days 1 to 3 for up to two 14-day induction cycles intervention 3: 100 mg/m\^2 administered intravenously daily on Days 1 to 7 for up to two 14-day cycles intervention 4: 20 mg/m\^2 administered intravenously intervention 5: 75 mg/m\^2 administered intravenously or subcutaneously

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1b/2 Study of Entospletinib (GS-9973) Monotherapy and 
in Combination with Chemotherapy in Patients with Acute 
Myeloid Leukemia (AML)
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
116416
2016-003353-16
NCT02343939
Indication:
Acute Myeloid Leukemia 
Protocol ID:
GS-US-339-1559
Gilead Medical Monitor:
Name:
Telephone:
E-mail:
Protocol Version/Date:
Original:
05 December 2014
Amendment 1:
21 January 2015
Amendment 2:
12 May 2015
Amendment 3:
24 November 2015
Amendment 4:
05 August 2016
Amendment 5: 
14 February 2017
Amendment 6: 
04 August 2017
Amendment 7: 
15 February 2018
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
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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....................................................................16
1.
INTRODUCTION ..............................................................................................................................................21
1.1.
Acute Myeloid Leukemia.......................................................................................................................21
1.1.1.
SYK Biology in Stem Cells and AML.................................................................................21
1.2.
Entospletinib ..........................................................................................................................................23
1.2.1.
Nonclinical Pharmacology ...................................................................................................23
1.2.2.
Nonclinical Drug Metabolism and Pharmacokinetics ..........................................................25
1.2.3.
Nonclinical Toxicology........................................................................................................26
1.2.4.
Clinical Trials of Entospletinib ............................................................................................27
1.2.5.
Entospletinib Target Drug Concentrations...........................................................................29
1.2.6.
Use of Concomitant Medications with Entospletinib...........................................................30
1.3.
Rationale for the Current Study and Design...........................................................................................30
1.3.1.
Rationale for the Entospletinib Dose Selection....................................................................31
1.4.
Cytarabine arabinoside...........................................................................................................................32
1.5.
Daunorubicin..........................................................................................................................................32
1.6.
Azacitidine .............................................................................................................................................32
1.7.
Decitabine ..............................................................................................................................................33
1.8.
Entospletinib ..........................................................................................................................................34
1.8.1.
Formulation..........................................................................................................................34
1.8.2.
Source...................................................................................................................................34
1.8.3.
Packaging and Labeling .......................................................................................................34
1.8.4.
Storage and Handling...........................................................................................................34
1.8.5.
Study Drug Accountability...................................................................................................35
1.9.
Compliance ............................................................................................................................................35
1.10.
Risk/Benefit Assessment for the Study..................................................................................................35
1.10.1.
Potential Risks Based on Nonclinical Safety Data with Entospletinib.................................35
1.10.2.
Potential Risks Based on Clinical Safety Data with Entospletinib.......................................36
1.10.3.
Potential Benefits with Entospletinib ...................................................................................37
2.
OBJECTIVES AND ENDPOINTS ....................................................................................................................38
2.1.
Objectives...............................................................................................................................................38
2.2.
Endpoints ...............................................................................................................................................38
3.
STUDY DESIGN................................................................................................................................................41
3.1.
Overview................................................................................................................................................41
3.1.1.
Group A Phase 1b (Dose Escalation): Entospletinib + cytarabine + 
daunorubicin (7+3)...............................................................................................................42
3.1.2.
Group A Phase 2 (Dose Expansion): Entospletinib + cytarabine + 
daunorubicin (7+3)...............................................................................................................44
3.1.3.
Group B Phase 1b (Dose Escalation):  Entospletinib + decitabine.......................................46
3.1.4.
Group B Phase 2 (Dose Expansion):  Entospletinib + Hypomethylating 
agent.....................................................................................................................................48
3.1.5.
Group C Phase 1b (Dose Escalation): Entospletinib Monotherapy......................................51
3.1.6.
Group C Phase 2 (Dose Expansion): Entospletinib Monotherapy .......................................52
3.2.
Dose Limiting Toxicities........................................................................................................................52


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3.2.1.
Guidelines for Phase 1b Dose Escalation and Phase 2 Group B Dose 
Expansion.............................................................................................................................54
3.3.
Dosing Delays/Dose Modifications Attributed to Entospletinib (Beyond Cycle 1)...............................54
3.3.1.
Management of Low Grade Chronic Toxicities...................................................................59
3.3.2.
Specific Considerations for Managing Hyperbilirubinemia.................................................60
3.4.
Duration of Treatment............................................................................................................................60
4.
SUBJECT POPULATION..................................................................................................................................63
4.1.
Number of Subjects and Subject Selection ............................................................................................63
4.2.
Inclusion Criteria....................................................................................................................................63
4.3.
Exclusion Criteria...................................................................................................................................65
5.
TREATMENT PLAN.........................................................................................................................................67
5.1.
Treatment Plan .......................................................................................................................................67
5.1.1.
Premedication.......................................................................................................................67
5.1.2.
Administration Instructions..................................................................................................67
5.1.3.
Dosing Schedule...................................................................................................................67
5.1.4.
Dose Schedule Interruptions and Vomited Doses ................................................................67
5.1.5.
Concomitant and Supportive Therapy..................................................................................67
5.2.
Restricted/Prohibited Medication...........................................................................................................68
5.3.
Study Drug Disposal ..............................................................................................................................69
6.
STUDY PROCEDURES ....................................................................................................................................70
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................70
6.2.
Pretreatment Assessments......................................................................................................................70
6.2.1.
Screening Visits....................................................................................................................70
6.3.
Treatment Assessments..........................................................................................................................71
6.3.1.
Group A................................................................................................................................72
6.3.2.
Group B................................................................................................................................77
6.3.3.
Group C................................................................................................................................82
6.4.
Assessments for Premature Discontinuation from Study.......................................................................84
6.4.1.
Criteria for Discontinuation of Study Treatment..................................................................84
6.4.2.
End of Study Treatment .......................................................................................................85
6.4.3.
30-day Follow-up .................................................................................................................86
6.5.
Long Term Follow-up ............................................................................................................................86
6.6.
Description of Study Procedures............................................................................................................86
6.6.1.
Prior/Concomitant Medications............................................................................................86
6.6.2.
Performance Assessment......................................................................................................86
6.6.3.
Laboratory Safety Tests........................................................................................................87
6.6.4.
.....................................87
6.6.5.
...............................................................88
6.6.6.
............................................89
6.6.7.
Biological Sample Storage ...................................................................................................90
6.6.8.
Efficacy Assessments...........................................................................................................90
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................91
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................91
7.1.1.
Adverse Events.....................................................................................................................91
7.1.2.
Serious Adverse Events........................................................................................................91
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................92
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................93
7.2.1.
Assessment of Causality for Study treatments and Procedures............................................93
7.2.2.
Assessment of Severity ........................................................................................................93
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7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................94
7.4.
Gilead Reporting Requirements.............................................................................................................95
7.5.
Toxicity Management ............................................................................................................................96
7.6.
Special Situations Reports......................................................................................................................96
7.6.1.
Definitions of Special Situations..........................................................................................96
7.6.2.
Instructions for Reporting Special Situations.......................................................................97
8.
STATISTICAL CONSIDERATIONS................................................................................................................99
8.1.
Analysis Objectives and Endpoints........................................................................................................99
8.1.1.
Analysis Objectives..............................................................................................................99
8.1.2.
Endpoints..............................................................................................................................99
8.2.
Analysis Sets........................................................................................................................................101
8.2.1.
Full Analysis Set ................................................................................................................101
8.2.2.
DLT Analysis Set...............................................................................................................102
8.2.3.
Pharmacokinetic Analysis Sets...........................................................................................102
8.3.
Data Handling Conventions .................................................................................................................102
8.3.1.
General Methods ................................................................................................................102
8.4.
Demographic Data and Baseline Characteristics .................................................................................102
8.5.
Efficacy Analysis .................................................................................................................................103
8.5.1.
Categorical Endpoints ........................................................................................................103
8.5.2.
Time-to-Event Endpoints ...................................................................................................103
8.5.3.
Continuous Endpoints ........................................................................................................103
8.6.
Safety Analysis.....................................................................................................................................103
8.6.1.
Extent of Exposure.............................................................................................................104
8.6.2.
Adverse Events...................................................................................................................104
8.6.3.
Laboratory Evaluations ......................................................................................................105
8.7.
Pharmacokinetic Analysis....................................................................................................................106
8.8.
..........................................................................106
8.9.
Sample Size..........................................................................................................................................106
8.9.1.
Statistical Basis for Dose Escalation ..................................................................................107
8.10.
Timing of Analyses..............................................................................................................................108
8.10.1.
Interim Analyses ................................................................................................................108
8.10.2.
Final Analysis.....................................................................................................................108
9.
RESPONSIBILITIES........................................................................................................................................109
9.1.
Investigator Responsibilities ................................................................................................................109
9.1.1.
Good Clinical Practice........................................................................................................109
9.1.2.
Institutional Review Board (IRB Review and Approval)...................................................109
9.1.3.
Informed Consent...............................................................................................................109
9.1.4.
Confidentiality....................................................................................................................110
9.1.5.
Study Files and Retention of Records ................................................................................110
9.1.6.
Case Report Forms.............................................................................................................111
9.1.7.
Investigational Medicinal Product Accountability and Return...........................................112
9.1.8.
Inspections..........................................................................................................................112
9.1.9.
Protocol Compliance..........................................................................................................112
9.2.
Sponsor Responsibilities ......................................................................................................................113
9.2.1.
Protocol Modifications.......................................................................................................113
9.2.2.
Study Report and Publications ...........................................................................................113
9.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................113
9.3.1.
Payment Reporting.............................................................................................................113
9.3.2.
Access to Information for Monitoring................................................................................114
9.3.3.
Access to Information for Auditing or Inspections ............................................................114
9.3.4.
Study Discontinuation........................................................................................................114
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10.
REFERENCES .................................................................................................................................................115
11.
APPENDICES ..................................................................................................................................................118
Appendix 1.
Investigator Signature Page..................................................................................................119
Appendix 2.
Study Procedures Tables ......................................................................................................120
Appendix 3.
Management of Clinical and Laboratory Adverse Events....................................................137
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................139
Appendix 5.
International Working Group Criteria for AML {Cheson 2003}.........................................141
Appendix 6.
Performance Scales: Karnofsky & ECOG Scores {Oken 1982}..........................................144
Appendix 7.
Minimal Residual Disease (MRD) Level Definition {Sanchez-Garcia 2013}.....................145
Appendix 8.
2017 European Leukemia Network (ELN) Risk Stratification by Geneticsa {Dohner 
2017}....................................................................................................................................146
LIST OF IN-TEXT TABLES
Table 3-1.
Group A Entospletinib Cohort Dose Escalation Table...........................................................43
Table 3-2.
Group B Entospletinib Dose Escalation Table .......................................................................46
Table 3-3.
Hypomethylating Agent Dose and Schedule Table (Induction).............................................49
Table 3-4.
Hypomethylating Agent Dose and Schedule Table (Maintenance)........................................50
Table 3-5.
Group C Entospletinib Cohort Dose Escalation Table ...........................................................51
Table 3-6.
Dose Escalation/ DLT Guidelines ..........................................................................................54
Table 3-7.
Azacitidine Dose Modifications .............................................................................................57
Table 3-8.
Azacitidine Dose Reductions..................................................................................................59
Table 4-1.
Required Screening Laboratory Values Organ System Parameter Required Value ...............63
Table 5-1.
Restricted Medications in this Study that Require Prior MM Discussion and 
Approval.................................................................................................................................69
Table 6-1.
Blood Samples Collected During the Course of the Study.....................................................90
Table 8-1.
Exact 90% CIs of Composite Complete Remission Rate for a Cohort  Size of 40 in 
Group A................................................................................................................................106
Table 8-2.
Exact 90% CIs of Composite Complete Remission Rate for a Cohort Size of 30 in 
Cohort C3 .............................................................................................................................107
Table 8-3.
Probability of Dose Escalation (N=3+3) ..............................................................................107
LIST OF IN-TEXT FIGURES
Figure 1-1.
Positive and Negative Regulators of Antigen-dependent BCR Signaling..............................23
Figure 1-2.
Entospletinib Kinome Scan ....................................................................................................24
Figure 1-3.
Inhibition of Basophil Activation (Original Formulation)......................................................29
Figure 1-4.
Inhibition of pSYK (Original Formulation) ...........................................................................29
Figure 3-1.
Study Schema.........................................................................................................................42
Figure 3-2.
Group A Phase 2 Dosing Schema...........................................................................................46
Figure 3-3.
Group B Phase 2 Randomization Dosing Schema..................................................................51


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc. 
333 Lakeside Drive
Foster City, CA 94404
Study Title:
A Phase 1b/2 Study of Entospletinib (GS-9973) Monotherapy and in 
Combination with Chemotherapy in Patients with Acute Myeloid 
Leukemia (AML)
IND Number:  
116416
Study Centers 
Planned:
Estimated 25 centers. 
Ohio State University (OSU) will be the coordinating center. The 
Phase 2 portion of the study will include centers in North America and 
Germany.
Objectives:
The primary objectives are:

To demonstrate the overall safety of entospletinib (ENTO) in 
combination with standard dose cytarabine and daunorubicin
chemotherapy (7+3) in subjects with previously untreated AML who 
are candidates for chemotherapy (fit subjects) and to assess the 
efficacy of ENTO at the recommended Phase 2 dose (RP2D)
(Group A)

To demonstrate the overall safety of ENTO in combination with
hypomethylating agents (decitabine or azacitidine) in subjects with 
previously untreated AML who are not candidates for 7+3 (unfit 
subjects) and to assess the efficacy of ENTO at the RP2D (Group B)

To demonstrate the overall safety of ENTO monotherapy in subjects 
with previously untreated AML who are not candidates for 
chemotherapy or in subjects with relapsed/refractory AML with or 
without mixed-lineage leukemia (MLL) and to assess the efficacy of 
ENTO at the RP2D (Group C)
The secondary objectives of this study are: 

To assess the qualitative and quantitative toxicities of ENTO
monotherapy or ENTO in combination with chemotherapy in 
subjects with AML

To document therapeutic response of subjects with AML when 
treated with ENTO monotherapy or ENTO in combination with 
chemotherapy
The exploratory objective of this study is:

 
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Study Design:
A Phase 1b/2 study evaluating the efficacy, safety, and tolerability of 
ENTO in subjects with AML. Subjects with AML will be dosed using a 
3 + 3 design for the dose escalation phase. During the dose escalation 
phase, ENTO will be administered at a dose of 200 mg and 400 mg 
every 12 hours either in combination with chemotherapy for Group A or 
with a hypomethylating agent for Group B. ENTO will be administered 
at a dose of 400 mg and 800 mg every 12 hours as monotherapy for 
Group C.
Following completion of the dose escalation phase, the sponsor in 
consultation with the coordinating center has selected ENTO at a dose 
level of 400 mg every 12 hours for all dose expansion cohorts.  
Group A Phase 1b (Dose Escalation)
Note: At the time of this amendment, Group A Phase 1b had completed 
enrollment.
ENTO will be administered at 2 dose levels for Group A during the dose 
escalation phase (see table below); the initial dosing level for the 
1st cohort is defined as level 0.
Intra-subject dose escalation will not be allowed.
Group A  Entospletinib Dose Escalation Table
Dose Level
Entospletinib
Daunorubicin
Cytarabine
0
200 mg
60mg/m2
100mg/m2
1
400 mg
ENTO will be administered orally every 12 hours as a monotherapy
lead-in on Days 1-14 (Cycle 0), and will be administered orally every 
12 hours in combination with cytarabine (Days 1-7) and IV 
daunorubicin (Days 1-3) during induction chemotherapy for up to 
two 14-day cycles (Cycles 1 and 2). Subjects with residual disease 
detected at the Cycle 1 Day 14 bone marrow evaluation will proceed 
with Cycle 2 of induction chemotherapy.
Group A Phase 2 (Dose Expansion)
Note: At the time of this amendment, Group A Phase 2 had completed 
enrollment.
Similar to Phase 1b, in Phase 2, ENTO 400 mg will be administered first 
as a 14-day lead-in monotherapy followed by ENTO in combination 
with 7+3 induction chemotherapy. Post-remission chemotherapy will be
offered to subjects who achieve CR/CRi and do not require or cannot 
proceed to allogeneic stem cell transplantation (SCT). In addition,


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subjects who are awaiting a donor or transitioning to allogeneic SCT are
allowed to receive post-remission chemotherapy per investigator 
discretion. Subjects who continue to maintain a CR/CRi after 3 or 4 
cycles of post-remission chemotherapy will be offered maintenance 
therapy with ENTO 400 mg every 12 hours for up to 12 cycles.
Extension of maintenance therapy may occur on an individual basis if 
approved by the Principal Investigator.
Group B Phase 1b (Dose Escalation)
Note: At the time of this amendment, Group B Phase 1b had completed 
enrollment.
ENTO will be administered at 2 dose levels for Group B during the dose 
escalation phase (see table below); the initial dosing level for the 
1st cohort is defined as level 0. Intra-subject dose escalation will not be 
allowed.
Group B Entospletinib Dose Escalation Table
Dose Level
Entospletinib
Decitabine
0
200 mg
20 mg/m2
1
400 mg
   
ENTO will be administered orally every 12 hours as a monotherapy 
lead-in on Days 1-14 (Cycle 0), and will be administered orally every 
12 hours on Days 1-28 in combination with decitabine on Days 1-10 of 
every 28-day cycle for at least 2 but no more than 4 cycles of induction 
chemotherapy.  Subject will undergo a bone marrow aspiration and 
biopsy on Cycle 2 Day 28.  Subjects who have a CR/CRi can proceed to 
SCT per investigator’s discretion or to maintenance therapy with ENTO
+ decitabine.  Subjects with persistent AML will receive 2 more cycles 
of induction chemotherapy and a bone marrow aspiration and biopsy 
will be performed at Cycle 4 Day 28.  Subjects who have persistent 
leukemia at this time point will be considered a treatment failure and 
come off study. Subjects ineligible for SCT will have the option to 
receive maintenance therapy with ENTO + decitabine. Subjects who are 
intolerant of decitabine after completing 2 cycles will switch to ENTO 
monotherapy maintenance. Maintenance will continue as long as the 
subject experiences benefit and does not meet criteria for study 
treatment discontinuation.  Extension of maintenance may occur on an 
individual basis if approved by the Principal Investigator.
Group B Phase 2 (Dose Expansion)
Note: At the time of this amendment, Group B Phase 2 safety run-in had 
completed enrollment. In Phase 2, the overall safety of ENTO in 
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will be evaluated. As part of the safety run-in, ENTO in combination 
with azacitidine will be administered to 6 evaluable subjects. Following 
completion of the safety run-in (DLT window, Section 3.2), the 
azacitidine arm will be evaluated to determine if enrollment of the 
expansion cohort may proceed with azacitidine. If 2 or more subjects 
experience DLTs, all ongoing subjects in the safety run-in will be 
discontinued, the azacitidine arm will be dropped from the study, and
subjects in the expansion phase will only receive ENTO in combination 
with decitabine.
If Phase 2 proceeds with an azacitidine arm, subjects will be randomized 
to receive ENTO in combination with either decitabine (Days 1-10) or 
azacitidine (Days 1-7) of every 28-day cycle for at least 2 but no more 
than 4 cycles of induction chemotherapy. Randomization will be 
stratified by age (≤ 75 or > 75 years) and by white blood cell (WBC) 
count (≤ 5,000/µL or > 5,000/µL). If subjects are not eligible for SCT 
after 2 cycles of induction, subjects will have the option to receive 
maintenance therapy with ENTO in combination with decitabine 
(Days 1-5) or azacitidine (Days 1-7). Subjects who are intolerant of the 
hypomethylating agent after completing 2 cycles may switch to ENTO 
monotherapy maintenance. Maintenance may continue as long as the 
subject is experiencing benefit and does not meet the criteria for study 
treatment discontinuation. Extension of maintenance may occur on an 
individual basis if approved by the Principal Investigator.
Group C Phase 1b (Dose Escalation)
Note: At the time of this amendment, Group C Phase 1b had completed 
enrollment.
ENTO will be administered at 2 dose levels for Group C during the dose 
escalation phase (see table below); the initial dosing level for the 
1st cohort is defined as level 0. 
Intra-subject dose escalation will not be allowed.
Group C ENTO Dose Escalation Table
Dose Level
ENTO
0
400 mg
1
800 mg
  
Group C Phase 2 (Dose Expansion)
Note: At the time of this amendment, Cohort C1A had completed 
enrollment (n=15). This amendment identifies the closure of Cohort C3 
to further enrollment (n=12).


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Relapsed/refractory and previously untreated subjects will be evaluated 
in separate cohorts during Phase 2 with ENTO monotherapy. ENTO
400 mg will be administered orally every 12 hours on Days 1-28 of 
every 28-day cycle as long as the subject is experiencing benefit and 
does not meet criteria for study treatment discontinuation.  
Cohort C1A: This cohort is designed to enroll 15 relapsed/refractory 
AML subjects. If 5 or more of the initial 15 subjects achieve CR/CRi 
after 1-2 cycles, an additional 15 subjects will be enrolled. However, if 
less than 5 of the initial 15 subjects achieve CR/CRi after 1-2 cycles, 
then treatment would be considered futile. At this time, futility has been
met and, thus, Cohort C1A will not move forward (ie, will not enroll any 
subjects).
Cohort C2: This cohort is designed to enroll 15 subjects with 
relapsed/refractory AML subjects with MLL gene rearrangement.
Cohort C3: This cohort is designed to enroll previously untreated AML 
subjects who are unfit (eg, very elderly, have multiple comorbidities, 
and a poor ECOG/performance status) for chemotherapy or 
hypomethylating agent, or refuse either of these 2 treatment options.
This amendment identifies enrollment closure of this cohort. 
Number of 
Subjects Planned:
Approximately 190 subjects
Target 
Population:
Subjects with Acute Myeloid Leukemia 
Duration of 
Treatment:
Subjects may continue receiving ENTO until treatment failure, planned 
completion of treatment, start of new therapy, unacceptable toxicity,
withdrawal of consent by subject, or withdrawal from study by investigator.
Safety Review:
Safety data will be reviewed continuously during the course of the 
study. The Cancer Therapy Evaluation Program (CTEP) Active Version 
of the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for Adverse 
Event (AE) reporting. 
Main Diagnosis 
and Disease  
Eligibility 
Criteria:
AML (de novo, therapy related [t-AML], or secondary AML)
All groups will build on ENTO backbone 
Group A

Subjects age > 18 years with previously untreated AML by World 
Health Organization (WHO) criteria, excluding acute promyelocytic 
leukemia (M3), who are able and should receive up to 2 cycles of
induction chemotherapy with 7+3 as determined by the treating 
physician 


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Group B 

Subjects age > 70 years with previously untreated AML by WHO 
criteria, excluding acute promyelocytic leukemia (M3)

Subjects age ≤ 70 years with previously untreated AML by WHO 
criteria, excluding acute promyelocytic leukemia (M3), who refuse 
or are unable to receive 7+3 as determined by the treating physician 
Group C Phase 1b (Dose Escalation)

Subjects age > 18 years with relapsed/refractory AML by WHO 
criteria, excluding acute promyelocytic leukemia (M3)

Subjects with previously untreated AML by WHO criteria, 
excluding acute promyelocytic leukemia (M3), and who would have 
met disease eligibility criteria for Group A or B but refuse or are 
unable to receive 7+3 or decitabine chemotherapy as determined by 
the treating physician
Group C Phase 2 (Dose Expansion)

Cohort C1A: Subjects age > 18 years with relapsed or refractory 
AML by WHO criteria, excluding acute promyelocytic leukemia
(M3)

Cohort C2: Subjects age > 18 years with relapsed/refractory AML
with MLL 

Cohort C3: Subjects with previously untreated AML by WHO 
criteria, excluding acute promyelocytic leukemia (M3), and who 
would have met disease eligibility criteria for Group A or B but 
refuse or are unable to receive chemotherapy and hypomethylating 
agent as determined by the treating physician
See Section 4 for complete eligibility criteria.
Test Product, 
Dose, and Mode 
of Administration:
ENTO is available as 200 mg strength tablets and will be administered 
orally every 12 hours while in a fasted state. During dose escalation, 
200, 400, or 800 mg of ENTO will be administered. There is no
intra-subject dose escalation.
The recommended Phase 2 dose is ENTO 400 mg.
Please refer to the respective packaging inserts for daunorubicin, 
cytarabine, decitabine, and azacitidine for more information.


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Criteria for 
Evaluation:
Safety:
Grading of adverse events and laboratory abnormalities. The CTEP 
Active Version of the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 will be utilized for Adverse Event (AE) 
reporting. The trial employs the standard National Cancer Institute 
(NCI) definition of MTD (starting dose associated with DLT in < 33.3% 
of subjects during the DLT assessment window) to determine dose 
escalation.
Efficacy:
Assessment of clinical response will be made according to the modified 
International Working Group criteria. The major criteria for evaluating 
response assessment will include physical examination and examination 
of blood and bone marrow.
Pharmacokinetics/ 
Biomarkers:
 
.
Endpoints:
Primary Endpoints:
Safety

Occurrence of adverse events and laboratory abnormalities defined 
as DLTs for ENTO in combination with standard dose cytarabine 
and daunorubicin in subjects with previously untreated AML 
(Group A)

Occurrence of adverse events and laboratory abnormalities defined 
as DLTs for ENTO in combination with hypomethylating agent in 
subjects with previously untreated AML who are unable to receive 
7+3 chemotherapy (Group B)

Occurrence of adverse events and laboratory abnormalities defined 
as DLTs for ENTO as a single agent in subjects with 
relapsed/refractory AML with or without MLL or previously 
untreated AML (Group C)
Efficacy

Complete remission rate at induction completion: defined as the 
proportion of subjects who achieved morphologic complete 
remission (CR) at induction completion. Note: CR includes a 
subcategory of cytogenetic CR (CRc).

Composite complete remission rate at induction completion: defined 
as the proportion of subjects who achieved CR or morphologic 
complete remission with incomplete blood count recovery (CRi) at 
induction completion.
CCI


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
Overall response rate at induction completion: defined as the 
proportion of subjects who achieved CR, CRi, or partial remission 
(PR) at induction completion.
Secondary Endpoints: 
Exposure

Drug administration and duration of exposure of study treatment
Safety

Occurrence of AEs and laboratory abnormalities not defined as 
DLTs
Efficacy

Event free survival (EFS) – defined for all subjects and is measured 
from the start of the study therapy until the date of treatment failure, 
AML relapse, or death from any cause, whichever occurs first. 

Overall survival (OS) – defined as the interval from the start of the 
study therapy to death from any cause.
Exploratory Endpoints:
 
 
 
 
 
 
 
 
 
 
 
CCI


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Statistical Methods:
Appropriate data analysis sets will be defined. The full analysis set
(FAS) will include data from all subjects who receive  1 dose of study 
drug. Other data sets will be defined and will include data from subjects 
who have the necessary baseline and on-study measurements to provide 
interpretable results for specific parameters of interest. 
Subject characteristics and study results will be described and 
summarized by group and dose level for the relevant analysis sets. 
Descriptive summaries will be prepared to show sample size, mean, 
standard deviation (StD), 95% confidence intervals (CIs) on the mean, 
median, minimum, and maximum for continuous variables and counts, 
percentages, and 95% CIs on the percentage for categorical variables.
Based on the FAS, information regarding study treatment 
administration, study drug compliance, safety variables, efficacy 
variables, and post-study therapies will be described and summarized. 
Using data from the relevant evaluable data sets, study drug plasma 
concentrations will also be described and summarized. 
Sample Size Calculation
Sequential dose-escalation is consistent with usual oncologic paradigms 
for dose ranging. The intent is to limit the number of subjects who are 
exposed to excessively toxic doses of a drug in an early phase evaluation 
of an anticancer agent. The trial employs the standard National Cancer 
Institute (NCI) definition of MTD (starting dose associated with DLT in 
< 33.3% of subjects during the DLT assessment window) to determine 
dose escalation. The cohort size and dose-escalation rules establish a 
low probability of increasing the dose if the true rate of DLT is high 
CCI


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while there is a high likelihood of escalating or proceeding to the next 
cohort of the study if the true underlying probability of DLT is low. For 
example, if the true underlying probability of DLT is low (eg, < 10%) at 
the current dose level, there is a high probability (≥0.91) of dose 
escalation to the next dose level. Conversely, if the true underlying 
proportion of DLT is high (eg,≥ 60%) at the current dose level, there is a 
low probability (≤ 0.08) of escalation to the next dose level.
Assuming 2 planned dose levels for escalation are tested with up to 
6 subjects per level and assuming 10% of subjects are unevaluable 
during dose escalation, up to 14 subjects will be enrolled in each group 
in phase 1b. In Group B, 6 subjects will be enrolled to evaluate the 
safety of ENTO in combination with azacitidine prior to enrollment of 
the expansion cohort.  
In Group B, following the safety run-in, approximately 40 subjects will 
be randomized in a 1:1 manner to ENTO in combination with decitabine 
or ENTO in combination with azacitidine.  
In Group C2, approximately 15 subjects will be enrolled.
See detailed sample size calculation in Section 8.9.
Note: This amendment identifies the closure of Cohort C3 to further 
enrollment (n=12). 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
7+3
cytarabine and daunorubicin chemotherapy
ADR
adverse drug reaction
AE
adverse event
AKT
protein kinase B (PKB)
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
AM
morning
AML
acute myeloid leukemia
ANC
absolute neutrophil count
ARA-C
cytarabine arabinoside
ARA-CTP
ARA-C triphosphate
ARA-CMP
ARA-C monophosphate
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the concentration versus time curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval (tau)
B-ALL
acute B-lympho blastic leukemia
BAT 
basophil activation test
BCR
B-cell receptor
BID
bis in die (twice a day)
BLNK
B-cell linker protein
BM
Bone Marrow
BTK
bruton tyrosine kinase
BUN
blood urea nitrogen
Cmax
maximum observed concentration of drug
CBC
complete blood count
CFR
(United States) Code of Federal Regulations
CI
confidence interval
CLL
chronic lymphocytic leukemia
CNS
central nervous system
cm/s
centimeter per second
CR
complete remission
CRc
cytogenetic complete remission
CRi
morphologic CR with incomplete blood count recovery
CRO
contract research organization
CT
computed tomography


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CTA
clinical trial application
CTC
circulating tumor cells
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLBCL
diffuse large B-cell lymphoma
dCMP
deoxycytidine monophosphate
DCR
disease control rate
DDI
drug to drug interaction
DICOM
Digital Imaging and Communication in Medicine
dL
deciliter
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
PVE
Pharmacovigilance and Epidemiology
EC
ethics committee
EC50
50% effective inhibitory concentration
ECG
electrocardiogram
eCRF
electronic case report form(s)
EDC
electronic data capture
EOS
end of study
EFS
event free survival
ENTO
Entospletinib, GS-9973
EU
European
FDA
(United States) Food and Drug Administration
FISH
fluorescent in situ hybridization
FL
follicular lymphoma
FLIPI
follicular lymphoma international prognostic index
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice (Guidelines)
G-CSF
granulocyte colony-stimulating factor
GM-CSF
granulocyte-macrophage colony-stimulating factor
GSI
Gilead Sciences, Inc.
h, hr
hour
H2RA
histamine 2 receptor antagonist 
HBc
hepatitis B core
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
-HCG
beta human chorionic gonadotropin
HCV
hepatitis C virus


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HIV
human immunodeficiency virus
IB
investigator’s brochure
IC
immune-complex
IC50
concentration necessary to achieve 50% inhibition of target
ICF
informed consent form
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
IFE
immunofixation electrophoresis
IND
Investigational New Drug (Application)
iNHL
indolent non-Hodgkin lymphoma
IRB
institutional review board
ITAM
immunoreceptor tyrosine-based activation motifs
IWCLL
International Workshop on Chronic Lymphocytic Leukemia
IxRS
Interactive Voice/Web Response System
IV
intravenous
IVD
intravenous drip
K2-EDTA
potassium-ethylenediaminetetraacetic acid
kg
kilogram
L
liter
LD
longest diameter
LDH
lactate dehydrogenase
LPD
longest perpendicular diameter 
LVD
longest vertical dimension
MAPK
mitogen-activated protein kinase
MCL
mantle cell lymphoma
mg
milligram
mL
milliliter
MLFS
morphologic leukemia free state
MLL
mixed lineage leukemia
mm
millimeter
MMRM
mixed model for repeated measures
Morphologic CR
morphologic complete remission
MRD
minimal residual disease
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
MTX
methotrexate
MZL
marginal zone lymphoma
NCI
National Cancer Institute
ND
no disease


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NE
not evaluable
ng
nanogram
NHL
non-Hodgkin lymphoma
nM
nanomolar
NOAEL
no observable adverse effect level
OS
overall survival
ORR
objective response rate
PBMC
peripheral blood mononuclear cells
PD
progressive disease
PET
positron-emission tomography
PI
prescribing information
PI
principal investigator
PI3K
phosphatidylinositol 3-kinase
PK
pharmacokinetic(s)
PLT
platelets
PM
evening
PO
by mouth (orally)
PPD
product of the perpendicular diameters
PR
partial remission
pSYK
phospho-spleen tyrosine kinase
PTM
Placebo to match
QD
once-daily
RA
refractory anemia
RBC
red blood cell
REB
research ethics board
RFS
relapse - free survival
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
SCT
stem cell transplant
SD
stable disease
SD
standard deviation
SDD
spray dried dispersion
SADR
serious adverse drug reactions
SAE
serious adverse event
sMTD
subject maximum tolerated dose
SOP
standard operating procedure
SPD
sum of the products
SPEP
serum protein electrophoresis
SUSAR
Suspected Unexpected Serious Adverse Reaction
SYK
spleen tyrosine kinase


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Tmax
time (observed time point) of Cmax
T½
an estimate of the terminal elimination half-life of the drug, calculated by dividing the 
natural log of 2 by the terminal elimination rate constant (λz)
TK
tyrosine kinase
TNF
tumour necrosis factor
TNF-α
tumour necrosis factor-α
TTC
time to peripheral blast clearance
TTF
time to treatment failure
TTR
time to remission
ULN
upper limit of the normal range
μL
microliter
μM
micromolar
US
United States
WBC
white blood cell
WHO
World Health Organization
WM
Waldenström macroglobulinemia
yr
year
αIgM
anti-IgM
β
population mean slope
z
terminal elimination rate constant, estimated by linear regression of the terminal 
elimination phase of the concentration of drug versus time curve


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1.
INTRODUCTION
1.1.
Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a biologically heterogeneous disease of the hematopoietic 
system characterized by clonal accumulation and expansion of immature myeloid cells within the 
bone marrow {Lowenberg 1999} and is one of the most common forms of leukemia in adults. 
The median patient age at diagnosis is approximately 67 years {American Cancer Society 2007}. 
At presentation, symptoms may include fever, fatigue, easy bruising or bleeding, or signs of 
infection. A number of clinical factors including age, hyperleukocytosis, prior chemotherapy, 
and extramedullary or central nervous system disease have been found to be important in 
predicting prognosis, but the most important factor in predicting risk of relapse are chromosomal 
abnormalities detected at diagnosis{Steelman 2004}. Non-random chromosomal abnormalities, 
identified in approximately 50% to 70% of all adult primary acute leukemia patients, have long 
been recognized as one of the most important independent prognostic indicators for achievement 
of complete remission (CR), duration of first CR, and survival following intensive chemotherapy 
treatment {Steelman 2004}.The predictive value of chromosomal abnormalities is used to guide 
the direction of initial treatment strategies, including allogeneic transplantation in first CR. 
Unfortunately, with current treatment strategies, only approximately 40% of patients achieve 
long-term remission. Of those patients who relapse, only a fraction undergo successful salvage 
treatment followed by allogeneic stem cell transplant with curative intent{Mrozek 2008}.
Outcomes for older patients are worse, as many elderly patients may not be candidates for 
standard therapy, such as stem cell transplantation, due to co-morbid illness, and other patients
refuse standard therapy due to concerns of high toxicity and poor outcomes. Additionally, these 
patients are much less likely to have “favorable risk” cytogenetics and more likely to have 
“adverse risk” {Stone 2004}. Even with adaptation of cytogenetically risk stratified therapies, 
20% to 30% of AML patients never achieve CR, and > 50% of patients who achieve CR 
subsequently experience very early disease relapse {Miller 2013}. The lack of significant 
advancements in the treatment of AML in adults highlights the need for development of novel 
therapeutic strategies.
1.1.1.
SYK Biology in Stem Cells and AML
SYK is a nonreceptor protein tyrosine kinase that is expressed in cells of hematopoietic lineage. 
It is an important mediator of immune receptor signaling in mast cells, neutrophils, macrophages, 
and B cells. SYK contains 2 adjacent Src Homology 2 (SH2) domains that bind to 
immunoreceptor tyrosine-based activation motifs (ITAMs). Upon receptor activation, ITAMs are 
phosphorylated, resulting in SYK recruitment to the receptor complex and activation of the 
enzyme. Phosphorylated-SYK (pSYK) can then phosphorylate its specific substrates including 
other enzymes and adaptor proteins, orchestrating a complex series of cellular responses such as 
cell proliferation, differentiation, survival, and phagocytosis {Ruzza 2009}. 


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SYK activation has been associated with both Type 1 (proliferation) and Type 2 (differentiation) 
effects {Carnevale 2013, Oellerich 2013}. In AML patients, high expression of pSYK is 
associated with increased risk of death following chemotherapy, independent of other AML 
prognostic indicators such as age, cytogenetics, and white blood cell count {Boros 2015}. SYK 
is expressed in 90% of AML samples and is constitutively activated (pSYK-Y526/6) in AML 
blasts {Hahn 2009}. In AML, SYK has been shown to regulate leukemic cell survival and 
proliferation. Furthermore, inhibition of SYK with small molecule inhibitors results in 
differentiation of AML blasts and decreased AML progression in preclinical models {Hahn 
2009}. 
SYK signaling pathways in AML are activated through stimulation of several receptors including 
Fc-γ chain and the β integrins, Mac-1 and CD61/Integrin β3 (Figure 1-1) {Behnen 2014, 
Oellerich 2013}. Integrins are known to play a role in multiple cellular processes relevant to 
cancer, including homing, adhesion, motility, proliferation, and apoptosis. Genetic knockdown of 
Integrin β3 impaired homing of primary leukemia cells and induced myeloid differentiation in 
both murine models and in human leukemia cell lines resulting in decreased levels of pSYK in 
mixed lineage leukemia (MLL) mutated primary cells. Furthermore, activation of the 
downstream transcription factors, signal transducer and activator of transcription 3 and 
5 (STAT3 and STAT5), which are responsible for the proliferation and survival of AML 
leukemic blasts, has also been demonstrated to be SYK-dependent {Oellerich 2013}. Ultimately, 
integrin signaling through SYK leads to SYK activation affecting transcription, differentiation, 
and leukemic stem cell survival {Oellerich 2013}. 
SYK has also been shown to directly phosphorylate the FLT3 receptor, modulate its activation, 
and possibly promote its role in leukemogenesis (Figure 1-1) {Puissant 2014}. Activating 
FLT3-ITD mutations have been found in 25% to 30% of patients with AML and are predictive of 
increased risk of AML relapse and reduced survival {Kottaridis 2003}. In FLT3 mutant AML, 
SYK is constitutively activated and has been shown to phosphorylate FLT3-ITD resulting in 
up-regulation of FLT3 signaling pathways, including downstream activation of STAT3, STAT5, 
and MYC transcriptional programs {Puissant 2014}. Notably in a FLT3-ITD mouse model, SYK 
was indispensable for myeloproliferative disease development, and SYK overexpression 
promoted overt transformation to AML and resistance to FLT3-ITD-targeted therapy {Puissant 
2014}. SYK inhibition resulted in increased survival of mice developing AML, and showed a 
marked reduction of leukocytosis and a decrease in leukemic blasts {Puissant 2014}. 
SYK signaling has also been implicated in HOXA9/MEIS1 high-risk form of AML. The 
homeodomain-containing transcription factors, HOXA9 and MEIS1, are overexpressed in 
approximately 30% to 40% of AML cases and expression is correlated with a poor AML 
prognosis {Drabkin 2002, Gao 2016, Heuser 2009, Zangenberg 2009}. Both HOXA9 and 
MEIS1 are critical to leukemic cell survival and high co-expression of HOXA9 and MEIS1 
result in increased SYK protein levels in AML {Mohr 2017}. In a murine model of 
HOXA9/MEIS1-induced leukemia, genetic knockdown or pharmacologic inhibition of SYK 
with fostamatinib resulted in a dramatic survival benefit, suggesting a therapeutic role in AML 
for small molecule inhibitors of SYK {Mohr 2017}.


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There is additional in vivo evidence to suggest that targeting SYK may be beneficial in treatment 
of AML. In multiple murine models of AML, treatment with a SYK inhibitor resulted in a 
significant decrease in the number of circulating AML cells after 6 days of dosing. In a human 
primary AML xenograft model, histopathological data from the bone marrow and spleen showed 
near resolution of AML cell infiltrates, including areas of necrosis and recovery, following 
treatment with a SYK inhibitor {Hahn 2009}. 
These studies have shown that inhibition of SYK can induce AML differentiation and impair 
leukemia progression. Given the multiple important roles for SYK in AML proliferation and 
survival, SYK is an attractive therapeutic target for AML.
Figure 1-1.
Positive and Negative Regulators of Antigen-dependent BCR 
Signaling
1.2.
Entospletinib
1.2.1.
Nonclinical Pharmacology
ENTO is an adenosine triphosphate (ATP) competitive inhibitor of SYK with an IC 50 of
8.5 ± 3.6 nM. ENTO binds in the ATP pocket of the SYK active site and disrupts the kinase
activity of the enzyme. Kinase selectivity profiling showed a > 14-fold selectivity of ENTO for 
SYK versus 359 nonmutant kinases. Furthermore, there was < 50% binding of ENTO at 1 uM to 
any of a panel of 67 ion channels, transporters, and receptors. Therefore, ENTO demonstrated at 
least 14-fold selectivity against a total of 426 biological targets tested (See Figure 1-2).


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Figure 1-2.
Entospletinib Kinome Scan
The cellular activity of ENTO was evaluated in 2 anti-IgM (αIgM)-stimulated CD86 expression 
assays in human peripheral and mouse splenic B-cells. ENTO potently inhibited αIgM-
stimulated CD86 expression with a mean EC50 of 125.0 ± 78.2 nM and 94.5 ± 19.6 nM in human 
peripheral and murine splenic B-cells, respectively. Additionally, ENTO was evaluated in vitro 
in an FcεRI-triggered αIgE stimulated β-hexosaminidase release assay in mouse bone marrow 
derived mast cell (BMMC) cultures. ENTO inhibited the FcεRI-stimulated hexosaminidase 
release into the media with a mean EC50 of 159.3 ± 14.8 nM. ENTO was evaluated in vitro in an 
immune-complex (IC) stimulated TNFα release assay in primary human monocytes. ENTO
inhibited the IC stimulated TNFα release with a mean EC50 of 147.0 ± 15.6 nM. These data 
support the concept that SYK inhibition blocks with similar potency, B-cell, αIgE, and Fcƴ
receptor signaling in vitro.
The potency of ENTO was evaluated in human whole blood by a αIgE-stimulated CD63 
expression assay in human basophils. ENTO inhibited the αIgE-stimulated CD63 expression on 
CD123+/HLADR- human basophils with a mean EC50 ± SD of 0.387 ± 0.220 nM. Additionally, 
ENTO inhibited the pervanadate-induced autophosphorylation of SYK at phospho-SYK (Y525) 
in whole blood with a mean EC50 ± SD of 830 ± 560 nM. These data support the concept that 
SYK inhibition can block SYK activity in whole blood as determined by functional inhibition of 
CD63 expression and direct target inhibition of SYK autophosphorylation.
ENTO was evaluated in a battery of safety pharmacology studies. The IC50for the inhibitory 
effect of ENTO on human ether-à-go-go-related gene (hERG) potassium current in vitro was 
estimated to be greater than 1 μM. Because ENTO is 97.3% protein bound in human plasma and 
the total plasma concentrations of ENTO are in the 1 to 3 μM range, with a corresponding range 
of free ENTO of 27 to 81 nM, it is unlikely that a clinically relevant effect on QT interval would 


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occur. No ENTO-related effects were noted on neurological or respiratory function in rats at 
doses up to 1000 mg/kg, the highest dose tested. In dogs, ENTO caused small increases in heart 
rates (during the night cycle) at doses ≥ 15 mg/kg but had no effects on electrocardiograms 
(ECGs) or blood pressure at up to 150 mg/kg, the highest dose evaluated.
ENTO is a potent and selective SYK inhibitor and disrupts the kinase activity of the enzyme. No 
significant off target or adverse pharmacological effects of clinical relevance were noted in 
preclinical evaluations.
Further information on the nonclinical pharmacology of ENTO is available in the Investigator’s 
Brochure.
1.2.2.
Nonclinical Drug Metabolism and Pharmacokinetics
Despite high plasma protein binding, ENTO had a moderate volume of distribution, close to that 
of total body water. The systemic clearance was low in rats, moderate in dogs, and moderate to 
high in monkeys.
Single-day dose escalation of ENTO administered orally to rats, dogs, and monkeys showed a 
less than dose proportional increase in ENTO systemic exposure in all species over the dose 
ranges tested.
Consistent with the moderate to high bioavailability seen in nonclinical species, ENTO showed 
high forward permeability across Caco-2 monolayers and low potential for efflux.
ENTO showed good metabolic stability with human hepatic material in vitro. In humans, 
clearance through metabolism is therefore expected to be low. The primary routes of metabolism 
of ENTO involved oxidative opening of the morpholine ring as well as further oxidation or 
conjugation. In humans, CYP2C9, CYP3A, and CYP1A2 were shown to oxidize ENTO.
Metabolism followed by biliary excretion is likely to be the major route of elimination of ENTO
and its metabolites, as < 5% of the radiolabeled dose administered orally to rats was recovered in 
urine.
ENTO will be unlikely to cause clinical drug interactions through inhibition of CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. ENTO is an inhibitor of 
UGT1A1 and may transiently inhibit UGT1A1 activity in vivo at the expected clinical 
concentrations. The effect may be mitigated by the high plasma protein binding of ENTO
(> 97%).
ENTO is an inhibitor of the uptake transporters OATP1B1 and OATP1B3 as well as the efflux 
transporters P-gp and BCRP with an IC50 value of approximately 2 µM for each of these 
transporters. ENTO may affect the activity of these transporters in vivo at the expected clinical 
concentrations and could transiently affect the disposition of other drugs. The high plasma 
protein binding of ENTO (> 97%) may mitigate some of the potential drug-drug interactions at 
clinically relevant doses.


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ENTO is not expected to be a clinically relevant inducer of cytochrome P450 enzymes CYP1A2 
or CYP3A4 and other drug metabolizing enzymes or transporters through activation of either the 
aryl hydrocarbon receptor (AhR) or pregnane-X-receptor (PXR).
Further information on the nonclinical drug metabolism and pharmacokinetics of ENTO is 
available in the Investigator’s Brochure.
1.2.3.
Nonclinical Toxicology
ENTO was well tolerated in single-dose studies at doses of 1000 mg/kg in dogs and cynomolgus 
monkeys. ENTO was well tolerated in rats for 14 days up to 1000 mg/kg/day and for 4 weeks at 
50 mg/kg/day. In dogs, ENTO was well tolerated for 7 days at 50 mg/kg/day and at 
10 mg/kg/day for 4 weeks. ENTO was well-tolerated in cynomolgus monkeys for 14 days or 
13 weeks at 100 mg/kg/day, the highest dose tested. The highest feasible dose in cynomolgus 
monkeys was 100 mg/kg/day, as no increase in exposure was achieved by higher doses.
The target organ(s) of toxicity identified in rats was the duodenum, and in rabbits and dogs were 
predominantly the gastrointestinal tract and lymphoid organs. No target organs were identified in 
the cynomolgus monkey. 
Because evidence of lymphoid tissue depletion was noted in rabbits and dogs at high doses, 
clinical assessments will also include monitoring for signs and symptoms of infection.
Increases in total and/or indirect bilirubin in rats, rabbits, and dogs at ≥ 30 mg/kg/day may have 
been due to the inhibition of the enzyme UGT1A1. ENTO inhibits this uridine glucuronyl 
transferase enzyme 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 2005} As no histological evidence 
of hepatobiliary toxicity was noted concurrently with bilirubin increases in ENTO treated rats or 
dogs, and ENTO levels above the IC50 for UGT1A1 were achieved in serum, this seems a 
plausible mechanism for the noted increases in bilirubin.
No evidence of altered coagulation parameters were noted at any dose level in the ENTO
nonclinical studies and no biologically relevant effects were noted in an in vitro study of platelet 
aggregation. Other inhibitors of SYK have been found to have no effect on platelet function at 
efficacious dose levels in patients with rheumatoid arthritis as determined by ex vivo assays, and 
similarly, SYK inhibition has not been found to affect bleeding time in rodents{Braselmann 
2006}.
Adverse effects on lymphoid tissues including spleen, lymph nodes, and/or the thymus were 
noted in rabbits and dogs, but not in rats or cynomolgus monkeys, despite higher exposures 
achieved in both the rat and monkey. The relevance of the findings in rabbits and dogs to humans 
is unknown.
ENTO was negative in the bacterial mutation, in vitro chromosomal aberration, and rat 
micronucleus assays. ENTO can be considered non-genotoxic.  


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Further information on the nonclinical toxicology of ENTO is available in the Investigator’s
Brochure.
1.2.4.
Clinical Trials of Entospletinib
To date, the ENTO clinical development programs consists of 18 clinical studies, which have 
been conducted in which 470 healthy subjects (including 16 subjects with hepatic impairment), 
464 subjects with hematologic malignancies, 7 subjects with cGVHD, and 7 subjects with RA 
have participated. Of these subjects, 948 received ENTO and 26 received placebo. 
Following administration under fasted conditions of 400 mg ENTO spray dried dispersion (SDD)
tablets twice daily (
 
, ENTO exposures were similar to 900 mg twice daily of the previous 
formulation (Mono-MSA ENTO). Under fed conditions, ENTO exposures were lower compared 
with those under fasted conditions (~30%). Co-administration of ENTO SDD with the H2RA, 
famotidine, did not show a clinically meaningful interaction, whereas ENTO exposures were 
reduced (~60%) when co-administered with the PPI, omeprazole.
Based on results from Study GS-US-339-1627, cobicistat, a potent inhibitor of CYP3A had no 
clinically relevant effect on ENTO PK; the CYP2C9 inhibitor, fluconazole, caused an increase in 
ENTO exposure at steady state (~1.4-fold). Rifampin, a potent inducer of CYP3A, CYP2C9, and 
CYP1A2, significantly reduced ENTO exposure at steady state (~70%). Multiple dose 
administration of 400 mg ENTO SDD twice daily resulted in a significant increase in 
rosuvastatin (OATP/BCRP substrate) exposure (~3.8-fold); in contrast, a marginal increase, in 
digoxin (P-gp substrate) exposure was observed (~1.4-fold). 
Entospletinib exposures were correlated with the PD responses observed with a surrogate CD63 
assay.
To date in clinical studies, ENTO has been fairly well tolerated. Treatment emergent AEs 
commonly reported across the studies involving healthy volunteer subjects include headache, 
somnolence, and GI symptoms (nausea and abdominal pain), all of which were mild. When a 
development formulation of ENTO was administered for 26 days at a dose of 900 mg twice daily 
it was well tolerated by subjects with RA on stable doses of methotrexate. This dose and 
treatment schedule produced levels of drug exposure similar to what is expected in subjects with 
hematologic malignancies receiving doses of ENTO 400 mg twice daily.
Among healthy volunteers, increased transaminases were noted in some subjects approximately 
2 weeks after completion of study drug. In the cohort of subjects with RA, 2 subjects had 
elevated transaminases while on study drug, which were also observed after completion of study 
drug. One subject with RA had elevated AST/ALT concurrent with bronchopneumonia while the 
other was diagnosed with acute hepatitis for which a specific etiology was not determined.
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Entospletinib is expected to produce asymptomatic and transient elevations of unconjugated 
(indirect) bilirubin potentially due to inhibition of UGT1A1. Eight of 178 healthy subjects 
treated in studies developed asymptomatic indirect bilirubin elevations (6 Grade 1 cases, 
1 Grade 2 case, and 1 Grade 3 case) that resolved following discontinuation of the drug. Three of 
7 subjects with RA who received ENTO for 26 days developed asymptomatic indirect bilirubin 
elevations (2 Grade 1 cases and 1 Grade 3 case) that improved despite continued dosing. In 
preliminary data from Study GS-US-339-0102, 52 of 291 subjects developed indirect bilirubin 
elevations. Three subjects in Study GS-US-339-0103 developed indirect bilirubin elevations.
Most subjects in Studies GS-US-339-0102 and GS-US-339-0103 with elevations in indirect 
bilirubin were asymptomatic. The elevations in indirect bilirubin were generally self-limited and 
did not result in discontinuation of ENTO.
Currently, 8 active clinical studies are being conducted in adult subjects with hematologic 
malignancies and 1 study is being conducted in adult subjects with cGVHD. At this time 
preliminary results from Studies GS-US-339-0102 and GS-US-339-0103 are available and 
summarized herein.
Study GS-US-339-0102 is ongoing and has enrolled and treated 196 subjects with Mono-MSA 
ENTO (41 subjects with relapsed/refractory CLL, 41 subjects with FL, 43 subjects with DLBCL, 
39 subjects with MCL, and 32 subjects with non-FL iNHL) and 95 subjects with ENTO SDD 
(35 subject with CLL with prior BCR therapy and 60 subjects with CLL in the dose-ranging 
cohort). Study GS-US-339-0103 is complete; the study has enrolled and treated 66 subjects with 
Mono-MSA ENTO and idelalisib: 35 subjects with CLL, 14 subjects with FL, 6 subjects with 
DLBCL, 3 subjects with MCL, and 8 subjects with non-FL iNHL (data cutoff date 
05 February 2015).
The most common cause of death in both studies was disease progression. Thirty seven deaths 
have been reported in Study GS-US-339-0102 and 10 deaths have been reported in Study 
GS-US-339-0103.
Commonly reported AEs and SAEs reported for subjects in Studies GS-US-339-0102 and 
GS-US-339-0103 are summarized in Sections 4.2.1.3 and 4.2.2.4 of the Investigator’s Brochure.
Study GS-US-339-0103 was closed to enrollment because an unacceptable number of subjects 
developed pneumonitis during the study. In this study subjects received combination treatment 
with Mono-MSA ENTO and idelalisib. Pneumonitis was reported for 12 subjects (18.2%). 
Eleven of the 12 pneumonitis cases (91.7%) were SAEs and were ≥Grade 3 in severity: 7 cases 
were Grade 3, 2 cases were Grade 4, and 2 cases were Grade 5. Five subjects required treatment 
in the intensive care unit. Due to the unacceptable incidence of pneumonitis, dosing with a 
combination of Mono-MSA ENTO and idelalisib was discontinued. Subjects were given the 
option to continue on study for treatment with Mono-MSA ENTO monotherapy after a 14- to 
28-day washout period. Of the 8 subjects (12.1%) who continued on with monotherapy, 
6 (75.0%) discontinued treatment because of progressive disease.


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1.2.5.
Entospletinib Target Drug Concentrations
In healthy patients, SYK inhibition, as measured by the ability to inhibit CD63 basophil 
activation and pSYK activation was evaluated in peripheral blood mononuclear cells (PBMCs) at 
multiple doses and schedules of ENTO. Plasma ENTO exposures were correlated with the 
degree of SYK inhibition. ENTO inhibited SYK as measured by ex-vivo basophil activation (see 
Figure 1-3) and pSYK (see Figure 1-4) assays with EC70s of 923 and 275 ng/mL, respectively.
Figure 1-3.
Inhibition of Basophil Activation (Original Formulation)
Figure 1-4.
Inhibition of pSYK (Original Formulation)


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1.2.6.
Use of Concomitant Medications with Entospletinib
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 strong CYP3A and CYP2C9 inducers and moderate 
CYP2C9 inducers are prohibited in this study. 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. Administration of strong 
CYP3A and CYP2C9 inducers and moderate CYP2C9 inducers should be avoided for 2 weeks 
prior to study drug administration. 
Studies in healthy volunteers have demonstrated a significant reduction in ENTO exposure when 
proton pump inhibitors are co-administered. Therefore, proton pump inhibitors are prohibited 
in combination with ENTO. Use of a proton pump inhibitor must be avoided for 1 week 
prior to study drug administration. Examples of prohibited medicines in this study are 
provided in Section 5.2 (Table 5-1). The management of subjects who are benefiting from the 
protocol treatment and who subsequently require treatment with proton pump inhibitors should 
be discussed with the Medical Monitor. 
In vitro data indicates that ENTO 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.
In a study in healthy volunteers, ENTO 400 mg twice daily increased rosuvastatin exposure by 
approximately 4-fold, which may increase the risk of rhabdomyolysis. However, in a review of 
safety data from patients who received a statin with ENTO, there were no reports of 
rhabdomyolysis nor was there a difference in the adverse events profile for this subset of 
patients. But in the interest of caution, restrictions apply to the use of HMG-CoA reductase 
inhibitors with ENTO in this study. These restrictions are included in Section 5.2.
1.3.
Rationale for the Current Study and Design
Despite progress made in understanding the biology and improvements in the treatment of AML, 
most patients unfortunately die of their disease, underscoring the need for novel therapeutic 
approaches. Increased activity of SYK in AML cells may play a role in leukemogenesis, and 
inhibition of SYK induces differentiation in myeloid effector cells both in vivo and in vitro.
Therefore, we propose an early phase clinical trial of dose escalated ENTO in combination with 
intensive induction with 7+3 for fit subjects with previously untreated AML, with 
hypomethylating agents for subjects with previously untreated AML who are not fit for intensive 
induction therapy, and as a single agent in subjects with relapsed/refractory AML.
ENTO is an adenosine triphosphate (ATP) competitive inhibitor that disrupts the kinase activity 
of purified SYK protein with a concentration that results in 50% inhibition (IC50) +/- standard 
deviation (SD) of 8.6 +/- 3.6 nM (Study PC-245-2006).


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1.3.1.
Rationale for the Entospletinib Dose Selection
An ENTO dose of 800 mg BID, original formulation, has been evaluated in a phase 2 program in 
subjects with CLL, indolent NHL, mantle cell lymphoma, and diffuse large B-cell lymphoma. 
This dosing regimen is supported by the safety and PK/PD data from single and multiple dose 
studies conducted with ENTO up to a 1200 mg dose in healthy volunteers and in subjects with 
rheumatoid arthritis.
A new SDD tablet formulation of ENTO demonstrated improved PK parameters and improved 
target coverage at trough. In a comparison of the new SDD vs. original ENTO formulation, 
400 mg BID SDD tablet provides exposures comparable to 900 mg BID of the original 
formulation. In a comparison of various doses of the new SDD formulation, moderately higher 
exposures were achieved with the 800 mg BID SDD compared to 400 mg BID SDD dose. The 
doses of ENTO SDD proposed in the dose escalation phase of the current study, from 100 mg 
BID to 800 mg BID,
 
 
. A top dose of 800 mg BID was selected to 
provide maximum exposures achievable with the SDD tablet in subjects with this rapidly 
progressing disease. A lower starting dose of ENTO 200 mg BID provides an adequate safety 
margin for evaluating interactions with the co-administered chemotherapeutic agents. Up to 
2 dose escalations are permitted to the highest dose level of 400 mg BID for Groups A and B and 
800 mg BID for Group C, which allows for a gradual dose increase and an adequate safety 
review of each dose level. 
As of August 2017, the GS-US-339-1559 Group A dose escalation phase of the trial has treated 
3 subjects in Group A at ENTO 200 mg BID and 9 subjects at ENTO 400 mg BID along with 
7+3 induction chemotherapy, 6 subjects in Group B at ENTO 200 mg and 400 mg, and 
9 subjects in Group C at ENTO 400 mg (n=3) and 800 mg (n=6) in evaluating DLT. No new 
safety signals have been identified with ENTO administration during the dose escalation phase. 
Three cases of Grade 3 transaminase elevations were observed in Group C in 2 subjects treated 
with ENTO monotherapy at the 800 mg dose level. Of these 3 cases, one Grade 3 ALT elevation 
met the protocol defined definition of DLT. Based on data from the dose escalation phase, the
sponsor, in consultation with the coordinating center, has selected ENTO dose level 400 mg BID 
for all dose expansion cohorts.
Safety analyses obtained from 53 fit and untreated AML subjects treated with ENTO + 7+3 from 
the Phase 1b and Phase 2 portions of this study indicate that the most common adverse events 
related to ENTO are mild and include fatigue, gastrointestinal symptoms, and rash. Of note, 
13.2% of subjects had persistent ≥ Grade 3 rash and 4 subjects stopped ENTO completely as a 
result of this. 7.5% of subjects were noted to have ≥ Grade 3 increase in total bilirubin. In 
addition, subjects were noted to have pancytopenia, including ≥ Grade 3 febrile neutropenia in 
41 out of 53 subjects, which is consistent with the expected effects from a myelosuppressive 
chemotherapy regimen, like 7+3. Induction mortality at 30 days was 0% and no deaths were 
reported from adverse events, febrile neutropenia, or sepsis.
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1.4.
Cytarabine arabinoside
Cytarabine arabinoside (or ARA-C) is a nucleoside that differs from the endogeneous 
counterpart for the presence of an arabinoside rather than a ribose sugar. The compound is 
carried into the cells by a nucleoside transporter, which becomes saturated at concentrations 
greater than 20 μM, above which the transport is by passive diffusion. To become an active 
compound ARA-C is converted to ARA-C triphosphate (ARA-CPT) by 3 sequential enzymes, 
deoxycitidine kinase, deoxycitidine monophosphate kinase, and nucleotide-disphosphate kinase. 
Competing with these enzymes are 2 other enzymes, cytidine deaminize and dCMP deaminase,
that convert ARA-C and ARA-CMP, respectively, to their corresponding inactive uridine 
compounds. The activated ARA-CTP competes with the natural deoxycytidine triphosphate for 
incorporation in DNA by DNA polymerase. Once incorporated in the DNA, ARA-CTP inhibits 
DNA polymerases resulting in termination of strand elongation important for DNA synthesis or 
repair. A relationship between intracellular levels of ARA-CTP and antileukemic effect has been 
identified, and strategies to increase these levels such as administration of high dose ARA-C or 
fludarabine prior to ARA-C are being studied. Side effects of this compound include 
myelosuppression, nausea, vomiting, mucositis, diarrhea, and neurotoxicity in particular with 
high doses. Cytarabine has served as the backbone of AML therapy for more than 50 years and is 
commonly used for AML consolidation treatment.
1.5.
Daunorubicin
Daunorubicin hydrochloride is a hydrochloride salt of an anthracycline cytotoxic antibiotic 
produced by a strain of Streptomyces coeruleorubidus. Daunorubicin has both antimitotic and 
cytotoxic activity through a number of proposed mechanisms of action. Daunorubicin forms 
complexes with DNA by intercalating between base pairs. It inhibits topoisomerase II activity by 
stabilizing the DNA-topoisomerase II complex resulting insingle  and double strand DNA 
breaks. Daunorubicin is rapidly and widely distributed in tissues where it binds to many cellular 
components, particularly nucleic acids. Daunorubicin is extensively metabolized in the liver and 
the primary metabolite, daunorubicinol, also has antineoplastic activity. Daunorubicin is  a 
backbone of AML therapy, commonly delivered by IV bolus for three days during the cytarabine 
infusion. Side effects of daunorubicin include myelosuppression, cumulative cardiotoxicity, 
nausea, vomiting, and mucositis.
1.6.
Azacitidine
Azacitidine for injection is a pyrimidine nucleoside analog of cytidine. Azacitidine for injection 
is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct 
cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of 
azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major 
suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are 
critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death 
of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth 
control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.


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The PK of azacitidine were studied in 6 MDS subjects following a single 75 mg/m2
subcutaneous (SC) dose and a single 75 mg/m2 intravenous (IV) dose. Azacitidine is rapidly 
absorbed after SC administration; the peak plasma azacitidine concentration of 750 ± 403 ng/ml 
occurred in 0.5 hour. The bioavailability of SC azacitidine relative to IV azacitidine is 
approximately 89%, based on area under the curve. Mean volume of distribution following IV 
dosing is 76 ± 26 L. Mean apparent SC clearance is 167 ± 49 L/hour and mean half-life after SC 
administration is 41 ± 8 minutes. The AUC and Cmax of SC administration of azacitidine in 
21 subjects with cancer were approximately dose proportional within the 25 to 100 mg/m2 dose 
range. Multiple dosing at the recommended dose-regimen does not result in drug accumulation.
Published studies indicate that urinary excretion is the primary route of elimination of azacitidine 
and its metabolites. Following IV administration of radioactive azacitidine to 5 cancer subjects, 
the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for 
<1% of administered radioactivity over 3 days. Mean excretion of radioactivity in urine 
following SC administration of 14C-azacitidine was 50%. The mean elimination half-lives of 
total radioactivity (azacitidine and its metabolites) were similar after IV and SC administrations, 
about 4 hours.
1.7.
Decitabine
Decitabine, 5-aza-2’-deoxycytidine, was initially developed 40 years ago as a cytotoxic agent to 
overcome resistance to cytarabine, and appears to have 2 different mechanisms of action {Blum 
2010, Pinto 1984}. At higher doses, the drug acts primarily as a cytotoxic agent. However, at a 
dose one log or more below that required for cytotoxic effects, decitabine induces demethylation 
of DNA and differentiation of hematopoietic cells {Blum 2010}. At these low doses, clinical 
activity with relatively low toxicity has been reported in subjects with myeloid malignancies 
such as AML and myelodysplastic syndromes (MDS) {Blum 2010, Blum 2007, Cashen 2010, 
Garcia-Manero 2006}. Blum, et al. have recently reported a phase II study with the 
azanucleoside decitabine in previously untreated AML subjects > 60 years of age who were not 
candidates for or refused standard induction treatment{Blum 2010}. All subjects received 
induction with an optimal biologic dose (OBD)/schedule of decitabine (20mg/m2 IV on days 
1-10 of a 28 day cycle) that was derived from a preceding phase I trial{Blum 2007}. A CR rate 
of 47% and an overall response rate of 64% was achieved in this high risk group of adult subjects 
with relatively low toxicity consisting mainly of cytopenias and infections typical of this disease.


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1.8.
Entospletinib
1.8.1.
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.
1.8.2.
Source
ENTO will be supplied free of charge by Gilead Sciences. Any questions or concerns regarding 
study treatment supply should be referred to your site monitor.
1.8.3.
Packaging and Labeling
Study drug (Entospletinib [GS-9973] 200 mg tablets) is packaged in white, high -density 
polyethylene (HDPE) bottles. Each bottle contains 60 tablets, a silica gel desiccant and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child-resistant, 
polypropylene screw cap fitted with an induction-sealed, aluminum-faced liner.
Study drug 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
1.8.4.
Storage and Handling
Study drug (Entospletinib [GS-9973]) 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 should not be stored in a container 
other than the container in which they were supplied. Keep the bottle tightly closed to protect 
from moisture. Consideration should be given to handling, preparation, and disposal through 
measures that minimize drug contact with the body. Appropriate precautions should be followed 
to avoid direct eye contact or exposure when handling.


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1.8.5.
Study Drug Accountability
The investigator or designee (eg, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug bottles during the study. This includes acknowledgement of 
receipt of each shipment of study drug (quantity and condition) and tracking of bottles 
assigned/utilized for subject dosing. All unused study drug bottles must be returned to the site by 
the subjects.
Investigational Drug Accountability records will be provided to each study site to:

Record the date received and quantity of ENTO lot number

Record the date, subject number, subject initials, and the ENTO lot number dispensed

Record the date, quantity of used and unused ENTO returned, along with the initials of the 
person recording the information.
1.9.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.
1.10.
Risk/Benefit Assessment for the Study
1.10.1.
Potential Risks Based on Nonclinical Safety Data with Entospletinib
Spleen tyrosine kinase (SYK) deficiency and SYK-deficient bone marrow in rodents have been 
associated with hemorrhage. In an ex vivo platelet function assay, ENTO showed no biologically 
relevant inhibition or activation of platelets at concentrations up to 12.3 μM. No evidence of 
altered coagulation parameters or effects on hemostasis were noted at any dose level in the 
ENTO nonclinical studies.
The target organ(s) of toxicity identified in rats was the duodenum, and in rabbits and dogs were 
predominantly the gastrointestinal (GI) tract and lymphoid organs. No target organs were 
identified in the cynomolgus monkey. Increases in total and/or indirect bilirubin in rats, rabbits 
and dogs administered ENTO may have been due to the inhibition of the enzyme UGT1A1 at 
ENTO exposure levels exceeding the IC50 for UGT1A1. No histological evidence of 
hepatobiliary toxicity was noted concurrent with bilirubin increases in any ENTO-treated 
species. Clinical assessments will monitor for signs and symptoms of infection, hemorrhage, GI 
distress, and changes in clinical pathology parameters (changes in hemoglobin, neutrophils, 
lymphocytes, liver enzymes, and total and indirect bilirubin) that could occur after ENTO
administration.
Administration of ENTO to pregnant female rats and rabbits resulted in dose-dependent 
developmental findings (decreased fetal weights and delayed ossification) only at dose levels 
associated with maternal toxicity (reduced body weights and food consumption). No gross 


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external, soft tissue, or skeletal fetal alterations (malformations or variations) were observed. 
This clinical study will exclude females who are pregnant or breastfeeding, and only include 
female subjects of child bearing potential who are willing to use a protocol-recommended 
method of contraception from the screening visit throughout the study and for 1 month following 
the last dose of ENTO or as recommended in the prescribing information for other 
co-administered study drug (whichever is later). Male subjects having intercourse with females 
of childbearing potential must be willing to abstain from heterosexual intercourse or use a 
protocol-recommended method of contraception from the start of ENTO throughout the study 
treatment period and for 3 months following the last dose of ENTO or as recommended in the 
prescribing information for other co-administered study drug (whichever is later).
1.10.2.
Potential Risks Based on Clinical Safety Data with Entospletinib
To date, 18 clinical studies have been conducted in which 470 healthy subjects (including
16 subjects with hepatic impairment), 464 subjects with hematologic malignancies, 7 subjects
with cGVHD, and 7 subjects with rheumatoid arthritis have participated.
The following events from ENTO clinical studies have been reviewed and determined by the 
sponsor to have a causal association with ENTO (ie, adverse drug reactions). Noted events are 
transaminases increased, hyperbilirubinaemia and rash. 
ENTO is an inhibitor of UGT1A1 and may transiently inhibit UGT1A1 activity in vivo at the 
expected clinical concentrations. Administration of drugs such as ENTO that inhibit UGT1A1 
are expected to increase total bilirubin due to decreased conjugation rather than liver 
dysfunction. The elevations in indirect bilirubin observed in clinical trials with ENTO were 
generally self-limited and did not result in discontinuation of ENTO. In the absence of symptoms 
or other hepatic laboratory abnormalities, ENTO dose modification is not required for elevated 
indirect bilirubin levels.
The bis-MSA spray-dried dispersion (SDD) formulation will be used in this study and was 
chosen because it had less interaction with acid reducing agents compared to the original 
mono-MSA formulation. Administration of the bis-MSA SDD formulation in Studies 
GS-US-339-0111 and GS-US-245-1222 demonstrated that the change in ENTO exposure upon 
co-administration with omeprazole was less than the reduction in exposure observed in Study 
GS-US-245-0106 using the original formulation. The new formulation did not completely annul 
the DDI effect of a co-administered PPI agent, however the interaction of the bis-MSA SDD 
formulation with an H2 receptor antagonist (H2RA) (eg, famotidine) is not considered clinically 
meaningful.
Dose adjustments in line with the approved product information of the standard of care therapies 
are permitted within the protocol.  Myelosuppression has been noted with the use of cytarabine, 
daunorubicin, decitabine, and azacitidine. To mitigate the risk of bone marrow suppression, 
hematology monitoring will be performed. 


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Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 37
15 February 2018
In addition, toxic myocardial damage has been associated with the use of daunorubicin; thus only 
subjects with Left Ventricular Ejection Fraction (LVEF) ≥ 45% (confirmed by ECHO) and no 
clinical evidence of congestive heart failure may be enrolled into the study. 
Refer to the Investigator’s Brochure (IB) for complete details of ENTO, including completed and 
ongoing nonclinical and clinical studies including summary safety and response data.
1.10.3.
Potential Benefits with Entospletinib
The available nonclinical and clinical data support the evaluation of ENTO in eligible subjects 
with AML. Given the impact of myeloid cancers to the subject, and the aggregate potential 
benefits considered in the context of potential risk, further development of ENTO in this study is 
justified.


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 38
15 February 2018
2.
OBJECTIVES AND ENDPOINTS
2.1.
Objectives
The primary objectives are:

To demonstrate the overall safety of ENTO in combination with standard dose cytarabine 
and daunorubicin chemotherapy (7+3) in subjects with previously untreated AML who are 
candidates for chemotherapy (fit subjects) and to assess the efficacy of ENTO at the
recommended Phase 2 dose (RP2D) (Group A)

To demonstrate the overall safety of ENTO in combination with hypomethylating agents 
(decitabine or azacitidine) in subjects with previously untreated AML who are not candidates
for 7+3 (unfit subjects) and to assess the efficacy of ENTO at the RP2D (Group B)

To demonstrate the overall safety of ENTO monotherapy in subjects with previously 
untreated AML who are not candidates for chemotherapy or in subjects with 
relapsed/refractory AML with or without mixed-lineage leukemia (MLL) and to assess the 
efficacy of ENTO at the RP2D (Group C)
The secondary objectives of this study are: 

To assess the qualitative and quantitative toxicities of ENTO monotherapy or ENTO in 
combination with chemotherapy in subjects with AML

To document therapeutic response of subjects with AML treated with ENTO monotherapy or
ENTO in combination with chemotherapy 
The exploratory objective of this study is:

 
2.2.
Endpoints
Primary Endpoints:
Safety

Occurrence of adverse events and laboratory abnormalities defined as DLTs for ENTO in 
combination with standard dose cytarabine and daunorubicin in subjects with previously 
untreated AML (Group A)

Occurrence of adverse events and laboratory abnormalities defined as DLTs for ENTO in 
combination with decitabine or azacitidine in subjects with previously untreated AML who 
are unable to receive 7+3 chemotherapy (Group B)
CCI


Entospletinib
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Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
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15 February 2018

Occurrence of adverse events and laboratory abnormalities defined as DLTs for ENTO as a 
single agent in subjects with relapsed/refractory AML (Group C)
Efficacy

Complete remission rate at induction completion: defined as the proportion of subjects who 
achieved morphologic complete remission (CR) at induction completion. Note: CR includes 
a subcategory of cytogenetic CR (CRc).

Composite complete remission rate at induction completion: defined as the proportion of 
subjects who achieved CR or morphologic complete remission with incomplete blood count 
recovery (CRi) at induction completion. 

Overall response rate at induction completion: defined as the proportion of subjects who 
achieved CR, CRi, or partial remission (PR) at induction completion.
Secondary Endpoints: 
Exposure

Drug administration and duration of exposure of study treatment
Safety

Occurrence of AEs and laboratory abnormalities not defined as DLTs
Efficacy

Event free survival (EFS) – defined for all subjects and it is measured from the start of the 
study therapy until the date of treatment failure, AML relapse or death from any cause, 
whichever occurs first. 

Overall survival (OS) – defined as the interval from the start of the study therapy to the death 
from any cause.
Exploratory Endpoints:
 
 
CCI


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 40
15 February 2018
 
 
 
 
 
 
 
 
 
CCII 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 41
15 February 2018
3.
STUDY DESIGN
3.1.
Overview
Approximately 190 subjects with previously untreated or relapsed/refractory AML will be dosed 
in 3 groups (Groups A, B, and C).
In Phase 1b (dose escalation), ENTO will be administered at 2 dose levels (200 mg and 400 mg)
every 12 hours either in combination with chemotherapy for Group A or with a hypomethylating 
agent for Group B. ENTO will be administered at 2 dose levels (400 mg and 800 mg) every 
12 hours as monotherapy for Group C. At the time of this amendment, Phase 1b had completed 
enrollment.
In Phase 2 (dose expansion), the recommended dose of 400 mg ENTO will be administered. At 
the time of this amendment, Group A had completed enrollment.
In Group B, the overall safety of ENTO in combination with a hypomethylating agent 
(decitabine or azacitidine) will be evaluated. Six evaluable subjects will initially be enrolled as 
part of the safety run-in to evaluate the safety of ENTO in combination with azacitidine. If 2 or 
more subjects experience DLTs, then this arm will be dropped from the study.  If Phase 2 
proceeds with an azacitidine arm, subjects will be randomized to receive ENTO in combination 
with either decitabine or azacitidine. At the time of this amendment, Group B safety run-in had 
completed enrollment and the Phase 2 portion of the trial is currently ongoing with plans to 
enroll 40 subjects in Group B, randomized equally to ENTO + decitabine vs. ENTO + 
azacitidine. Randomization will be stratified by the following 2 factors:
Stratification Factor
Stratification Levels
Age
< 75 or > 75 years
White Blood Count
≤ 5,000/µL or > 5,000/µL
In Group C, relapsed/refractory and previously untreated AML subjects will be evaluated in 
separate cohorts. At the time of this amendment, Cohort C1A had completed enrollment. This 
amendment identifies the closure of Cohort C3 to further enrollment. 


Entospletinib
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Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
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15 February 2018
Figure 3-1.
Study Schema
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the subject’s leukemia.  
3.1.1.
Group A Phase 1b (Dose Escalation): Entospletinib + cytarabine + 
daunorubicin (7+3)
Note: At the time of this amendment, Group A Phase 1b had completed enrollment.
ENTO lead-in will be administered orally every 12 hours on Days 1-14 as a single agent
(Cycle 0), and will continue to be given daily in combination with IV cytarabine (Days 1-7) and 


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 43
15 February 2018
IV daunorubicin (Days 1- 3) during induction chemotherapy of every 14-day cycle for up to 
2 cycles. Subjects must be able to receive up to 2 cycles of induction chemotherapy.
Intra-subject dose escalation will not be allowed.
Table 3-1.
Group A Entospletinib Cohort Dose Escalation Table
Dose Level
Entospletinib
Daunorubicin
Cytarabine
0
200 mg
60mg/m2
100mg/m2
1
400 mg
Although ENTO lead-in therapy (Cycle 0) is scheduled to end on Day 14, cytarabine and 
daunorubicin (7+3) treatment (Cycle 1) may be started after 5 days of exposure to ENTO if the 
Principal Investigator agrees with the treating physician that treatment should start sooner. 
Examples of such situations include but are not limited to:

WBC count is increasing and greater than 20,000/µL

Leukemic related complications that in the opinion of the treating physician require initiation 
of cytotoxic chemotherapy sooner
Hydroxyurea is allowed during the lead-in period per investigator discretion and after discussion 
with the medical monitor. Hydroxyurea should be discontinued prior to initiating 7+3 chemotherapy.
A bone marrow aspirate for disease assessment will be performed at the end of the monotherapy 
lead-in period (ie, Cycle 0 Day 14 or after the minimum 5-days of ENTO), and prior to initiating 
induction chemotherapy. 
A bone marrow aspirate and biopsy will be performed on Cycle 1 Day 14. If the bone marrow 
cellularity at this time point is < 20%, a repeat bone marrow examination will occur within 2 
weeks or at count recovery, whichever comes first. Subjects with residual disease detected at the 
Cycle 1 Day 14 bone marrow evaluation will proceed with Cycle 2 of induction chemotherapy.
The start of Cycle 2 will depend on the timing and result of the disease assessment. Subjects are 
to continue receiving ENTO while awaiting disease assessment results.
Subjects with cytogenetic and molecular mutations at screening must have cytogenetic and 
molecular mutation testing repeated at subsequent bone marrow examinations (Cycle 0 Day 14, 
Cycle 1 Day 14, count recovery, End of Study).  
Subjects will undergo a daily complete blood count (CBC) from Cycle 1 Day 14 (ie, count nadir)
until count recovery, at which time a bone marrow aspirate and biopsy is performed.
If a subject discontinues study treatment (eg, as a result of an AE), every attempt should be made 
to keep the subject in the study to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.  


Entospletinib
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Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
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15 February 2018
3.1.2.
Group A Phase 2 (Dose Expansion): Entospletinib + cytarabine + daunorubicin
(7+3)
Note: At the time of this amendment, Group A Phase 2 had completed enrollment.
Entospletinib lead-in (Cycle 0): ENTO 400 mg will be administered orally every 12 hours on 
Days 1-14 as a single agent during the lead-in (Cycle 0).  However, cytarabine and daunorubicin 
(7+3) treatment (Cycle 1) may be started earlier, after 5 days of exposure to ENTO, if the 
Principal Investigator agreed with the treating physician that treatment should start sooner.
Examples of such situations may include but are not limited to:

White blood cell count is increasing and greater than 20,000/µL

Leukemic related complications that in the opinion of the treating physician require the 
initiation of cytotoxic chemotherapy sooner
Hydroxyurea is allowed during the lead-in period per investigator discretion and after discussion 
with the medical monitor.  Hydroxyurea should be discontinued prior to initiating cytarabine and 
daunorubicin (7+3) chemotherapy.
A bone marrow aspirate for disease assessment will be performed at the end of the monotherapy 
lead-in period (ie, Cycle 0 Day 14 or after the minimum 5 days of ENTO), and prior to initiating 
induction chemotherapy.  
Subjects with cytogenetic and molecular mutations at screening must have cytogenetic and 
molecular mutation testing repeated at subsequent bone marrow examinations (Cycle 0 Day 14, 
Cycle 1 Day 14, count recovery, End of Study). 
ENTO 400 mg will continue to be given every 12 hours from Cycle 0 Day 1 to the completion of 
induction therapy as determined by bone marrow response.
Entospletinib + 7+3 (Cycle 1-2): ENTO 400 mg will be administered every 12 hours in 
combination with IV cytarabine (Days 1-7) and IV daunorubicin (Days 1-3) for up to 2 induction 
cycles (Cycle 1 and 2). Subjects must be able to receive 2 cycles of induction chemotherapy.
A bone marrow aspirate and biopsy will be performed on Cycle 1 Day 14. If the bone marrow 
cellularity at this time point is ≤ 20%, a repeat bone marrow examination will occur within 
2 weeks or at count recovery, whichever came first. Subjects with residual disease detected at the 
Cycle 1 Day 14 bone marrow evaluation will proceed with Cycle 2 of induction chemotherapy. 
The start of Cycle 2 will depend on the timing and result of the disease assessment. Subjects will
continue receiving ENTO while awaiting disease assessment results. 
The investigator must consult the medical monitor if subjects have not obtained a CR after 
Cycle 1 and prior to Cycle 2, and if there is any consideration to omit Cycle 2 of induction 
chemotherapy.


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 45
15 February 2018
Subjects with cytogenetic and molecular mutations at screening must have cytogenetic and 
molecular mutation testing repeated at subsequent bone marrow examinations (Cycle 0 Day 14, 
Cycle 1 Day 14, count recovery, End of Study). 
Subjects will undergo a daily CBC from Cycle 1 Day 14 (ie, count nadir) until count recovery at 
which time a bone marrow aspirate and biopsy will be performed.  
Once a CR/CRi is confirmed on a recovery bone marrow examination (ie, the subject achieves 
< 5% blasts by morphology and flow cytometry), the subject will proceed to either allogeneic 
stem cell transplantation (SCT) or post-remission chemotherapy with cytarabine.
If CR/CRi is not achieved by the end of Cycle 2, the subject will be considered a treatment 
failure and will have met study efficacy endpoint criteria, but will remain on study for required 
study-related follow-up procedures. 
Entospletinib + cytarabine post-remission (at least 3 cycles, and up to 4 cycles):
Post-remission chemotherapy will be offered to eligible subjects who have achieved CR/CRi and
do not require or cannot proceed to allogeneic SCT. In addition, subjects who are awaiting a 
donor or transitioning to allogeneic SCT will be allowed to receive post-remission chemotherapy 
per investigator discretion. Therapy will consist of 3g/m2 high dose cytarabine administered IV 
every 12 hours on Days 1, 3, and 5 (< 60 years of age) or 1g/m2 cytarabine administered once 
daily on Days 1-5 (≥60 years of age) in combination with 400 mg ENTO every 12 hours on 
Days 1-28 of each 28-day cycle. 
Subjects in whom definitive post-remission chemotherapy is planned will receive at least 3 and
up to 4 cycles of cytarabine. Subjects who are awaiting a donor or transitioning to SCT may 
receive at least 1 and up to 4 cycles of cytarabine.
A bone marrow aspirate sample will be collected for disease assessment and biomarker research 
at the end of every 2 cycles (Cycle 2 Day 28 and Cycle 4 Day 28) and at suspected disease 
progression. Subjects who continue to maintain a CR/CRi after 3-4 cycles of post-remission 
chemotherapy will be offered maintenance with ENTO 400 mg every 12 hours for up to 
12 cycles.
Entospletinib maintenance (up to 12 cycles): ENTO 400 mg will be administered orally every 
12 hours on Days 1-28 of each 28-day cycle and will continue for up to maximum 12 cycles as 
long as the subject is experiencing benefit or until the subject becomes a candidate for SCT.  A 
bone marrow aspirate sample will be collected for disease assessment and biomarker research at 
the end of every 4 cycles (eg, Cycle 4 Day 28, Cycle 8 Day 28, etc.) or as clinically indicated. 
Subjects who achieve CR/CRi that is stable for 2 consecutive bone marrow evaluations are not 
required to have further bone marrow aspirate samples collected, unless clinically indicated.
If a subject discontinues study treatment (eg, as a result of an AE), every attempt should be made 
to keep the subject in the study to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.  


Entospletinib 
Protocol GS-US-339-1559 
Final 
Gilead Sciences, Inc. 
Amendment 7 
Figure 3-2. 
Group A Phase 2 Dosing Schema 
+ 
Stem Cell 
• 
Transplant 
CR/CRi Post-remission 
ENTO+ 
.... 
cytarabine 
-
( 3-4 cycles) 
Maintenance 
Cycle 0 Lead-in 
• 
ENTO 
Screen 
f-+ 
ENTO 
___. 
Cycle 1-2 
r-
(up to 12 cycles) 
14 days 
ENTO + 7+3 
.... 
Treatment 
____., 
Long Term 
Non-CR 
Failure 
Follow-up 
3.1.3. 
Group B Phase lb (Dose Escalation): Entospletinib + decitabine 
Note: At the time of this amendment, Group B Phase 1b had completed enrollment. 
During the dose escalation, the initial dosing level for the 1st coh01i is defmed as level 0 in 
table below. Intra-subject dose escalation will not be allowed. 
Table 3-2. 
Group B Entospletinib Dose Escalation Table 
DoseLeve1 
Entospletinib 
Decitabine 
0 
200mg 
20mglm2 
1 
400mg 
Entospletinib lead-in (Cycle 0): ENTO will be administered orally every 12 hours on 
r-
r-
Days 1-14 as a single agent during the lead-in (Cycle 0). However, decitabine treatment may be 
struied eru·Iier, after 5 days of exposure to ENTO, if the Principal Investigator agrees with the 
treating physician that treatment should stati sooner. Examples of such situations may include 
but are not limited to: 
• 
White blood cell count is increasing and greater than 20,000/j.!L 
• 
Leukemic related complications that in the opinion of the treating physician require the 
initiation of cytotoxic chemotherapy sooner 
Hydroxyurea is allowed during the lead-in period per investigator discretion and after discussion 
with the medical monitor. Hydroxyurea should be discontinued prior to initiating decitabine 
induction. 
CONFIDENTIAL 
Page46 
15 Februa1y 2018 


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
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15 February 2018
A bone marrow aspirate for disease assessment will be performed at the end of the monotherapy 
lead-in period (ie, Cycle 0 Day 14 or after the minimum 5 days of ENTO), and prior to initiating 
decitabine induction.
Entospletinib + decitabine induction (Cycles 1-4): ENTO will be administered orally every 
12 hours on Days 1-28 in combination with decitabine on Days 1-10 of every 28-day cycle for at 
least 2 but no more than 4 cycles of induction chemotherapy.  
A bone marrow aspirate and biopsy sample will be collected for disease assessment and 
biomarker research at the end of every 2 cycles (Cycle 2 Day 28 and Cycle 4 Day 28) or as 
clinically indicated. Subjects with cytogenetic and molecular mutations at screening must have 
cytogenetic and molecular mutation testing repeated at subsequent bone marrow examinations 
(Cycle 0 Day 14, Cycle 1 Day 28, count recovery, End of Study).
If the subject achieves < 5% blasts by morphology and flow cytometry or has evidence of clinical 
benefit after completing 2-4 induction cycles but is not eligible for SCT, the subject will have the 
option to receive maintenance therapy with ENTO in combination with decitabine.  Subjects 
with persistent evidence of disease (ie, blasts ≥5%) after Cycle 2 may receive up to 2 more 
induction cycles until subject achieves < 5% blasts.
If < 5% blasts by morphology and flow cytometry is not achieved or the subject does not show 
evidence of clinical benefit after 4 induction cycles, the subject is considered a treatment failure 
and will have met study efficacy endpoint criteria, but will remain on study for required study-
related follow-up procedures.
Entospletinib + decitabine maintenance (at least 2 cycles): ENTO will be administered orally 
every 12 hours on Days 1-28 in combination with decitabine on Days 1-5 of every 28-day cycle.  
A bone marrow aspirate sample will be collected at the end of every 4 cycles (eg, Cycle 4 
Day 28, Cycle 8 Day 28) or as clinically indicated for disease assessment and biomarker 
research.  Subjects who achieve CR/CRi that is stable for 2 consecutive bone marrow evaluations 
are not required to have further bone marrow aspirate samples collected, unless clinically 
indicated.  After completing at least 2 cycles, the subject may proceed to SCT.  If not eligible for 
SCT, subjects will have the option to continue on maintenance therapy with ENTO in 
combination with decitabine.  Subjects who are intolerant of decitabine may switch to ENTO
monotherapy maintenance at any time after completing the first 2 cycles.  Maintenance may 
continue as long as the subject is experiencing benefit and does not meet the criteria for study 
treatment discontinuation.  
Entospletinib maintenance (up to 12 cycles): ENTO will be administered orally every 12 hours 
as monotherapy on Days 1-28 of each 28-day cycle and continued for up to 12 cycles as long as 
the subject is experiencing benefit and does not meet the criteria for study treatment 
discontinuation.  A bone marrow aspirate sample will be collected for disease assessment and 
biomarker research at the end of every 4 cycles (eg, Cycle 4 Day 28, Cycle 8 Day 28) or as 
clinically indicated.  Subjects who achieve CR/CRi that is stable for 2 consecutive bone marrow 
evaluations are not required to have further bone marrow aspirate samples collected, unless 
clinically indicated.  Extension of maintenance may occur on an individual basis if approved by 
the Principal Investigator.


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 48
15 February 2018
If a subject discontinues study treatment (eg, as a result of an AE), every attempt should be made 
to keep the subject in the study to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.  
Note: At the time of this amendment, Group B Phase 1b had completed enrollment.  
3.1.4.
Group B Phase 2 (Dose Expansion): Entospletinib + Hypomethylating agent
The overall safety of ENTO in combination with a hypomethylating agent (decitabine or 
azacitidine) will be evaluated. As part of the safety run-in, ENTO 400 mg in combination with 
azacitidine 75mg/m2 will be administered to 6 evaluable subjects.
Following completion of the safety run-in (DLT window, Section 3.2), the safety of the 
azacitidine arm will be reviewed to determine if enrollment of the expansion cohort may proceed 
with azacitidine. If 2 or more subjects experience DLT, all ongoing subjects in the safety run-in 
will be discontinued and the azacitidine arm will be dropped from the study.  If Phase 2 proceeds
with an azacitidine arm, subjects will be randomized to receive ENTO in combination with either 
decitabine or azacitidine.
Note: At the time of this amendment, Group B Phase 2 safety run-in had completed enrollment.
Entospletinib Safety lead-in (Cycle 0): ENTO 400 mg will be administered orally every 
12 hours on Days 1-14 as a single agent during the lead-in (Cycle 0). However, chemotherapy 
with the assigned hypomethylating agent (Cycle 1) may be started earlier, after 5 days of 
exposure to ENTO, if the Principal Investigator agrees with the treating physician that treatment 
should start sooner. Examples of such situations may include but are not limited to:

White blood cell count is increasing and greater than 20,000/µL

Leukemic related complications that in the opinion of the treating physician require the 
initiation of cytotoxic chemotherapy sooner
Hydroxyurea is allowed during the lead-in period per investigator discretion and after discussion 
with the medical monitor.  Hydroxyurea should be discontinued prior to initiating
hypomethylating agent.
A bone marrow aspirate for disease assessment will be performed at the end of the monotherapy 
lead-in period (ie, Cycle 0 Day 14 or after the minimum 5 days of ENTO) and prior to initiating 
therapy with hypomethylating agent.
Subjects with cytogenetic and molecular mutations at screening must have cytogenetic and 
molecular mutation testing repeated at subsequent bone marrow examinations (Cycle 0 Day 14, 
Cycle 1 Day 28, count recovery, End of Study).


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
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Entospletinib Randomization lead-in (Cycle 0): ENTO 400 mg will be administered orally 
every 12 hours on Days 1-5 as a single agent during the lead-in. 
Hydroxyurea is allowed during the lead-in period per investigator discretion and after discussion 
with the medical monitor.  Hydroxyurea should be discontinued prior to initiating 
hypomethylating agent.
If circulating blasts have cleared at the end of monotherapy lead-in (Cycle 0 Day 5), then a bone 
marrow aspirate will be performed for disease assessment.
Subjects with cytogenetic and molecular mutations at screening must have cytogenetic and 
molecular mutation testing repeated at subsequent bone marrow examinations (Cycle 0 Day 5, 
Cycle 1 Day 28, count recovery, End of Study).
Entospletinib + Hypomethylating agent induction (Cycles 1-4): In subsequent induction 
cycles (Cycles 1-4), ENTO 400 mg will be administered orally every 12 hours on Days 1-28 in 
combination with the assigned hypomethylating agent dose and schedule. All subjects will 
receive at least 2 but no more than 4 cycles of induction chemotherapy.
Table 3-3.
Hypomethylating Agent Dose and Schedule Table (Induction)
Agent
Dose
Days
Cycle Duration
decitabine
20mg/m2
1-10
28 days
azacitidine
75mg/m2
1-7
A bone marrow aspirate and biopsy sample will be collected for disease assessment and 
biomarker research at the end of every 2 cycles (Cycle 2 Day 28 and Cycle 4 Day 28) or as 
clinically indicated. Subjects with cytogenetic and molecular mutations at screening must have 
cytogenetic and molecular mutation testing repeated at subsequent bone marrow examinations 
(Cycle 0 Day 14, Cycle 1 Day 28, count recovery, End of Study).
If the subject achieves < 5% blasts by morphology and flow cytometry or has evidence of clinical 
benefit after completing 2-4 induction cycles but is not eligible for SCT, the subject will have the 
option to receive maintenance therapy with ENTO in combination with decitabine or azacitidine.  
Subjects with persistent evidence of disease (ie, blasts ≥5%) after Cycle 2 may receive up to 
2 more induction cycles until subject achieves < 5% blasts.
If < 5% blasts by morphology and flow cytometry is not achieved or the subject does not show 
evidence of clinical benefit after 4 induction cycles, the subject is considered a treatment failure 
and will have met study efficacy endpoint criteria, but will remain on study for required study-
related follow-up procedures.
Entospletinib + Hypomethylating agent maintenance (at least 2 cycles): ENTO will be 
administered orally every 12 hours on Days 1-28 in combination with assigned hypomethylating 
agent dose and schedule. 


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 50
15 February 2018
Table 3-4.
Hypomethylating Agent Dose and Schedule Table (Maintenance)
Agent
Dose
Days
Cycle Duration
decitabine
20mg/m2
1-5
28 days
azacitidine
75mg/m2
1-7
A bone marrow aspirate sample will be collected at the end of every 4 cycles (eg, Cycle 4 
Day 28, Cycle 8 Day 28) or as clinically indicated for disease assessment and biomarker 
research.  Subjects who achieve CR/CRi that is stable for 2 consecutive bone marrow evaluations 
are not required to have further bone marrow aspirate samples collected, unless clinically 
indicated. 
After completing at least 2 cycles, the subject may proceed to SCT. If not eligible for SCT, 
subjects will have the option to continue on maintenance therapy with ENTO in combination 
with the assigned hypomethylating agent. Subjects who are intolerant of the hypomethylating 
agent after completing 2 cycles may switch to ENTO monotherapy maintenance. Maintenance 
may continue as long as the subject is experiencing benefit and does not meet the criteria for 
study treatment discontinuation.  
Entospletinib maintenance (maximum up to 12 cycles): ENTO 400 mg will be administered 
every 12 hours as a single agent on Days 1-28 of each 28-day cycle and will continue for up to 
12 cycles as long as the subject is experiencing benefit and does not meet the criteria for study 
treatment discontinuation.  
A bone marrow aspirate sample will be collected for disease assessment and biomarker research 
at the end of every 4 cycles (eg, Cycle 4 Day 28, Cycle 8 Day 28) or as clinically indicated.  
Subjects who achieve CR/CRi that is stable for 2 consecutive bone marrow evaluations are not 
required to have further bone marrow aspirate samples collected, unless clinically indicated.  
If a subject discontinues study treatment (eg, as a result of an AE), every attempt should be made 
to keep the subject in the study to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.  


Entospletinib 
Protocol GS-US-339-1559 
Final 
Gilead Sciences, Inc. 
Amendment 7 
Figure 3-3. 
Group B Phase 2 Randomization Dosing Schema 
Cycle 0 Lead-in 
Screen 
f--. Randomization -
ENTO -
5 days 
•subjects not eligible for SCT after at least 2 maintenance 
. 
. 
cycles may contmue on mamtenance therapy woth ENTO + 
hypomethylating agent or switch to maintenance therapy with 
ENTO monotherapy. 
< 5% blasts,\ 
clinical 
Mamtenance 
benefit 
ENTO + . 
r-. Hypomethylatlng I--
Cycles 1-4 
agent 
(at least 2 cvtles\• 
ENTO + 
Hypomethylating I--
agent 
(2-4 cycles\ 
L._. 
Treatment 
5% blasts/ 
Failure 
no clinical 
benefit 
+ 
,...... 
Stem Cell 
Transplant 
Maintenance 
L..._.. 
ENTO 
(up to 12 cycles) 
Long Term 
Follow-up 
3.1.5. 
Group C Phase lb (Dose Escalation): Entospletinib Monotherapy 
Note: At the titne of this amendment, Group C Phase 1 b had completed enrollment. 
-
-
.... 
ENTO monotherapy will be administered orally eve1y 12 hours at the dose level indicated in the 
table below for every 28-day cycle until the subject meets criteria for study treatment 
discontinuation. The initial dosing level for the 1st cohort is defined as level 0 in table below. 
Intra-subject dose escalation will not be allowed. 
Table 3-5. 
Group C Entospletinib Cohort Dose Escalation Table 
Dose Level 
Entospletinib 
0 
400 mg 
800 mg 
Subjects will receive ENTO continuously on Days 1-28 of a 28-day cycle until the subject meets 
criteria for study treatment discontinuation (see Section 6.4.1). A bone manow biopsy and 
aspirate sample will be collected for disease assessment and biomarker research on Cycle 1 
Day 28 and Cycle 2 Day 28. 
A bone manow aspit·ate sample will be collected for disease assessment and biomarker research 
every 4 cycles starting on Cycle 4 Day 28 of subsequent cycles (ie, Cycle 4 Day 28, Cycle 8 
Day 28) unless the subject achieved CR/CRi, in which case fmther manow aspit·ations are not 
requit·ed, unless clinically indicated (exception: if the subject clearly has circulating leukelnia 
cells in the peripheral blood, bone manow aspiration after Cycle 2 or beyond is not mandated). 
CONFIDENTIAL 
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If a subject discontinues study treatment (eg, as a result of an AE), every attempt should be made 
to keep the subject in the study to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.  
3.1.6.
Group C Phase 2 (Dose Expansion): Entospletinib Monotherapy
Note: At the time of this amendment, Cohort C1A had completed enrollment (n=15). This 
amendment identifies the closure of Cohort C3 to further enrollment (n=12). 
Relapsed/refractory and previously untreated subjects will be evaluated in separate cohorts 
during phase 2 as monotherapy. ENTO 400 mg will be administered orally every 12 hours on 
Days 1-28 of every 28-day cycle as long as the subject is experiencing benefit and does not meet 
criteria for study treatment discontinuation.  
A bone marrow biopsy and aspirate sample will be collected for disease assessment and 
biomarker research at the end of Cycles 1 and 2 on Day 28.  A bone marrow aspirate sample will 
also be collected for disease assessment and biomarker research on Day 28 of every 4 cycles 
beginning on Cycle 4 Day 28 (eg, Cycle 4 Day 28, Cycle 8 Day 28) and at suspected disease 
progression.  Subjects who achieve CR/CRi that is stable for 2 consecutive bone marrow 
evaluations are not required to have further bone marrow aspirate samples collected, unless 
clinically indicated.
Cohort C1A: This cohort is designed to enroll 15 relapsed/refractory AML subjects. If 5 or 
more of the initial 15 subjects achieve CR/CRi after 1-2 cycles, an additional 15 subjects would 
then be enrolled.  However, if less than 5 of the initial 15 subjects achieve CR/CRi after 
1-2 cycles, then treatment would be considered futile. At this time, futility has been met and, 
thus, Cohort C1A will not move forward (ie, will not enroll any subjects).
Cohort C2: 15 relapsed/refractory AML subjects with MLL.
Cohort C3: 30 previously untreated AML subjects who are unfit (eg, very elderly, have multiple 
comorbidities, and a poor ECOG/performance status) for chemotherapy or hypomethylating 
agent, or refuse either of these 2 treatment options. 
If a subject discontinues study treatment (eg, as a result of an AE), every attempt should be made 
to keep the subject in the study to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.  
3.2.
Dose Limiting Toxicities
It is recognized that drug-related toxicity in this population may be difficult to ascertain given 
the aggressive hematologic disease. Investigators will attempt to assign attribution of toxicities to 
each drug when possible. The CTEP Active Version of the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting.


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The assessment of DLTs for dose escalation decisions will occur during the DLT assessment 
window. DLTs will also be assessed in Phase 2 during the Group B safety run-in to evaluate the 
safety of ENTO in combination with azacitidine. The DLT assessment window for each group is 
as follows:
Group A: begins on Cycle 0 Day 1 and ends 28 days after Cycle 1 Day 1 or 28 days after Cycle 2 
Day 1 (if Cycle 2 is needed); for subjects with < 5% blasts in the bone marrow, the DLT window 
may be expanded for hematologic toxicity recovery as noted below
Group B (including Phase 2 safety run-in): begins on Cycle 0 Day 1 and ends 28 days after
Cycle 1 Day 1
Group C: 28 days (Cycle 1); for subjects with < 5% blasts in the bone marrow, the DLT window 
may be expanded for hematologic toxicity recovery as noted below
During the DLT assessment window, subjects who fail to complete 21 days of ENTO, or miss
any doses of cytarabine and daunorubicin in Group A, or decitabine (or azacitidine during the 
Phase 2 safety run-in) in Group B for reasons other than DLT, will not be evaluable for the 
ENTO DLT assessment. Additional subjects will be enrolled to the appropriate dose level to 
replace unevaluable DLT subjects in order to provide adequate safety data on which to base dose 
escalation decisions as well as expansion decisions. Non-hematologic toxicity of Grade 4 
attributable to ENTO with the exception of alopecia, nausea and vomiting controllable with 
anti-emetic therapy, line associated venous thrombosis, infection (infection-related toxicities 
such as fever/sepsis), and fatigue will be considered DLT.
Subjects with transient Grade 4 electrolyte abnormalities that are not clinically significant and 
are correctable within 24 hours will not be considered DLT. 
Subjects with transient liver function test abnormalities (AST, ALT, bilirubin, or alkaline 
phosphatase) that resolve to < Grade 2 within 10 days will not be considered DLT.  
In general, infection will not constitute a DLT unless it is felt that the infection resulted from 
unexpectedly complicated prolonged myelosuppression.
Toxicities that require temporary interruption of treatment with ENTO (but not permanent 
discontinuation) will not be considered DLT unless the toxicity does not resolve to < Grade 2 in 
10 days.
In subjects with < 5% blasts in the bone marrow, absence of myelodysplastic changes, and/or 
absence of AML by flow cytometry in the bone marrow, hematologic toxicity will be defined as: 
failure to recover neutrophil count (ANC > 500/µL) or platelet count (> 25000/µL) within 
4 weeks after achieving < 5% blasts in Group A and Group C. Hematologic toxicities will not be 
used to assess DLTs in Group B.


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3.2.1.
Guidelines for Phase 1b Dose Escalation and Phase 2 Group B Dose 
Expansion
In Phase 1b, the trial employs the standard NCI definition of MTD (starting dose associated with 
DLT in < 33.3% of subjects during the DLT assessment window). After considering the available 
safety and efficacy data and in consultation with the study PI, a dose at or below MTD will be 
chosen by the sponsor for further evaluation. 
Dose escalation for Groups A, B, and C will proceed independently and in parallel per Table 3-6.  
Table 3-6.
Dose Escalation/ DLT Guidelines
Number of Subjects with 
DLT at a given level
Escalation Decision Rule
0 out of 3
Enroll 3 subjects at the next dose level.  An additional 3 subjects can be enrolled at 
the current dose level without a DLT if additional evaluation is warranted after 
discussion with the study PI and medical monitor.
≥ 2
Dose escalation will be stopped. This dose level will be declared maximally 
administered dose (highest dose administered). Three (3) additional Pts. will be 
entered at next lower dose level if only 3 subjects were treated previously at that dose.
1 out of 3
Enroll at least 3 more subjects at this dose level.
If 0 of these 3 subjects experience DLT, proceed to the next dose level.
If 1 or more of this group suffer DLT, then dose escalation is stopped, and this dose is 
declared the maximally administered dose. Three (3) additional subjects will be 
entered at the next lower dose level if only 3 subjects were treated previously at that 
dose.
≤ 1 out of 6 at highest 
dose level below the 
maximally administered 
dose
This is the maximum tolerated dose (MTD) and generally the effective dose. At least 
6 subjects must be entered at the effective dose.  The recommended expansion dose 
may be a dose lower than the MTD. 
In Phase 2 Group B (ENTO + azacitidine) safety run-in cohort, if 2 or more subjects experience 
DLT, all ongoing subjects in the cohort will be discontinued and the cohort will be closed.
3.3.
Dosing Delays/Dose Modifications Attributed to Entospletinib (Beyond 
Cycle 1)
If the following signs or symptoms are medically manageable, they are not to be a consideration 
with respect to the subject’s dosing or continuation on study: nausea/mild vomiting/diarrhea, 
drug-related fever or chills, transient and correctable laboratory test abnormalities, line 
associated thrombosis, or alopecia (see Appendix 3).  Subjects who are intolerant of dose beyond 
Cycle 1, may either stop study drug (permanent discontinuation) or have a dose hold in 
consultation with the Medical Monitor if the AE or lab has resolved to Grade 1 or less which
may not be re-escalated.  If there is loss of disease control during drug interruption which has 
resolved to Grade 1 or less, subjects may re-start ENTO per the dose modification guidelines 
below. 


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Group A: 
Subjects experiencing toxicity attributed to any of the study medication during Cycle 1 requiring 
permanent discontinuation of either drug shall be removed from study. There will be no dose 
modifications for ENTO for hematologic toxicity during Cycle 1.
Dose modification of ENTO in subsequent cycles is permitted following guidelines provided 
below. Subjects who experience a non-hematologic toxicity assessed as ENTO related that is 
Grade 3 or higher will hold dosing of ENTO until the toxicity resolves to Grade 1, and then 
restart at the next lower dose and continue through the end of the cycle. Missed doses are not to 
be made up.
Adverse events and laboratory abnormalities will be graded using the CTCAE, Version 4.03.
Dose Modifications for Non-Hematologic Toxicity for Entospletinib and Daunorubicin and 
Cytarabine and High Dose Cytarabine Maintenance
In subjects who experience florid heart failure (EF < 45%) or cerebellar toxicity, protocol 
treatment will be held and no further anthracyclines or cytarabine will be permitted while on the 
trial. To re-administer and continue with protocol treatment, EF will need to recover to ≥ 45%.
If a subject experiences any non-hematologic clinically significant Grade 3 or greater toxicity 
felt to be related to the combination agents, or high dose cytarabine maintenance, hold the 
protocol therapy until it resolves to less than Grade 2. Then, if determined related to ENTO, 
restart ENTO with one dose level reduction. If a subject experiences pneumonitis at Grade 4, 
study treatment must be discontinued.
Dose Modifications for Hematologic Toxicity for Entospletinib and Daunorubicin and 
Cytarabine and High Dose Cytarabine Maintenance
No dose modifications are planned for hematological toxicity for cytarabine and daunorubicin
during induction chemotherapy. In subjects who require Cycle 2 induction, an ECHO/MUGA is 
recommended prior to starting Cycle 2 and daunorubicin will be administered if EF is ≥ 45% per 
investigator discretion.   
No renal dose reductions are necessary when standard dose cytarabine is used 
(100-200mg/m2/24hrs). Reduced doses should be considered when using high dose cytarabine as 
indicated below:
Glomerular Filtration Rate (mL/min)
Dose Administered
> 60
100%
46-60
60%
31-45
50%
< 30
Contraindicated


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For cerebellar neurotoxicity ≥ Grade 2 due to high dose cytarabine, discontinue high dose 
cytarabine for the remainder of the induction cycle.
If prolonged hematologic clinically significant Grade 3 or greater toxicity felt to be related to 
ENTO occur after Cycle 1, hold ENTO until it resolves to less than Grade 2. Then, restart ENTO
with one dose level reduction.
Group B:
Cycle 0 will be defined as Days 1-14. Cycles 1-4 and maintenance therapy will be defined as 
Days 1-28. Subsequent cycles of therapy are to begin as soon as possible after Day 28. Delays of 
up to 14 days will not constitute a protocol violation.
Delays of longer than 14 days must be discussed with the PI and Medical Monitor; repeat BM 
aspiration and biopsy is required if treatment is delayed more than 4 weeks. Delays longer than 
14 days are only permitted (but not required) under special circumstances after discussion with 
PI and Medical Monitor and permissible reasons for these extended delays include:

Drug related myelosuppression (defined here as ANC < 500/µL or platelet count 
< 25,000/µL, with no evidence of AML in blood or marrow – including flow cytometry or 
cytogenetics). A repeat BM aspiration and biopsy is required if treatment is delayed more 
than 4 weeks. 

Ongoing febrile neutropenia or active infection in subjects with no evidence of AML. 
Note - this does not apply to subjects with febrile neutropenia/infection in the setting of 
active AML.

Serious hemorrhagic complication in a subject who is refractory to platelet transfusions. 
For subjects entering the maintenance phase of treatment, drug related myelosuppression is a 
greater concern. However, it should again be noted that subjects with continued evidence of 
AML such as by flow or cytogenetics (even if morphologic blasts are < 5%) should proceed with 
therapy in a timely way as described above. 
For subjects with no evidence of AML, the first cycle of maintenance should proceed on Day 29 
as long as marrow cellularity is > 10%. However, the second (or subsequent) cycles of 
maintenance therapy may be held until ANC is greater than or equal to 1000. If there is no 
evidence of ANC recovery after 14 days, repeat marrow evaluation is needed. If negative for 
disease and cellularity is > 10%, proceed with decitabine and ENTO at decreased doses. Bone 
marrow evaluation may be done sooner than 14 days at the discretion of the treating physician.
Dose Modifications for Non-Hematologic Toxicity for Entospletinib, Decitabine or 
Azacitidine
If the subject experiences any non-hematologic clinically significant Grade 3 or greater toxicity 
felt to be related to either agent during the induction phase beyond DLT assessment, hold the 
protocol therapy until it resolves to less than Grade 2. Then, if related to ENTO, restart ENTO


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with one dose level reduction. If related to decitabine or azacitidine, the respective package insert 
should be followed for any dose reductions. If institutional guidelines are to be followed, contact 
the study team for additional guidance. If the toxicity recurs, subject will be removed from study. 
If protocol therapy is withheld for more than 2 weeks for toxicity related to protocol-based 
therapy or up to 4 weeks for any other reason, subjects will be removed from protocol.  If a 
subject experiences pneumonitis at Grade 4, study treatment must be discontinued. For additional 
safety information, reference the package insert for decitabine and azacitidine. 
Subjects who have been dose-reduced cannot be returned to a higher dose level.
Toxicities in an individual subject must resolve to less than Grade 2 or to baseline levels before 
proceeding with the next cycle of treatment.  
Dose Modifications for Hematologic Toxicity for Entospletinib, Decitabine or Azacitidine
It is recognized that drug-related hematologic toxicity in this population may be difficult to 
ascertain given the aggressive hematologic disease and the fact that multiple cycles of therapy 
may need to be administered for maximal clinical response. Therefore, there will be no dose 
modifications for hematologic toxicity due to ENTO, decitabine or azacitidine during the first 
3 cycles for subjects with active AML. However, after the third cycle of ENTO and decitabine is 
administered, subjects suspected to have study treatment related ANC and/or platelet count 
toxicity (ie, fail to recover to at least 50% of the prior cycle’s baseline value) will have the dose 
of decitabine reduced to 20 mg/m2/d on Days 1-9 and the dose of ENTO reduced one dose level. 
Similarly, after the third cycle of ENTO and azacitidine administration, subjects suspected to 
have study treatment related ANC and/or platelet count toxicity (ie, fail to recover to at least 
50% of the prior cycle’s baseline value) will have the dose of azacitidine reduced according to 
Table 3-7 and the dose of ENTO reduced one dose level. Dose modifications because of concern 
for drug induced cytopenias prior to Cycle 4 will be discussed with the medical monitor. Dose 
modifications for hematologic toxicity for subjects who have achieved a CR or CRi are detailed 
below. For additional safety information, reference the package insert for decitabine and 
azacitidine.
Table 3-7.
Azacitidine Dose Modifications
Nadir Counts
% Dose in the Next Course
ANC (x109/L)
< 0.5
0.5 –1.5
> 1.5
Platelets (x109/L)
< 25.0
25.0-50.0
> 50.0
50%
67%
100%


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Dose Modifications for Hematologic Toxicity for Subjects Who HAVE Achieved < 5%
Blasts and Receive Maintenance Therapy With Decitabine or Azacitidine
Subjects who have had a previous dose reduction of decitabine and ENTO and then subsequently 
have a decrease in blasts to < 5% by morphology, the number of days of decitabine will be 
reduced to Days 1-4 of each cycle, but the daily dose will remain the same. For example, a 
subject receiving 20 mg/m2/day on Days 1-9 will move on to receive 20 mg/m2/day on Days 1-4. 
Subjects will receive the same dose reduction of ENTO. For azacitidine, no dose reduction 
regimen is necessary.
Neutropenia 
In the event of Grade 4 neutropenia (ANC < 500/μL) that occurs with the second or subsequent 
cycles of maintenance and persists for 14 days or more or is associated with febrile neutropenia,
further cycles of ENTO/decitabine shall be administered once ANC recovers to ≥1000/μL with a 
decrease in the number of days of decitabine and the dose of ENTO will be decreased by 1 dose 
level (ie, for the first occurrence omit the final day 5 dose of decitabine; for the second 
occurrence omit the final day 4 dose of decitabine). If there is no evidence of ANC recovery after 
14 days, repeat marrow evaluation should be considered.  Subjects who require a dose reduction 
below dose level -1 will not receive ENTO and instead will continue maintenance treatment with
decitabine alone. If Grade 4 neutropenia that persists for 14 days or more (or grade 4 neutropenia 
associated with fever) recurs for the third time, discontinue the ENTO/decitabine. Similarly, in 
the event of neutropenia that occurs with the second or subsequent cycles of maintenance with 
azacitidine, and persists for 14 days or more or is associated with febrile neutropenia, the dose of 
azacitidine will be reduced according to Table 3-8.
Thrombocytopenia 
In the event of Grade 4 thrombocytopenia (platelets < 25,000/μL) that occurs with the second or 
subsequent cycles of maintenance and persists for more than 14 days (or >25,000/µL but 
requiring prophylactic platelet transfusions to maintain this over the 14 day period), further 
cycles of ENTO/decitabine shall be administered with a decrease in the number of days of 
decitabine and the dose of ENTO will be decreased by 1 dose level (ie, for the first occurrence 
omit the final day 5 dose of decitabine; for the second occurrence omit the final day 4 dose of 
decitabine). Subjects who require a dose reduction below dose level -1 will not receive ENTO
and instead will continue maintenance with decitabine alone. If Grade 4 thrombocytopenia 
persisting for more than 14 days (or subject requires prophylactic platelet transfusions to 
maintain >25,000/µL over the 14 day period) recurs for the third time, discontinue the 
ENTO/decitabine. Similarly, in the event of thrombocytopenia that occurs with the second or 
subsequent cycles of maintenance with azacitidine, and persists for 14 days or more or is 
associated with prophylactic platelet transfusions, the dose of azacitidine will be reduced 
according to Table 3-8.


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Table 3-8.
Azacitidine Dose Reductions
WBC or Platelet
Nadir
% decrease in
counts
from baseline
Bone Marrow Biopsy Cellularity at Time of Nadir (%)
30-60
15-30
<15
% Dose in the Next Course
50 - 75
100
50
33
>75
75
50
33
Dose Modifications for Non-hematologic Toxicity for Subjects Who HAVE Achieved CR or 
CRi and Receive Maintenance Therapy With Decitabine or Azacitidine
Subjects who experience any significant Grade 3 or greater toxicity attributed to decitabine, 
azacitidine, or ENTO will hold the protocol therapy until it resolves to ≤ Grade 2. Then restart 
ENTO with one dose level reduction and reduce the dose of decitabine to 20 mg/m2/d on 
Days 1-4 for the first occurrence and decrease the dose of decitabine to 20 mg/m2/d on Days 1-3 
for the second occurrence and restart ENTO at the next lower dose. For azacitidine specifically, 
50% dose reduction will be applied in combination with ENTO at the next lower dose. Subjects 
who require a dose reduction below dose level -1 will not receive ENTO and instead will 
continue maintenance with decitabine or azacitidine alone. If the toxicity recurs for a third time 
during treatment period, therapy should be discontinued. Decitabine/ENTO or azacitidine/ENTO
should not be restarted until the toxicity has resolved to Grade 2 or better. Subjects with 
controlled Grade 3 infection or febrile neutropenia may continue decitabine or azacitidine in 
combination with ENTO. If a subject experiences pneumonitis at Grade 4, study treatment must 
be discontinued but may continue with decitabine or azacitidine alone.
Dose reductions (for either hematologic or non-hematologic toxicity) for subjects with 
< 5% blasts by morphology may be done twice during the course of maintenance therapy, if 
necessary.
Group C:
Dose modifications and delays attributed to ENTO for hematologic and non-hematologic 
toxicities will follow the guidelines in Appendix 3. 
3.3.1.
Management of Low Grade Chronic Toxicities 
Since subjects will be receiving the study treatments daily, low grade chronic side effects, such 
as nausea, fatigue and diarrhea, while not meeting the above definition for dose limiting 
toxicities, may not be tolerable when experienced for long periods of time. Following discussion 
with the Gilead Sciences Medical Monitor, dose reduction may be permitted if low grade chronic 
side effects cannot be managed effectively with supportive care.


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3.3.2.
Specific Considerations for Managing Hyperbilirubinemia
3.3.2.1.
Unconjugated (Indirect) Bilirubin Elevations
ENTO is an inhibitor of UGT1A1 and reversible increases in unconjugated (indirect) bilirubin 
values occurred in healthy subjects receiving ENTO. In the absence of symptoms or other 
hepatic laboratory abnormalities, ENTO dose modification is not required for elevated indirect 
bilirubin levels.
3.4.
Duration of Treatment
For subjects enrolled to Group A Phase 1b (Dose Escalation):
ENTO lead-in will be administered daily on Days 1-14 as a single agent (Cycle 0) and will 
continue to be given daily in combination with IV daunorubicin (Days 1-3 for Cycle 1 and 2) and 
cytarabine (Days 1-7 for Cycle 1 and 2) during induction chemotherapy of every 14-day cycle 
for up to 2 cycles (Cycle 1 and 2). Subjects must be able to receive up to 2 cycles of induction 
chemotherapy. Cytarabine and daunorubicin (7+3) treatment (Cycle 1) may be started after 
5 days of exposure to ENTO if the Principal Investigator agrees with the treating physician that 
treatment should start sooner.  Subjects that experience a DLT may continue on protocol at a 
de-escalated dose.  
Subjects with residual disease detected at the Cycle 1 Day 14 bone marrow evaluation will 
proceed with Cycle 2 of induction chemotherapy. The start of Cycle 2 will depend on the timing 
and result of the disease assessment. Subjects are to continue receiving ENTO while awaiting 
disease assessment results.
The investigator must consult the medical monitor if subjects have not obtained a CR after 
Cycle 1 and prior to Cycle 2, and if there is any consideration to omit Cycle 2 of induction 
chemotherapy.
If a subject discontinues study treatment (eg, as a result of an AE), every attempt should be made 
to keep the subject in the study to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.  
For subjects enrolled to Group A Phase 2 (Dose Expansion):
ENTO 400 mg lead-in will be administered daily every 12 hours on Days 1-14 as a single agent 
(Cycle 0) to the completion of induction therapy as determined by bone marrow response. 
However, 7+3 treatment (Cycle 1) may be started earlier, after at least 5 days of exposure to 
ENTO, if the Principal Investigator agrees with the treating physician that treatment should start 
sooner.  


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ENTO 400 mg will be administered daily every 12 hours in combination with IV daunorubicin
(Days 1-3) and cytarabine (Days 1-7) for up to 2 induction cycles (Cycle 1 and 2).  Subjects must 
be able to receive 2 cycles of induction chemotherapy. Subjects with residual disease detected at 
the Cycle 1 Day 14 bone marrow evaluation proceed with Cycle 2 of induction chemotherapy.  
The start of Cycle 2 will depend on the timing and result of the disease assessment. Subjects are 
to continue receiving ENTO while awaiting disease assessment results.
The investigator must consult the medical monitor if subjects have not obtained a CR after 
Cycle 1 and prior to Cycle 2, and if there is any consideration to omit Cycle 2 of induction 
chemotherapy.
If CR/CRi is achieved at the end of Cycle 1 or 2, the subject may proceed to SCT or will receive 
post-remission chemotherapy. If CR/CRi is not achieved by the end of Cycle 2, the subject is 
considered a treatment failure and will have met study efficacy endpoint criteria, but will remain 
on study for required study-related follow-up procedures. 
Post-remission chemotherapy will consist of 3g/m2 cytarabine every 12 hours on Days 1, 3, and 5
(< 60 years of age) or 1g/m2 high dose cytarabine once daily on Days 1-5 (≥60 years of age) in 
combination with ENTO every 12 hours on Days 1-28 of each 28-day cycle for at least 3 cycles 
and up to 4 cycles.  Subjects who are awaiting a donor or transitioning to allogeneic SCT may 
receive at least 1 cycle and up to 4 cycles of cytarabine.
Maintenance therapy will consist of ENTO 400 mg as a single agent every 12 hours on 
Days 1-28 of each 28-day cycle and will continue for up to 12 cycles as long as the subject is 
experiencing benefit or until the subject becomes a candidate for SCT. Extension of maintenance 
may occur on an individual basis if approved by the Principal Investigator.
If a subject discontinues study treatment (eg, as a result of an AE), every attempt should be made 
to keep the subject in the study to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.  
For subjects enrolled to Group B Phase 1b/2 (Dose Escalation and Expansion):
ENTO lead-in will be administered every 12 hours on Days 1-14 as a single agent (Cycle 0) for 
subjects enrolled to Group B Phase 1b and Group B Phase 2 safety run-in. However,
chemotherapy with the assigned hypomethylating agent (Cycle 1) may be started earlier, after 
5 days of exposure to ENTO, if the Principal Investigator agrees with the treating physician that 
treatment should start sooner.
For subjects enrolled to Group B Phase 2 randomization, ENTO lead-in will be administered 
every 12 hours on Days 1-5 as a single agent (Cycle 0).
In subsequent induction cycles (Cycles 1-4), ENTO will be administered every 12 hours on 
Days 1-28 in combination with assigned hypomethylating agent dose and schedule. Only 
azacitidine will be given during the Phase 2 safety run-in. Subjects will receive at least 2 cycles 


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of induction therapy but no more than 4 cycles. If the subject achieves < 5% blasts by 
morphology and flow cytometry or has evidence of clinical benefit after completing 
2-4 induction cycles but is not eligible for SCT, the subject will have the option to receive 
maintenance therapy with ENTO in combination with decitabine or azacitidine.  Subjects with 
persistent evidence of disease (ie, blasts ≥5%) after Cycle 2 may receive up to 2 more induction 
cycles until subject achieves < 5% blasts. If < 5% blasts by morphology and flow cytometry is 
not achieved or the subject does not show evidence of clinical benefit after 4 induction cycles, 
the subject is considered a treatment failure and will be discontinued from the study. 
During ENTO + hypomethylating agent maintenance therapy, ENTO will be administered every 
12 hours on Days 1-28 in combination with assigned hypomethylating agent dose and schedule.  
ENTO will be administered every12 hours on Days 1-28 in combination with decitabine on 
Days 1-5 or in combination with azacitidine on Days 1-7 of every 28-day cycle for at least 
2 cycles.  Subjects who are intolerant of the hypomethylating agent after completing 2 cycles 
may switch to ENTO monotherapy maintenance.  Maintenance may continue as long as the 
subject is experiencing benefit and does not meet the criteria for study treatment discontinuation.  
During ENTO maintenance therapy, ENTO will be administered as monotherapy every 12 hours 
on Days 1-28.  Treatment may continue until the subject meets the criteria for study treatment 
discontinuation or up to 12 cycles.  Extension of maintenance may occur on an individual basis if 
approved by the Principal Investigator.
If a subject discontinues study treatment (eg, as a result of an AE), every attempt should be made 
to keep the subject in the study to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.  
For subjects enrolled to Group C Phase 1b (Dose Escalation):
ENTO monotherapy will be administered every 12 hours on Days 1-28 of every 28-day cycle 
until the subject meets the criteria for study treatment discontinuation (see Section 6.4.1).  
Subjects who experience a DLT may continue on protocol at a de-escalated dose.
If a subject discontinues study treatment (eg, as a result of an AE), every attempt should be made 
to keep the subject in the study to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.  
For subjects enrolled to Group C Phase 2 (Dose Expansion):
ENTO monotherapy will be administered every 12 hours on Days 1-28 of every 28-day cycle 
and may continue as long as the subject is experiencing benefit and does not meet criteria for 
study treatment discontinuation.  
If a subject discontinues study treatment (eg, as a result of an AE), every attempt should be made 
to keep the subject in the study to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.  


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Subjects with AML and who meet the eligibility criteria will be studied. Approximately
190 subjects with newly diagnosed, relapsed/refractory AML will be dosed in 3 groups, using a 
3 + 3 design for the dose escalation phase.
Screening laboratory data is required within 2 weeks prior to administration of study treatment as 
shown in Table 4-1. Note: Confirmation should be considered for out of range values to 
determine if the abnormality is real or artifactual. Values should be obtained within the screening 
period and should be the most recent measurement obtained. Subjects with any degree of 
neutropenia, thrombocytopenia, or anemia due to malignancy may enroll.
Table 4-1.
Required Screening Laboratory Values Organ System Parameter 
Required Value
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome or hemolysis)
Serum ALT
2.5 x ULN
Serum AST
Renal
Serum creatinine
< 1.5 x ULN
Coagulation
INRa
< 1.7
Pregnancy
-HCGb
Negative
Infection
HIV
Negative HIV antibody
HBV
Negative HBsAg and negative HBc antibody
HCV
Negative viral RNA (if HCV antibody is positive)
a
For subjects on warfarin, the required value is < 3.0
b
A negative serum pregnancy test is required for female subjects (unless surgically sterile or menopausal). Female subjects 
with medically documented ovarian failure must also have serum FSH levels within the institutional postmenopausal range.
4.2.
Inclusion Criteria
Group A

Subjects age ≥ 18 with previously untreated AML by WHO criteria, excluding acute 
promyelocytic leukemia (M3), who are able and should receive up to 2 cycles of induction 
chemotherapy with 7+3 as determined by the treating physician
Group B 

Subjects age > 70 years with previously untreated AML by WHO criteria, excluding acute 
promyelocytic leukemia (M3)

Subjects age ≤ 70 years with previously untreated AML by WHO criteria, excluding acute 
promyelocytic leukemia (M3), who refuse or are unable to receive 7+3 as determined by the 
treating physician


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Group C Phase 1b (Dose Escalation)

Subjects age ≥ 18 years with relapsed/refractory AML by WHO criteria, excluding acute 
promyelocytic leukemia (M3)

Subjects with previously untreated AML by WHO criteria, excluding acute promyelocytic 
leukemia (M3), and who would have met disease eligibility criteria for Group A or B but 
refuse or are unable to receive 7+3 or decitabine chemotherapy as determined by the treating 
physician
Group C Phase 2 (Dose Expansion)

Cohort C1A: Subjects age ≥ 18 years with relapsed/refractory AML by WHO criteria, 
excluding acute promyelocytic leukemia (M3)

Cohort C2: Subjects age ≥ 18 years with relapsed/refractory AML with MLL 

Cohort C3: Subjects with previously untreated AML by WHO criteria, excluding acute 
promyelocytic leukemia (M3), and who would have met disease eligibility criteria for 
Group A or B but refuse or are unable to receive chemotherapy and hypomethylating agent 
as determined  by the treating physician
ALL subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study:
1) Male or female ≥ 18 years of age with a diagnosis AML (M0-M7, except M3)
2) All acute toxic effects of any prior anti-leukemia therapy resolved to Grade < 1 before the 
start of study treatment (with the exception of alopecia [any grade permitted], or bone 
marrow parameters [any grade permitted] due to leukemia in the investigators opinion)
3) ECOG performance status less than or equal to 2  
4) Life expectancy of at least 3 months
5) Meet required screening laboratory criteria unless leukemia related, as shown in Table 4-1.  
6) Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO or MUGA (only 
ECHO for Germany) and no clinical evidence of congestive heart failure 
7) For female subjects of childbearing potential, willingness to abstain from heterosexual 
intercourse or use a protocol-recommended method of contraception from the screening visit 
throughout the study treatment period and for 30 days following the last dose of ENTO or as 
recommended in the prescribing information for other co-administered study drugs 
(whichever is later).
Note: See Appendix 4 for definition of childbearing potential and information regarding 
recommendations for contraception.


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For male subjects of childbearing potential having intercourse with females of childbearing 
potential, willingness to abstain from heterosexual intercourse or use a protocol 
recommended method of contraception from the start of study treatment throughout the study 
treatment period and for 90 days following the last dose of ENTO or as recommended in the 
prescribing information for other co-administered study drugs (whichever is later), and to 
refrain from sperm donation from the start of study treatment throughout the study treatment 
period and for 90 days following the last dose of ENTO or as recommended in the 
prescribing information for other co-administered study drugs (whichever is later). 
Note: See Appendix 4 for definition of childbearing potential and information regarding 
recommendations for contraception.
8) Willingness to comply with scheduled visits, drug administration plan, imaging studies, 
laboratory tests, other study procedures, and study restrictions 
9) Have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of study procedures
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not eligible for study participation:
1) Subjects with acute promyelocytic leukemia (M3)
2) Known active central nervous system or leptomeningeal leukemic involvement. 
Note: Central nervous system testing (CSF analysis) is only required in subjects with 
suspected involvement based on symptoms or signs.
3) Treatment with proton pump inhibitors (PPIs) within 7 days prior to enrollment. Note: PPIs 
are likely to interfere with ENTO absorption, thus requiring a 7-day washout period. H2 
blockers and antacids will be allowed for use during the protocol.
4) History of active non-myeloid malignancy except for the following: adequately treated local 
basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial 
bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no 
requirement for therapy or requiring only hormonal therapy and with normal prostate specific 
antigen for > 1 year prior to start of study therapy, or any other cancer that has been in 
complete remission without treatment for ≥5 years prior to enrollment. Subjects who are on 
prophylaxis with long-term adjuvant hormonal therapy and are ≥ 5 years from therapy for 
their primary tumor are eligible for enrollment.
5) Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection at the time of 
start of study treatment. Note: Subjects with localized fungal infections of skin or nails are 
eligible. 
6) Ongoing, drug-induced liver injury, known chronic active hepatitis C Virus (HCV), chronic 
active hepatitis B Virus (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary 
biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the 
liver, or portal hypertension


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7) Ongoing (within the past 6 weeks) hepatic encephalopathy
8) Ongoing drug-induced pneumonitis
9) Ongoing inflammatory bowel disease
10) Ongoing alcohol or drug addiction as determined by investigator
11) Pregnancy or breastfeeding
12) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation. 
Note: prior allogeneic bone marrow progenitor cell or solid organ transplantation is NOT an 
exclusion criteria for Cohort C2 ie, MLL cohort.
13) Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of 
leukemia. Subjects may not have received AML-directed therapy prior to enrollment other 
than Hydroxyurea or apheresis, if de-novo or for current relapse, except for subjects defined 
as refractory disease at study enrollment.  Concurrent use of methotrexate for rheumatologic 
conditions is permitted.
Note: Subjects may use topical, enteric, or inhaled corticosteroids as therapy for comorbid 
conditions and systemic steroids for autoimmune anemia and/or thrombocytopenia. Ongoing 
use of low-dose systemic corticosteroids (< 5 mg/day of methylprednisolone or equivalent) 
for rheumatologic conditions is permitted. During study participation, subjects may receive 
systemic or other corticosteroids needed for treatment-emergent comorbid conditions 
14) Concurrent participation in an investigational drug trial with therapeutic intent defined as 
prior study therapy within 14 days prior to study treatment  
15) Any other prior or ongoing condition that, in the opinion of the investigator, could adversely 
affect the safety of the subject or impair the assessment of study results 
16) Inability to tolerate oral medications, symptomatic disease significantly affecting 
gastrointestinal function manifested from resection of the stomach or small bowel or active 
ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel 
obstruction
17) Uncontrolled intercurrent illness including, but not limited to:
a) unstable angina pectoris 
b) psychiatric illness/social situations that would limit compliance with study requirements 
c) subjects with active infection are permitted to enroll provided that the infection is 
documented to be under control
18) Known hypersensitivity to ENTO, decitabine, azacitidine, cytarabine and daunorubicin, the 
metabolites, or formulation excipient


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5.
TREATMENT PLAN
5.1.
Treatment Plan
5.1.1.
Premedication
No specific premedications or supporting medications are required in conjunction with ENTO
administration.
For cytarabine, daunorubicin, decitabine, and azacitidine please follow the currently approved
version of the package insert and institutional guidelines when administering. 
5.1.2.
Administration Instructions
ENTO 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.
If a subject is unable to take the whole pill, contact the Sponsor and Medical Monitor for further 
instructions.
5.1.3.
Dosing Schedule
ENTO will be administered orally every 12 hours. ENTO should be taken at approximately the 
same time each day. Doses should be taken at approximately 12-hour intervals, while in a fasted 
state. While it is realized that variations in the dosing schedule may occur, the prescribed 
regimen should be followed as closely as possible. Compliance with the protocol dosing 
schedule will be documented in the subject’s chart and the electronic data capture (EDC) at each 
scheduled visit. Counseling regarding subject compliance may be required.
5.1.4.
Dose Schedule Interruptions and Vomited Doses 
Subjects who have a delay in administration of a dose of ENTO of < 6 hours should take the 
planned dose as soon as possible after the intended time of administration. For subjects who have 
a delay in administration of ENTO of  6 hours, the dose should not be taken. ENTO
administration may continue but the missed dose should not be made up and the planned timing 
of subsequent ENTO dosing should not be altered.
Vomited doses should be retaken, but only if the tablets are visible in the vomitus.
5.1.5.
Concomitant and Supportive Therapy
Subjects should receive full supportive care including transfusions of blood and blood products, 
antibiotics, antiemetics, antifungals, allopurinol, etc., when appropriate.
No other direct anti-leukemia therapy is permitted.


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Growth Factor use in Cycle 1 is discouraged and may not be used without PI approval as it may 
impact the determination of DLT. Beyond Cycle 1, the use of myeloid growth factors is 
permitted according to guidelines for use in AML but is generally discouraged.
rEPO is not permitted at any time on the study.
Palliative radiation therapy may not be administered while the subject is on study.  
5.2.
Restricted/Prohibited Medication
During the course of the clinical trial, study subjects are anticipated to continue the use of 
prescribed medications identified during the screening procedures, consistent with study 
inclusion and exclusion criteria.
The following therapies are not permitted at any point during the trial beginning with the first 
dose of study treatment (if administered, the subject may be discontinued from the trial).  

Any non-study leukemia directed therapy or non-study leukemia directed immunotherapy 
(approved or investigational), except steroids used as anti-emetics. Prophylaxis with 
intrathecal chemotherapy will not be considered as leukemia directed therapy.
The following restricted medications are only permitted under the circumstances given. Each 
concomitant medication must be individually assessed against all exclusion criteria. If in doubt, 
the investigator should contact the GSI Medical Monitor before enrolling the subject or allowing 
a new medication to be started. 

Proton Pump Inhibitors (PPIs) have been shown by PK drug-drug interaction studies to 
decrease absorption and exposure of ENTO by ~60%. Thus, use of a proton pump inhibitor 
must be avoided for 7 days prior to and along with study drug administration. Examples 
include but are not limited to: esomeprazole, omeprazole, lansoprazole, etc.
Note: H2 blockers and antacids will be allowed for use during the protocol. In addition, if a 
subject experiences a gastrointestinal bleed and must be placed on PPIs eg, IV pantoprazole, 
please contact the Medical Monitor and hold ENTO for the duration of use of the PPI until 
the subject is clinically stable. 

Co-administration of moderate CYP2C9 and strong CYP3A and CYP2C9 inducers are 
prohibited in this study.   Administration of these medications should be avoided for 2 weeks 
prior to study drug administration. Examples of these medicines are provided in Table 5-1.
Caution should be exercised when co-administering drugs that are moderate or strong inhibitors 
of CYP2C9 (eg, fluconazole, voriconazole or amiodarone) as they may increase ENTO exposure. 
Caution should be exercised when co-administering medications that are transported by 
UGT1A1, OATP1B1, OATP1B3, MATE1, P-gp and BCRP; dose adjustment or switching to an 
alternative medication may be necessary if clinically indicated. 


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Table 5-1.
Restricted Medications in this Study that Require Prior MM 
Discussion and Approval
Strong
Moderate
CYP3A Inducer
carbamazepine, phenytoin, rifampin, 
St. John’s Wort, enzalutamide, rifabutin, 
phenobarbital, mitotane, avasimibe
Not prohibited
CYP2C9 Inducer
carbamazepine, rifampin, ritonavir, 
enzalutamide
Proton Pump Inhibitors
omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, dexlansoprazole
In a study in healthy volunteers, ENTO 400 mg every 12 hours increased rosuvastatin exposure 
by approximately 4-fold, which may increase the risk of rhabdomyolysis. In reviewing the safety 
of subjects who have received a statin with ENTO, there have been no reports of rhabdomyolysis 
or a different adverse events profile, but in the interest of caution, the following restrictions 
apply to the use of HMG-CoA reductase inhibitors with ENTO:
Concomitant Medication
Restriction
Atorvastatin
Maximum dose 20 mg QD
Rosuvastatin
Maximum dose 10 mg QD
Pravastatin
Maximum dose 40 mg QD
Simvastatin
Maximum dose 20 mg QD
Lovastatin
Maximum dose 20 mg QD
Fluvastatin
Maximum dose 20 mg BID or 40 mg QD
Pitavastatin
Maximum dose 1 mg QD
The management of subjects who are benefiting from the protocol treatment and who 
subsequently require treatment with the above medications should be discussed with the 
Medical Monitor.  
5.3.
Study Drug Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has a process instruction (eg, Standard Operating Procedures [SOPs]) for 
on-site drug destruction which is reviewed by the study monitor, then the site should destroy 
used (empty bottles) and unused study drug supplies performed in accordance with the site’s 
(hospital/pharmacy) procedure. The destruction process should include records noting the 
identification and quantity of each unit destroyed the method of destruction, and person who 
disposed of the drug. A copy of the site’s SOP/process document will be obtained for central 
files at the pre-study or otherwise applicable monitoring visit. Upon study completion, a copy of 
the relevant Investigational Drug Accountability records must be filed at the site and provided 
for the sponsor files. If the site does not have acceptable procedures in place for drug destruction, 
arrangements will be made between the site and Gilead Sciences (or Gilead Sciences’ 
representative) for return of unused study drug supplies.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2: Study Procedure Tables 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
The screening number and/or subject ID will be assigned for the individual subject by the 
designed IxRS. This is an open-label study. 
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study. Once consent is obtained, all screening tests 
and procedures are assessed, and study eligibility is confirmed, subjects will be enrolled to 
receive ENTO.
In Phase 2 Group B, subjects will be randomized in a 1:1 manner in IxRS to treatment arm 
ENTO in combination with decitabine or ENTO in combination with azacitidine. 
6.2.
Pretreatment Assessments
6.2.1.
Screening Visits 
Subjects will be screened within 14 days before the first administration of study treatment to 
determine eligibility for participation in the study. Bone marrow biopsy and aspirate may be 
performed within 21 days before the first administration of study treatment.  The following will 
be performed and documented at screening:

Obtain written informed consent

Obtain medical history

Obtain current smoking status 

Review prior/concomitant medication

Complete physical examination including body weight, and height

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

12-lead ECG

ECHO or MUGA (Note: For German sites, only ECHO to be performed)


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
Obtain blood samples for:
Chemistry 
Hematology 
Coagulation
Serum pregnancy test (for all female subjects unless surgically sterile or menopausal) and
serum FSH (for female subjects with medically documented ovarian failure)
HIV/HBV/HCV

Urinalysis

X-ray (Note: For German sites, X-ray not to be performed)

Bone marrow aspirate (FISH will be performed) and biopsy (mutational testing for FLT3, 
NPM1, and CEBPA will be performed) for disease assessment and biomarker testing. If the 
bone marrow aspirate and biopsy could not be obtained, diagnostic samples should be used.

ECOG performance status

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form

Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for their first administration of study treatment within 14 days after screening 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 (CRF/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 CRF/eCRF.
See Section 7 Adverse Events and Toxicity Management for additional details.
6.3.
Treatment Assessments
Subjects who have met all eligibility criteria will come to the clinic on Cycle 0 Day 1
(Cycle 1 Day 1 for Group C) to perform study required procedures prior to dosing, review 
prior/concomitant medications, and record adverse events at each clinic visit.
CCI


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For study purposes, the ENTO lead-in (Cycle 0) is 14 days for Groups A, B, and C. One cycle of 
induction therapy is 14 days (or up to 28 days depending on count recovery) for Group A, and 28 
days for Groups B and C.  
6.3.1.
Group A
The following procedures will be conducted during the Lead-in (Cycle 0) on Days 1, 8, and 
14 (unless otherwise specified).

ENTO will be administered orally every 12 hours on Days 1-14 as a single agent

Review prior/concomitant medication

Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level 

Complete physical examination (Day 1)

Obtain current smoking status (Day 1)

ECOG performance status (Day 1)


Urine pregnancy test (negative pregnancy test required for all female subjects unless 
surgically sterile or menopausal prior to dose on Day 1)

Obtain blood samples:
Chemistry (Days 1, 8, and 14)
Hematology (Days 1, 8, and 14)
Coagulation (Day 14)
PK (Days 1, 8, and 14 at pre-dose and 2 hours post-dose of ENTO)
Biomarkers (Days 1, 8, and 14 at pre-dose of ENTO)
Note:  ENTO should be held until the pre-dose blood samples have been drawn.  Record the 
approximate time of the last 2 doses of ENTO on PK collection days and the time the PK 
blood samples are obtained.
CCI


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
A bone marrow aspirate for disease assessment will be performed at the end of the 
monotherapy lead-in period (ie, Cycle 0 Day 14 or after the minimum 5-days of ENTO), and 
prior to initiating 7+3 chemotherapy. Biopsy will be used in the event the aspirate cannot be 
collected or analyzed (eg, dry-tap, hemodiluted specimen, or lack of spicules).
Subjects with cytogenetic and molecular mutations at screening must have cytogenetic
and molecular mutation testing repeated at subsequent bone marrow examinations 
(Cycle 0 Day 14, Cycle 1 Day 14, count recovery, End of Study).
The following procedures will be conducted during Cycle 1 (and Cycle 2, if needed) on 
Days 1, 3, 7, and 14 (unless otherwise specified). 

ENTO will continue to be administered orally every 12 hours for 14 days in combination 
with IV cytarabine (Days 1-7) and IV daunorubicin (Days 1-3). Subjects are to continue 
receiving ENTO while awaiting disease assessment results. Subjects must be able to receive 
2 cycles of induction chemotherapy.

Review prior/concomitant medication 

Record any adverse events 

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level (daily during hospitalization and at the Investigator’s discretion after discharge)

Weight (Day 1)

ECOG performance status (Day 14)

Physical exam (Day 1 and at the Investigator’s discretion after hospital discharge)

Obtain smoking status for past 28 days (Day 1 of each cycle)

12-lead ECG (at the investigator’s discretion)

ECHO or MUGA prior to re-induction, if applicable (Note: For German sites, only ECHO to 
be performed)

Urine pregnancy test (for all female subjects unless surgically sterile or menopausal prior to 
dose on Day 1)

Obtain blood samples for: 
Chemistry (Days 7 and 14)
Hematology (Days 7, 14, and up to blood count recovery)


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Coagulation (Days 7 and 14)
PK 
o
Phase 1b (Dose Escalation): Cycle 1 Day 3 and Cycle 1 Day 7 at pre-dose, 2 hours, 
and 4 hours post-dose of ENTO; Cycle 1 Day 14 at pre-dose and 2 hours post-dose of 
ENTO
o
Phase 2 (Dose Expansion): Cycle 1 Day 3 (and Cycle 2, if needed) at pre-dose, 2
hours, and 4 hours post-dose of ENTO; Intensive PK on Cycle 1 Day 7 at pre-dose, 1, 
2, 3, 4, 6, 8, and 12 hours post-dose of ENTO; Cycle 1 Day 14 at pre-dose and 2 
hours post-dose of ENTO
Biomarkers (Cycle 1 Day 7 and Cycle 1 Day 14 or at the end of Cycle 1 at the time of 
blood count recovery at pre-dose)
Note:  ENTO should be held until the pre-dose blood samples have been drawn.  Record the 
approximate time of the last 2 doses of ENTO on PK collection days and the time the PK 
blood samples are obtained.

Obtain bone marrow aspirate and biopsy samples on Cycle 1 Day 14 for disease assessment
and biomarker testing. If the bone marrow is consistent with Morphologic CR or CRi status 
per Appendix 5, evaluate MRD as per institutional practice and Appendix 7.  Biopsy will be 
used in the event the aspirate cannot be collected or analyzed (eg, dry-tap, hemodiluted 
specimen, or lack of spicules).
If the bone marrow cellularity is ≤ 20% at Cycle 1 Day 14, a repeat bone marrow 
examination will occur within 2 weeks or at count recovery. Subjects with residual 
disease detected at the Cycle 1 Day 14 bone marrow evaluation will proceed with Cycle 2
of induction chemotherapy. The start of Cycle 2 will depend on the timing and result of 
the disease assessment. Subjects are to continue receiving ENTO while awaiting disease 
assessment results. 
The investigator must consult the medical monitor if subjects have not obtained a CR 
after Cycle 1 and prior to Cycle 2, and if there is any consideration to omit Cycle 2 of 
induction chemotherapy.
Subjects with cytogenetic and molecular mutations at screening must have cytogenetic
and molecular mutation testing repeated at subsequent bone marrow examinations 
(Cycle 0 Day 14, Cycle 1 Day 14, count recovery, End of Study).
If CR/CRi is not achieved by the end of Cycle 2, the subject will be considered a treatment 
failure and will have met study efficacy endpoint criteria, but will remain on study for required 
study-related follow-up procedures.


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Phase 2 only: The following procedures will be conducted during each 28-day 
Post-Remission cycle on Days 1 and 28 (unless otherwise specified) for 3-4 cycles. 

ENTO will be administered orally every 12 hours for 28 days in combination with 
3g/m2 high dose cytarabine administered every 12 hours on Days 1, 3, and 5 (< 60 years of 
age) or 1g/m2 cytarabine administered once daily on Days 1-5 (≥ 60 years of age)

Review prior/concomitant medication 

Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level (Day 1 of Cycle 2 and Cycle 4)

Complete physical examination (Day 1 of Cycle 2 and Cycle 4)

Obtain smoking status for past 28 days (Day 1 of each cycle)

ECOG performance status (Day 28 of Cycle 2 and Cycle 4)

Urine pregnancy test (for all female subjects unless surgically sterile or menopausal prior to 
dose on Day 1)

Obtain blood samples for:
Chemistry (Day 28 of Cycle 2 and Cycle 4)
Hematology (Day 28 of Cycle 2 and Cycle 4)
Coagulation (Day 28 of Cycle 2 and Cycle 4)
PK at pre-dose and 2 hours post-dose of ENTO (Day 5 and Day 28 of each cycle)

Obtain bone marrow aspirate samples for disease assessment and biomarker testing on 
Cycle 2 Day 28 and Cycle 4 Day 28 or as clinically indicated.  Biopsy will be used in the 
event the aspirate cannot be collected or analyzed (eg, dry-tap, hemodiluted specimen, or 
lack of spicules).
Phase 2 only: The following procedures will be conducted during each 28-day Maintenance 
cycle on Days 1 and 28 (unless otherwise specified). 

ENTO will be administered orally every 12 hours for 28 days and may continue up to 
12 cycles as long as the subject is experiencing benefit or becomes a candidate for SCT.  
Extension of maintenance may occur on an individual basis if approved by the Principal 
Investigator.


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Amendment 7
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
Review prior/concomitant medication 

Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level every 2 cycles (eg, Cycle 1 Day 1, Cycle 3 Day 1)

Complete physical examination every 2 cycles (eg, Cycle 1 Day 1, Cycle 3 Day 1)

Obtain smoking status for past 28 days (Day 1 of each cycle)

ECOG performance status every 2 cycles on Day 28 (eg, Cycle 2 Day 28, Cycle 4 Day 28) 

Urine pregnancy test (for all female subjects unless surgically sterile or menopausal prior to 
dose on Day 1)

Obtain blood samples for:
Chemistry (every 2 cycles from Cycle 1 Day 28)
Hematology (every 2 cycles from Cycle 1 Day 28)
Coagulation (every 2 cycles from Cycle 1 Day 28)
PK at pre-dose and 2 hours post-dose of ENTO (Day 28 of each cycle)

Obtain bone marrow aspirate samples for disease assessment and biomarker testing at the end 
of every 4 cycles on Day 28 (eg, Cycle 4 Day 28, Cycle 8 Day 28, etc.) or as clinically 
indicated.  Biopsy will be used in the event the aspirate cannot be collected or analyzed 
(eg, dry-tap, hemodiluted specimen, or lack of spicules).  Subjects who achieve CR/CRi that 
is stable for 2 consecutive bone marrow evaluations are not required to have further bone 
marrow aspirate samples collected, unless clinically indicated.  
The following procedures will be conducted at Blood Count Recovery/Remission/Relapse.

Obtain blood samples for:
Chemistry
Hematology
Biomarkers

Obtain bone marrow aspirate samples for disease assessment and biomarker testing. Biopsy 
will be used in the event the aspirate cannot be collected or analyzed (eg, dry-tap, 
hemodiluted specimen, or lack of spicules). Subjects who achieve CR/CRi that is stable for 
2 consecutive bone marrow evaluations are not required to have further bone marrow aspirate 
samples collected, unless clinically indicated.


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Gilead Sciences, Inc.
Amendment 7
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6.3.2.
Group B
The following procedures will be conducted during the Phase 1b and Phase 2 Safety run-in
Lead-in (Cycle 0) on Days 1, 8, and 14 (unless otherwise specified). 

ENTO will be administered orally every 12 hours on Days 1-14 as a single agent 

Review prior/concomitant medication 

Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level 

Complete physical examination (Day 1)

Obtain current smoking status (Day 1)


ECOG performance status (Day 1)

Urine pregnancy test (negative pregnancy test required for all female subjects unless 
surgically sterile or menopausal prior to dose on Day 1)

Obtain blood samples for: 
Chemistry (Days 1, 8, and 14)
Hematology (Days 1, 8, and 14)
Coagulation (Day 14 only)
PK (Days 1, 8, and 14 at pre-dose and 2 hours post-dose of ENTO)
Biomarkers (Days 1, 8, and 14 at pre-dose)
Note:  ENTO should be held until the pre-dose blood samples have been drawn.  Record 
approximate times of the last 2 doses of ENTO on PK collection days and the time the PK 
blood samples are obtained.  

A bone marrow aspirate sample for disease assessment and biomarker research will be 
collected at the end of the monotherapy lead-in period (ie, Cycle 0 Day 14 or after the 
minimum 5 days of ENTO), and prior to initiating therapy with hypomethylating agent. 
Biopsy will be used in the event the aspirate cannot be collected or analyzed (eg, dry-tap, 
hemodiluted specimen, or lack of spicules).  
Subjects with cytogenetic and molecular mutations at screening must have cytogenetic
and molecular mutation testing repeated at subsequent bone marrow examinations 
(Cycle 0 Day 14, Cycle 1 Day 28, count recovery, End of Study).
CCI


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The following procedures will be conducted during the Phase 2 Randomization Lead-in 
(Cycle 0) on Days 1 and 5 (unless otherwise specified). 

ENTO will be administered orally every 12 hours on Days 1-5 as a single agent 

Review prior/concomitant medication 

Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level 

Complete physical examination (Day 1)

Obtain current smoking status (Day 1)


ECOG performance status (Day 1)

Urine pregnancy test (negative pregnancy test required for all female subjects unless 
surgically sterile or menopausal prior to dose on Day 1)

Obtain blood samples for: 
Chemistry (Days 1 and 5)
Hematology (Days 1 and 5)
Coagulation (Day 5 only)
PK (Days 1 and 5 at pre-dose and 2 hours post-dose of ENTO)
Biomarkers (Days 1 and 5 at pre-dose) 
Note:  ENTO should be held until the pre-dose blood samples have been drawn.  Record 
approximate times of the last 2 doses of ENTO on PK collection days and the time the PK 
blood samples are obtained.  

If circulating blasts have cleared at the end of monotherapy lead-in (Cycle 0 Day 5), then a 
bone marrow aspirate sample will be performed for disease assessment. Biopsy will be used 
in the event the aspirate cannot be collected or analyzed (eg, dry-tap, hemodiluted specimen, 
or lack of spicules).  
Subjects with cytogenetic and molecular mutations at screening must have cytogenetic
and molecular mutation testing repeated at subsequent bone marrow examinations 
(Cycle 0 Day 5, Cycle 1 Day 28, count recovery, End of Study).
CCI


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Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
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15 February 2018
The following procedures will be conducted on Days 1, 8, and 28 of induction Cycles 1-4
(unless otherwise specified).

ENTO will continue to be administered orally every 12 hours on Days 1-28 in combination 
with IV decitabine 20 mg/m2 daily on Days 1-10 or IV/SC azacitidine 75mg/m2 daily on 
Days 1-7 of each 28-day cycle. Subjects enrolled in the Phase 2 safety run-in will only 
receive ENTO in combination with azacitidine.  Subjects enrolled in Phase 2 randomization 
will receive ENTO in combination with decitabine or azacitidine.  Subjects will receive at 
least 2 cycles of induction therapy but no more than 4 cycles.

Review prior/concomitant medication 

Record any adverse events 

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level (Days 1 and 8 of each cycle)

Weight (Day 1 of each cycle) 

ECOG performance status (Day 1 of each cycle)

Physical exam (Day 1 of each cycle)

Obtain smoking status for past 28 days (Day 1 of each cycle)

Urine pregnancy test (for all female subjects unless surgically sterile or menopausal prior to 
dose on Day 1)

Obtain blood samples for: 
Chemistry (Days 8 and 28 of each cycle)
Hematology (Days 8 and 28 of each cycle)
Coagulation (Day 8 of each cycle)
PK (Cycle 1 Day 8 at pre-dose, 2 hours, and 4 hours post-dose of ENTO; Day 8 of 
subsequent cycles at pre-dose and 2 hours post-dose of ENTO; Day 28 of every cycle at 
pre-dose and 2 hours post-dose of ENTO)
Biomarkers (Cycle 1 Days 8 and 28 at pre-dose) 
Note:  ENTO should be held until the pre-dose blood samples have been drawn.  Record 
approximate times of the last 2 doses of ENTO on PK collection days and the time the PK blood 
samples are obtained.  


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Gilead Sciences, Inc.
Amendment 7
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15 February 2018

Obtain bone marrow aspirate and biopsy samples at the end of every 2 cycles (Cycle 2 
Day 28 and Cycle 4 Day 28) or as clinically indicated for disease assessment and biomarker 
research.  If the bone marrow is consistent with Morphologic CR or CRi status per 
Appendix 5, then evaluate MRD as per institutional practice and Appendix 7.  Biopsy will be 
used in the event the aspirate cannot be collected or analyzed (eg, dry-tap, hemodiluted 
specimen, or lack of spicules).
If the subject achieves < 5% blasts by morphology and flow cytometry or has evidence of 
clinical benefit after completing 2-4 induction cycles but is not eligible for SCT, the 
subject will have the option to receive maintenance therapy with ENTO in combination 
with decitabine or azacitidine.  Subjects with persistent evidence of disease (ie, blasts 
≥ 5%) after Cycle 2 may receive up to 2 more induction cycles until subject achieves
< 5% blasts.
If < 5% blasts by morphology and flow cytometry is not achieved or the subject does not show 
evidence of clinical benefit after 2-4 induction cycles, the subject is considered a treatment 
failure and will have met study efficacy endpoint criteria, but will remain on study for required 
study-related follow-up procedures.
The following procedures will be conducted on Days 1 and 28 of each 28-day cycle of 
Entospletinib + Hypomethylating agent Maintenance Therapy. 

ENTO will be administered orally every 12 hours on Days 1-28 in combination with IV 
decitabine 20 mg/m2 daily on Days 1-5 or IV/SC azacitidine 75mg/m2 daily on Days 1-7 of 
each cycle for at least 2 cycles.  Subjects enrolled in the safety run-in will only receive 
ENTO in combination with azacitidine. 
After completing at least 2 cycles, the subject may proceed to SCT.  If not eligible for
SCT, subjects will have the option to continue on maintenance therapy with ENTO in 
combination with the assigned hypomethylating agent.  Subjects who are intolerant of the 
hypomethylating agent may switch to ENTO monotherapy maintenance at any time after 
completing the first 2 cycles.  Maintenance may continue as long as the subject is 
experiencing benefit and does not meet the criteria for study treatment discontinuation.  

Review prior/concomitant medication 

Record any adverse events 

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level (Day 1 of each cycle)

Physical exam (Day 1 of each cycle)

Obtain smoking status for past 28 days (Day 1 of each cycle)

Urine pregnancy test (for all female subjects unless surgically sterile or menopausal prior to 
dose on Day 1)


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 81
15 February 2018

Obtain blood samples on Day 28 of each cycle:
Chemistry 
Hematology
PK (pre-dose and 2 hours post-dose of ENTO)
Note:  ENTO should be held until the pre-dose blood samples have been drawn.  Record 
approximate times of the last 2 doses of ENTO on PK collection days and the time the PK blood 
samples are obtained.  

Obtain a bone marrow aspirate for disease assessment and biomarker research at the end of 
every 4 cycles on Day 28 (eg, Cycle 4 Day 28, Cycle 8 Day 28) or as clinically indicated.  
Subjects who achieve CR/CRi that is stable for 2 consecutive bone marrow evaluations are 
not required to have further bone marrow aspirate samples collected, unless clinically 
indicated.  Biopsy will be used in the event the aspirate cannot be collected or analyzed 
(eg, dry-tap, hemodiluted specimen, or lack of spicules).  
The following procedures will be conducted on Days 1 and 28 of each 28-day cycle of 
Entospletinib Maintenance Therapy. 

ENTO will be administered orally every 12 hours as a single agent on Days 1-28 and may
continue up to 12 cycles as long as the subject is experiencing benefit and does not meet the 
criteria for study treatment discontinuation.  Extension of maintenance may occur on an 
individual basis if approved by the Principal Investigator.

Review prior/concomitant medication 

Record any adverse events 

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level (Day 1 of each cycle)

Physical exam (Day 1 of each cycle)

Obtain smoking status for past 28 days (Day 1 of each cycle)

Urine pregnancy test (for all female subjects unless surgically sterile or menopausal prior to 
dose on Day 1)

Obtain blood samples on Day 28 of each cycle:
Chemistry 
Hematology 
PK (pre-dose and 2 hours post-dose of ENTO)


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 82
15 February 2018
Note:  ENTO should be held until the pre-dose blood samples have been drawn.  Record 
approximate times of the last 2 doses of ENTO on PK collection days and the time the PK 
blood samples are obtained.  

Obtain a bone marrow aspirate for disease assessment and biomarker research at the end of 
every 4 cycles on Day 28 (eg, Cycle 4 Day 28, Cycle 8 Day 28) or as clinically indicated.  
Subjects who achieve CR/CRi that is stable for 2 consecutive bone marrow evaluations are 
not required to have further bone marrow aspirate samples collected, unless clinically 
indicated.   Biopsy will be used in the event the aspirate cannot be collected or analyzed 
(eg, dry-tap, hemodiluted specimen, or lack of spicules).
The following procedures will be conducted at Remission/Relapse.

Obtain blood samples for:
Chemistry
Hematology
Biomarkers

Obtain bone marrow aspirate samples for disease assessment and biomarker testing. Biopsy 
will be used in the event the aspirate cannot be collected or analyzed (eg, dry-tap, 
hemodiluted specimen, or lack of spicules). Subjects who achieve CR/CRi that is stable for 
2 consecutive bone marrow evaluations are not required to have further bone marrow aspirate 
samples collected, unless clinically indicated.
6.3.3.
Group C
The following procedures will be conducted on Days 1, 8, 14, and 28 of each 28-day cycle
(unless otherwise specified). 

ENTO will be administered orally every 12 hours on Days 1-28 as a single agent as long as 
the subject is experiencing benefit and does not meet criteria for study treatment 
discontinuation.

Review prior/concomitant medication 

Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level (Day 1 of each cycle and Cycle 1 Days 8, 14, and 28)

Weight (Day 1 of each cycle)

ECOG performance status (Day 1 of each cycle and Cycle 1 Day 14)

Physical exam (Day 1 of each cycle and Cycle 1 Day 14)


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Amendment 7
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15 February 2018

Obtain smoking status for past 28 days (Day 1 of each cycle)


Urine pregnancy test (negative pregnancy test required for all female subjects unless 
surgically sterile or menopausal prior to dose on Day 1)

Obtain blood samples for: 
Chemistry (Cycle 1 Days 1, 8, 14, and 28; Days 1 and 28 of each subsequent cycle)
Hematology (Cycle 1 Days 1, 8, 14, and 28; Days 1 and 28 of each subsequent cycle)
Coagulation (Day 1 of each cycle)
PK (Cycle 1 Days 1, 8, 14, and 28; Day 28 of each subsequent cycle at pre-dose and 
2 hours post-dose of ENTO)
Biomarkers (Cycle 1 Days 1, 8, 14, and 28 at pre-dose)
Phase 1b only: For subjects dosed with 400 mg and 800 mg ENTO, pharmacodynamic 
(BAT assay) samples will be collected (Cycle 1 Days 1, 8, 14, and 28 at pre-dose and 
2 hours post-dose of ENTO). BAT assay samples may also be collected at pre-dose on 
Day 28 of subsequent cycles during the escalation phase.
Note:  ENTO should be held until the pre-dose blood samples have been drawn.  Record 
approximate times of the last 2 doses of ENTO on PK collection days and the time the PK 
blood samples are obtained.  

Obtain a bone marrow aspirate and biopsy on Day 28 of Cycles 1 and 2 for disease 
assessment and biomarker testing.  If the bone marrow is consistent with Morphologic CR or 
CRi status per Appendix 5, then evaluate MRD as per institutional practice and Appendix 7.

Obtain a bone marrow aspirate sample for disease assessment and biomarker testing every 
4 cycles beginning on Cycle 4 Day 28 of subsequent cycles (eg, Cycle 4 Day 28, Cycle 8 
Day 28) or as clinically indicated.  Subjects who achieve CR/CRi that is stable for 
2 consecutive bone marrow evaluations are not required to have further bone marrow aspirate 
samples collected, unless clinically indicated. Biopsy will be used in the event the aspirate 
cannot be collected or analyzed (eg, dry-tap, hemodiluted specimen, or lack of spicules).  
The following procedures will be conducted at Remission/Relapse.

Obtain blood samples for:
Chemistry
Hematology
Biomarkers
CCI


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Amendment 7
CONFIDENTIAL
Page 84
15 February 2018

Obtain bone marrow aspirate samples for disease assessment and biomarker testing. Biopsy 
will be used in the event the aspirate cannot be collected or analyzed (eg, dry-tap, 
hemodiluted specimen, or lack of spicules). Subjects who achieve CR/CRi that is stable for 
2 consecutive bone marrow evaluations are not required to have further bone marrow aspirate 
samples collected, unless clinically indicated.
6.4.
Assessments for Premature Discontinuation from Study
If a subject discontinues study treatment (eg, as a result of an AE), every attempt should be made 
to keep the subject in the study to perform the required study-related follow-up and procedures.
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.
6.4.1.
Criteria for Discontinuation of Study Treatment
Study treatment 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

Group C subjects with the following increases in pre-treatment baseline blast percentage in 
the bone marrow:  
< 5% blasts at baseline with an increase to ≥ 10% blasts
5 to 10% blasts at baseline with an increase to ≥ 20% blasts
11 to 20% blasts at baseline with an increase to ≥ 30% blasts
Exception: Subjects will be allowed to continue therapy for up to 2 cycles. If at the time 
of the post Cycle 2 disease assessment there has not been an improvement in cytopenias 
or blast count, peripheral blood or marrow, that would suggest clinical benefit, the subject
is to be removed from study. Decisions regarding continuation of therapy in subjects on 
Group C past Cycle 2 will be reviewed with the PI and Medical Monitor.

Subjects may be removed in the case of new CNS disease or other new sites of 
extramedullary involvement

Groups B and C: requires continued treatment with hydroxyurea after Cycle 1


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Amendment 7
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
Subject request to discontinue for any reason. Subjects who withdraw from the study 
treatment phase of the study should still be followed for survival until 3 years from study 
start (see Section 6.5, Long term follow up)

Subject noncompliance with study treatment administration, study procedures, or study 
requirements should be withdrawn from study treatment in circumstances that increase risk 
or substantially compromise the interpretation of study results

Pregnancy during the study (refer to Appendix 4)

The investigator, in consultation with the Gilead Sciences Medical Monitor or designee, may 
withdraw any subject from the study treatment, if, in the investigator’s opinion, it is not in 
the subject’s best interest to continue. 

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)

If allowed by local regulations, Gilead Sciences may transition subjects from study treatment 
to commercial drug supply when ENTO becomes commercially available in the country 
where the subject is living.
6.4.2.
End of Study Treatment
Subjects will be removed from study treatment when any of the criteria listed in Section 6.4.1
apply.  The following procedures will be conducted when a subject discontinues study treatment 
and prior to initiating a new therapy.

Review prior/concomitant medication 

Record any adverse events

ECOG performance status

Physical exam 

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

Weight

Obtain blood samples for: 
Chemistry
Hematology
Coagulation


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Biomarker testing
Phase 1b only: For Group C subjects dosed with 400 mg and 800mg ENTO, a BAT 
assay sample may be collected

Obtain bone marrow aspirate and biopsy samples for disease assessment and biomarker 
testing (if not performed within the last 2 weeks).  If the bone marrow is consistent with 
Morphologic CR or CRi status per Appendix 5, then evaluate MRD as per institutional 
practice and Appendix 7.

6.4.3.
30-day Follow-up
After the last dose of study drug, subjects should be followed for any drug-related AEs and/or 
ongoing serious adverse events (SAEs) until those events have resolved or become stable, 
whichever occurs later. The site will contact the study subject regardless of AE/SAE status 
approximately 30 days after the subject’s last dose of study drug to assess adverse events since 
the last study visit and review concomitant medications. Contact the subject by phone 
(or in person, if necessary) to assess the subject’s condition and record any adverse events 
reported during the follow-up contact. Document the phone call or visit.
6.5.
Long Term Follow-up
Long term follow-up for survival will be conducted every 6 months (± 4 weeks) after the End of 
Study Treatment visit for up to 3 years (since the start of study therapy). Information to be 
gathered includes leukemia treatments, other malignancies, and survival. This follow-up can be 
done during a routine clinic visit, other contact with the subject, or via telephone. Gilead reserves 
the right to discontinue or shorten the duration of participation in the long term follow-up period 
at any time. See section 9.3.4 for details regarding study discontinuation.
6.6.
Description of Study Procedures
6.6.1.
Prior/Concomitant Medications
At screening all medication taken up to 30 days prior to the screening visit will be recorded on 
the eCRF. At each study visit, the site will capture any and all medications taken by the subject
since the last visit or during the visit (as applicable). Concomitant medications include 
prescription, non-prescription medications, vitamins, and minerals.
6.6.2.
Performance Assessment
Performance assessments should be completed using the ECOG scale. If performance is assessed 
using the Karnofsky scale, scores should be converted to ECOG as outlined in Appendix 6.
CCI


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6.6.3.
Laboratory Safety Tests
Blood will be collected for laboratory safety tests according to the Study Procedures Table in 
Appendix 2 and may be collected as clinically indicated. The date and time of blood collection 
will be recorded in the subject’s source documentation. The tests will be analyzed using standard 
procedures. All laboratory tests must be reviewed by the Investigator or qualified designee.
See Table 6-1 for tests to be conducted.
6.6.4.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI


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6.6.5.
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI


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6.6.6.
 
 
 
 
 
 
 
CCI
CCI
CCI


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Blood Collection
Table 6-1.
Blood Samples Collected During the Course of the Study
Serum Chemistry
Hematology
Other
Sodium
Potassium
Chloride
Lipase
Amylase
Bicarbonate
Creatinine
BUN
Phosphorus
LDHa
Uric acida
Magnesiuma
Total bilirubin 
Direct bilirubin
Indirect bilirubin
ALT
AST  
Alkaline phosphatase
Total CPK b
Beta-2 microglobulinc
Hemoglobin
Hematocrit
Red Blood Cell (RBC) count
White Blood Cell (WBC) Count 
Neutrophils 
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Basophil Activation Assay (400 mg and 800 mg 
ENTO dose levels in Group C during Phase 1b
only)
Pharmacokinetic Sampling
Biomarker Sampling

Blood

Bone marrow aspirate

Bone marrow biopsy
Coagulation
Prothrombin time
APTT
INR
Pregnancy Testing
Virology
Serum Qualitative -HCG 
and FSHa
Hep B (antigen, antibody)
Hep C (antibody)
HIV
a
Screening only.  Serum FSH also required for female subjects with medically documented ovarian failure.
b
At screening, end of every cycle (ie, Day 14 of every cycle for Group A, Cycle 0 Day 14 and Day 28 of every cycle 
thereafter for Group B, and  Day 28 of every cycle for Group C), and End of Study Treatment.
c
For all groups at screening, end of Cycle 0 (Group A Cycle 0 Day 14), Cycle 1 Day 28, and Cycle 2 Day 28.
6.6.7.
Biological Sample Storage
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period up to 15 years for purposes of this study.
6.6.8.
Efficacy Assessments
Assessment of clinical response will be made according to the revised International Working 
Group criteria {Cheson 2003} (See Appendix 5). The major criteria for judging response will 
include physical examination and examination of blood and bone marrow.  


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject
administered a medicinal product, which does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an 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 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) or serious adverse drug reaction (SADR) is defined as an event 
that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)


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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.
7.1.2.1.
Protocol-Specific Serious Adverse Event Instructions
Disease Progression and Death Related to Disease Progression: Given the endpoints of the study, 
in order to maintain the integrity of the study, the following events that are assessed as unrelated 
to study drugs will not be considered SAEs:

Progression of malignancy being studied

Death due to malignancy being studied
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the study drugs caused or contributed to the disease 
progression (ie, by a means other than lack of effect). Unrelated disease progression should be 
captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports.
Protocol-specific SAE reporting exemptions: subjects with AML at initial diagnosis or relapse 
will require transfusional support with red cells and platelets and these will be considered 
exemptions to reporting.
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 ENTO interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 


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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).
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 treatments and Procedures
The investigator or qualified sub-investigator is responsible for assessing the relationship to 
ENTO therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease,
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the CTCAE, Version 4.03. For each episode, increasing 
grade changes should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the AE. For purposes of consistency with 
the CTCAE, these intensity grades are defined below.


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Grading of Adverse Event Severity
Grade
Adjective Description  
Grade 1
Mild Sign or symptom is present, but it is easily tolerated, is not expected to have a clinically 
significant effect on the subject’s overall health and well-being, does not interfere with the 
subject’s usual function, and is not likely to require medical attention.  
Grade 2
Moderate Sign or symptom causes interference with usual activity or affect clinical status, and may 
require medical intervention.  
Grade 3
Severe Sign or symptom is incapacitating or significantly affects clinical status and likely requires 
medical intervention and/or close follow-up.  
Grade 4
Life-threatening Sign or symptom results in a potential threat to life.  
Grade 5
Fatal Sign or symptom results in death. 
The distinction between the seriousness and the severity of an AE should be noted. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead 
Requirements for collection prior to study treatment initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/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 treatment must be reported to the CRF/eCRF 
database as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Pharmacovigilance and Epidemiology (PVE) as instructed. This 
also includes any SAEs resulting from protocol-associated procedures performed after informed 
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Any SAEs and deaths that occur after the post treatment follow-up visit and throughout the 
duration of the study, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead PVE.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead PVE within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:  
Gilead PVE Email: 
 and Fax:

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/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 
PPD
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suspected unexpected serious adverse reactions (SUSARs). In accordance with the 
EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Toxicity Management
It is recognized that drug-related toxicity in this population may be difficult to ascertain given 
the aggressive hematologic disease. Investigators will attempt to assign attribution of toxicities to 
each drug if possible. The CTEP Active Version of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting.
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.  


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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 treatment
follow-up period, to the Gilead PVE using the pregnancy report form within 24 hours of 
becoming aware of the pregnancy.
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 PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead PVE. Gilead PVE contact information is as follows: 
Email: 
 and Fax: 
Pregnancies of female partners of male study subjects exposed to Gilead or other study 
treatments must also be reported and relevant information should be submitted to Gilead PVE 
using the pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject
should continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after 
the study has been completed, the outcome should be reported directly to Gilead PVE,
fax number 
 or email 
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
PPD
PPD
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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.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/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 primary objectives are:

To demonstrate the overall safety of ENTO in combination with 7+3 in subjects with 
previously untreated AML who are candidates for chemotherapy (fit subjects) and to assess
the efficacy of ENTO at the RP2D (Group A)

To demonstrate the overall safety of ENTO in combination with hypomethylating agents 
(decitabine or azacitidine) in subjects with previously untreated AML who are not candidates
for 7+3 (unfit subjects) and to assess the efficacy of ENTO at the RP2D (Group B)

To demonstrate the overall safety of ENTO monotherapy in subjects with previously 
untreated AML who are not candidates for chemotherapy or in subjects with 
relapsed/refractory AML with or without MLL and to assess the efficacy of ENTO at the 
RP2D (Group C)
The secondary objectives of this study are: 

To assess the qualitative and quantitative toxicities of ENTO monotherapy or ENTO in 
combination with chemotherapy in subjects with AML

To document therapeutic response of subjects with AML treated with ENTO monotherapy or 
ENTO in combination with chemotherapy 
The exploratory objective of this study is:

 
8.1.2.
Endpoints
Primary Endpoints: 
Safety

Occurrence of adverse events and laboratory abnormalities defined as DLTs for ENTO in 
combination with standard dose cytarabine and daunorubicin (7+3) in subjects with 
previously untreated AML (Group A)

Occurrence of adverse events and laboratory abnormalities defined as DLTs for ENTO in 
combination with decitabine or azacitidine in subjects with previously untreated AML who 
are unable to receive 7+3 chemotherapy (Group B)
CCI


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
Occurrence of adverse events and laboratory abnormalities defined as DLTs for ENTO as a 
single agent in subjects with relapsed/refractory AML with or without MLL or previously 
untreated AML (Group C)
Efficacy

Complete remission rate at induction completion: defined as the proportion of subjects who 
achieved morphologic complete remission (CR) at induction completion. Note: CR includes 
a subcategory of cytogenetic CR (CRc).

Composite complete remission rate at induction completion: defined as the proportion of 
subjects who achieved CR or morphologic complete remission with incomplete blood count 
recovery (CRi) at induction completion.

Overall response rate at induction completion: defined as the proportion of subjects who 
achieved CR, CRi, or partial remission (PR) at induction completion.
Secondary Endpoints: 
Exposure 

Drug administration and duration of exposure of study treatment
Safety

Occurrence of AEs and laboratory abnormalities not defined as DLTs
Efficacy

Event free survival (EFS) – defined for all subjects and it is measured from the start of the 
study therapy until the date of treatment failure, AML relapse or death from any cause, 
whichever occurs first 

Overall survival (OS) – defined as the interval from the start of the study therapy to death 
from any cause
Exploratory Endpoints:
 
CCI


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8.2.
Analysis Sets
8.2.1.
Full Analysis Set
The full-analysis set (FAS) includes all subjects who receive at least 1 dose of study treatment 
ENTO. This analysis set will be used in the analyses of subject characteristics, exposure, safety, 
and efficacy. Summary and listing will be presented by study group, dose level, treatment arm, 
cohort, and overall if applicable.   
For analysis by dose levels, subjects from phase 1b and phase 2 will be pooled and analyzed by 
the dose level first received, unless otherwise specified.  
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8.2.2.
DLT Analysis Set
DLT analysis set includes subjects in FAS with sufficient drug exposure or experience a DLT 
during the DLT assessment window (see Section 3.2). 
8.2.3.
Pharmacokinetic Analysis Sets
The pharmacokinetic analysis sets include data from subjects in the full analysis set who have 
the necessary baseline and on-study measurements to provide interpretable results for the 
specific parameters of interest.
These analysis sets will be used in the analyses of ENTO plasma pharmacokinetics.
8.3.
Data Handling Conventions
8.3.1.
General Methods 
By-subject listings will be created for important variables from each eCRF module. Summary 
tables for continuous variables will contain the following statistics: N (number in population), 
n (number with data), mean, standard deviation, 95% confidence intervals (CIs) on the mean, 
median, minimum, and maximum. Summary tables for categorical variables will include: N, n, 
percentage, and 95% CIs on the percentage. Unless otherwise indicated, 95% CIs for binary 
variables will be calculated using the binomial distribution (exact method) and will be 2 sided. 
Data will be described and summarized by dose level, analysis set, and timepoint. As 
appropriate, changes from baseline to each subsequent timepoint will be described and 
summarized. Similarly, as appropriate, the best change from baseline during the study will also 
be described and summarized. Graphical techniques (eg, waterfall plots, Kaplan-Meier curves, 
line plots) may be used when such methods are appropriate and informative. 
The baseline value used in each analysis will be the last (most recent) pre-treatment value. Data 
from all sites will be pooled for all analyses. Analyses will be based upon the observed data 
unless methods for handling missing data are specified. If there is a significant degree of 
non-normality, analyses may be performed on log-transformed data or nonparametric tests may 
be applied, as appropriate. 
Unless otherwise specified, all analyses will be 2-sided at the 0.05 level of significance.
8.4.
Demographic Data and Baseline Characteristics
A listing of all full-analysis subjects will be generated to describe site, subject number, 
first screening date, first treatment date, stage (escalation and expansion), dose level, duration of 
study treatment, and the reason for discontinuing study treatment. Available information on 
subjects who were screened or registered but not treated may be listed separately. A table will be 
created summarizing these categories in terms of number and percent for the full analysis set.
Subject baseline characteristics will be listed and summarized by stage and dose level for the full 
analysis set. 


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8.5.
Efficacy Analysis
The efficacy of ENTO when used as monotherapy or in combination with chemotherapy will be 
evaluated using the International Working Group criteria {Cheson 2003}, which is documented 
in Appendix 5.
8.5.1.
Categorical Endpoints
Categorical endpoints, such as complete remission rate, composite complete remission (CR/CRi) 
rate, and overall response (CR/CRi/PR) rate at initial induction, will be summarized. For all 
analyses, the corresponding 95% exact CIs will be presented.
8.5.2.
Time-to-Event Endpoints
For a subject who is not known to have relapsed or died by the end of the study follow-up or data 
cutoff, RFS is censored on the date of the last available assessment of the subject.  
For subjects with none of the events defined in EFS before the end of the study follow-up or data 
cutoff, EFS is censored at the date of the last available assessment of the subject. 
For a subject who is not known to have died by the end of study follow-up or data cutoff, OS is 
censored on the date the subject was last known to be alive.
RFS, EFS and OS will be analyzed using Kaplan-Meier (KM) methods. The KM estimate of the 
survival function will be computed and the results will be presented using KM curves. The 
median will be provided along with the corresponding 95% CI. Additionally, the 25% and 
75% percentiles for these endpoints will also be provided. 
For subjects who die without report of relapse, remission duration is censored on the date of 
death, regardless of cause. For a subject with no report of relapse by the end of the study follow-
up or data cutoff date, observation is censored on the date of the last available assessment of the 
subject. 
Analysis of remission duration will be analyzed using cumulative incidence by considering 
competing risks. The estimate of the cumulative incidence of relapse (CIR) will be reported with 
the associated 95% CI. 
8.5.3.
Continuous Endpoints
Continuous endpoints (eg, TTR and TTC) will be summarized using descriptive statistics. 
8.6.
Safety Analysis
All safety data collected on or after the date that ENTO was first dispensed up to 30 days after 
the date of last dose of ENTO will be summarized by dose level. For Group A and Group B, 
safety data will be presented by the lead-in ENTO therapy phase and the induction chemotherapy 
phase separately, and overall.


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8.6.1.
Extent of Exposure
Descriptive information will be provided by dose level regarding the number of doses of study 
therapy prescribed, the total number of doses taken, the percent of expected doses taken, duration 
of treatment, and the number and timing of prescribed dose reductions and interruptions.
ENTO compliance will be described in terms of the proportion of study treatment actually taken 
based on returned pill count relative to the amount that was dispensed (taking into account 
physician-prescribed reductions and interruptions).
8.6.2.
Adverse Events
All adverse events will be listed. The focus of adverse event summarization will be on treatment 
emergent adverse events. A treatment-emergent adverse event is defined as an adverse event that
onset in the period from the first dose of study treatment to 30 days after the permanent 
discontinuation of study treatment or that leads to permanent discontinuation of study treatment. 
Adverse events that occur before the first dose of study treatment or >30 days after the subject
has been discontinued from study treatment will be included in data listings.
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High Level Term, Preferred 
Term, and Lower-Level Term. The severity of adverse events will be graded by the investigator 
according to the CTCAE, Version 4.03 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010 
06-14_QuickReference_8.5x11.pdf), whenever possible. If a CTCAE criterion does not exist for 
a specific type of adverse event, the grade corresponding to the appropriate adjective will be used 
by the investigator to describe the maximum intensity of the adverse event: Grade 1 (mild), 
Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal). The 
relationship of the adverse event to the study treatment will be categorized as related or 
unrelated.
Treatment-emergent adverse events will be summarized. Summary tables will be presented to 
show the number of subjects reporting treatment-emergent adverse events by severity grade and 
corresponding percentages. A subject who reports multiple treatment-emergent adverse events 
within the same Preferred Term (or System Organ Class) is counted only once for that Preferred 
Term (or System Organ Class) using the worst severity grade. Adverse event descriptions will be 
presented in alphabetical order of System Organ Class, then by decreasing frequency in the 
“overall” column for a given Preferred Term.
Separate listings and summaries will be prepared for the following types of treatment emergent 
adverse events:

Study-drug-related adverse events

Adverse events that are Grade ≥3 in severity

Adverse events leading to study treatment interruption and/or dose modification


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
Adverse events leading to study treatment discontinuation

Serious adverse events (with categorization of the primary reason that the adverse event is 
considered serious, eg, death, hospitalization, etc.)

DLT will be listed and summarized and the DLT rate will be presented by study group and 
dose cohort and the corresponding 90% CIs will be presented
8.6.3.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data 
and will be reported using conventional units. The focus of laboratory data summarization will 
be on treatment-emergent laboratory abnormalities. A treatment emergent laboratory abnormality 
is defined as an abnormality that, compared to baseline, worsens by ≥ 1 grade in the period from 
the first dose of study treatment to 30 days after the last dose of study treatment. If baseline data 
are missing, then any graded abnormality (ie, an abnormality that is Grade ≥ 1 in severity) will be 
considered treatment emergent. Laboratory abnormalities that occur before the first dose of study 
treatment or > 30 days after the subject has been discontinued from study treatment will be 
included in data listings.
Hematological, serum biochemistry, and urine data will be programmatically graded according 
to CTCAE severity grade, when applicable. For parameters for which a CTCAE scale does not 
exist, reference ranges from the central laboratory will be used to determine programmatically if 
a laboratory parameter is below, within, or above the normal range for the subject’s age, sex, etc.
Hematological and serum biochemistry and their changes from baseline will be summarized. 
Summary tables will be presented for each relevant assay to show the number of subjects by 
CTCAE severity grade with corresponding percentages. For parameters for which a CTCAE 
scale does not exist, the frequency of subjects with values below, within, and above the normal 
ranges will be summarized. Subjects will be characterized only once for a given assay, based on 
their worst severity grade observed during a period of interest (eg, during the study or from 
baseline to a particular visit).
Shift tables for hematology and serum biochemistry will also be presented by showing change in 
CTCAE severity grade from baseline to each visit. For parameters for which a CTCAE scale 
does not exist, shift tables will be presented showing change in results from baseline 
(normal, low and high [or abnormal]) to each visit (normal, low and high [or abnormal]). Tables 
will be prepared to show frequencies adjusted for baseline values; for this frequency, subjects 
with the same or worse toxicity grade at baseline are not considered.
Separate listings and summaries will be prepared for laboratory abnormalities that are Grade ≥ 3 
in severity.


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8.7.
Pharmacokinetic Analysis
Concentrations of ENTO in plasma will be determined using a validated bioanalytical assay. 
Plasma concentrations will be displayed as individual concentration vs. time using scheduled 
sampling times. Concentrations of ENTO will be listed by subject and summarized using 
descriptive statistics (eg, n, arithmetic mean, geometric mean, % coefficient of variation [CV], 
StD, median, Q1, Q3, min, and max). Mean (± StD) plasma concentration-time curves will be 
plotted in both semi-logarithmic and linear formats.
8.8.
 
 
8.9.
Sample Size
In Phase 1b, each group will enroll up to 12 subjects, assuming 2 planned dose levels for 
escalation are tested with up to 6 subjects per level. Assuming 10% of the subjects are 
unevaluable during dose escalation, up to 14 subjects may be enrolled in each group for a total of 
up to 42 subjects. In Group B, an additional 6 subjects will be enrolled to evaluate the safety of 
ENTO in combination with azacitidine prior to the dose expansion.
In Phase 2, approximately 40 additional subjects will be enrolled in Group A. Table 8-1 provides 
the 90% confidence interval (CI) of 40 subjects for the assumed composite complete remission 
rate. This sample size ensures a narrow CI (~ 7-14% distance from the point estimates). The 
composite complete remission rate of standard chemotherapy (7+3) has been reported as 52% in 
the CALGB study of over 1000 subjects. 
Table 8-1.
Exact 90% CIs of Composite Complete Remission Rate for a Cohort  
Size of 40 in Group A
Expected Composite Complete Remission Rate of Entospletinib + 7+3
Exact 90% CI
70%
(56% – 82%)
80%
(67% – 90%)
90%
(79% – 97%)
In the Group B phase 2, approximately 40 additional subjects will be randomized in a 
1:1 manner to either treatment arm ENTO + decitabine or ENTO + azacitidine. Randomization
will be stratified by age (≤ 75 or > 75 years) and WBC (≤ 5,000/µL or > 5,000/µL). Assuming an 
composite complete remission rate of 50% for both treatment arms, the 90% CI would be 30% to 
70% with a sample size of 20. The composite complete remission rate of standard chemotherapy 
is reported as 20% – 30%. Evaluation between the treatment arms will be based on the totality of 
clinical data. 
Approximately 60 additional subjects will be enrolled in the Group C dose expansion.  
CCI
CCI


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A total of 15 initial subjects in Cohort C1A will be evaluated for futility. An additional 
15 subjects will be enrolled if greater or equal to 5 (out of 15) CR/CRi are observed. This futility 
boundary will provide a high chance (84%) of early stopping of the trial if the composite 
complete remission rate is undesirable (20%) and a low chance (22%) of early stopping if the 
composite complete remission rate is clinically meaningful (40%). At this time, futility has been
met, and thus, Cohort C1A will not move forward.
The sample size is 15 for Cohort C2. This sample size is based on practical considerations. The 
sample size is 30 for Cohort C3, which will provide adequate precision of efficacy estimates.
Table 8-2 provides the 90% confidence interval (CI) of 30 subjects for the assumed composite 
complete remission rate.  
Table 8-2.
Exact 90% CIs of Composite Complete Remission Rate for a Cohort 
Size of 30 in Cohort C3
Expected Composite Complete Remission Rate of Entospletinib Monotherapy in 
Cohort C3
Exact 90% CI
30%
(17% – 47%)
50%
(34% – 66%)
70%
(53% – 83%)
Therefore, a total of approximately 54 subjects (including 14 in Phase 1b and 40 in Phase 2) in 
Group A, approximately 60 subjects (including 14 in Phase 1b, 6 in the safety run-in of 
ENTO + azacitidine, and 40 in Phase 2) in Group B, and approximately 74 subjects (including 
14 in Phase 1b and 60 in Phase 2) in Group C will be enrolled for the duration of the study.
8.9.1.
Statistical Basis for Dose Escalation 
A total of 3 to 6 subjects will be treated at each of the proposed ENTO dose levels. Based on the 
3+3 dose-escalation scheme, Table 8-3 shows the probability of escalating to the next dose level 
or proceeding to the next stage, based on the true rate of DLT at the current dose level.
Table 8-3.
Probability of Dose Escalation (N=3+3)
True Incidence of DLT
Probability of Escalating
10%
0.91
20%
0.71
30%
0.49
40%
0.31
50%
0.17
60%
0.08


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Thus, if the true underlying proportion of DLT is low (eg, ≤ 10% at the current dose level, there 
is a high probability (≥ 0.91) of dose escalation to the next dose level. Conversely, if the true 
underlying proportion of DLT is high (eg, ≥ 60%) at the current dose level, there is a low 
probability (≤ 0.08) of escalation to the next dose level.
The trial employs the standard NCI definition of MTD (starting dose associated with DLT in 
< 33.3% of subjects during the DLT assessment window).
8.10.
Timing of Analyses
8.10.1.
Interim Analyses 
No formal interim analyses are planned in this Phase 2 trial with lead-in. The Gilead Sciences 
study team and the investigators will collectively discuss study conduct and accumulating safety 
and other data through teleconferences. In phase 1b, it is expected that these discussions will be 
scheduled to occur immediately following DLT window for the third subject of each cohort 
unless accrual to the study and the need for decisions regarding dose escalation or stage 
progression indicate the need for more frequent reviews.  In Phase 2, it is expected that these 
discussions will occur immediately following completion of the DLT window for the Group B 
safety run-in cohort unless accrual to the study and the need for decisions regarding dose 
expansion indicate the need for more frequent reviews.
8.10.2.
Final Analysis
Final study reporting is expected to occur after all subjects have discontinued study treatment.


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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 Review and Approval)
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB. The investigator will not begin any study subject activities until 
approval from the IRB and/or appropriate committees 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 any modifications made to the protocol or any accompanying material to be provided to 
the subject after initial IRB 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-approved consent form for documenting written 


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informed consent. Each informed consent (or assent as applicable) will be appropriately signed 
and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB or local 
requirements. The consent form will inform subjects about genomic testing and sample retention, 
and their right to receive clinically relevant genomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB, or laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The investigator 
must keep a screening log showing codes, names, and addresses for all subjects screened and for 
all subjects enrolled in the trial. Subject data will be processed in accordance with all applicable 
regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/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 2 categories: (1) investigator’s study file, and (2) subject
clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB
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;


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


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audit trail of the system. Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that 
the forms have been reviewed, and that the entries accurately reflect the information in the 
source documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (eg, data entry 
error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy of 
the data entered by that site. This archive must be stored in accordance with the records retention 
requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB, 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.


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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 in 
accordance with local requirements and receive documented IRB approval before modifications 
can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years.
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.


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9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/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 CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
The sponsor reserves the right to terminate the study at any time due to safety concerns, concerns 
regarding efficacy of the treatment, serious non-compliance at an investigator site that could 
affect subject safety, or new or emerging scientific or clinical developments in the field. Should 
this be necessary, both Gilead and the investigator 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. Should the primary objective of the trial not be met after primary analysis, 
Gilead will assess if further development of ENTO in AML is warranted and may determine to 
discontinue the trial. Subjects that remain on study may be considered for continued treatment 
with Gilead investigational product until disease progression, unacceptable toxicity, withdrawal 
of consent, or the Investigator or Sponsor deems treatment is no longer appropriate. Subjects will 
be reviewed for evidence of individual benefit by the investigator, and in consultation with the 
sponsor will ensure that the appropriate risk to benefit ratio is maintained for each subject. 
However, Gilead reserves the right, at its sole discretion, to determine whether to supply Gilead 
investigational product, and by what mechanism, after termination of the trial.


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10.
REFERENCES
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Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, et al. Clinical response and 
miR-29b predictive significance in older AML patients treated with a 10-day 
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alone or in combination with valproic acid in acute myeloid leukemia. J Clin 
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Boros K, Puissant A, Back M, Alexe G, Bassil CF, Sinha P, et al. Increased SYK activity is 
associated with unfavorable outcome among patients with acute myeloid 
leukemia. Oncotarget 2015;6 (28):25575-87.
Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom M, et al. R406, an orally available 
spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune 
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Carnevale J, Ross L, Puissant A, Banerji V, Stone RM, DeAngelo DJ, et al. SYK regulates 
mTOR signaling in AML. Leukemia 2013;27 (11):2118-28.
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Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group for Diagnosis, 
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Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 
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Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and 
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expression in chromosomally defined subsets of acute myelogenous leukemia. 
Leukemia 2002;16 (2):186-95.


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Gao L, Sun J, Liu F, Zhang H, Ma Y. Higher expression levels of the HOXA9 gene, closely 
associated with MLL-PTD and EZH2 mutations, predict inferior outcome in acute 
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Ruzza P, Biondi B, Calderan A. Therapeutic prospect of Syk inhibitors. Expert Opin Ther Pat 
2009;19 (10):1361-76.
Sanchez-Garcia J, Serrano J, Serrano-Lopez J, Gomez-Garcia P, Martinez F, Garcia-Castellano 
JM, et al. Quantification of minimal residual disease levels by flow cytometry at 
time of transplant predicts outcome after myeloablative allogeneic transplantation 
in ALL. Bone Marrow Transplant 2013;48 (3):396-402.
Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA. JAK/STAT, 
Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and 
leukemogenesis. Leukemia 2004;18 (2):189-218.
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Program of the American Society of Hematology. American Society of 
Hematology 2004:98-117.
Zangenberg M, Grubach L, Aggerholm A, Silkjaer T, Juhl-Christensen C, Nyvold CG, et al. The 
combined expression of HOXA4 and MEIS1 is an independent prognostic factor 
in patients with AML. Eur J Haematol 2009;83 (5):439-48.
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.
Study Procedures Tables
Appendix 3.
Management of Clinical and Laboratory Adverse Events
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 5.
International Working Group Criteria for AML {Cheson 2003}
Appendix 6.
Performance Scales: Karnofsky & ECOG Scores {Oken 1982}
Appendix 7.
Minimal Residual Disease (MRD) Level Definition {Sanchez-Garcia 2013}
Appendix 8.
2017 European Leukemia Network (ELN) Risk Stratification by Geneticsa {Dohner 
2017}


PPD
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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
GS-US-339-1559: A Phase lb/2 Study ofEntospletinib (GS-9973) Monotherapy and in 
Combination with Chemotherapy in Patients with Acute Myeloid Leukemia (AML) 
Protocol GS-US-339-1559, Amendment 7, 15 February 2018 
This protocol has been approved by Gilead Sciences, n c....I.be-fnllomino..cionJJiure_dnt:•JJ_"fnPnf 
this approval. 
Signature 
Medical Monitor 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
1 will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
SiteNwnber 
CONFIDENTIAL 
Page 121 
15 February 2018 


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 120
15 February 2018
Appendix 2.
Study Procedures Tables
Group A: Phase 1b Dose Escalation (Entospletinib + cytarabine + daunorubicin)
Study Phase
Screening
Cycle 0
Entospletinib Lead-in
Cycle 1 (and Cycle 2, if needed)
Entospletinib + 7+3
At Blood Count 
Recovery/
Remission/
Relapse
End of Study 
Treatment
30-day
Follow-up
3-year Long 
Term
Follow-up
Study Day
Screening
1
8
14
1
3
7
14
Window (day) 
-14
±2
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
General and Safety 
Assessments
Informed Consent
X
Medical & Medication 
History 
X
Adverse Events/
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Physical Exama
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
Height and Weightc
X
X
X
X
ECGd
X
ECHO/MUGAe
X
X
ECOG Performance Status
X
X
X
X
Overall survival, leukemia 
treatments, and other 
malignancies
X
(every 6 months)
X-raym
(Investigator’s discretion)
X
Study Treatment
Entospletinib
Administrationf
X
X
X
X
X
X
X
IV daunorubicinf
X
X
IV cytarabinef
X
X
X


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 121
15 February 2018
Study Phase
Screening
Cycle 0
Entospletinib Lead-in
Cycle 1 (and Cycle 2, if needed)
Entospletinib + 7+3
At Blood Count 
Recovery/
Remission/
Relapse
End of Study 
Treatment
30-day
Follow-up
3-year Long 
Term
Follow-up
Study Day
Screening
1
8
14
1
3
7
14
Window (day) 
-14
±2
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
Laboratory Assessments
Chemistryg
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
Urinalysis
X
Serum Pregnancy Test and 
FSHh
X
HIV/HBV/HCV
X
Bone Marrow 
Assessments
Biopsy1
X
X
X
X
Aspiratej
X
X
X
X
X
PKk
X
X
X
X
X
X
Biomarkersl
X
X
X
X
X
X
X
a
After discharge from the hospital, a focused physical exam may be completed at the Investigator’s discretion.
b
Vital signs include measurement of blood pressure, respiratory rate, pulse, temperature, and oxygen saturation level.  Vitals signs may be measured daily during 
hospitalization and at the Investigator’s discretion after discharge from the hospital.
c
Height and weight will be measured at Screening. Only weight will be measured on Days 1 and 7 of Cycles 1 and 2 and at End of Study Treatment.
d
ECG is required at Screening and may be performed at the Investigator’s discretion following enrollment.
e
An ECHO or MUGA must be performed at Screening and prior to re-induction on Cycle 1 Day 14. For German sites only ECHO to be performed.
f
ENTO will be administered orally  every 12 hours on Days 1-14 as a single agent in Cycle 0 then in combination with IV daunorubicin (Days 1-3) and IV cytarabine (Days 1-7) 
during induction chemotherapy of every 14-day cycle (Cycle 1 and up to Cycle 2).  Subjects are to continue receiving ENTO while awaiting disease assessment results.
g
Include Total CPK at Screening, Day 14 of every cycle, and End of Study Treatment (see Table 6-1). 
h
A negative serum pregnancy test is required for female subjects (unless surgically sterile or menopausal) at Screening. Female subjects with medically documented ovarian 
failure must also have serum FSH levels within the institutional postmenopausal range.
CCI


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 122
15 February 2018
i
A bone marrow biopsy will be performed at Screening (within 21 days before the first administration of study treatment), Cycle 1 Day 14 or at the time of blood count 
recovery (whichever comes first), remission/relapse, and End of Study Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker research. If 
the bone marrow biopsy could not be obtained at Screening, diagnostic samples should be used. At all bone marrow biopsy time points, slides for biomarker research and 
disease assessment will be requested from the bone marrow biopsy core. Refer to the most current Covance Lab Manual for collection instructions. If the bone marrow is 
consistent with Morphologic CR or CRi status per Appendix 5, perform cytogenetics, flow cytometry and FISH or PCR for MRD evaluation as per institutional practice and 
Appendix 7.
j
A bone marrow aspirate will be collected at Screening (within 21 days before the first administration of study treatment), Cycle 1 Day 14 or at the time of blood count 
recovery (whichever comes first), remission/relapse, and End of Study Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker research.
Perform FISH analysis on Screening bone marrow aspirate. If the bone marrow aspirate could not be obtained at Screening, diagnostic samples should be used. A bone 
marrow aspirate will also be collected at Cycle 0 Day 14 for flow cytometry and biomarker research (see section 6.6.4).  Biopsy will be used in the event the aspirate is not 
collectable or analyzable.  If the bone marrow is consistent with Morphologic CR or CRi status per Appendix 5, perform cytogenetics, flow cytometry and FISH or PCR for 
MRD evaluation as per institutional practice and Appendix 7.
k
Peripheral blood samples for PK will be obtained on Cycle 0 Days 1, 8, and 14 at pre-dose and 2 hour post-dose of ENTO; Cycle 1 Days 3 and 7 at pre-dose, 2hrs, and 4hrs
post-dose of ENTO; Cycle 1 Day 14 at pre-dose and 2hrs post-dose of ENTO.
l
Blood samples for biomarker testing will be obtained on Cycle 0 Day 1 at pre-dose and 6hrs post-dose of ENTO or end of day; Cycle 0 Days 8, 14 and Cycle 1 Day 7 at 6hrs 
post-dose of ENTO or end of day; Cycle 1 Day 14 or at the end of Cycle 1 at the time of blood count recovery (whichever comes first) at 6 hours post-dose of ENTO or end of 
day; at time of remission/relapse; End of Study Treatment.
m
X-ray not to be performed for German sites.


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 123
15 February 2018
Group A: Phase 2 Dose Expansion (Entospletinib + cytarabine + daunorubicin)
Study Phase
Screening
Cycle 0
Entospletinib 
Lead-in
Cycle 1 (and Cycle 2, if needed)
Entospletinib + 7+3
Post-Remission 
Entospletinib + 
cytarabine
(3-4 cycles)
Maintenance 
Entospletinib
(up to 
12 cycles)
At Blood 
Count 
Recovery/ 
Remission/ 
Relapse
End of 
Study 
Treatment
30-day 
Follow-
up
3-year  
Long Term 
Follow-up
Study Day
Screening
1
8
14
1
3
7
14
15 to 
Count 
Recovery
1
3
5
28
1
28
Window (day)
-14
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
General and 
Safety 
Assessments
Informed Consent
X
Medical & 
Medication 
History 
X
Adverse Events/
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IxRS Registration
X
X
X
X
X
X
Smoking statusa
X
X
X
X
X
Physical Examb
X
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
Height and 
Weightd
X
X
X
ECGe
X
ECHO/MUGAf
X
X
ECOG 
Performance 
Statusg
X
X
X
X
X
X
Overall survival, 
leukemia 
treatments, and 
other malignancies
X
(every 
6 months)


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 124
15 February 2018
Study Phase
Screening
Cycle 0
Entospletinib 
Lead-in
Cycle 1 (and Cycle 2, if needed)
Entospletinib + 7+3
Post-Remission 
Entospletinib + 
cytarabine
(3-4 cycles)
Maintenance 
Entospletinib
(up to 
12 cycles)
At Blood 
Count 
Recovery/ 
Remission/ 
Relapse
End of 
Study 
Treatment
30-day 
Follow-
up
3-year  
Long Term 
Follow-up
Study Day
Screening
1
8
14
1
3
7
14
15 to 
Count 
Recovery
1
3
5
28
1
28
Window (day)
-14
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
X-rayu
X
Study Treatment
Entospletinib 
Administrationh,i
X
X
X
X
X
X
X
X
X
X
X
X
X
IV daunorubicinh
X
X
IV cytarabineh,i 
X
X
X
X
X
X
Laboratory 
Assessments
Chemistryj,k,r
X
X
X
X
X
X
X
X
X
X
Hematologyj,k,t
X
X
X
X
X
X
X
X
X
X
X
Coagulationk
X
X
X
X
X
X
X
Urinalysis
X
Pregnancy Test 
and FSHl
X
X
X
X
X
HIV/HBV/HCV
X
Sparse ENTO PKm
X
X
X
X
X
X
X
X
Intensive ENTO 
PKn
X
Biomarkerso
X
X
X
X
X
X
X
CCI


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 125
15 February 2018
Study Phase
Screening
Cycle 0
Entospletinib 
Lead-in
Cycle 1 (and Cycle 2, if needed)
Entospletinib + 7+3
Post-Remission 
Entospletinib + 
cytarabine
(3-4 cycles)
Maintenance 
Entospletinib
(up to 
12 cycles)
At Blood 
Count 
Recovery/ 
Remission/ 
Relapse
End of 
Study 
Treatment
30-day 
Follow-
up
3-year  
Long Term 
Follow-up
Study Day
Screening
1
8
14
1
3
7
14
15 to 
Count 
Recovery
1
3
5
28
1
28
Window (day)
-14
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
Bone Marrow 
Assessments
Biopsyp
X
X
X
X
Aspirateq
X
X
X
X
X
X
X
a
Collect smoking status at Screening and Day 1 of each cycle.  
b
After discharge from the hospital, a focused physical exam may be completed at the Investigator’s discretion.  During Post-remission and Maintenance, a physical exam is to 
be completed every 2 cycles (eg, Cycle 1 Day 1, Cycle 3 Day 1, etc.)
c
Vital signs include measurement of blood pressure, respiratory rate, pulse, temperature, and oxygen saturation level.  Vitals signs may be measured daily during 
hospitalization and at the Investigator’s discretion after discharge from the hospital.  During Post-remission and Maintenance, vital signs to be performed every 2 cycles
(eg, Cycle 1 Day 1, Cycle 3 Day 1, etc.)
d
Height and weight will be measured at Screening. Only weight will be measured on Day 1 of induction Cycle 1 (and 2, if needed) and at End of Study Treatment.
e
ECG is required at Screening and may be performed at the Investigator’s discretion following enrollment.
f
An ECHO or MUGA must be performed at Screening and prior to re-induction, if applicable. For German sites only ECHO to be performed, if applicable.
g
ECOG performance status to be completed at the end of every 2 cycles on Day 28 during Post-remission and Maintenance (eg, Cycle 2 Day 28, Cycle 4 Day 28, etc.).
h
ENTO will be administered orally  every 12 hours on Days 1-14 as a single agent in Cycle 0 then in combination with IV daunorubicin (Days 1-3) and IV cytarabine (Days 1-7) 
during induction chemotherapy of every 14-day cycle (Cycle 1 and up to Cycle 2).  Subjects are to continue receiving ENTO while awaiting disease assessment results.  
i
Subjects will receive 3-4 cycles of 3g/m2 high dose cytarabine administered every 12 hours on Days 1, 3, and 5 (< 60 years of age) or 1g/m2 cytarabine administered once 
daily on Days 1-5 (≥ 60 years of age) in combination with ENTO  every 12 hours on Days 1-28 during Post-remission chemotherapy.  Subjects continuing to Maintenance 
therapy will receive ENTO monotherapy every 12 hours on Days 1-28 for up to 12 cycles.
j
Include Total CPK at Screening, Cycle 1 and 2 Day 14, every 2 cycles on Day 28 during Post-remission and Maintenance, and End of Study Treatment (see Table 6-1). 
k
Chemistry and hematology is collected every 2 cycles from Cycle 1 Day 28 (eg, Cycle 1 Day 28, Cycle 3 Day 28, etc.) during Post-remission and Maintenance therapy.
l
A negative serum pregnancy test is required for female subjects (unless surgically sterile or menopausal) at Screening. Female subjects with medically documented ovarian 
failure must also have serum FSH levels within the institutional postmenopausal range at Screening.  A urine pregnancy test will be performed for all females on Day 1 of 
each cycle (unless surgically sterile or postmenopausal).
m
Peripheral blood samples for PK will be obtained on Cycle 1 (and 2, if needed) Day 3 at pre-dose, 2 hours, and 4 hours post-dose of ENTO; all other sparse PK samples will 
be obtained at pre-dose and 2 hour post-dose of ENTO.
n
Intensive peripheral blood samples for PK will be obtained on Cycle 1 Day 7 at 0 (predose), 1, 2, 3, 4, 6, 8 and 12 hours post-dose of ENTO.
o
Blood samples for biomarker testing will be obtained on Cycle 0 Days 1, 8, and 14 at pre-dose; Cycle 1 Days 7 and 14 at pre-dose; at time of remission/relapse; End of Study 
Treatment.
CCI


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 126
15 February 2018
p
A bone marrow biopsy will be performed at Screening (within 21 days before the first administration of study treatment), on Cycle 1 Day 14 or at the time of blood count 
recovery, remission/relapse, and End of Study Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker research. If the bone marrow biopsy 
could not be obtained at Screening, diagnostic samples should be used. At all bone marrow biopsy time points, slides for biomarker research and disease assessment will be 
requested from the bone marrow biopsy core. Refer to the most current Covance Lab Manual for collection instructions. If the bone marrow is consistent with Morphologic 
CR or CRi status per Appendix 5, perform cytogenetics, flow cytometry and FISH or PCR for MRD evaluation as per institutional practice and Appendix 7.
q
A bone marrow aspirate will be collected at Screening (within 21 days before the first administration of study treatment), at the end of the monotherapy lead-in period (ie,
Cycle 0 Day 14 or after the minimum 5-days of ENTO), prior to chemotherapy, Cycle 1 Day 14 or at the time of blood count recovery, remission/relapse, and End of Study 
Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker research. Perform FISH analysis on Screening bone marrow aspirate. If the bone 
marrow aspirate could not be obtained at Screening, diagnostic samples should be used. Subjects with cytogenetic and molecular mutations at Screening must have 
cytogenetic and molecular mutation testing repeated at subsequent bone marrow examinations (Cycle 0 Day 14, Cycle 1 Day 14, count recovery, End of Study). A bone 
marrow aspirate will also be collected during Post-remission on Cycle 2 Day 28 and Cycle 4 Day 28 and during Maintenance at the end of every 4 cycles on Day 28 (eg,
Cycle 4 Day 28, Cycle 8 Day 28, etc.) or as clinically indicated for disease assessment and biomarker research (see section 6.6.4).   Subjects who achieve CR/CRi that is 
stable for 2 consecutive bone marrow evaluations are not required to have further bone marrow aspirate samples collected, unless clinically indicated.  Biopsy will be used in 
the event the aspirate cannot be collected or analyzed (eg, dry-tap, hemodiluted specimen, or lack of spicules).  If the bone marrow is consistent with Morphologic CR or CRi 
status per Appendix 5, perform cytogenetics, flow cytometry and FISH or PCR for MRD evaluation as per institutional practice and Appendix 7.
r
Include beta-2 microglobulin at Screening, Cycle 0 Day 14, and induction Cycle 1 (and 2, if needed) Day 28.
s
.
t
Collect hematology (complete blood count) starting at CRi bone marrow until complete blood count demonstrates recovery or 14 days after bone marrow collection date, 
whichever is earlier.
u
X-ray not to be performed for German sites.
CCI


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 127
15 February 2018
Group B: Phase 1b Dose Escalation and Safety Run-in (Entospletinib + decitabine or azacitidine)
Study Phase
Screening
Cycle 0
Entospletinib 
Lead-in
Cycles 1-4 
Entospletinib + 
Hypomethylating 
agent (2-4 cycles)
Entospletinib +
Hypomethylating 
agent Maintenance
(at least 2 cycles)
Entospletinib 
Maintenance
(up to 
12 cycles)
Remission/ 
Relapse
End of 
Study 
Treatment
30-day 
Follow-
up
3-year
Long Term 
Follow-up
Study Day
Screening
1
8
14
1
8
28
1
28
1
28
Window (day)
-14
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
General and Safety 
Assessments
Informed Consent
X
Medical & Medication 
History
X
Adverse Events/
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
IxRS Registration
X
X
X
X
X
X
Smoking statusa
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
X
Height and Weightc
X
X
X
ECG
X
ECHO/MUGAm
X
ECOG Performance 
Status
X
X
X
X
X-rayn
X
Overall survival, 
leukemia treatments, and 
other malignancies
X
(every 
6 months)
Study Treatment
Entospletinib 
Administrationd,e
X
X
X
X
X
X
X
X
X
X
IV decitabined,e
X
X
X


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 128
15 February 2018
Study Phase
Screening
Cycle 0
Entospletinib 
Lead-in
Cycles 1-4 
Entospletinib + 
Hypomethylating 
agent (2-4 cycles)
Entospletinib +
Hypomethylating 
agent Maintenance
(at least 2 cycles)
Entospletinib 
Maintenance
(up to 
12 cycles)
Remission/ 
Relapse
End of 
Study 
Treatment
30-day 
Follow-
up
3-year
Long Term 
Follow-up
Study Day
Screening
1
8
14
1
8
28
1
28
1
28
Window (day)
-14
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
IV/SC azacitidined,e
X
X
Laboratory 
Assessments
Chemistryf
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
Urinalysis
X
Pregnancy Test and 
FSHg
X
X
X
X
X
HIV/HBV/HCV
X
ENTO PKh
X
X
X
X
X
X
X
Biomarkersi
X
X
X
X
X
X
X
Bone Marrow 
Assessments
Biopsyj
X
X
X
X
Aspiratek
X
X
X
X
X
X
X
a
Collect smoking status at Screening and Day 1 of each cycle.  
b
Vital signs include measurement of blood pressure, respiratory rate, pulse, temperature, and oxygen saturation level. 
c
Height and weight will be measured at Screening.  Only weight will be measured on Day 1 of Cycles 1-4 and at End of Study Treatment.
d
ENTO will be administered orally every 12 hours on the following days: Days 1-14 as a single agent in Cycle 0; Days 1-28 in combination with IV decitabine 20mg/m2 on 
Days 1-10 or IV/SC azacitidine 75mg/m2 on Days 1-7 of every 28-day cycle for at least 2 and up to 4 induction cycles (Cycles 1-4); Days 1-28 in combination with IV 
decitabine 20mg/m2 on Days 1-5 or IV/SC azacitidine 75mg/m2 on Days 1-7 of every 28-day cycle for at least 2 cycles (ENTO with decitabine or azacitidine maintenance);
Days 1-28 of every 28-day cycle as a single agent for up to 12 cycles (ENTO monotherapy maintenance).  Subjects enrolled in the safety run-in will only receive ENTO in 
combination with azacitidine during induction and maintenance cycles.  
CCI
CCI


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 129
15 February 2018
e
Subjects who achieve < 5% blasts by morphology and flow cytometry may continue beyond induction to ENTO in combination with decitabine or azacitidine maintenance 
therapy.  After 2 cycles, subjects not eligible for SCT will have the option to continue on ENTO in combination with decitabine or azacitidine maintenance or switch to ENTO
monotherapy maintenance at anytime. Subjects may continue on ENTO in combination with decitabine or azacitidine maintenance therapy as long as the subject is 
experiencing benefit and does not meet criteria for study treatment discontinuation.  Subjects may continue on ENTO monotherapy maintenance therapy for up to 12 cycles as 
long as the subject is experiencing benefit and does not meet criteria for study treatment discontinuation.
f
Include Total CPK at Screening, Cycle 0 Day 14, Day 28 of every cycle, and End of Study Treatment (see Table 6-1). 
g
A negative serum pregnancy test is required for female subjects (unless surgically sterile or menopausal) at Screening. Female subjects with medically documented ovarian 
failure must also have serum FSH levels within the institutional postmenopausal range at Screening.  A urine pregnancy test will be performed for all female subjects on
Day 1 of each cycle (unless surgically sterile or postmenopausal).
h
Peripheral blood samples for PK will be obtained on Cycle 1 Day 8 at pre-dose, 2 hours, and 4 hours post-dose of ENTO; all other PK samples will be obtained at pre-dose 
and 2 hours post-dose of ENTO.
i
Blood samples for biomarker testing will be obtained on Cycle 0 Days 1, 8, and 14 at pre-dose; Cycle 1 Days 8 and 28 at pre-dose; at time of remission/relapse; End of Study 
Treatment. 
j
A bone marrow biopsy will be performed at Screening (within 21 days before the first administration of study treatment), at the end of induction Cycles 2 and 4 on Day 28, 
remission/relapse, and End of Study Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker research. If the bone marrow biopsy could not 
be obtained at Screening, diagnostic samples should be used. At all bone marrow biopsy time points, slides for biomarker research and disease assessment will be requested 
from the bone marrow biopsy core. Refer to the most current Covance Lab Manual for collection instructions. If the bone marrow is consistent with Morphologic CR or CRi 
status per Appendix 5, perform cytogenetics, flow cytometry and FISH or PCR for MRD evaluation as per institutional practice and Appendix 7. If the bone marrow is 
consistent with Morphologic CRi, reassessment of lineages recovery can occur within 14 days of bone marrow assessment.
k
A bone marrow aspirate will be collected at Screening (within 21 days before the first administration of study treatment), Cycle 0 Day 14 (must be prior to start of 
chemotherapy), induction Cycles 2 and 4 on Day 28, remission/relapse, and End of Study Treatment (if not performed within the last 2 weeks) for disease assessment and 
biomarker research. Perform FISH analysis on Screening bone marrow aspirate. If the bone marrow aspirate could not be obtained at Screening, diagnostic samples should be 
used. Subjects with cytogenetic and molecular mutations at Screening must have cytogenetic and molecular mutation testing repeated at subsequent bone marrow 
examinations (Cycle 0 Day 14, Cycle 1 Day 28, count recovery, End of Study). During ENTO + Hypomethylating agent maintenance and ENTO maintenance therapy, a bone 
marrow aspirate will be collected at the end of every 4 cycles on Day 28 (eg, Cycle 4 Day 28, Cycle 8 Day 28, etc.) or as clinically indicated for disease assessment and
biomarker research.  Biopsy will be used in the event the aspirate cannot be collected or analyzed (eg, dry-tap, hemodiluted specimen, or lack of spicules). Subjects who 
achieve CR/CRi that is stable for 2 consecutive bone marrow evaluations are not required to have further bone marrow aspirate samples collected, unless clinically indicated.
If the bone marrow is consistent with Morphologic CR or CRi status per Appendix 5, perform cytogenetics, flow cytometry and FISH or PCR for MRD evaluation as per 
institutional practice and Appendix 7.
l
m
For German sites only ECHO to be performed.
n
X-ray not to be performed for German sites.
CCI


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 130
15 February 2018
Group B: Phase 2 Dose Expansion Randomization (Entospletinib + decitabine or azacitidine)
Study Phase
Screening
Cycle 0
Entospletinib 
Lead-in
Cycles 1-4 
Entospletinib + 
Hypomethylating 
agent
(2-4 cycles)
Entospletinib +
Hypomethylating 
agent Maintenance
(at least 2 cycles)
Entospletinib 
Maintenance
(up to 
12 cycles)
Remission/ 
Relapse
End of 
Study 
Treatment
30-day 
Follow-
up
3-year
Long Term 
Follow-up
Study Day
Screening
1
5
1
8
28
1
28
1
28
Window (day)
-14
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
General and Safety 
Assessments
Informed Consent
X
Medical & Medication 
History
X
Adverse Events/
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
IxRS Registration
X
X
X
X
X
X
Smoking statusa
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
Height and Weightc
X
X
X
ECG
X
ECHO/MUGAm
X
ECOG Performance 
Status
X
X
X
X
X-rayn 
X
Overall survival, 
leukemia treatments, and 
other malignancies
X
(every 
6 months)
Study Treatment
Entospletinib
Administrationd,e
X
X
X
X
X
X
X
X
X
IV decitabined,e
X
X
X


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 131
15 February 2018
Study Phase
Screening
Cycle 0
Entospletinib 
Lead-in
Cycles 1-4 
Entospletinib + 
Hypomethylating 
agent
(2-4 cycles)
Entospletinib +
Hypomethylating 
agent Maintenance
(at least 2 cycles)
Entospletinib 
Maintenance
(up to 
12 cycles)
Remission/ 
Relapse
End of 
Study 
Treatment
30-day 
Follow-
up
3-year
Long Term 
Follow-up
Study Day
Screening
1
5
1
8
28
1
28
1
28
Window (day)
-14
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
IV/SC azacitidined,e
X
X
Laboratory 
Assessments
Chemistryf
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
Urinalysis
X
Pregnancy Test and 
FSHg
X
X
X
X
X
HIV/HBV/HCV
X
ENTO PKh
X
X
X
X
X
X
Biomarkersi
X
X
X
X
X
X
Bone Marrow 
Assessments
Biopsyj
X
X
X
X
Aspiratek
X
X
X
X
X
X
X
a
Collect smoking status at Screening and Day 1 of each cycle.  
b
Vital signs include measurement of blood pressure, respiratory rate, pulse, temperature, and oxygen saturation level. 
c
Height and weight will be measured at Screening.  Only weight will be measured on Day 1 of Cycles 1-4 and at End of Study Treatment.
d
ENTO will be administered orally every 12 hours on the following days: Days 1-5 as a single agent in Cycle 0; Days 1-28 in combination with IV decitabine 20mg/m2 on 
Days 1-10 or IV/SC azacitidine 75mg/m2 on Days 1-7 of every 28-day cycle for at least 2 and up to 4 induction cycles (Cycles 1-4); Days 1-28 in combination with IV 
decitabine 20mg/m2 on Days 1-5 or IV/SC azacitidine 75mg/m2 on Days 1-7 of every 28-day cycle for at least 2 cycles (ENTO with decitabine or azacitidine maintenance); 
Days 1-28 of every 28-day cycle as a single agent for up to 12 cycles (ENTO monotherapy maintenance).
CCI
CCI


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 132
15 February 2018
e
Subjects who achieve < 5% blasts by morphology and flow cytometry may continue beyond induction to ENTO in combination with decitabine or azacitidine maintenance 
therapy.  After 2 cycles, subjects not eligible for SCT will have the option to continue on ENTO in combination with decitabine or azacitidine maintenance or switch to ENTO 
monotherapy maintenance at anytime. Subjects may continue on ENTO in combination with decitabine or azacitidine maintenance therapy as long as the subject is
experiencing benefit and does not meet criteria for study treatment discontinuation.  Subjects may continue on ENTO monotherapy maintenance therapy for up to 12 cycles as 
long as the subject is experiencing benefit and does not meet criteria for study treatment discontinuation.
f
Include Total CPK at Screening, Cycle 0 Day 5, Day 28 of every cycle, and End of Study Treatment (see Table 6-1). 
g
A negative serum pregnancy test is required for female subjects (unless surgically sterile or menopausal) at Screening. Female subjects with medically documented ovarian 
failure must also have serum FSH levels within the institutional postmenopausal range at Screening.  A urine pregnancy test will be performed for all female subjects on 
Day 1 of each cycle (unless surgically sterile or postmenopausal).
h
Peripheral blood samples for PK will be obtained on Cycle 1 Day 8 at pre-dose, 2 hours, and 4 hours post-dose of ENTO; all other PK samples will be obtained at pre-dose 
and 2 hours post-dose of ENTO.
i
Blood samples for biomarker testing will be obtained on Cycle 0 Days 1 and 5 at pre-dose; Cycle 1 Days 8 and 28 at pre-dose; at time of remission/relapse; End of Study 
Treatment. 
j
A bone marrow biopsy will be performed at Screening (within 21 days before the first administration of study treatment), at the end of induction Cycles 2 and 4 on Day 28, 
remission/relapse, and End of Study Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker research. If the bone marrow biopsy could not 
be obtained at Screening, diagnostic samples should be used. At all bone marrow biopsy time points, slides for biomarker research and disease assessment will be requested 
from the bone marrow biopsy core. Refer to the most current Covance Lab Manual for collection instructions. If the bone marrow is consistent with Morphologic CR or CRi 
status per Appendix 5, perform cytogenetics, flow cytometry and FISH or PCR for MRD evaluation as per institutional practice and Appendix 7. If the bone marrow is 
consistent with Morphologic CRi, reassessment of lineages recovery can occur within 14 days of bone marrow assessment.
k
A bone marrow aspirate will be collected at Screening (within 21 days before the first administration of study treatment), Cycle 0 Day 5 if circulating blasts have cleared,
induction Cycles 2 and 4 on Day 28, remission/relapse, and End of Study Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker research. 
Perform FISH analysis on Screening bone marrow aspirate. If the bone marrow aspirate could not be obtained at Screening, diagnostic samples should be used. Subjects with 
cytogenetic and molecular mutations at Screening must have cytogenetic and molecular mutation testing repeated at subsequent bone marrow examinations (Cycle 0 Day 5, 
Cycle 1 Day 28, count recovery, End of Study). During ENTO + Hypomethylating agent maintenance and ENTO maintenance therapy, a bone marrow aspirate will be 
collected at the end of every 4 cycles on Day 28 (eg Cycle 4 Day 28, Cycle 8 Day 28, etc.) or as clinically indicated for disease assessment and biomarker research.  Biopsy 
will be used in the event the aspirate cannot be collected or analyzed (eg dry-tap, hemodiluted specimen, or lack of spicules). Subjects who achieve CR/CRi that is stable for 
2 consecutive bone marrow evaluations are not required to have further bone marrow aspirate samples collected, unless clinically indicated. If the bone marrow is consistent 
with Morphologic CR or CRi status per Appendix 5, perform cytogenetics, flow cytometry and FISH or PCR for MRD evaluation as per institutional practice and 
Appendix 7.
l
.
m
For German sites only ECHO to be performed. 
n
X-ray not to be performed for German sites.
CCI


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 133
15 February 2018
Group C: Phase 1b Dose Escalation (Entospletinib Monotherapy)
Study Phase
Screening
Cycle 1
Subsequent Cycles
Remission/
Relapse
End of Study 
Treatment
30 Day
Follow-Up
3-year
Long Term
Follow-up
Study Day
Screening
1
8
14
28
1
28
Window (day) 
-14
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
General and Safety 
Assessments
Informed Consent
X
Medical & Medication 
History
X
Adverse Events/
Concomitant Medications
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
Vital Signsa
X
X
X
X
X
X
X
Height and Weightb
X
X
X
X
ECG
X
ECHO/MUGAk
X
ECOG Performance Status
X
X
X
X
X
X-rayl
X
Overall survival, leukemia 
treatments, and other 
malignancies
X
(every 6 months)
Study Treatment
Entospletinib Administrationc
X
X
X
X
X
X
Laboratory Assessments
Chemistryd
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
Urinalysis
X
Pregnancy Test and FSHe
X
X
X
HIV/HBV/HCV
X


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 134
15 February 2018
Study Phase
Screening
Cycle 1
Subsequent Cycles
Remission/
Relapse
End of Study 
Treatment
30 Day
Follow-Up
3-year
Long Term
Follow-up
Study Day
Screening
1
8
14
28
1
28
Window (day) 
-14
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
Bone Marrow Assessments
Biopsyf
X
X
X
X
X
Aspirateg
X
X
X
X
X
PKh
X
X
X
X
Biomarkersi
X
X
X
X
X
X
Pharmacodynamics (BAT 
assay)j
X
X
X
X
X
X
a
Vital signs include measurement of blood pressure, respiratory rate, pulse, temperature, and oxygen saturation level.
b
Height and weight will be measured at Screening.  Only weight will be measured on Day 1 of each cycle and at End of Study Treatment.  
c
ENTO monotherapy will be administered orally every 12 hours for every 28-day cycle
d
Include Total CPK at Screening, Day 28 of every cycle, and End of Study Treatment (see Table 6-1). 
e
A negative serum pregnancy test is required for female subjects (unless surgically sterile or menopausal) at Screening, and a negative urine test is required on Cycle 1 Day 1 
prior to dose. Female subjects with medically documented ovarian failure must also have serum FSH levels within the institutional postmenopausal range.  A urine pregnancy 
test will be performed for all female subjects on Day 1 of each subsequent cycle (unless surgically sterile or menopausal).
f
A bone marrow biopsy will be performed at Screening (within 21 days before the first administration of study treatment), at the end of Cycles 1 and 2, remission/relapse, and 
End of Study Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker research. If the bone marrow biopsy could not be obtained at 
Screening, diagnostic samples should be used. At all bone marrow biopsy time points, slides for biomarker research and disease assessment will be requested from the bone 
marrow biopsy core. Refer to the most current Covance Lab Manual for collection instructions. If the bone marrow is consistent with Morphologic CR or CRi status per 
Appendix 5, perform cytogenetics, flow cytometry and FISH or PCR for MRD evaluation as per institutional practice and Appendix 7.
g
A bone marrow aspirate will be collected at Screening (within 21 days before the first administration of study treatment), at the end of Cycles 1 and 2, remission/relapse, and 
End of Study Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker research. Perform FISH analysis on Screening bone marrow aspirate.
If the bone marrow aspirate could not be obtained at Screening, diagnostic samples should be used. A bone marrow aspirate will also be collected every 4 cycles on Day 28 
starting on Cycle 4 Day 28 of subsequent cycles (eg, Cycle 4 Day 28, Cycle 8 Day 28) or as clinically indicated for disease assessment  and biomarker research (see 
section 6.6.4).    Subjects who achieve CR/CRi that is stable for 2 consecutive bone marrow evaluations are not required to have further bone marrow aspirate samples 
collected, unless clinically indicated. Biopsy will be used in the event the aspirate is not collectable or analyzable. If the bone marrow is consistent with Morphologic CR or 
CRi status per Appendix 5, perform cytogenetics, flow cytometry and FISH or PCR for MRD evaluation as per institutional practice and Appendix 7.
h
Peripheral blood samples for PK will be obtained on Cycle 1 Days 1, 8, 14 and 28 at pre-dose and 2hrs post-dose of ENTO. 
i
Blood samples for biomarker testing will be obtained on Cycle 1 Days 1, 8, 14, and 28 at pre-dose; at time of remission/relapse; End of Study Treatment.
j
To be collected only for subjects dosed with 400 mg and 800 mg ENTO during phase 1b. Peripheral blood samples for pharmacodynamics (BAT Assay) will be obtained on 
Cycle 1 Days 1, 8, 14 and 28 at pre-dose and 2hrs post-dose of ENTO and may be collected at pre-dose on Day 28 of subsequent cycles and at End of Study Treatment.
k
For German sites only ECHO to be performed.
l
X-ray not to be performed for German sites.
CCI


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 135
15 February 2018
Group C: Phase 2 Dose Expansion (Entospletinib Monotherapy)
Study Phase
Screening
Cycle 1
Subsequent 
Cycles
Remission/ 
Relapse
End of Study 
Treatment
30 Day 
Follow-Up
3-year
Long Term
Follow-up
Study Day
Screening
1
5
8
14
28
1
28
Window (day)
-14
±2
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
General and Safety 
Assessments
Informed Consent
X
Medical & Medication 
History
X
Adverse Events/
Concomitant Medications
X
X
X
X
X
X
X
X
X
IxRS Registration
X
X
X
X
Smoking statusa
X
X
X
Physical Exam
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
Height and Weightc
X
X
X
X
ECG
X
ECHO/MUGAl
X
ECOG Performance Status
X
X
X
X
X
X-raym
X
Overall survival, leukemia 
treatments, and other 
malignancies
X
(every 
6 months)
Study Treatment
Entospletinib 
Administrationd
X
X
X
X
X
X
X
Laboratory Assessments
Chemistrye
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
Urinalysis
X
Pregnancy Test and FSHf
X
X
X
HIV/HBV/HCV
X


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 136
15 February 2018
Study Phase
Screening
Cycle 1
Subsequent 
Cycles
Remission/ 
Relapse
End of Study 
Treatment
30 Day 
Follow-Up
3-year
Long Term
Follow-up
Study Day
Screening
1
5
8
14
28
1
28
Window (day)
-14
±2
±2
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
ENTO PKg
X
X
X
X
X
Biomarkersh
X
X
X
X
X
X
Bone Marrow 
Assessments
Biopsyi
X
X
X
X
X
Aspiratej
X
X
X
X
X
a
Collect smoking status at Screening and Day 1 of each cycle.  
b
Vital signs include measurement of blood pressure, respiratory rate, pulse, temperature, and oxygen saturation level.
c
Height and weight will be measured at Screening.  Only weight will be measured on Day 1 of each cycle and at End of Study Treatment.  
d
ENTO will be administered orally every 12 hours on Days 1-28 for every 28-day cycle as long as the subject is experiencing benefit and does not meet criteria for study 
treatment discontinuation..
e
Include Total CPK at Screening, Day 28 of every cycle, and End of Study Treatment (see Table 6-1). 
f
A negative serum pregnancy test is required for female subjects (unless surgically sterile or menopausal) at Screening, and a negative urine pregnancy test is required on 
Cycle 1 Day 1 prior to dose. Female subjects with medically documented ovarian failure must also have serum FSH levels within the institutional postmenopausal range at 
Screening. Urine pregnancy tests will be performed for all female subjects on Day 1 of each subsequent cycle (unless surgically sterile or menopausal).
g
Peripheral blood samples for PK will be obtained on Cycle 1 Days 1, 8, 14 and 28, and Day 28 of subsequent cycles at pre-dose and 2hrs post-dose of ENTO.
h
Blood samples for biomarker testing will be obtained on Cycle 1 Days 1, 8, 14, and 28 at pre-dose; at time of remission/relapse; End of Study Treatment. 
i
A bone marrow biopsy will be performed at Screening (within 21 days before the first administration of study treatment), at the end of Cycles 1 and 2 on Day 28, 
remission/relapse, and End of Study Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker research. If the bone marrow biopsy could not 
be obtained at Screening, diagnostic samples should be used. At all bone marrow biopsy time points, slides for biomarker research and disease assessment will be requested 
from the bone marrow biopsy core. Refer to the most current Covance Lab Manual for collection instructions. If the bone marrow is consistent with Morphologic CR or CRi 
status per Appendix 5, perform cytogenetics, flow cytometry and FISH or PCR for MRD evaluation as per institutional practice and Appendix 7. If the bone marrow is 
consistent with Morphologic CRi, reassessment of lineages recovery can occur within 7 to 14 days of bone marrow assessment.
j
A bone marrow aspirate will be collected at Screening (within 21 days before the first administration of study treatment), at the end of Cycles 1 and 2 on Day 28, 
remission/relapse, and End of Study Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker research. Perform FISH analysis on Screening 
bone marrow aspirate. If the bone marrow aspirate could not be obtained at Screening, diagnostic samples should be used. A bone marrow aspirate will also be collected on
Day 28 of every 4 cycles beginning on Cycle 4 Day 28 of subsequent cycles (eg, Cycle 4 Day 28, Cycle 8 Day 28) for disease assessment  and biomarker research (see 
Section 6.6.4) or as clinically indicated.  Subjects who achieve CR/CRi that is stable for 2 consecutive bone marrow evaluations are not required to have further bone marrow 
aspirate samples collected, unless clinically indicated.  Biopsy will be used in the event the aspirate cannot be collected or analyzed. If the bone marrow is consistent with 
Morphologic CR or CRi status per Appendix 5, perform cytogenetics, flow cytometry and FISH or PCR for MRD evaluation as per institutional practice and Appendix 7. 
k
.
l
For German sites only ECHO to be performed.
m
X-ray not to be performed for German sites.
CCI
CCI
CCI


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 137
15 February 2018
Appendix 3.
Management of Clinical and Laboratory Adverse Events
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Dermatological
Maintain current 
dose level and 
schedule.
Maintain current dose 
level and schedule.
Withhold dosing until 
≤ Grade 1.  Resume 
dosing at current dose 
level. If re-challenge 
at current dose level 
results in recurrence, 
may resume dosing at 
same or lower dose 
level at investigator 
discretion.
Withhold dosing 
until Grade < 1
May resume at 
lower dose level or 
discontinue dosing 
at investigator 
discretion.
Gastrointestinal 
Inflammation-
Diarrhea
Provide 
anti-diarrheal per PI 
discretion 
(eg, loperamide) and 
maintain current 
dose level and 
schedule
Provide anti-diarrheal
per PI discretion (eg, 
loperamide). 
Withhold dosing until 
Grade < 1. Resume 
dosing at current dose 
level.
If re-challenge results 
in recurrence, may 
resume at initial or 
lower dose level at 
investigator 
discretion.
Consider addition of 
anti-inflammatory 
(eg, sulfasalazine, 
budesonide).
Provide anti-diarrheal 
per PI discretion (eg, 
loperamide). 
Withhold dosing until 
Grade < 1. Resume at 
lower dose level.
Consider addition of 
anti-inflammatory 
(eg, sulfasalazine, 
budesonide).
Provide 
anti-diarrheal per PI 
discretion 
(eg, loperamide). 
Withhold dosing 
until Grade < 1. May 
resume at lower 
dose level or 
discontinue dosing 
at investigator 
discretion.
Consider addition of 
anti-inflammatory 
(eg, sulfasalazine, 
budesonide).
Hepatic
(elevations in ALT, 
AST, or bilirubin)
ALT/AST<3xULN)
(Direct Bilirubin
<1.5xULN)
(ALT/AST
>3-5xULN)
(Direct Bilirubin
>1.5-<3xULN)
Withhold dosing. 
Monitor ALT, AST, 
ALP, and direct 
bilirubin at least 
1x per week until all 
abnormalities are 
Grade < 1.
Withhold dosing. 
Monitor ALT, AST, 
ALP, and direct 
bilirubin at least 
1x per week until all 
abnormalities are 
Grade < 1
Maintain current 
dose level and 
schedule
Maintain current dose 
level and schedule
If direct bilirubin was 
Grade < 3, resume 
dosing at same dose 
level. If direct 
bilirubin was 
Grade > 3, resume at 
lower dose level.
If direct bilirubin 
was Grade <4, 
resume dosing at 
lower dose level. If 
direct bilirubin was 
Grade 4, discontinue 
dosing.


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 138
15 February 2018
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Pneumonitis 
(dyspnea, cough, 
hypoxia and/or 
diffuse interstitial 
pattern or 
ground-glass 
opacities on chest 
CT and no obvious 
infectious cause)
Maintain current 
dose level and 
schedule. Consider 
Pneumocystis 
therapy
Withhold dosing until 
Grade < 1.
Consider systemic 
corticosteroids and 
Pneumocystis 
treatment.
May resume at initial 
or lower dose level at 
investigator 
discretion.
Withhold dosing until 
Grade < 1.
May resume dosing 
at initial or lower 
dose level or 
discontinue dosing at 
investigator 
discretion.
Discontinue study 
treatment
Other Study Drug 
Related, Non 
hematological 
Adverse Events
Maintain current 
dose level and 
schedule
Maintain current dose 
level and schedule
Withhold dosing until 
Grade < 1.
May resume dosing 
at initial or lower 
dose level or 
discontinue dosing at 
investigator 
discretion
Withhold dosing 
until Grade < 1.
May resume dosing 
at initial or lower 
dose level or 
discontinue dosing 
at investigator 
discretion


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 139
15 February 2018
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered 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 the risks of treatment with ENTO during pregnancy 
have not been evaluated. 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 
Screening and negative urine pregnancy test on Cycle 0 Day 1 (Cycle 1 Day 1 for Group C) prior 
to dosing.  Pregnancy tests will be performed at 28 day intervals thereafter until the end of study 
treatment.  Female subjects must agree to one of the following from Screening until 30 days 
following the end of relevant systemic exposure or as recommended in the prescribing 
information for other co-administered study drugs (whichever is later).

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual lifestyle.
Or


Entospletinib
Protocol GS-US-339-1559
Final
Gilead Sciences, Inc.
Amendment 7
CONFIDENTIAL
Page 140
15 February 2018

Consistent and correct use of one of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of < 1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure or as recommended in the 
prescribing information for other co-administered study drugs (whichever is later).
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 90 days after the 
end of relevant systemic exposure or as recommended in the prescribing information for other 
co-administered study drugs (whichever is later). Additional contraception recommendations 
should also be considered if the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the end of relevant systemic exposure or as recommended in the prescribing information for 
other co-administered study drugs (whichever is later).
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM).  Female condom and male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
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 7.6.2.1.


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Appendix 5.
International Working Group Criteria for AML {Cheson 2003}
Assessment of clinical response will be made according to the International Working Group 
criteria {Cheson 2003}. The major criteria for judging response will include physical 
examination and examination of blood and bone marrow. All laboratory studies that are 
abnormal prior to study will be repeated to document the degree of maximal response.
Early Treatment Assessment (ETA)

Evaluation is made at approximately 7-10 days after completing the last dose of the initial 
course of treatment (ie, Group A Cycle 1 Day 14)

Guides subsequent treatment (eg, need for or timing of second induction course)
Morphologic Leukemia-free State (MLFS)
MLFS requires all of the following:

< 5% blasts in bone marrow aspirate

No extramedullary disease

No blasts with Auer rods detected
Morphologic Complete Remission (CR)
CR requires all of the following:

< 5% blasts in bone marrow aspirate

Neutrophils ≥ 1,000/µL

Platelets ≥ 100,000/µL

No extramedullary disease

No blasts with Auer rods detected

Independent of transfusions
Cytogenetic Complete Remission (CRc)
CRc requires all of the following:

< 5% blasts in bone marrow aspirate

Neutrophils ≥ 1,000/µL


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
Platelets ≥ 100,000/µL

No extramedullary disease

No blasts with Auer rods detected

Independent of transfusions

Reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis
Morphologic CR with incomplete blood count recovery (CRi)
CRi requires all of the following:

< 5% blasts in bone marrow aspirate

Neutrophils < 1,000/µL or Platelets < 100,000/µL

No extramedullary disease

No blasts with Auer rods detected
If blood counts recover within 14 days of a bone marrow evaluation that is consistent with CRi, 
the patient will be considered CR at the time when both neutrophil and platelet count recover
(neutrophils ≥ 1,000/µL, platelets  ≥ 100,000/µL). 
Partial Remission (PR)
PR requires all of the following:

≥ 50% decrease in blasts in bone marrow aspirate to a range of 5-25%

Neutrophils ≥ 1,000/µL

Platelets ≥ 100,000/µL

Independent of transfusions

A value of ≤ 5% blasts may also be considered a PR if Auer rods are detected
Treatment Failure (TF)
Treatment failure will be classified as one of the following:

Resistant disease: Failure to achieve a complete remission (CR, CRc, or CRi) or partial 
remission.  Patients who survive ≥ 7 days following completion of initial treatment, with 
evidence of persistent leukemia by blood and/or bone marrow examination.


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
Death in Aplasia: Patients who survive ≥ 7 days following completion of initial treatment, 
but die while cytopenic, with an aplastic or hypoplastic marrow obtained within 7 days of 
death, without evidence of persistent leukemia

Death from Indeterminate cause: Patients who die before completion of treatment or < 7 days 
following completion of initial treatment; patients who die ≥ 7 days following completion of 
initial treatment with no peripheral blood blasts, but no bone marrow examination is 
available; patients who fail to complete the first cycle of therapy
Relapse
Relapse is defined as:

Evidence of morphologic relapse with the reappearance of leukemic blasts in the peripheral 
blood, blasts with Auer rods, ≥ 5% blasts in the bone marrow, or evidence of extramedullary 
disease not attributable to any other cause. In the setting of recent treatment, if there are no 
circulating blasts and the bone marrow contains 5-20% blasts, a bone marrow biopsy should 
be repeated within 1 week to distinguish relapse from bone marrow regeneration.  

The reappearance of cytologically proven extramedullary disease also indicates relapse. 
Reappearance of a cytogenetic abnormality is considered a cytogenetic relapse.  Evidence of 
bone marrow morphologic involvement or extramedullary disease required.  


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Appendix 6.
Performance Scales: Karnofsky & ECOG Scores {Oken 1982}
Karnofsky Status
Karnofsky 
Grade
ECOG 
Grade
ECOG Status
Normal, no complaints
100
0
Fully active, able to carry on all pre-disease 
performance without restriction
Able to carry on normal 
activities. Minor signs or 
symptoms of disease
90
0
Fully active, able to carry on all pre-disease 
performance without restriction
Normal activity with effort
80
1
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light 
or sedentary nature, eg, light house work, 
office work
Care for self. Unable to carry on 
normal activity or to do active 
work
70
1
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light 
or sedentary nature, eg, light house work, 
office work
Requires occasional assistance, 
but able to care for most of his 
needs
60
2
Ambulatory and capable of all selfcare but unable 
to carry out any work activities. Up and about 
more than 50% of waking hours
Requires considerable assistance 
and frequent medical care
50
2
Ambulatory and capable of all selfcare but unable 
to carry out any work activities. Up and about 
more than 50% of waking hours
Disabled. Requires special care 
and assistance
40
3
Capable of only limited selfcare, confined to bed 
or chair more than 50% of waking hours
Severly disabled. Hospitalisation 
indicated though death 
nonimminent
30
3
Capable of only limited selfcare, confined to bed 
or chair more than 50% of waking hours
Very sick. Hospitalisation 
necessary. Active supportive 
treatment necessary
20
4
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair
Moribund
10
4
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair
Dead
0
5
Dead


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Appendix 7.
Minimal Residual Disease (MRD) Level Definition {Sanchez-Garcia 
2013}
MRD Level (by flow cytometry)
% of Leukemia Cells
No Measurable
≤ 0.01
Low
> 0.01 and ≤0.1
Intermediate
> 0.1 and ≤ 1
High
> 1


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Appendix 8.
2017 European Leukemia Network (ELN) Risk Stratification by 
Geneticsa {Dohner 2017}
Risk Category
Genetic Abnormality
Favorable
t(8;21)(q22;q22.1); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow(c)
Biallelic mutated CEBPA
Intermediate
Mutated NPM1 and FLT3-ITDhigh(c)
Wild type NPM1 without FLT3-ITD or with FLT3-ITDlow(c) (w/o
adverse risk genetic lesions)
t(9;11)(p21.3;q23.3); MLLT3-KMT2Ad
Cytogenetic abnormalities not classified as favorable or adverse
Adverse
t(6;9)(p23;q34.1); DEK-NUP214
t(v;11q23.3); KMT2A rearranged
t(9;22)(q34.1;q11.2); BCR-ABL1
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)
-5 or del(5q); -7; -17/abn(17p)
Complex karyotype,e monosomal karyotypef
Wild type NPM1 and FLT3-ITDhigh(c)
Mutated RUNX1g
Mutated ASXL1g
Mutated TP53h
a
Frequencies, response rates and outcome measures should be reported by risk category, and, if sufficient numbers are
available, by specific genetic lesions indicated.
b
Prognostic impact of a marker is treatment-dependent and may change with new therapies.
c
Low, low allelic ratio (<0.5); high, high allelic ratio (>0.5); semi-quantitative assessment of FLT3-ITD allelic ratio (using 
DNAfragment analysis) is determined as ratio of the area under the curve (AUC) “FLT3-ITD” divided by AUC “FLT3-wild 
type”;recent studies indicate that acute myeloid leukemia with NPM1 mutation and FLT3-ITD low allelic ratio may also 
have a more favorable prognosis and patients should not routinely be assigned to allogeneic hematopoietic-cell 
transplantation.
d
The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations.
e
Three or more unrelated chromosome abnormalities in the absence of one of the World Health Organization-designated
recurring translocations or inversions, ie, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); AML
with BCR-ABL1.
f
Defined by the presence of one single monosomy (excluding loss of X or Y) in association with at least one additional
monosomy or structural chromosome abnormality (excluding core-binding factor AML).
g
These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML subtypes.
h
TP53 mutations are significantly associated with AML with complex and monosomal karyotype.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 1b/2 Study of Entospletinib (GS-9973) 
Monotherapy and in Combination with Chemotherapy in 
Patients with Acute Myeloid Leukemia (AML)
Name of Test Drug:
Entospletinib (GS-9973)
Study Number:
GS-US-339-1559
Protocol Version:
Amendment 7
Protocol Date:
15 February 2018
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
19 June 2019
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF ABBREVIATIONS........................................................................................................................................5
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Design............................................................................................................................................8
1.3.
Sample Size and Power..........................................................................................................................14
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................16
2.1.
Interim Analysis.....................................................................................................................................16
2.2.
Final Analysis ........................................................................................................................................16
2.3.
Follow-up Analysis ................................................................................................................................16
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................17
3.1.
Analysis Sets..........................................................................................................................................17
3.1.1.
All Enrolled Analysis Set.....................................................................................................17
3.1.2.
All Randomized Analysis Set...............................................................................................17
3.1.3.
Full Analysis Set ..................................................................................................................17
3.1.4.
Safety Analysis Set...............................................................................................................18
3.1.5.
DLT Analysis Set.................................................................................................................18
3.1.6.
Pharmacokinetic Analysis Set..............................................................................................18
3.2.
Subject Grouping ...................................................................................................................................19
3.3.
Strata and Covariates..............................................................................................................................21
3.4.
Examination of Subject Subgroups........................................................................................................21
3.5.
Multiple Comparisons............................................................................................................................23
3.6.
Missing Data and Outliers......................................................................................................................23
3.6.1.
Missing Data ........................................................................................................................23
3.6.2.
Outliers.................................................................................................................................23
3.7.
Data Handling Conventions and Transformations .................................................................................23
3.8.
Analysis Visit Windows.........................................................................................................................24
3.8.1.
Definition of Baseline and Study Day..................................................................................24
3.8.2.
Analysis Visit Windows.......................................................................................................25
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................25
4.
SUBJECT DISPOSITION ..................................................................................................................................27
4.1.
Subject Enrollment and Disposition.......................................................................................................27
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................29
4.2.1.
Exposure to ENTO...............................................................................................................29
4.2.2.
Adherence to ENTO.............................................................................................................29
4.2.3.
Exposure to Chemotherapy ..................................................................................................30
4.3.
Protocol Deviations................................................................................................................................30
5.
BASELINE CHARACTERISTICS....................................................................................................................32
5.1.
Demographics ........................................................................................................................................32
5.2.
Other Baseline Characteristics ...............................................................................................................32
5.3.
Medical History......................................................................................................................................32
5.4.
Prior Anticancer Therapy.......................................................................................................................33
6.
EFFICACY ANALYSES ...................................................................................................................................34
6.1.
Primary Efficacy Endpoints ...................................................................................................................34


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6.1.1.
Definition of the Primary Efficacy Endpoints......................................................................34
6.1.2.
Analysis of the Primary Efficacy Endpoints ........................................................................34
6.2.
Secondary Efficacy Endpoints ...............................................................................................................37
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................37
6.2.2.
Analysis of the Secondary Endpoints...................................................................................37
6.3.
Exploratory Efficacy Endpoints.............................................................................................................39
6.3.1.
Definition of the Exploratory Efficacy Endpoints................................................................39
6.3.2.
Analysis of the Exploratory Efficacy Endpoints ..................................................................40
6.4.
Other Efficacy Measures........................................................................................................................43
6.5.
Changes From Protocol-Specified Efficacy Analyses............................................................................43
7.
SAFETY ANALYSES........................................................................................................................................44
7.1.
Adverse Events and Deaths....................................................................................................................44
7.1.1.
Adverse Event Dictionary ....................................................................................................44
7.1.2.
Adverse Event Severity........................................................................................................44
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................44
7.1.4.
Serious Adverse Events........................................................................................................44
7.1.5.
Treatment-Emergent Adverse Events...................................................................................45
7.1.5.1.
Definition of Treatment-Emergent Adverse Events .......................................45
7.1.5.2.
Incomplete Dates ............................................................................................45
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................45
7.1.6.1.
Summaries of AE Incidence by Severity........................................................45
7.1.6.2.
Summary of Deaths ........................................................................................47
7.1.7.
Dose Limiting Toxicity ........................................................................................................47
7.2.
Laboratory Evaluations ..........................................................................................................................47
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................48
7.2.2.
Graded Laboratory Values ...................................................................................................48
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities.............................................48
7.2.2.2.
Summaries of Laboratory Abnormalities........................................................48
7.2.3.
Shift in CTCAE Grade Relative to Baseline ........................................................................49
7.2.4.
Graphics of Numeric Laboratory Results.............................................................................49
7.3.
Body Weight and Vital Signs.................................................................................................................49
7.4.
Prior and Concomitant Medications.......................................................................................................50
7.4.1.
Prior Medications .................................................................................................................50
7.4.2.
Concomitant Medications.....................................................................................................50
7.5.
Electrocardiogram Results .....................................................................................................................51
7.6.
Other Safety Measures ...........................................................................................................................51
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................52
8.
PHARMACOKINETIC (PK) ANALYSES........................................................................................................53
8.1.
PK Sample Collection............................................................................................................................53
8.2.
ENTO Plasma Concentrations Analysis.................................................................................................54
8.3.
Statistical Analysis Methods ..................................................................................................................54
9.
BIOMARKER ANALYSES...............................................................................................................................55
10.
REFERENCES ...................................................................................................................................................56
11.
SOFTWARE.......................................................................................................................................................57
12.
APPENDICES ....................................................................................................................................................58
Appendix 1.
List of FAB/WHO Classification Subtypes............................................................................59
Appendix 2.
List of Conditioning Regimen ................................................................................................60


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LIST OF TABLES
Table 1-1.
Treatment Groups/Cohorts .......................................................................................................9
Table 1-2.
Exact 90% CIs of Composite Complete Remission Rate for a Cohort Size of 40 in 
Group A..................................................................................................................................14
Table 1-3.
Exact 90% CIs of Composite Complete Remission Rate for a Cohort Size of 30 in 
Subjects with Previously Untreated AML (Unfit for Group A or B) .....................................15
Table 3-1.
Analysis Sets ..........................................................................................................................19
Table 3-2.
Column Headers of the Summary Tables...............................................................................20
Table 3-3.
Pooled Analyses of Group C ..................................................................................................21
Table 6-1.
Event/Censoring Rules for EFS..............................................................................................37
Table 6-2.
Event/Censoring Rules for RFS .............................................................................................41
LIST OF FIGURES
Figure 1-1.
Study Schema...........................................................................................................................8


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LIST OF ABBREVIATIONS
7+3
cytarabine and daunorubicin chemotherapy
AE
adverse event
ATC
Anatomical Therapeutic Chemical
AML
acute myeloid leukemia
BID
bis in die (twice a day)
BLQ
below the limit of quantitation
BMI
body mass index
BM-MNCs
bone marrow mononuclear cells
CI
confidence interval
CR
complete remission
CRc
cytogenetic complete remission
CRF
case report form
CRi
morphologic CR with incomplete blood count recovery
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EFS
event free survival
ELN
European LeukemiaNet
ENTO
Entospletinib, GS-9973
EOS
end of study
ETA
early treatment assessment
FAB
French-American-British
FISH
fluorescent in situ hybridization
HLT
high-level term
HOXA9
Homeobox A9
ID
identification
IWRS
Interactive Web Response System
IV
intravenous
KM
Kaplan-Meier
LLT
lower-level term
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MEIS1
Myeloid Ecotropic Viral Integration Site 1
MLFS
morphologic leukemia free state
MLL
mixed lineage leukemia
MRD
minimal residual disease
MTD
maximum tolerated dose


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OS
overall survival
PK
pharmacokinetic(s)
PR
partial remission
PT
preferred term
Q1
first quartile
Q3
third quartile
RFS
relapse - free survival
R/R
relapsed/refractory
SAP
statistical analysis plan
SAE
serious adverse event
SCT
stem cell transplant
SOC
system organ class
StD
standard deviation
TEAE
treatment-emergent adverse event
TF
treatment failure
TFLs
tables, figures, and listings
WBC
white blood cell
WHO
World Health Organization


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-339-1559. This SAP is based on the study protocol amendment 7 dated 
15 February 2018 and the electronic case report form (eCRF). This study was intended to 
evaluate the efficacy, safety, and tolerability of entospletinib (ENTO) in subjects with Acute 
Myeloid Leukemia (AML). Due to the lack of responses to ENTO monotherapy and the evolving 
treatment landscape for AML, the recruitment of Group B Phase 2 was permanently closed prior 
to the planned sample size being reached. The enrollments of other treatment groups/cohorts 
were either completed or terminated, and, as such, this study will be terminated early. The SAP 
will be finalized before database finalization. Any changes made after the finalization of the SAP 
will be documented in the CSR.
1.1.
Study Objectives
The primary objectives of this study are as follows:

To demonstrate the overall safety of ENTO in combination with standard dose cytarabine 
and daunorubicin chemotherapy (7+3) in subjects with previously untreated AML who are 
candidates for chemotherapy (fit subjects) and to assess the efficacy of ENTO at the 
recommended Phase 2 dose (RP2D) (Group A)

To demonstrate the overall safety of ENTO in combination with hypomethylating agents 
(decitabine or azacitidine) in subjects with previously untreated AML who are not candidates
for 7+3 (unfit subjects) and to assess the efficacy of ENTO at the RP2D (Group B)

To demonstrate the overall safety of ENTO monotherapy in subjects with previously 
untreated AML who are not candidates for chemotherapy or in subjects with 
relapsed/refractory (R/R) AML with or without mixed-lineage leukemia (MLL) and to assess 
the efficacy of ENTO at the RP2D (Group C)
The secondary objectives of this study are as follows: 

To assess the qualitative and quantitative toxicities of ENTO monotherapy or ENTO in 
combination with chemotherapy in subjects with AML

To document therapeutic response of subjects with AML treated with ENTO monotherapy or
ENTO in combination with chemotherapy 
The exploratory objective of this study is as follows:

 
CCI


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1.2.
Study Design
This is a Phase 1b/2 study evaluating the efficacy, safety, and tolerability of ENTO in subjects 
with AML. Subjects with AML will be dosed using a 3 + 3 design for the dose escalation phase. 
During the dose escalation phase, ENTO will be administered at a dose of 200 mg and 400 mg 
every 12 hours either in combination with chemotherapy for Group A or with a hypomethylating 
agent for Group B. ENTO will be administered at a dose of 400 mg and 800 mg every 12 hours 
as monotherapy for Group C.
Following completion of the dose escalation phase, the sponsor in consultation with the 
coordinating center has selected ENTO at a dose level of 400 mg every 12 hours for all dose 
expansion cohorts. 
Figure 1-1.
Study Schema


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Table 1-1.
Treatment Groups/Cohorts
Treatment Group/Cohort
Treatment
Primary Objective
Group A Phase 1b 
(Dose Escalation)
ENTO + Daunorubicin + 
Cytarabine
(ENTO: 200 and 400 mg)
To determine maximum tolerated dose (MTD)
and to demonstrate the overall safety of ENTO 
+ Daunorubicin + Cytarabine in subjects with 
previously untreated AML
Group A Phase 2 
(Dose Expansion)
ENTO + Daunorubicin + 
Cytarabine
(ENTO: 400 mg)
To assess the efficacy of ENTO + 
Daunorubicin + Cytarabine in subjects with 
previously untreated AML
Group B Phase 1b
(Dose Escalation)
ENTO + Decitabine 
(ENTO: 200 and 400 mg)
To determine MTD and to demonstrate the 
overall safety of ENTO + Decitabine in 
subjects with previously untreated AML
Group B Phase 2 Safety Run-in
ENTO + Azacitidine 
(ENTO: 400 mg)
To demonstrate the overall safety of ENTO + 
Azacitidine in subjects with previously 
untreated AML
Group B Phase 2 
Randomization
(Dose Expansion)
ENTO + Decitabine
vs.
ENTO + Azacitidine
(ENTO: 400 mg)
To assess the efficacy of ENTO + Decitabine
or Azacitidine in subjects with previously 
untreated AML
Group C Phase 1b
(Dose Escalation)
ENTO Monotherapy
(ENTO: 400 and 800 mg)
To determine MTD and to demonstrate the 
overall safety of ENTO monotherapy in 
subjects with R/R AML or previously untreated 
AML but unfit for Group A or B
Group C Phase 2 Cohort 1A
(Dose Expansion)
ENTO Monotherapy
(ENTO: 400 mg)
To assess the efficacy of ENTO monotherapy 
in subjects with R/R AML
Group C Phase 2 Cohort C2
(Dose Expansion)
ENTO Monotherapy
(ENTO: 400 mg)
To assess the efficacy of ENTO monotherapy 
in subjects with R/R AML with MLL gene 
rearrangement
Group C Phase 2 Cohort C3
(Dose Expansion)
ENTO Monotherapy
(ENTO: 400 mg)
To assess the efficacy of ENTO monotherapy 
in subjects with previously untreated AML and
unfit for Group A or B
Group A Phase 1b (Dose Escalation)
Note: At the time of amendment 7, Group A Phase 1b had completed enrollment.
ENTO will be administered at 2 dose levels for Group A during the dose escalation phase 
(see table below); the initial dosing level for the 1st cohort is defined as level 0.
Intra-subject dose escalation will not be allowed.


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Group A Entospletinib Dose Escalation Table
Dose Level
Entospletinib
Daunorubicin
Cytarabine
0
200 mg
60mg/m2
100mg/m2
1
400 mg
ENTO will be administered orally every 12 hours as a monotherapy lead-in on 
Days 1-14 (Cycle 0) and will be administered orally every 12 hours in combination with 
cytarabine (Days 1-7) and intravenous (IV) daunorubicin (Days 1-3) during induction 
chemotherapy for up to two 14-day cycles (Cycles 1 and 2). Subjects with residual disease 
detected at the Cycle 1 Day 14 bone marrow evaluation will proceed with Cycle 2 of induction 
chemotherapy.
A bone marrow aspirate will be collected at Screening, Cycle 1 Day 14 (and Cycle 2, if needed) 
or at the time of blood count recovery (whichever comes first), remission/relapse, and End of 
Study Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker 
research.
Group A Phase 2 (Dose Expansion)
Note: At the time of amendment 7, Group A Phase 2 had completed enrollment.
Similar to Phase 1b, in Phase 2, ENTO 400 mg will be administered first as a 14-day lead-in 
monotherapy followed by ENTO in combination with 7+3 induction chemotherapy. 
Post-remission chemotherapy will be offered to subjects who achieve complete remission 
(CR)/ morphologic CR with incomplete blood count recovery (CRi) and do not require or cannot 
proceed to allogeneic stem cell transplantation (SCT). In addition, subjects who are awaiting a 
donor or transitioning to allogeneic SCT are allowed to receive post-remission chemotherapy per 
investigator discretion. Subjects who continue to maintain a CR/CRi after 3 or 4 cycles of 
post-remission chemotherapy will be offered maintenance therapy with ENTO 400 mg every 
12 hours for up to 12 cycles. Extension of maintenance therapy may occur on an individual basis 
if approved by the Principal Investigator. 
A bone marrow aspirate will be collected at Screening, at the end of the monotherapy lead-in 
period (ie, Cycle 0 Day 14 or after the minimum 5-days of ENTO) and prior to chemotherapy, 
Cycle 1 Day 14 (and Cycle 2, if needed) or at the time of blood count recovery, 
remission/relapse, and End of Study Treatment (if not performed within the last 2 weeks) for 
disease assessment and biomarker research. A bone marrow aspirate will also be collected during 
Post-remission on Cycle 2 Day 28 and Cycle 4 Day 28 and during Maintenance at the end of 
every 4 cycles on Day 28 (eg, Cycle 4 Day 28, Cycle 8 Day 28, etc.) or as clinically indicated for 
disease assessment and biomarker research. Subjects who achieve CR/CRi that is stable for 
2 consecutive bone marrow evaluations are not required to have further bone marrow aspirate 
samples collected, unless clinically indicated. 


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Group B Phase 1b (Dose Escalation)
Note: At the time of amendment 7, Group B Phase 1b had completed enrollment.
ENTO will be administered at 2 dose levels for Group B during the dose escalation phase 
(see table below); the initial dosing level for the 1st cohort is defined as level 0. Intra-subject dose 
escalation will not be allowed.
Group B Entospletinib Dose Escalation Table
Dose Level
Entospletinib
Decitabine
0
200 mg
20 mg/m2
1
400 mg
ENTO will be administered orally every 12 hours as a monotherapy lead-in on Days 1-14 
(Cycle 0) and will be administered orally every 12 hours on Days 1-28 in combination with 
decitabine on Days 1-10 of every 28-day cycle for at least 2 but no more than 4 cycles of 
induction chemotherapy. Subject will undergo a bone marrow aspiration and biopsy on Cycle 2 
Day 28.  Subjects who have a CR/CRi can proceed to SCT per investigator’s discretion or to 
maintenance therapy with ENTO + decitabine. Subjects with persistent AML will receive 2 more 
cycles of induction chemotherapy and a bone marrow aspiration and biopsy will be performed at 
Cycle 4 Day 28.  Subjects who have persistent leukemia at this time point will be considered a 
treatment failure and come off study. Subjects ineligible for SCT will have the option to receive 
maintenance therapy with ENTO + decitabine. Subjects who are intolerant of decitabine after 
completing 2 cycles will switch to ENTO monotherapy maintenance. Maintenance will continue 
as long as the subject experiences benefit and does not meet criteria for study treatment 
discontinuation. Extension of maintenance may occur on an individual basis if approved by the 
Principal Investigator.
A bone marrow aspirate will be collected at Screening, Cycle 0 Day 14 (must be prior to start of
chemotherapy), induction Cycles 2 and 4 on Day 28, remission/relapse, and End of Study 
Treatment (if not performed within the last 2 weeks) for disease assessment and biomarker 
research. During ENTO + Hypomethylating agent maintenance and ENTO maintenance therapy, 
a bone marrow aspirate will be collected at the end of every 4 cycles on Day 28 (eg, Cycle 4 Day 
28, Cycle 8 Day 28, etc.) or as clinically indicated for disease assessment and biomarker 
research. Subjects who achieve CR/CRi that is stable for 2 consecutive bone marrow evaluations 
are not required to have further bone marrow aspirate samples collected, unless clinically 
indicated.
Group B Phase 2 (Dose Expansion)
Note: At the time of amendment 7, Group B Phase 2 safety run-in had completed enrollment. 


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In Phase 2, the overall safety of ENTO in combination with a hypomethylating agent (decitabine 
or azacitidine) will be evaluated. As part of the safety run-in, ENTO in combination with 
azacitidine will be administered to 6 evaluable subjects. Following completion of the safety 
run-in (dose limiting toxicity (DLT) window), the azacitidine arm will be evaluated to determine 
if enrollment of the expansion cohort may proceed with azacitidine. If 2 or more subjects 
experience DLTs, all ongoing subjects in the safety run-in will be discontinued, the azacitidine 
arm will be dropped from the study, and subjects in the expansion phase will only receive ENTO 
in combination with decitabine.
If Phase 2 proceeds with an azacitidine arm, subjects will be randomized to receive ENTO in 
combination with either decitabine (Days 1-10) or azacitidine (Days 1-7) of every 28-day cycle 
for at least 2 but no more than 4 cycles of induction chemotherapy. Randomization will be 
stratified by age (≤ 75 or > 75 years) and by white blood cell (WBC) count (≤ 5,000/μL or 
> 5,000/μL). If subjects are not eligible for SCT after 2 cycles of induction, subjects will have the 
option to receive maintenance therapy with ENTO in combination with decitabine (Days 1-5) or 
azacitidine (Days 1-7). Subjects who are intolerant of the hypomethylating agent after 
completing 2 cycles may switch to ENTO monotherapy maintenance. Maintenance may continue 
as long as the subject is experiencing benefit and does not meet the criteria for study treatment 
discontinuation. Extension of maintenance may occur on an individual basis if approved by the 
Principal Investigator. 
A bone marrow aspirate will be collected at Screening, Cycle 0 Day 5 if circulating blasts have 
cleared, induction Cycles 2 and 4 on Day 28, remission/relapse, and End of Study Treatment 
(if not performed within the last 2 weeks) for disease assessment and biomarker research. During 
ENTO + Hypomethylating agent maintenance and ENTO maintenance therapy, a bone marrow 
aspirate will be collected at the end of every 4 cycles on Day 28 (eg Cycle 4 Day 28, Cycle 8 
Day 28, etc.) or as clinically indicated for disease assessment and biomarker research. Subjects 
who achieve CR/CRi that is stable for 2 consecutive bone marrow evaluations are not required to 
have further bone marrow aspirate samples collected, unless clinically indicated. 
Group C Phase 1b (Dose Escalation)
Note: At the time of amendment 7, Group C Phase 1b had completed enrollment.
ENTO will be administered at 2 dose levels for Group C during the dose escalation phase 
(see table below); the initial dosing level for the 1st cohort is defined as level 0. 
Intra-subject dose escalation will not be allowed.
Group C ENTO Dose Escalation Table
Dose Level
ENTO
0
400 mg
1
800 mg


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A bone marrow aspirate will be collected at Screening, at the end of Cycles 1 and 2, 
remission/relapse, and End of Study Treatment (if not performed within the last 2 weeks) for 
disease assessment and biomarker research. A bone marrow aspirate will also be collected every 
4 cycles on Day 28 starting on Cycle 4 Day 28 of subsequent cycles (eg, Cycle 4 Day 28, Cycle 
8 Day 28) or as clinically indicated for disease assessment and biomarker research. Subjects who 
achieve CR/CRi that is stable for 2 consecutive bone marrow evaluations are not required to 
have further bone marrow aspirate samples collected, unless clinically indicated. 
Group C Phase 2 (Dose Expansion)
R/R and previously untreated subjects will be evaluated in separate cohorts during Phase 2 with 
ENTO monotherapy. ENTO 400 mg will be administered orally every 12 hours on Days 1-28 of 
every 28-day cycle as long as the subject is experiencing benefit and does not meet criteria for 
study treatment discontinuation. 
A bone marrow aspirate will be collected at Screening, at the end of Cycles 1 and 2 on Day 28,
remission/relapse, and End of Study Treatment (if not performed within the last 2 weeks) for 
disease assessment and biomarker research. A bone marrow aspirate will also be collected on
Day 28 of every 4 cycles beginning on Cycle 4 Day 28 of subsequent cycles (eg, Cycle 4 
Day 28, Cycle 8 Day 28) for disease assessment and biomarker research or as clinically 
indicated. Subjects who achieve CR/CRi that is stable for 2 consecutive bone marrow 
evaluations are not required to have further bone marrow aspirate samples collected, unless 
clinically indicated.
Cohort C1A: This cohort is designed to enroll 6 R/R AML subjects first. Nine Group C Phase 
1b subjects who were R/R AML and received at least 21 days of ENTO (400 mg or 800 mg) and 
Cohort C1A subjects will be pooled to provide an adequate sample size (n=15) for the following 
futility analysis for subjects with R/R AML. If 5 or more of the initial 15 subjects achieve 
CR/CRi after 1-2 cycles, an additional 15 subjects will be enrolled. However, if less than 5 of the 
initial 15 subjects achieve CR/CRi after 1-2 cycles, then treatment would be considered futile. At 
the time of amendment 7, futility has been met and, thus, Cohort C1A will not move forward 
(ie, will not enroll any subjects).
Cohort C2: This cohort is designed to enroll 15 subjects with R/R AML subjects with MLL 
gene rearrangement.
Cohort C3: This cohort is designed to enroll 27 previously untreated AML subjects who are 
unfit (eg, very elderly, have multiple comorbidities, and a poor Eastern Cooperative Oncology 
Group (ECOG) performance status) for chemotherapy or hypomethylating agent, or refuse either 
of these 2 treatment options. Three Group C Phase 1b subjects who were previously untreated
AML, unfit for Group A or B, and received at least 21 days of ENTO (400 mg or 800 mg), and 
Cohort C3 subjects will be pooled to provide an adequate sample size (n=30) for the efficacy 
analysis for subjects with previously untreated AML and unfit for Group A or B. Amendment 7
identifies early enrollment closure of this cohort. 


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The study procedures for all treatment groups/cohorts are presented in Appendix 2 of the study
protocol.
1.3.
Sample Size and Power
Sequential dose-escalation is consistent with usual oncologic paradigms for dose ranging. The 
intent is to limit the number of subjects who are exposed to excessively toxic doses of a drug in 
an early phase evaluation of an anticancer agent. The trial employs the standard National Cancer 
Institute (NCI) definition of MTD (starting dose associated with DLT in <33.3% of subjects 
during the DLT assessment window) to determine dose escalation. The cohort size and 
dose-escalation rules establish a low probability of increasing the dose if the true rate of DLT is 
high while there is a high likelihood of escalating or proceeding to the next cohort of the study if 
the true underlying probability of DLT is low. For example, if the true underlying probability of 
DLT is low (eg, ≤10%) at the current dose level, there is a high probability (≥0.91) of dose 
escalation to the next dose level. Conversely, if the true underlying proportion of DLT is high 
(eg, ≥60%) at the current dose level, there is a low probability (≤0.08) of escalation to the next 
dose level.
In Phase 1b, each group will enroll up to 12 subjects, assuming 2 planned dose levels for 
escalation are tested with up to 6 subjects per level. Assuming 10% of the subjects are 
unevaluable during dose escalation, up to 14 subjects may be enrolled in each group for a total of 
up to 42 subjects. In Group B, an additional 6 subjects will be enrolled to evaluate the safety of 
ENTO in combination with azacitidine prior to the dose expansion. 
In the Group A Phase 2, approximately an additional 40 subjects will be enrolled. Table 1-2
provides the 90% confidence interval (CI) of 40 subjects for the assumed composite complete
remission rate. This sample size ensures a narrow CI (~ 7-14% distance from the point 
estimates). The complete remission rate of standard chemotherapy (7+3) has been reported as 
52% in the CALGB study of over 1000 subjects.
Table 1-2.
Exact 90% CIs of Composite Complete Remission Rate for a Cohort 
Size of 40 in Group A
Assumed Composite Complete Remission Rate of Entospletinib + 7+3
Exact 90% CI
70%
(56% – 82%)
80%
(67% – 90%)
90%
(79% – 97%)


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In the Group B Phase 2, approximately 40 additional subjects will be randomized in a 
1:1 manner to either treatment arm ENTO + decitabine or ENTO + azacitidine. Randomization 
will be stratified by age (≤ 75 years or > 75 years) and WBC (≤ 5,000/uL or > 5,000/uL).
Assuming a composite complete remission rate of 50% for both treatment arms, the 90% CI 
would be 30% to 70% with a sample size of 20. The composite complete remission rate of 
standard chemotherapy is reported as 20% to 30%. Evaluation between the treatment arms will 
be based on the totality of clinical data.  
Approximately 63 additional subjects will be enrolled in Group C dose expansion. 
A total of 15 initial subjects, including 9 subjects in Group C Phase 1b who were R/R AML and 
received at least 21 days of ENTO (400 mg or 800 mg) and 6 subjects in Cohort C1A, will be 
pooled for evaluation of futility in subjects with R/R AML. An additional 15 subjects will be 
enrolled if greater or equal to 5 (out of 15) CR/CRi are observed. This futility boundary will 
provide a high chance (84%) of early stopping of the trial if the composite complete remission 
rate is undesirable (20%) and a low chance (22%) of early stopping if the composite complete 
remission rate is clinically meaningful (40%). 
The sample size is 15 for Cohort C2. This sample size is based on practical considerations. The 
sample size is 30 for previously untreated AML (unfit for Group A or B), including 3 subjects in 
Group C Phase 1b who were previously untreated AML, unfit for Group A or B, and received at 
least 21 days of ENTO (400 mg or 800 mg), and 27 subjects in Cohort C3, which will provide 
adequate precision of efficacy estimates. Table 1-3 provides the 90% CI of 30 subjects for the 
assumed composite complete remission rate.  
Table 1-3.
Exact 90% CIs of Composite Complete Remission Rate for a Cohort 
Size of 30 in Subjects with Previously Untreated AML (Unfit for 
Group A or B)
Assumed Composite Complete Remission Rate of ENTO Monotherapy in 
Subjects with Previously Untreated AML (Unfit for Group A or B)
Exact 90% CI
30%
(17% – 47%)
50%
(34% – 66%)
70%
(53% – 83%)
Therefore, a total of approximately 54 subjects (including 14 in Phase 1b and 40 in Phase 2) in 
Group A, approximately 60 subjects (including 14 in Phase 1b, 6 in the safety run-in of 
ENTO + azacitidine, and 40 in Phase 2) in Group B, and approximately 77 subjects (including 14 
in Phase 1b and 63 in Phase 2) in Group C will be enrolled for the duration of the study.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analysis
No formal interim analysis is planned.
2.2.
Final Analysis
After all subjects have discontinued/completed the study, outstanding data queries have been 
resolved or adjudicated as unresolvable, and the data have been cleaned and finalized, the final 
analysis of the data will be performed.
2.3.
Follow-up Analysis
No follow-up analysis is planned.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (StD) or standard error (SE), median, first 
quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Enrolled Analysis Set or All 
Randomized Analysis Set. Data collected on log forms, such as adverse events (AEs), will be 
presented in chronological order within the subject. The treatment group to which subjects were 
randomized or initially assigned will be used in the listings.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
For each analysis set, the number and percentage of subjects eligible for inclusion will be 
summarized by treatment group, phase, and dose level, treatment arm, or cohort if applicable, as 
elaborated in Table 3-2 in Section 3.2.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all subjects who received a study subject identification 
number in the study after screening and were not screen failures.
The All Enrolled Analysis Set will be used for by-subject listings for all treatment groups/cohorts 
except for Group B Phase 2 randomization.
3.1.2.
All Randomized Analysis Set
All Randomized Analysis Set includes all subjects in Group B Phase 2 who were randomized. 
The Randomized Analysis Set will be used for by-subject listings for Group B Phase 2 
randomization.
3.1.3.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who received at least 1 dose of study drug with 
treatment designated according to the planned treatment. 
This analysis set will be used in the analyses of subject characteristics and efficacy.


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3.1.4.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. This
analysis set will be used for safety analyses.
3.1.5.
DLT Analysis Set
The DLT assessment window for each group is as follows:

Group A Phase 1b: begins on Cycle 0 Day 1 and ends 28 days from Cycle 1 Day 1 or 28 days 
from Cycle 2 Day 1 (if Cycle 2 is needed); for subjects with < 5% blasts in the bone marrow,
the DLT window may be expanded for hematologic toxicity recovery as noted in Section 3.2
of the study protocol

Group B Phase 1b/Phase 2 Safety Run-in: begins on Cycle 0 Day 1 and ends 28 days from 
Cycle 1 Day 1

Group C Phase 1b: 28 days (Cycle 1); for subjects with < 5% blasts in the bone marrow the 
DLT window may be expanded for hematologic toxicity recovery as noted in Section 3.2 of 
the study protocol
The DLT Analysis Set includes all subjects in the Safety Analysis Set who 

received 21 days of ENTO (applicable to all groups) and all doses of cytarabine and 
daunorubicin in Group A Phase 1b, decitabine in Group B Phase 1b, or azacitidine in Group 
B Phase 2 safety run-in during the DLT assessment window; or

experienced a DLT during the DLT assessment window.
Subjects who expired prior to the end of DLT assessment window without experiencing a DLT 
will be considered not evaluable for DLT.
The DLT Analysis Set will be used for analyses related to DLT.
3.1.6.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set includes all enrolled/randomized subjects who took at 
least 1 dose of study drug and have at least 1 nonmissing postdose concentration value reported 
by the PK laboratory. This is the primary analysis set for all PK analyses. 
Table 3-1 summarizes the applicable treatment group(s)/cohort(s) for each analysis set.


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Table 3-1.
Analysis Sets
Analysis Set
Treatment Group/Cohort
All Enrolled Analysis Set
Group A Phase 1 and Phase 2
Group B Phase 1b and Phase 2 Safety Run-in
Group C Phase 1b and Phase 2 Cohort 1A/C2/C3
All Randomized Analysis Set
Group B Phase 2 Randomization
FAS
All Treatment Groups/Cohorts
Safety Analysis Set
All Treatment Groups/Cohorts
DLT Analysis Set
Group A Phase 1b
Group B Phase 1b and Phase 2 Safety Run-in
Group C Phase 1b
PK Analysis Set
All Treatment Groups/Cohorts
3.2.
Subject Grouping
For analyses based on the FAS, subjects will be grouped according to the treatment to which 
they were assigned or randomized: 

For the dose escalation of each treatment group, subjects will be grouped according to the 
ENTO dose level first received.

For all dose expansion cohorts, all the subjects were assigned to a dose level of 400 mg.

For Group B Phase 2 randomization, subjects will be grouped according to the treatment to 
which they were randomized. 
For analyses based on the Safety Analysis Set and the PK Analysis Set, subjects will be grouped 
according to the actual treatment received. The actual treatment received will differ from the 
assigned/randomized treatment only when their actual treatment differs from 
assigned/randomized treatment for the entire treatment duration.
As all treated subjects in this study received the assigned/randomized treatment, the FAS will be 
the same as the Safety Analysis Set for all treatment groups/cohorts.
Table 3-2 shows the column headers of the summary tables for all treatment groups/cohorts.
Column “Total” is not applicable to the efficacy summary tables for Group B Phase 2 
randomization and Group C Phase 2.


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Table 3-2.
Column Headers of the Summary Tables
Treatment Group/Cohort
Column Header
Group A Phase 1b
Dose Level 0
200 mg BID
Dose Level 1
400 mg BID
Total
Group A Phase 2
Dose Level 1
400 mg BID
Group A (Phase 1b + Phase 
2)
Dose Level 0
200 mg BID
Dose Level 1
400 mg BID
Total
Group B Phase 1b
Dose Level 0
200 mg BID
Dose Level 1
400 mg BID
Total
Group B Phase 2 Safety 
Run-in
Dose Level 1
400 mg BID
Group B Phase 2 
Randomization
ENTO (400 mg) + 
Decitabine
ENTO (400 mg) + 
Azacitidine
Total
Group C Phase 1b
Dose Level 0
400 mg BID
Dose Level 1
800 mg BID
Total
Group C Phase 2
Cohort C1A
ENTO (400 mg BID)
Cohort C2
ENTO (400 mg BID)
Cohort C3
ENTO (400 mg BID)
Total
Group C (Phase 1b + 
Phase 2)
Dose Level 0
400 mg BID
Dose Level 1
800 mg BID
Total
In addition, in Group C, Phase 1b subjects who meet the following criteria will be pooled with 
Phase 2 Cohort C1A or Cohort C3 as described in Section 1.2:

Pooled analysis (1): Group C Phase 1b subjects who were R/R AML and received at least 
21 days of ENTO (400 mg or 800 mg) and Group C Phase 2 Cohort C1A (400 mg) will be 
pooled to provide an adequate sample size for futility analysis for subjects with R/R AML.

Pooled analysis (2): Group C Phase 1b subjects who were previously untreated AML, unfit 
for Group A or B, and received at least 21 days of ENTO (400 mg or 800 mg), and Group C 
Phase 2 Cohort C3 will be pooled to provide an adequate sample size for efficacy analyses 
for subjects with previously untreated AML and unfit for Group A or B.
Only efficacy analyses will be done for the pooled Group C cohorts. Summary will be based on 
FAS.
Table 3-3 presents the titles and column headers of the summary tables for the pooled analyses of 
Group C.


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Table 3-3.
Pooled Analyses of Group C
Pooled Analysis
Title
Column Header
(1)
Pooled Analysis of Group C 
Phase 1b and Phase 2 of 
Cohort C1A (All Doses) in 
R/R AML
Dose Level 0
400 mg BID
Dose Level 1
800 mg BID
Total
(2)
Pooled Analysis of Group C 
Phase 1b and Phase 2 of
Cohort C3 (All Doses) in 
Untreated AML
Dose Level 0
400 mg BID
Dose Level 1
800 mg BID
Total
3.3.
Strata and Covariates
In Group B Phase 2 randomization, approximately 40 subjects were planned to be randomly 
assigned to treatment arm ENTO + decitabine or ENTO + azacitidine via the interactive web 
response system (IWRS) in a 1:1 ratio using a stratified randomization schedule. Stratification 
will be based on the following variables:

Age: ≤ 75 years vs > 75 years

WBC: ≤ 5,000/uL vs > 5,000/uL
Here age will be calculated as (date of randomization – date of birth+1) / 365.25. Subject with 
age at randomization ≤ 75 years or > 75 years will be assigned to “Age ≤ 75 years” or 
“Age > 75 years” respectively.
If there are discrepancies in the value used for stratification assignment between the IWRS and 
the clinical database, the value collected in the clinical database will be used for the summary. 
No covariates will be included in the efficacy analyses.
3.4.
Examination of Subject Subgroups
Primary efficacy endpoints will be examined in the following subgroups:

Age (applicable to Groups A and C)
< 60 years
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
Age (applicable to Group B)
≤ 75 years
> 75 years

European LeukemiaNet (ELN) Risk Group
Favorable
Intermediate-I
Intermediate-II
Adverse

Age and ELN risk group (applicable to Group A)

AML Type
De novo AML
Secondary AML
Note that the CRF didn’t collect AML type directly and this will be derived from the AML 
subtype collected in the CRF Form “Staging”. Subject with the WHO classification subtype 
“AML with myelodysplasia-related changes” will be considered as “Secondary AML”. 
Subjects with other WHO classification subtypes as well as all the French-American-British 
(FAB) classification subtypes will be considered as “De novo AML”. See Appendix 1 for the 
list of FAS and WHO classification subtypes. 

MLL
With MLL
Without MLL

FLT3-ITD Mutation (applicable to Groups A and B)
FLT3-ITD+
FLT3-ITD-


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
NPM1 Mutation (applicable to Groups A and B)
NPM1+
NPM1-
For Group B Phase 2 randomization cohort, subgrouping of subjects based on randomization 
stratification factors will be explored for subgroup analyses as well.
3.5.
Multiple Comparisons
Not applicable.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for disease diagnosis is described in Section 5.3, for 
SCT and new anticancer therapy in Section 6.1.2, for death in Section 6.2.2, for AE onset in 
Section 7.1.5.2, and for prior and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:

If only month and year of birth is collected, then “15” will be imputed as the day of birth

If only year of birth is collected, then “01 July” will be imputed as the day and month of birth

If year of birth is missing, then date of birth will not be imputed


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In general, age collected at Day 1 (the first dosing date of study drug) (in years) will be used for 
analyses and presented in listings. If age at Day 1 is not available for a subject, then age derived 
based on date of birth and the Day 1 visit date will be used instead. If an enrolled subject was not 
dosed with any study drug, the randomization or enrollment date will be used instead of the Day 
1 visit date. For screen failures, the date the first informed consent was signed will be used for 
the age derivation. Age required for longitudinal and temporal calculations and analyses 
(eg, estimates of creatinine clearance, age at date of AE) will be based on age derived from date 
of birth and the date of the measurement or event, unless otherwise specified.
Non-PK 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 to calculate descriptive statistics if the 
datum is reported in the form of “x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤x” or “≥x” (where x is considered the LOQ).
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data or nonparametric analysis methods may be used, 
as appropriate.
Sparse PK concentration values that are below the limit of quantitation (BLQ) will be presented 
as “BLQ” in the data listing.
3.8.
Analysis Visit Windows
3.8.1.
Definition of Baseline and Study Day
Baseline is defined as the last observation prior to the first dose of study drug, unless otherwise 
specified.  
Study Day 1 is defined as the day of first dose of study drug. Study day will be calculated from 
the first dosing date of study drug and derived as follows:

For post-dose study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date


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3.8.2.
Analysis Visit Windows
The nominal visit as recorded on the CRF will be used when data are summarized by visit. Any 
data relating to unscheduled visits will not be assigned to a particular visit or time point. 
However, the following exceptions will be made:

An unscheduled visit prior to the first dosing of study drug may be included in the calculation 
of the baseline value, if applicable.

Unscheduled visits after the first dosing of study drug will be included in determining the 
maximum postbaseline toxicity grade.

The analysis window for Morphologic Leukemia-free State (MLFS) rate at Cycle 1 Day 14 is 
defined as Cycle 1 Day 1 + 13 (± 2) days.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing, continuous measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

For baseline, if there are multiple measurements with the same time or no time recorded on 
the same day, the average of these measurements (for continuous data) will be used.

For postbaseline values:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.


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If multiple valid, nonmissing, categorical measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

For baseline, if there are multiple records with the same time or no time recorded on the same 
day, the value with the lowest severity will be selected (eg, normal will be selected over 
abnormal for safety electrocardiogram [ECG] findings).

For postbaseline visits, if there are multiple records with the same time or no time recorded 
on the same day, the value with the worst severity within the window will be selected 
(eg, abnormal will be selected over normal for safety ECG findings).


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by treatment group, phase, and dose level, 
treatment arm, or cohort if applicable, as elaborated in Table 3-2 in Section 3.2, for each 
investigator within a country. The summary will present the number and percentage of subjects 
enrolled. For each column, the denominator for the percentage calculation will be the total 
number of subjects analyzed for that column.
A similar enrollment table will be provided by randomization stratum for Group B Phase 2 
randomization. If there are discrepancies in the value used for stratification assignment between 
the IWRS and the clinical database, the value collected in the clinical database will be used for 
the summary. A listing of subjects with discrepancies in the value used for stratification 
assignment between the IWRS and the clinical database at the time of data finalization will be 
provided.
The randomization schedule used for Group B Phase 2 randomization will be provided as an 
appendix to the CSR.
A summary of subject disposition will be provided by treatment group, phase, and dose level, 
treatment arm, or cohort if applicable, as elaborated in Table 3-2 in Section 3.2. This summary 
will present the number of subjects enrolled/randomized, and the number of subjects in each of 
the categories listed below:

Full Analysis Set

Safety Analysis Set

Not Treated with ENTO
Treated with ENTO
Completed ENTO dosing as specified per protocol 
Prematurely discontinued ENTO with reasons

Not Treated with cytarabine (applicable to Group A only)
Treated with cytarabine (applicable to Group A only)
Completed cytarabine dosing as specified per protocol
Prematurely discontinued cytarabine with reasons


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
Not Treated with daunorubicin (applicable to Group A only)
Treated with daunorubicin (applicable to Group A only)
Completed daunorubicin dosing as specified per protocol
Prematurely discontinued daunorubicin with reasons

Not Treated with decitabine or azacitidine (applicable to Group B only)
Treated with decitabine or azacitidine (applicable to Group B only)
Completed decitabine or azacitidine dosing as specified per protocol
Prematurely discontinued decitabine or azacitidine with reasons

Study Completion Status
Completed the protocol-planned duration of the study 
Prematurely discontinued study with reasons
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the All Enrolled Analysis Set or All 
Randomized Analysis Set corresponding to that column. A summary of subject disposition with 
all treatment groups combined will also be provided, presenting the number of subjects screened, 
the number of subjects enrolled/randomized, the number of subjects in the FAS, the number of 
subjects in the Safety Analysis Set, and the number of subjects in different study completion 
statuses. In addition, flowcharts will be provided to depict the disposition.
The following by-subject listings will be provided by subject identification (ID) number in 
ascending order to support the above summary tables:

Reasons for discontinuing study treatment or study

Reasons for screen failure (will be provided by screening ID number in ascending order)

Lot number
Listings of ID numbers of the subjects who will be included in the pooled analyses of Group C 
will be provided.


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4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
ENTO, the number of treatment cycles, the level of adherence to ENTO, and the number of 
doses of chemotherapy if applicable. The following analyses will be presented by treatment 
group, phase, and dose level, treatment arm, or cohort if applicable, as elaborated in Table 3-2 in 
Section 3.2. Summaries will be provided for the Safety Analysis Set.
4.2.1.
Exposure to ENTO
Total duration of exposure to ENTO will be defined as (last dosing date of ENTO - first dosing
date of ENTO + 1), regardless of temporary interruptions in ENTO administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). If the last study drug dosing date 
is missing, the latest date among the study drug end date, clinical visit date, laboratory sample 
collection date, and vital signs assessment date that occurred during the on-treatment period will 
be used.
The total duration of exposure to ENTO will be summarized using descriptive statistics and 
using the number and percentage of subjects exposed for at least 1 day, 14 days, and 1, 2, 3, 6, 9, 
12, and 15 months (if appropriate). 
The number of induction cycles for Groups A and B and the number of cycles for Group C will 
be summarized using descriptive statistics. The number and percentage of subjects exposed to a 
given cycle category for induction therapy for Groups A and B, ENTO monotherapy for Group 
C, post-remission therapy for Group A Phase 2, and ENTO + Hypomethylating agent 
maintenance for Group B will be presented. The number and percentage of subjects who 
received ENTO monotherapy maintenance will also be summarized for Groups A and B.
The number and percentage of subjects who had dose reduction will be summarized.
4.2.2.
Adherence to ENTO
The presumed total number of doses administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:
Total Number of Doses Administered =
No. of Doses Dispensed
No. of Doses Returned

















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The level of on-treatment adherence to the study drug regimen will be determined by the total 
amount of study drug administered relative to the total amount of study drug expected to be 
administered during a subject’s actual on-treatment period based on the study drug regimen. 
Investigator-prescribed interruption and reductions as specified in the protocol will be taken into 
account. If there are treatment periods that bottles are not returned or the return information is 
missing, these periods will be excluded from the on-treatment adherence calculation for both 
total amount of study drug administered and study drug expected to be administered. If subjects 
never returned any bottle, the adherence will be set as missing.
The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Total Amount of Study Drug Administered
On-Treatment Adherence (%) = 
 x 100
Study Drug Expected to be Administered on Treatment






Descriptive statistics for the level of on-treatment adherence to ENTO with the number and 
percentage of subjects belonging to adherence categories (eg, < 75%, ≥ 75%) will be provided.
No formal statistical testing is planned.
By-subject listings of ENTO administration and accountability will be provided separately by 
subject ID number and visit (in chronological order).
4.2.3.
Exposure to Chemotherapy
The exposure to each of the chemotherapies will be summarized by the number of doses received 
using descriptive statistics. The number and percentage of subjects for each distinct number of 
doses will be provided.
By-subject listings of chemotherapy administration will be provided.
4.3.
Protocol Deviations
Subjects who did not meet the eligibility criteria for study entry, but enrolled in the study will be 
summarized regardless of whether they were exempted by the sponsor or not. The summary will 
present the number and percentage of subjects who did not meet at least 1 eligibility criterion and 
the number of subjects who did not meet specific criteria based on the All Enrolled Analysis Set
or All Randomized Analysis Set. A by-subject listing will be provided for those subjects who did 
not meet at least 1 eligibility (inclusion or exclusion) criterion. The listing will present the 
eligibility criterion (or criteria if more than 1 deviation) that subjects did not meet and related 
comments, if collected.


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Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation categories will be summarized for the All Enrolled Analysis Set or All Randomized 
Analysis Set. The deviation categories are as follows:

IC=Informed consent 

EN=Eligibility Criteria

XM=Excluded concomitant medication 

NW=Not withdrawn, despite meeting withdrawal criteria

TA=Wrong treatment or incorrect dose

TC=Other treatment compliance issue

OS=Off schedule procedure

MD=Missing data

OT=Other
A by-subject listing will be provided for those subjects with important protocol deviation.


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5.
BASELINE CHARACTERISTICS
The following analyses will be presented by treatment group, phase, and dose level, treatment 
arm, or cohort if applicable, as elaborated in Table 3-2 in Section 3.2. Summaries will be 
provided for the FAS.
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized using 
descriptive statistics for age, and using number and percentage of subjects for sex, race, ethnicity, 
and age groups (<65 years vs >=65 years; and the age group defined in Section 3.4 if applicable). 
A by-subject demographic listing will be provided.
5.2.
Other Baseline Characteristics
Other baseline characteristics include body weight (in kg), height (in cm), body mass index 
(BMI; in kg/m2), bone marrow blasts (in %), ECOG performance status, cytogenetics (normal or 
abnormal), ELN risk group, de novo/secondary AML, MLL status, and molecular mutation 
assessment. Bone marrow blasts will be based on the blasts in bone marrow aspirate. If blasts in 
bone marrow aspirate are not available, blasts in bone marrow biopsy will be used. These 
baseline characteristics will be summarized using descriptive statistics for continuous variables 
and using number and percentage of subjects for categorical variables. 
By-subject listings of other baseline characteristics will be provided.
5.3.
Medical History
Medical history will be collected at screening for disease-specific and general conditions 
(ie, conditions not specific to the disease being studied).
A summary of disease-specific medical history will be provided. AML classification at screening 
will be presented by the FAB and the WHO classification subtypes. Subtypes will be 
summarized using summary statistics for a categorical variable. Time since AML diagnosis 
(weeks) will be calculated as (date of first dose of study drug – date of diagnosis)/7. Time since 
AML diagnosis will be summarized by using summary statistics for continuous variables.
General medical history data will not be coded.
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In deriving the time since AML diagnosis, partial dates of diagnosis will be identified, and the 
partial dates will be imputed as follows:

If day and month are missing but year is available, then the imputed day and month will be 
01 Jan. 

If day is missing but the month and year are available, then the imputed day will be the first 
day of the month. 

Partial date will not be imputed if the year is missing.
5.4.
Prior Anticancer Therapy
For Group C, number of prior regimens and time since the completion of last regimen will be 
summarized using descriptive statistics. A partial completion date will be imputed using the 
algorithm defined in Section 5.3.
The prior anticancer therapies, the last regimens subjects received prior to study entry, and the 
best response to the last regimen will also be summarized.


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6.
EFFICACY ANALYSES
Assessment of clinical response will be made according to the International Working Group 
criteria for AML {Cheson 2003}, which is documented in Appendix 5 of the study protocol. The 
major criteria for judging response assessment include physical examination and examination of 
blood and bone marrow.
Efficacy analysis will be presented by treatment group, phase, and dose level, treatment arm, or 
cohort if applicable, as elaborated in Table 3-2 in Section 3.2. In addition, the pooled analyses of 
Group C for efficacy specified in Sections 6.1, 6.2, and 6.3 will be present by dose level and total 
as elaborated in Table 3-3 in Section 3.2. Summaries will be provided for the FAS.
6.1.
Primary Efficacy Endpoints
6.1.1.
Definition of the Primary Efficacy Endpoints

Complete remission rate at induction completion: defined as the proportion of subjects who 
achieved morphologic complete remission (CR) at induction completion. Note that CR 
includes a subcategory of cytogenetic CR (CRc)

Composite complete remission rate at induction completion: defined as the proportion of 
subjects who achieved morphologic complete remission (CR) or morphologic complete 
remission with incomplete blood count recovery (CRi) at induction completion 

Overall response rate at induction completion: defined as the proportion of subjects who 
achieved morphologic complete remission (CR), morphologic complete remission with 
incomplete blood count recovery (CRi), or partial remission (PR) at induction completion  
6.1.2.
Analysis of the Primary Efficacy Endpoints
Complete remission rate, composite complete remission (CR/CRi) rate, and overall response 
(CR/CRi/PR) rate at induction completion for Groups A and B will be summarized and the 
corresponding 95% exact CIs based on Clopper-Pearson method will be presented.
Response at induction completion is defined as the best response across the time points that 
occurred after day 1 of last cycle of induction therapy, and prior to the earliest of cycle 1 day 1 of 
post-remission or maintenance therapy, date of SCT and date of other anticancer therapy
(excluding SCT and conditioning regimen (listed in Appendix 2)). Best response is the best 
outcome according to the ranking below by decreasing favorable level:
1) Cytogenetic Complete Remission [CRc]
2) Morphologic Complete Remission [CR]
3) Morphologic Complete Remission with Incomplete Blood Count Recovery [CRi]


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4) Partial Remission [PR]
5) Morphologic Leukemia-free State [MLFS]
6) Relapse
7) Other
The category “Other” includes 3 subcategories: Treatment Failure [TF], Early Treatment 
Assessment [ETA], and No Assessment Done. For subjects who had response assessment in the 
last cycle but didn’t achieve any of the first 6 categories listed above at induction completion, TF
will be the response at induction completion for those who received 2 induction cycles in Group 
A or received >= 2 induction cycles in Group B, and ETA will be the response at induction 
completion for those who only received <= 1 induction cycle. All subjects in “Other” will be 
considered as nonresponders and will be included in the denominator when calculating the 
remission rates at induction completion.
Complete remission rate, composite complete remission (CR/CRi) rate, and overall response 
(CR/CRi/PR) rate per best overall response ever achieved during the treatment for Group C will 
be summarized and the corresponding 95% exact CIs based on Clopper-Pearson method will be 
presented.
Best overall response is defined as the best response across all time points prior to SCT and other 
anticancer therapy (excluding SCT and conditioning regimen). Best response is the best outcome 
according to the ranking below by decreasing favorable level:
1) Cytogenetic Complete Remission [CRc]
2) Morphologic Complete Remission [CR]
3) Morphologic Complete Remission with Incomplete Blood Count Recovery [CRi]
4) Partial Remission [PR]
5) Morphologic Leukemia-free State [MLFS]
6) Other
The category “Other” includes 2 subcategories: Treatment Failure [TF] and No Assessment 
Done. All subjects in “Other” will be considered as nonresponders and will be included in the 
denominator when calculating the remission rates per best overall response.
As a sensitivity analysis, complete remission rate, composite complete remission (CR/CRi) rate, 
and overall response (CR/CRi/PR) rate per best overall response ever achieved during the 
treatment will be summarized for Groups A and B. The category “Other” includes 3 
subcategories: Treatment Failure [TF], Early Treatment Assessment [ETA], and No Assessment 
Done. For subjects who had response assessment but didn’t achieve any of the first 5 categories


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listed above as the best overall response, TF will be the best overall response for those who 
received 2 induction cycles in Group A or received >= 2 induction cycles in Group B, and ETA 
will be the best overall response for those who only received <= 1 induction cycle. All subjects 
in “Other” will be considered as nonresponders and will be included in the denominator when 
calculating the remission rates per best overall response.
As an example, assuming a subject in Group A received two induction cycles and discontinued 
all study drugs, if subject achieved PR at end of Cycle 1 but relapsed at end of Cycle 2, the best 
overall response is PR while the response assessment at induction completion is relapse.
When the date of initiation of SCT/anticancer therapy other than the study treatment is 
incomplete or missing, the following algorithm will be followed:

If the day is missing but the month and year are available, then the imputed day will be the 
last day of the month.

If day and month are missing but year is available, then the imputed day and month will be 
01Jan or the last day of the month for the last adequate disease assessment if they have the 
same year, whichever is later.
The following subgroup analyses will be provided for primary analysis:

Age (<60 years, >=60 years; applicable to Groups A and C)

Age (≤75 years, >75 years; applicable to Group B)

ELN risk group (Favorable, Intermediate -I, Intermediate -II, Adverse)

De novo and Secondary AML

Age and ELN risk group (applicable to Group A)

With and without MLL

FLT3-ITD mutation (applicable to Groups A and B)

NPM1 mutation (applicable to Groups A and B)
For Group B phase 2 randomization, similar analyses will be provided by randomization stratum
if there is sufficient sample size in the subgroup. The denominator for the percentage of subjects 
in the stratum will be the total number of randomized subjects. If there are discrepancies in the 
value used for stratification assignment between the IWRS and the clinical database, the value 
collected in the clinical database will be used for the summary. 
Data listings for the clinical responses will be presented.


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6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints

Event free survival (EFS) - defined for all subjects and it is measured from the start of the 
study therapy until the date of treatment failure, AML relapse or death from any cause, 
whichever occurs first 

Overall survival (OS) – defined as the interval from the start of the study therapy to the death 
from any cause
Every attempt will be made to ensure that complete death dates are recorded. In those rare 
instances where complete death dates are not recorded, the following algorithm will be used:

If day is missing but the month and year are available, then the imputed day will be the 
first day of the month or the last known alive date + 1, whichever is later.

If day and month are missing but year is available, then the imputed date will be 01Jan of
that year or the last known alive date + 1, whichever is later.
6.2.2.
Analysis of the Secondary Endpoints
Subjects will be considered as treatment failure if having at least one efficacy assessment prior to 
SCT and other anticancer therapy (excluding SCT and conditioning regimen) but none of these 
efficacy assessments is CRc, CR, CRi, or PR; date of treatment failure will be the date of last 
adequate efficacy assessment prior to SCT and other anticancer therapy (excluding SCT and 
conditioning regimen). The events and censoring rules are detailed in Table 6-1. Of note, other 
anti-cancer therapy excludes SCT and conditioning regimen in this table, and the criteria are 
hierarchical: subjects who meet the criteria on the top will be excluded from the criteria on the 
bottom.
Table 6-1.
Event/Censoring Rules for EFS
Criteria
Event or 
Censored
Date of Event/Censoring
Relapse, no other anti-cancer therapy or prior to the start of 
other anti-cancer therapy, and 

had SCT prior to relapse, OR

no SCT prior to relapse, and days from last response 
assessment prior to relapse to relapse was within the 
following window (2 consecutive response 
assessments):
For Group A:

<=60 days (2 cycles (including the time waiting for 
Event
Date of first relapse


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count recovery) + 4 days) if didn’t receive 
post-remission cycle

<=120 days (4 cycles + 8 days) if received 
post-remission cycle but didn’t receive ENTO 
mono maintenance cycle
<=240 days (8 cycles + 16 days) if received ENTO 
mono maintenance cycle
For Group B:

<=120 days (4 cycles + 8 days) if didn’t receive 
maintenance cycle
<= 240 days (8 cycles + 16 days) if received 
maintenance cycle
For Group C:

<= 60 days (2 cycles + 4 days) if received <= 
2 cycles

<= 120 days (4cycles + 8 days) if received 
3-4 cycles

<= 240 days (8 cycles + 16 days) if received > 
4 cycles
Treatment failure, and days from last response assessment 
prior to treatment failure or first dosing date, whichever is 
later, to treatment failure was within the window defined 
above
Event
Date of treatment failure
Death without treatment failure/relapse/other anti-cancer 
therapy, and 

had SCT, OR

no SCT, and days from the date of last assessment or 
first dosing date, whichever is later, to the date of death 
was within the window defined above
Event
Date of death
No postbaseline assessment, no death
Censored
Date of first dose
No treatment failure/relapse/death
Censored
Date of last response 
assessment (and prior to other 
anti-cancer therapy if any) or 
first dosing date, whichever is 
later


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Other anti-cancer therapy started prior to treatment 
failure/relapse/death
Censored
Date of last response 
assessment prior to other anti-
cancer therapy or first dosing 
date, whichever is later
Days from last response assessment prior to treatment 
failure/relapse/death or first dosing date, whichever is later, 
to treatment failure/relapse/death was not within the
window defined above
Censored
Date of last response 
assessment prior to treatment 
failure/relapse/death or first 
dosing date, whichever is later
Censoring Rules for OS:

For a subject who is not known to have died by the end of study follow-up, OS is censored 
on the date the subject was last known to be alive.
For EFS or OS in months, the calculation is based on the following formula:
(date of event/censoring- date of first dose + 1)/30.4375.
EFS and OS will be analyzed using Kaplan-Meier (KM) methods. The KM estimate of the 
survival function will be computed and the results will be presented using KM curves. The 
median will be provided along with the corresponding 95% CI. Additionally, the 25% and 
75% percentiles for these endpoints will also be provided. 
Follow up time for OS will be summarized as continuous variable with descriptive statistics.  

For a subject who is not known to have died by the end of study follow-up, duration of OS 
follow up in months = (date of last known to be alive – date of first dose + 1)/30.4375

For the remaining subjects, duration of OS follow up in months = (date of follow-up cutoff –
date of first dose + 1)/30.4375
Data listing for EFS and OS will be presented.
6.3.
Exploratory Efficacy Endpoints
6.3.1.
Definition of the Exploratory Efficacy Endpoints

 
CCI


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6.3.2.
Analysis of the Exploratory Efficacy Endpoints
 
 
 
 
 
 
 
 
CCI
CCI


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Table 6-2.
Event/Censoring Rules for RFS
Criteria
Event or 
Censored
Date of Event/Censoring
Relapse, no other anti-cancer therapy or prior to the start of 
other anti-cancer therapy, and 

had SCT prior to relapse, OR

no SCT prior to relapse, and days from last response 
assessment prior to relapse to relapse was within the 
following window (2 consecutive response 
assessments):
For Group A:

<=60 days (2 cycles (including the time waiting 
for count recovery) + 4 days) if didn’t receive 
post-remission cycle

<=120 days (4 cycles + 8 days) if received 
post-remission cycle but didn’t receive ENTO 
mono maintenance cycle
<=240 days (8 cycles + 16 days) if received ENTO 
mono maintenance cycle
For Group B:

<=120 days (4 cycles + 8 days) if didn’t receive 
maintenance cycle
<= 240 days (8 cycles + 16 days) if received 
maintenance cycle
For Group C:

<= 60 days (2 cycles + 4 days) if received <= 
2 cycles

<= 120 days (4cycles + 8 days) if received 3-
4 cycles

<= 240 days (8 cycles + 16 days) if received > 
4 cycles
Event
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Death without relapse/other anti-cancer therapy, and 

had SCT, OR

no SCT, and days from the date of last assessment or 
first dosing date, whichever is later, to the date of death 
was within the window defined above
Event
Date of death
No relapse/death
Censored
Date of last response 
assessment (and prior to other 
anti-cancer therapy if any) or 
first dosing date, whichever is 
later
Other anti-cancer therapy started prior to relapse/death
Censored
Date of last response
assessment prior to other 
anti-cancer therapy or first 
dosing date, whichever is later
Days from last response assessment prior to relapse/death 
or first dosing date, whichever is later, to relapse/death was 
not within the window defined above
Censored
Date of last response 
assessment prior to
relapse/death or first dosing 
date, whichever is later
Remission duration will be analyzed using cumulative incidence by considering competing risks. 
Relapse (the first situation in Table 6-2) is considered as the event of interest. Death without 
relapse (the second situation in Table 6-2) is a competing risk as death eliminates the occurrence 
of relapse. The other situations described in Table 6-2 are considered as censored. There are 
three statuses: 0=censored, 1=relapse, and 2=death without relapse. SAS 9.4 PROC LIFETEST 
with statement TIME and option EVENTCODE=1 will be used. The estimates of the cumulative 
incidence of relapse (CIR) at 1, 3, 6, 12, 18, and 24 months (if appropriate) will be reported with 
the associated 95% CIs.
TTR will be summarized using descriptive statistics.
Data listing of TTR, RFS, and remission duration will be presented.
TTC will not be analyzed as data are not intensively measured/collected.
MRD rates will not be summarized as data are not measured/collected at all visits. A by-subject 
listing of MRD level will be provided.
The number and percentage of subjects who underwent SCT will be summarized and the 
corresponding 95% exact CI will be presented. In addition, the same analysis will be performed 
for subjects who underwent SCT at induction completion, post-remission, and maintenance 
completion, if applicable. A by-subject listing of SCT will be provided.


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6.4.
Other Efficacy Measures
Spaghetti plots of blasts (%) in bone marrow aspirate through the induction cycles for Group A 
and Group B and all cycles for Group C will be provided. For visits at which blasts in bone 
marrow aspirate are not available, blasts in bone marrow biopsy will be used. Since different 
subjects will be treated for different time periods per cycle and different number of cycles, the 
x-axis of the spaghetti plot, which is the study day, will be adjusted as follows to distinguish 
bone marrow results among the cycles: 
Group A 
For results in Cycle 1: Relative Day to Cycle 1 Day 1 + 15
For results in Cycle 2: Relative Day to Cycle 2 Day 1 + 102
Group B 
For results in Cycle 1: Relative Day to Cycle 1 Day 1 + 16
For results in Cycle 2: Relative Day to Cycle 2 Day 1 + 61
For results in Cycle 3: Relative Day to Cycle 3 Day 1 + 106
For results in Cycle 4: Relative Day to Cycle 4 Day 1 + 151
A by-subject listing of bone marrow assessments, including both bone marrow aspirate and bone 
marrow biopsy, will be provided. 
By-subject listings of ECOG performance status, cytogenetics, fluorescent in situ hybridization 
(FISH) analysis, and molecular mutation will be provided separately. 
6.5.
Changes From Protocol-Specified Efficacy Analyses
TTC will not be analyzed as data are not intensively measured/collected.
MRD rates will not be summarized as data are not measured/collected at all visits. A by-subject 
listing of MRD level will be provided.


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7.
SAFETY ANALYSES
Safety analysis will be presented by treatment group, phase, and dose level, treatment arm, or 
cohort if applicable, as elaborated in Section 3.2. Dose level for phase 1b is defined as the initial 
dose level a subject actually received.
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 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 
provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to toxicity 
criteria specified in the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03. 
The severity grade of events for which the investigator did not record severity will be
categorized as “missing” for tabular summaries and data listings. The missing category will be 
listed last in data presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment GS-9973”, “Related to Study Treatment Cytarabine”,
“Related to Study Treatment Daunorubicin”, “Related to Study Treatment Decitabine”, or 
“Related to Study Treatment Azacitidine”. Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationships to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE specified in the study protocol. SAEs captured and stored in the clinical database will be 
reconciled with the SAE database from the Gilead Pharmacovigilance and Epidemiology before 
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7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug
7.1.5.2.
Incomplete Dates
AEs with incomplete onset dates will be identified and the incomplete dates will be imputed for 
TEAE determination. The imputation rules are as follows:

If the day is missing but the month and year are available, then the imputed day will be the 
first day of the month or the first dosing date if they have the same month and year, 
whichever is later.

If the day and month are missing but year is available, then the imputed day and month will 
be 01Jan or the first dosing date if they have the same year, whichever is later.
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
7.1.6.1.
Summaries of AE Incidence by Severity 
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, HLT, and PT. For other AEs described below, summaries will be provided 
by SOC, PT, and maximum severity:

TEAEs

Grade 3 or higher TEAE

TEAEs related to ENTO

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
TE SAEs related to ENTO

TEAEs leading to ENTO discontinuation

TEAEs leading to ENTO dose reduction or interruption
For AEs described below, summaries will be provided by SOC and PT:

TEAEs

TEAEs related to ENTO

TE SAEs

TE SAES related to ENTO

TEAEs leading to ENTO discontinuation

TEAEs leading to death
A brief, high-level summary of TEAEs described above will be provided by the number and 
percentage of subjects who experienced the above TEAEs. This summary table will also include 
TEAE related to chemotherapy (Groups A and B), Grade 3 or higher TEAE related to ENTO, 
Grade 3 or higher TEAE related to chemotherapy (Groups A and B), TE SAEs related to 
chemotherapy (Groups A and B), TEAEs leading to chemotherapy discontinuation
(Groups A and B), TEAE leading to chemotherapy dose reduction or interruption (Groups A and 
B), and death.
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and HLT within each SOC (if applicable) 
and then by PT in descending order of total frequency within each SOC. For summaries by 
severity, the most severe severity will be used for those AEs that occurred more than once in a 
given subject during the study.
In addition to the above summary tables, TEAEs and TE SAEs will be summarized by PT only 
in descending order of total frequency.
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

SAEs

Deaths

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7.1.6.2.
Summary of Deaths
A summary (number and percentage of subjects) of deaths will be provided. The summary will 
include the following categories:

All deaths

Deaths within 30 days of the last dosing of study drug

Deaths beyond 30 days of the last dosing of study drug
The attribution of death will also be summarized.
7.1.7.
Dose Limiting Toxicity
DLT will be analyzed with the DLT Analysis Set. 
A listing of the DLT AEs will be provided by treatment group, dose level, subject ID, DLT 
category, preferred term, associated severity grade, and date of onset/resolution, if available.
A summary of DLT will be presented by SOC and PT.
7.2.
Laboratory Evaluations
Local laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set. The analysis will be based on values reported in conventional units. When 
values are below the LOQ, they will be listed as such, and the closest imputed value will be used 
for the purpose of calculating summary statistics as specified in Section 3.7. Hemolized test 
results will not be included in the analysis, but they will be listed in by-subject laboratory 
listings.
A by-subject listing for laboratory test results will be provided by subject ID number and time 
point in chronological order for hematology, serum chemistry, coagulation, urinalysis, and 
serology separately. Values falling outside of the relevant reference range and/or having a 
severity grade of 1 or higher on the CTCAE severity grade will be flagged in the data listings, as 
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7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided for each laboratory test specified in the study protocol as 
follows:

Baseline values 

Values at each postbaseline visit

Postbaseline maximum value

Postbaseline minimum value

Change from baseline to postbaseline maximum value

Change from baseline to postbaseline minimum value
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; StD values will be displayed to the 
reported number of digits plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.
7.2.2.
Graded Laboratory Values
CTCAE Version 4.03 will be used for assigning toxicity grades (0 to 4) to laboratory results for 
analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at least 
Grade 1. For laboratory tests with criteria for both increased and decreased levels; analyses for 
each direction (ie, increased, decreased) will be presented separately.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of 
last dose of study drug plus 30 days. If the relevant baseline laboratory value is missing, any 
abnormality of at least Grade 1 observed within the time frame specified above will be 
considered treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
The summary (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test; subjects will be categorized according to the most 
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For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dosing date.
A by-subject listing of treatment-emergent laboratory abnormalities will be provided by subject 
ID number and time point in chronological order. This listing will include all test results that 
were collected throughout the study for the lab test of interest, with all applicable severity grades 
displayed.
7.2.3.
Shift in CTCAE Grade Relative to Baseline
Shift tables will be presented by showing change in CTCAE grade from baseline to the worst 
postbaseline grade up to 30 days after last dosing date. The percentage will be based on subjects 
with values available at both baseline and postbaseline.
7.2.4.
Graphics of Numeric Laboratory Results
Spaghetti plots of circulating blasts (%), neutrophils, platelets, and WBC through the induction 
treatment for Group A and Group B and all cycles for Group C will be provided. Since different 
subjects will be treated for different time periods per cycle and different number of cycles, the 
x-axis of the spaghetti plot, which is the study day, will be adjusted following the algorithms in 
Section 6.4 to distinguish laboratory results among the cycles.
7.3.
Body Weight and Vital Signs
Descriptive statistics will be provided for body weight and vital signs as follows:

Baseline value

Values at each postbaseline visit

Postbaseline maximum value

Postbaseline minimum value

Change from baseline to postbaseline maximum value

Change from baseline to postbaseline minimum value
A baseline value will be defined as the last available value collected on or prior to the date/time 
of first dose of study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value. Body weight and vital signs measured at 
unscheduled visits will be included for the baseline value selection.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.


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A by-subject listing of vital signs will be provided by subject ID number and time point in 
chronological order. Body weight will be included in the vital signs listing.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the WHO Drug dictionary.  
7.4.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first study drug.
Prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) drug class 
Level 2 and preferred name using the number and percentage of subjects. A subject reporting the 
same medication more than once will be counted only once when calculating the number and 
percentage of subjects who received that medication. The summary will be ordered 
alphabetically by ATC medical class and then by preferred term in order of descending overall 
frequency within each ATC medical class. For drugs with the same frequency, sorting will be 
done alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dosing date of 
study drug will be included in the prior medication summary regardless of when the stop date is. 
If a partial start date is entered the medication will be considered prior unless the month and year 
(if day is missing) or year (if day and month are missing) of the start date are after the first 
dosing date. Medications with a completely missing start date will be included in the prior 
medication summary, unless otherwise specified.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by ATC drug class Level 2 and preferred name 
using the number and percentage of subjects for each treatment group. A subject reporting the 
same medication more than once will be counted only once when calculating the number and 
percentage of subjects who received that medication. The summary will be ordered 
alphabetically by ATC medical class and then by preferred term in descending overall frequency 
within each ATC medical class. For drugs with the same frequency, sorting will be done 
alphabetically.
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken after the first dosing date, or started after the first dosing 
date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date or the last 
dosing date of study drug will also be considered concomitant. Medications with a stop date prior 
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will be excluded from the concomitant medication summary. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication summary. If a partial start date is entered, any medication with the month and year 
(if day is missing) or year (if day and month are missing) after the study drug stop date will be 
excluded from the concomitant medication summary. Medications with completely missing start 
and stop dates will be included in the concomitant medication summary, unless otherwise 
specified. 
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.5.
Electrocardiogram Results
Electrocardiogram (ECG) was performed at screening and may be performed at the 
Investigator’s discretion following enrollment.
A by-subject listing for ECG assessment results will be provided by subject ID number and time 
point in chronological order.
7.6.
Other Safety Measures
Platelet transfusions through induction cycles will be summarized for each induction cycle for 
Groups A and B. For Group C, platelet transfusions will be summarized for each cycle. Number 
of platelet transfusions per subject and number of platelet transfusions per week will be 
presented using descriptive statistics. For each cycle,
Number of platelet transfusions per week=
Number of platelet transfusions within the cycle
Number of days of the cycle
× 7
For the last cycle, the number of days of cycle will be calculated as the date of last dose of the 
study drug – the start date of the cycle+1.
Summaries will be based on the Safety Analysis Set.
A by-subject listing of different types of transfusions required through the study will be 
provided.
A by-subject listing will be provided for the results of all pregnancy tests conducted in the study.
On-treatment and post-treatment anticancer therapies will be listed for applicable subjects.


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7.7.
Changes From Protocol-Specified Safety Analyses
For Groups A and B, safety data will not be presented by the lead-in ENTO therapy phase and 
the induction chemotherapy phase separately due to no washout period. 


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8.
PHARMACOKINETIC (PK) ANALYSES
8.1.
PK Sample Collection
PK blood samples will be collected on
Group A:

Phase 1b: Cycle 0 Days 1, 8, and 14 at pre-dose and 2 hour post-dose of ENTO; Cycle 1 
Days 3 and 7 at pre-dose, 2 hours, and 4 hours post-dose of ENTO; Cycle 1 Day 14 at 
pre-dose and 2 hours post-dose of ENTO

Phase 2: Cycle 0 Days 1, 8, and 14 at pre-dose and 2 hour post-dose of ENTO; Cycle 1 (and 
2, if needed) Day 3 at pre-dose, 2 hours, and 4 hours post-dose of ENTO; Intensive PK on 
Cycle 1 Day 7 at pre-dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose of ENTO; Cycle 1 Day 14 
at pre-dose and 2 hours post-dose of ENTO; Day 5 and Day 28 of each Post-Remission cycle 
at pre-dose and 2 hours post-dose of ENTO; Day 28 of each Maintenance cycle at pre-dose 
and 2 hours post-dose of ENTO
Group B:

Phase 1b and Phase 2 Safety Run-in: Cycle 0 Days 1, 8, and 14 at pre-dose and 2 hour 
post-dose of ENTO; Induction Cycle 1 Day 8 at pre-dose, 2 hours, and 4 hours post-dose of 
ENTO; Day 8 of subsequent induction cycles at pre-dose and 2 hours post-dose of ENTO; 
Day 28 of every induction cycle at pre-dose and 2 hours post-dose of ENTO; Day 28 of 
every Entospletinib + Hypomethylating agent Maintenance cycle at pre-dose and 2 hours 
post-dose of ENTO; Day 28 of every Entospletinib Maintenance cycle at pre-dose and 
2 hours post-dose of ENTO

Phase 2 Randomization: Cycle 0 Days 1 and 5 at pre-dose and 2 hour post-dose of ENTO; 
Induction Cycle 1 Day 8 at pre-dose, 2 hours, and 4 hours post-dose of ENTO; Day 8 of 
subsequent induction cycles at pre-dose and 2 hours post-dose of ENTO; Day 28 of every 
induction cycle at pre-dose and 2 hours post-dose of ENTO; Day 28 of every Entospletinib + 
Hypomethylating agent Maintenance cycle at pre-dose and 2 hours post-dose of ENTO; 
Day 28 of every Entospletinib Maintenance cycle at pre-dose and 2 hours post-dose of ENTO
Group C:

Phase 1b: Cycle 1 Days 1, 8, 14, and 28 at pre-dose and 2 hours post-dose of ENTO

Phase 2: Cycle 1 Days 1, 8, 14, and 28, and Day 28 of each subsequent cycle at pre-dose and 
2 hours post-dose of ENTO


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8.2.
ENTO Plasma Concentrations Analysis
Concentrations of ENTO in plasma will be determined using a validated bioanalytical assay.
8.3.
Statistical Analysis Methods
The following listing will be provided:

ENTO plasma concentrations and PK sampling details by subject including deviations in 
scheduled and actual draw times and procedures
No PK parameters will be generated.


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9.
BIOMARKER ANALYSES
Baseline bone marrow mononuclear cells (BM-MNCs) from bone marrow aspirates will be
analyzed for mRNA expression of Homeobox A9 (HOXA9)/Myeloid Ecotropic Viral Integration 
Site 1 (MEIS1) using a custom Nanostring assay. Expression data will be first normalized using 
the NanoStringNorm R package with 18 housekeeping genes. HOXA9/MEIS1 expression will 
then be compared to that in pooled BM-MNCs from healthy donors (n=20). Subjects will be
classified into HOXA9/MEIS1 high and low groups using a cutoff of 3-fold higher than a pooled 
healthy donor samples:

HOXA9/MEIS1 status=high: sample/normal >= 3 for both HOXA9 and MEIS1

HOXA9/MEIS1 status=low: sample/normal < 3 for either HOXA9 or MEIS1
The following analyses will be performed by HOXA9/MEIS1 status for Group A subjects who 
are in the FAS and have baseline HOXA9/MEIS1 expression data:

Complete remission rate, composite complete remission (CR/CRi) rate, and overall response 
(CR/CRi/PR) rate at induction completion will be summarized and the corresponding 95% 
exact CIs based on Clopper-Pearson method will be presented.

EFS and OS will be analyzed using KM methods and KM curves will be provided.
In addition, a by-subject level listing of HOXA9/MEIS1 expression values, classified 
HOXA9/MEIS1 status, response at induction completion, EFS, and OS will be provided for 
these subjects.


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10.
REFERENCES
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials 
in Acute Myeloid Leukemia. J Clin Oncol 2003;21 (24):4642-9.


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11.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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12.
APPENDICES
Appendix 1.
List of FAB/WHO Classification Subtypes
Appendix 2.
List of Conditioning Regimen


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Appendix 1.
List of FAB/WHO Classification Subtypes
FAB Classification
WHO Classification
M0: Undifferentiated acute myeloblastic leukemia
AML with certain genetic abnormalities
M1: Acute myeloblastic leukemia with minimal 
maturation
AML with myelodysplasia-related changes
M2: Acute myeloblastic leukemia with maturation
AML related to previous chemotherapy or radiation
M3: Acute promyelocytic leukemia (APL)

AML not otherwise specified:

AML with minimal differentiation (M0)

AML without maturation (M1)

AML with maturation (M2)

Acute myelomonocytic leukemia (M4)

Acute monocytic leukemia (M5)

Acute erythroid leukemia (M6)

Acute megakaryoblastic leukemia (M7)

Acute basophilic leukemia

Acute panmyelosis with fibrosis
M4: Acute myelomonocytic leukemia
M4 eos: Acute myelomonocytic leukemia with 
eosinophilia
M5: Acute monocytic leukemia
M6: Acute erythroid leukemia
M7: Acute megakaryoblastic leukemia


Entospletinib (GS-9973)
GS-US-339-1559
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 60
19 June 2019
Appendix 2.
List of Conditioning Regimen
Conditioning Regimen (Preferred Term)
ANTITHYMOCYTE IMMUNOGLOBULIN
BUSULFAN
CYCLOPHOSPHAMIDE
ETOPOSIDE
FLUDARABINE
MELPHALAN
MELPHALAN HYDROCHLORIDE
THIOTEPA