Conditions: Hematologic Malignancy Acute Myeloid Leukemia
Keywords: Relapsed or Refractory Hematologic Malignancy Previously untreated AML
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 9
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the safety and tolerability of entospletinib (ENTO) monotherapy and in combination with chemotherapy in Japanese participants.

Detailed description:

Arms:
arm 1: Participants with relapsed or refractory hematologic malignancies will receive ENTO twice daily of every 28-day cycle until participants meet treatment discontinuation criteria or do not experience clinical benefit. arm 2: Lead-in (Cycle 0): Participants with previously untreated AML will receive ENTO twice daily for 14 days.

Induction (Up to 2 cycles): ENTO in combination with daunorubicin and cytarabine for up to two 28-day cycles.

Post-remission chemotherapy (at least 2 cycles, up to 4 cycles): Some participants (who have achieved complete remission \[CR\] or morphologic complete remission with incomplete blood count recovery \[CRi\] and do not require or cannot proceed to allogeneic stem cell transplantation \[SCT\] and participants who are awaiting a donor or transitioning to allogeneic SCT per investigator discretion) will have the option to receive post-remission chemotherapy with ENTO twice daily in combination with high-dose cytarabine (Hi-DAC) for up to four 28-day cycles.

Interventions: intervention 1: Entospletinib intervention 2: Daunorubicin intervention 3: Cytarabine
Intervention descriptions: intervention 1: 400 mg (2 × 200 mg tablets) orally twice daily intervention 2: 60 mg/m\^2 administered intravenously daily on Days 1 to 3 of each 28-day induction cycle intervention 3: 100 mg/m\^2 intravenous administration twice daily on Days 1 to 7 of each 28-day induction cycle

Hi-DAC: 3 g/m\^2 IV administration twice daily on days 1, 3, and 5 (≤ 60 years of age) or 1 g/m\^2 IV administration once daily on Days 1 to 5 (\> 60 years of age) of each 28-day post-remission cycle

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1b Study to Investigate the Safety, Tolerability, and 
Pharmacokinetics of Entospletinib (ENTO) as Monotherapy in 
Japanese Subjects with Relapsed or Refractory Hematologic 
Malignancies and in Combination with Chemotherapy in 
Japanese Subjects with Previously Untreated 
Acute Myeloid Leukemia (AML)
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
Not applicable
Not applicable
NCT03135028
Indication:
Hematologic Malignancies, Acute Myeloid Leukemia 
Protocol ID:
GS-US-429-4104
Gilead Clinical Program 
Manager:
Name:
Office Telephone:
E-mail:
Gilead Medical Monitor:
Name:
Office Telephone:
E-mail:
Protocol Version/Date:
Original:
13 December 2016
Amendment 1:
11 January 2017
Amendment 2:
21 February 2017
Amendment 3:
23 August 2017
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in the 
protocol. You will not disclose any of the information to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
PPD
PPD
(rJ GILEAiJ 


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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.
Background ............................................................................................................................................21
1.2.
Spleen Tyrosine Kinase Biology in AML..............................................................................................22
1.3.
Entospletinib ..........................................................................................................................................23
1.3.1.
Nonclinical Pharmacology ...................................................................................................24
1.3.2.
Nonclinical Drug Metabolism and Pharmacokinetics ..........................................................25
1.3.3.
Nonclinical Toxicology........................................................................................................26
1.3.4.
Clinical Trials of ENTO.......................................................................................................27
1.4.
Information about Cytarabine ................................................................................................................30
1.5.
Information about Daunorubicin............................................................................................................30
1.6.
Rationale for This Study ........................................................................................................................31
1.6.1.
Rationale for Dose Selection................................................................................................31
1.7.
Risk/Benefit Assessment for the Study..................................................................................................32
1.7.1.
Potential Risks Based on Nonclinical Safety Data with ENTO ...........................................32
1.7.2.
Potential Risks Based on Clinical Safety Data with ENTO .................................................33
1.8.
Compliance ............................................................................................................................................33
2.
OBJECTIVES.....................................................................................................................................................34
3.
STUDY DESIGN................................................................................................................................................35
3.1.
Endpoints ...............................................................................................................................................35
3.2.
Study Design..........................................................................................................................................36
3.2.1.
Dose Limiting Toxicities......................................................................................................36
3.2.2.
Group A (ENTO monotherapy)............................................................................................37
3.2.3.
Group B (ENTO + cytarabine + daunorubicin)....................................................................38
3.3.
Study Treatments ...................................................................................................................................40
3.4.
Duration of Treatment............................................................................................................................40
3.5.
Discontinuation Criteria.........................................................................................................................40
3.5.1.
Discontinuation of Study Treatment ....................................................................................40
3.5.2.
Discontinuation of Study......................................................................................................41
3.6.
End of Treatment....................................................................................................................................41
4.
SUBJECT POPULATION..................................................................................................................................42
4.1.
Number of Subjects and Subject Selection ............................................................................................42
4.2.
Inclusion Criteria....................................................................................................................................42
4.3.
Exclusion Criteria...................................................................................................................................44
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................47
5.1.
Description and Handling.......................................................................................................................47
5.1.1.
Formulation..........................................................................................................................47
5.1.2.
Packaging and Labeling .......................................................................................................47
5.1.3.
Storage and Handling...........................................................................................................48
5.2.
Premedication.........................................................................................................................................48
5.3.
Dosage and Administration....................................................................................................................48


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5.3.1.
Entospletinib.........................................................................................................................48
5.3.2.
Cytarabine and Daunorubicin...............................................................................................51
5.4.
Prior and Concomitant Medications.......................................................................................................51
5.5.
Excluded Medication .............................................................................................................................51
5.6.
Accountability for IMP ..........................................................................................................................53
5.6.1.
Investigational Medicinal Products Return or Disposal .......................................................53
6.
STUDY PROCEDURES ....................................................................................................................................54
6.1.
Subject Enrollment.................................................................................................................................54
6.2.
Study Procedure Descriptions ................................................................................................................54
6.2.1.
Informed Consent.................................................................................................................54
6.2.2.
Medical History....................................................................................................................54
6.2.3.
Prior and Concomitant Medications.....................................................................................54
6.2.4.
Physical Examination...........................................................................................................55
6.2.5.
Vital Signs............................................................................................................................55
6.2.6.
Electrocardiogram................................................................................................................55
6.2.7.
Echocardiogram ...................................................................................................................55
6.2.8.
ECOG Performance Status...................................................................................................56
6.2.9.
Adverse Events.....................................................................................................................56
6.2.10.
Laboratory Assessments.......................................................................................................56
6.2.11.
Pharmacokinetic Samples.....................................................................................................57
6.2.12.
Chest X-ray ..........................................................................................................................57
6.2.13.
Bone Marrow Biopsy and Aspirate......................................................................................58
6.2.14.
Biological Sample Storage ...................................................................................................58
6.3.
Screening Visit.......................................................................................................................................58
6.4.
Treatment Assessments – Group A (ENTO Monotherapy) ...................................................................59
6.4.1.
Cycle 1 .................................................................................................................................60
6.4.2.
Subsequent Cycles................................................................................................................60
6.5.
Treatment Assessments – Group B (ENTO + cytarabine + daunorubicin)............................................61
6.5.1.
Lead-in (Cycle 0) .................................................................................................................61
6.5.2.
Induction ..............................................................................................................................62
6.5.3.
Post-remission chemotherapy...............................................................................................64
6.6.
Assessments for Premature Discontinuation from Study.......................................................................65
6.7.
End of Treatment....................................................................................................................................65
6.8.
Follow-up...............................................................................................................................................66
6.8.1.
Remission/Relapse ...............................................................................................................66
6.8.2.
30-day Follow-up .................................................................................................................66
6.8.3.
Long Term Follow-up ..........................................................................................................66
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................67
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................67
7.1.1.
Adverse Events.....................................................................................................................67
7.1.2.
Serious Adverse Events........................................................................................................67
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................68
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................69
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................69
7.2.2.
Assessment of Severity ........................................................................................................69
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................70
7.4.
Gilead Reporting Requirements.............................................................................................................71
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................72
7.6.
Toxicity Management ............................................................................................................................72


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7.7.
Special Situations Reports......................................................................................................................72
7.7.1.
Definitions of Special Situations..........................................................................................72
7.7.2.
Instructions for Reporting Special Situations.......................................................................73
7.7.3.
Reporting Other Special Situations ......................................................................................74
8.
STATISTICAL CONSIDERATIONS................................................................................................................75
8.1.
Analysis Objectives and Endpoints........................................................................................................75
8.1.1.
Analysis Objectives..............................................................................................................75
8.1.2.
Primary Endpoints................................................................................................................75
8.1.3.
Secondary Endpoints............................................................................................................76
8.1.4.
Other Endpoints of Interest ..................................................................................................76
8.2.
Analysis Conventions.............................................................................................................................77
8.2.1.
Analysis Sets ........................................................................................................................77
8.3.
Data Handling Conventions ...................................................................................................................77
8.4.
Demographic Data and Baseline Characteristics ...................................................................................78
8.5.
Efficacy Analysis ...................................................................................................................................78
8.6.
Safety Analysis.......................................................................................................................................79
8.6.1.
Extent of Exposure...............................................................................................................79
8.6.2.
Adverse Events.....................................................................................................................79
8.6.3.
Laboratory Evaluations ........................................................................................................80
8.7.
Pharmacokinetic Analysis......................................................................................................................81
8.8.
Sample Size............................................................................................................................................81
8.9.
Timing of Analyses................................................................................................................................81
8.9.1.
Interim Analyses ..................................................................................................................81
8.9.2.
Final Analysis.......................................................................................................................81
9.
RESPONSIBILITIES..........................................................................................................................................82
9.1.
Investigator Responsibilities ..................................................................................................................82
9.1.1.
Good Clinical Practice..........................................................................................................82
9.1.2.
Independent Ethics Committee (IEC) Review and Approval...............................................82
9.1.3.
Informed Consent.................................................................................................................82
9.1.4.
Confidentiality......................................................................................................................83
9.1.5.
Study Files and Retention of Records ..................................................................................83
9.1.6.
Case Report Forms...............................................................................................................84
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................85
9.1.8.
Inspections............................................................................................................................85
9.1.9.
Protocol Compliance............................................................................................................85
9.2.
Sponsor Responsibilities ........................................................................................................................86
9.2.1.
Protocol Modifications.........................................................................................................86
9.2.2.
Study Report and Publications .............................................................................................86
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................86
9.3.1.
Payment Reporting...............................................................................................................86
9.3.2.
Access to Information for Monitoring..................................................................................87
9.3.3.
Access to Information for Auditing or Inspections ..............................................................87
9.3.4.
Study Discontinuation..........................................................................................................87
10.
REFERENCES ...................................................................................................................................................88
11.
APPENDICES ....................................................................................................................................................91
Appendix 1.
Investigator Signature Page....................................................................................................92
Appendix 2.
Study Procedures Table: Group A (ENTO Monotherapy) .....................................................93
Appendix 3.
Study Procedures Table: Group B (ENTO + cytarabine + daunorubicin)..............................95


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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................98
Appendix 5.
Performance Scales: Karnofsky & ECOG Scores {Oken 1982}..........................................100
Appendix 6.
Modified International Working Group Criteria for AML...................................................101
LIST OF IN-TEXT TABLES
Table 5-1.
ENTO Dose Modification Guidelines ....................................................................................50
Table 5-2.
Contraindicated Medications in this Study that require prior MM discussion and 
approval..................................................................................................................................52
Table 6-1.
Analytes..................................................................................................................................57
LIST OF IN-TEXT FIGURES
Figure 1-1.
SYK Regulation of AML Cell Survival and Proliferation......................................................23
Figure 1-2.
ENTO Kinome Scan...............................................................................................................24
Figure 1-3.
GS-US-339-1559: Group A Bone Marrow Blasts Trajectory Through Induction 
Treatment (Full Analysis Set).................................................................................................29
Figure 1-4.
GS-US-339-1559: Group A Circulating Blasts Through Induction Treatment (Full 
Analysis Set)...........................................................................................................................29
Figure 3-1.
Group B Dosing Schema........................................................................................................38


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 1b Study to Investigate the Safety, Tolerability, and 
Pharmacokinetics of Entospletinib (ENTO) as Monotherapy in 
Japanese Subjects with Relapsed or Refractory Hematologic 
Malignancies and in Combination with Chemotherapy in Japanese 
Subjects with Previously Untreated Acute Myeloid Leukemia 
(AML)
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
Not applicable
Not applicable
NCT03135028
Study Centers Planned:
Approximately 10 centers in Japan
Objectives:
The primary objectives of this study are:

To evaluate the safety and tolerability of ENTO monotherapy in 
Japanese subjects with relapsed or refractory hematologic 
malignancies

To evaluate the safety and tolerability of ENTO in combination 
with cytarabine and daunorubicin (7+3) in Japanese subjects with 
previously untreated AML who are candidates for chemotherapy
The secondary objectives of this study are: 

To evaluate the pharmacokinetics (PK) of ENTO in Japanese 
subjects with relapsed or refractory hematologic malignancies 

To evaluate the PK of ENTO in Japanese subjects with 
previously untreated AML who are candidates for chemotherapy

To evaluate the safety and tolerability of ENTO in combination 
with age-adjusted high-dose cytarabine (HiDAC) in Japanese 
subjects with previously untreated AML who are candidates for
chemotherapy
The exploratory objectives of this study are: 
CCI


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Study Design:
A Phase 1b, open-label, multicenter study evaluating the safety, 
tolerability, and PK of ENTO as monotherapy in Japanese subjects 
with relapsed or refractory hematologic malignancies and ENTO in 
combination with cytarabine and daunorubicin (7+3) in Japanese 
subjects with previously untreated AML. Up to 24 subjects will be 
dosed in 2 groups using a rolling 6 design to evaluate 12 subjects for 
DLT assessment.
Group A: Approximately 6 subjects (approximately 12 subjects if 
reduced dose level [-1] is also evaluated) with relapsed or refractory 
hematologic malignancies will receive ENTO monotherapy
Group B: Approximately 6 subjects with previously untreated AML 
will receive  ENTO monotherapy lead-in followed by ENTO in 
combination with 7+3
The starting ENTO dose level of 400 mg twice daily (BID) is 
defined as dose level 0. The safety and tolerability of dose level 0 
will be assessed in Group A before proceeding with Group B. The 
dose limiting toxicity (DLT) assessment window for Group A begins 
on Cycle 1 Day 1 and ends on Cycle 1 Day 28 and for Group B 
begins on lead-in Cycle 0 Day 1 and ends 28 days from Cycle 1 
Day 1 of induction chemotherapy. The subjects in this study should 
be in hospital during the DLT assessment window, and the window
for Group B may be expanded for bone marrow recovery as noted 
below. During the DLT assessment window, subjects who fail to 
complete a total of 21 days of ENTO (or in Group B, miss any doses 
of cytarabine and daunorubicin) for reasons other than a DLT will 
not be evaluable for DLT assessment and may be replaced in a 
timely manner as determined by the Gilead Medical Monitor, the 
Japanese CRO Medical Monitor, and the Principal Investigator.
Dose Level
ENTO
-1
200 mg twice daily
0
400 mg twice daily
The first 6 subjects in Group A will be enrolled at dose level 0. Once 
the sixth evaluable subject has completed the DLT assessment 
window, the safety review team will evaluate the safety data from all 
enrolled subjects.. 

If 0 or 1 out of the 6 subjects experiences a DLT, Group B will 
open and 6 subjects will be enrolled in Group B at dose level 0

If ≥ 2 out of the 6 subjects experience a DLT, 6 additional 
subjects will be enrolled in Group A at the reduced dose level -1 
(200 mg BID) and Group B will not open


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Group A (ENTO monotherapy)
Eligible subjects with relapsed or refractory hematologic 
malignancies will receive ENTO BID on Days 1-28 of every 28-day 
cycle and will continue on study treatment as long as the subject is 
experiencing clinical benefit and does not meet criteria for study 
treatment discontinuation.
Disease assessments will be performed at the end of Cycle 1 on 
Day 28, as clinically indicated after Cycle 1, at remission/relapse, 
and End of Treatment (EOT). A bone marrow biopsy and aspirate 
sample will be collected for disease assessment for subjects with 
AML. Subjects with hematologic malignancies other than AML will 
undergo disease assessment using the appropriate clinical, 
radiographic, and laboratory procedures per the standard of care or 
institutional practice.
Group B (ENTO + cytarabine + daunorubicin)
Eligible subjects with previously untreated AML will receive ENTO 
BID as a single agent on Cycle 0 Days 1-14, and will receive ENTO 
BID in combination with cytarabine on Days 1-7 and IV 
daunorubicin on Days 1-3 during induction chemotherapy for up to 
two 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.  Up to 4 cycles of 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, subjects who are awaiting a 
donor or transitioning to allogeneic SCT are allowed to receive 
post-remission chemotherapy per investigator discretion up to 4
cycles.  
Number of Subjects 
Planned:
Up to 24 subjects
Target Population:
Japanese subjects with relapsed or refractory hematologic 
malignancies or previously untreated AML who are fit for 
chemotherapy, excluding AML with recurrent genetic abnormalities 
involving chromosomal translocation t(15;17) (q22;q12) and/or the 
fusion gene PML/RARA (FAB classification M3)
Duration of 
Treatment:
Subjects may continue to receive ENTO until treatment failure, 
planned completion of treatment, start of new therapy, unacceptable 
toxicity, withdrawal of consent by the subject, or withdrawal from 
study by the investigator.


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Main Diagnosis and 
Disease Eligibility 
Criteria:
Inclusion Criteria:
Subjects must meet all of the following applicable inclusion criteria 
to be eligible for participation in this study:
1) Group A: Subjects age > 18 with relapsed or refractory
hematologic malignancies by WHO criteria and who are not 
eligible to receive standard of care
2) Group B: Subjects age > 18 with previously untreated AML by 
WHO criteria, who are deemed fit for cytarabine and 
daunorubicin (7+3) induction chemotherapy and are able to 
undergo up to 2 cycles of induction chemotherapy, as determined 
by the treating physician
3) Subjects must have been born in Japan and must not have lived 
outside of Japan for a period > 1 year in the 5 years prior to 
Day 1 of study treatment
4) Subjects must be able to confirm the Japanese origin of their 
maternal and paternal ancestry 
5) ECOG performance status less than or equal to 2
6) Life expectancy of at least 3 months
7) Meet required screening laboratory criteria unless disease
related, as shown below
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
or Estimated 
creatinine 
clearance
< 1.5 x ULN or CrCl ≥ 30 ml/min as calculated by the 
Cockroft-Gault method
Hematology
Hemoglobin
> 8.0 g/dL (without transfusion support, except if due 
to disease marrow involvement)
Coagulation
INRa
< 1.7
Pregnancy
-HCGb
Negative
Infection
HIV
Negative HIV antibody
HBV
Negative HBsAg and negative HBc antibody or positive 
HBc and negative HBV DNA by quantitative PCR
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 post-menopausal). Female subjects with medically documented ovarian 
failure must also have serum FSH levels within the institutional postmenopausal range.


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8) Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by 
ECHO or MUGA and no clinical evidence of congestive heart 
failure 
9) Male subjects and female subjects of childbearing potential who 
engage in heterosexual intercourse must agree to use protocol 
specified method(s) of contraception as described in Appendix 4
10) Lactating females must agree to discontinue nursing from 
screening until 30 days (Group A ENTO monotherapy) or 
6 months (Group B ENTO + cytarabine + daunorubicin) 
following the end of relevant systemic exposure
11) Willingness to comply with scheduled visits, drug administration 
plan, imaging studies, laboratory tests, other study procedures, 
and study restrictions 
12) Have the ability to understand and sign a written informed 
consent form, which must be obtained prior to initiation of study 
procedures
Exclusion Criteria:
Subjects who meet any of the following exclusion criteria are not 
eligible for study participation:
1) Subjects with untreated AML with recurrent genetic 
abnormalities involving chromosomal translocation 
t(15;17) (q22;q12) and/or the fusion gene PML/RARA 
(FAB classification M3) 
2) Known active central nervous system or leptomeningeal 
leukemic involvement. Note: Central nervous system testing 
(CSF analysis) is required in subjects with suspected 
involvement based on symptoms at elevated clinical risk, or 
signs 
3) Current therapy with proton pump inhibitors. Note: H2 receptor 
antagonists and antacids will be allowed for use during the 
protocol
4) Current therapy with medicines that are strong CYP3A or 
CYP2C9 inducers, or moderate CYP2C9 inducers. 
See Section 5.5 Excluded Medication
5) History of active malignancy except for hematologic 
malignancies and 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 


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therapy, early gastric cancer cured by endoscopic mucosal 
resection (EMR) or endoscopic submucosal dissection (ESD), or 
any other cancer that has been in complete remission without 
treatment for ≥ 5 years prior to enrollment
6) Evidence of ongoing uncontrolled 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 
7) Ongoing 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
8) Ongoing (within the past 6 weeks) hepatic encephalopathy
9) Ongoing pneumonitis
10) Ongoing inflammatory bowel disease
11) Ongoing alcohol or drug addiction as determined by investigator
12) Pregnancy or breastfeeding
13) History of prior allogeneic bone marrow progenitor cell or solid 
organ transplantation
14) Group A: Ongoing therapy for the treatment of hematologic 
malignancies (including radiotherapy, chemotherapy, tyrosine-
kinase inhibitors [TKIs], immunotherapy, or investigational 
therapy).
Group B: AML directed therapy prior to enrollment other than 
hydroxyurea or leukapheresis, if indicated for rapidly rising 
white blood cell count.
For Group A, ongoing therapy must be discontinued prior to 
study drug initiation as follows:
a) Prior anti-cancer therapy must be discontinued at least 1 
week or 5 half-lives (whichever is longer) prior to the
initiation of study therapy
b) Exceptions or modifications to the above are as follows: 
Medications that are typically part of a maintenance therapy 
may be administered up to 3 days prior to the first dose 
(eg, mercaptopurine, methotrexate, steroids for acute 
lymphoblastic leukemia (ALL)).  Tyrosine kinase inhibitors 
are not permitted to be continued at screening (eg Imatinib)
and should be discontinued 3 days prior to first dose of
ENTO.


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c) CNS prophylaxis in subjects with relapsed ALL should be 
discontinued at least 1 week prior to first dose of study 
treatment
d) For biologics (eg, monoclonal antibodies), a washout period 
of at least 4 weeks or 5 half-lives (whichever is shorter) since 
the last dose
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
15) Concurrent participation in an investigational drug trial with 
therapeutic intent defined as prior study therapy within 14 days 
prior to study treatment  
16) 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 
17) 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
18) Prior treatment with SYK inhibitors
19) 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
20) Known hypersensitivity to ENTO. Also for Group B, known 
hypersensitivity to cytarabine or daunorubicin, their metabolites, 
or formulation excipients
Study Procedures/
Frequency:
See Study Procedures Table  


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Test Product, Dose, and 
Mode of 
Administration: 
ENTO is available as 200 mg strength tablets and will be 
administered orally BID approximately every 12 hours while in a 
fasted state. The selected starting ENTO dose level in Group A is 
400 mg BID.
Reference Therapy, 
Dose, and Mode of 
Administration: 
Induction chemotherapy (Group B): IV daunorubicin 60 mg/m2 on 
Days 1- 3 and IV cytarabine 100 mg/m2 on Days 1-7 for up to 
2 cycles.
Post-remission chemotherapy (Group B): 3g/m2 HiDAC 
administered BID on Days 1, 3, and 5 (≤ 60 years of age) or 1g/m2
HiDAC administered once daily on Days 1-5 (> 60 years of age) for 
up to 4 cycles.
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.
Efficacy:
Assessment of clinical response in subjects with hematologic 
malignancies other than AML will be according to the latest set of 
published response criteria. Assessment of clinical response in 
subjects with AML will be according to the modified International 
Working Group criteria and will include findings on examination of 
blood, bone marrow and physical examination.
Pharmacokinetics:
Plasma drug concentrations will be analyzed for determination of 
ENTO PK parameters.
Endpoints:
Primary Endpoints:
Safety:

Occurrence of AEs and laboratory abnormalities defined as 
DLTs for ENTO monotherapy in subjects with relapsed or 
refractory hematologic malignancies

Occurrence of AEs and laboratory abnormalities defined as 
DLTs for ENTO in combination with cytarabine and 
daunorubicin in subjects with previously untreated AML who are 
candidates for chemotherapy


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Secondary Endpoints: 
Safety

Occurrence of AEs, laboratory findings and findings on physical 
exam not defined as DLTs 
Pharmacokinetics

Determination of the PK parameters of ENTO based on plasma 
concentrations
Exploratory Endpoints: 
CCI


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Statistical Methods:
Appropriate data analysis sets will be defined. The full-analysis set 
(FAS) will include all subjects who receive at least 1 dose of study 
drug (ENTO). The DLT analysis set includes subjects in FAS with 
sufficient drug exposure or who experience a DLT during the DLT 
assessment window. Other data sets will be defined and will include 
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 for the relevant analysis sets. Descriptive summaries 
will be prepared to show the number of subjects, mean, standard 
deviation (StD), 95% confidence intervals (CIs) the mean, median, 
minimum, and maximum for continuous variables; counts, 
percentages, and 95% CIs on the percentage for categorical 
variables. Time-to-event endpoints (eg, 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 with the corresponding 
95% CI, the 25%, and 75% percentiles for these endpoints will be 
provided.
Data regarding study treatment administration, study drug 
compliance, safety variables, and post study therapies will be 
described and summarized using FAS. Using data from the relevant 
evaluable data sets, study drug plasma concentrations will also be 
described and summarized.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.
CCI


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
ADR
adverse drug reaction
AE
adverse event
AKT
protein kinase B (PKB)
ALC
ALL
absolute lymphocyte count
acute lymphoblastic leukemia
ALT
alanine aminotransferase
AM
morning
AML
acute myeloid leukemia
ANC
absolute neutrophil count
ARA-C
cytarabine (Cytosine 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
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
CTA
clinical trial application


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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
DSPH
Drug Safety and Public Health
EC
ethics committee
EC50
50% effective inhibitory concentration
ECG
electrocardiogram
eCRF
electronic case report form(s)
EDC
electronic data capture
ENTO
entospletinib
EOT
end of treatment
EFS
event free survival
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
HiDAC
high-dose cytarabine


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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
IMP
investigational medicinal product
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 
LTFU
long term follow up
LVD
longest vertical dimension
MAPK
mitogen-activated protein kinase
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
mL
milliliter
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


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NCI
National Cancer Institute
ND
no disease
NE
not evaluable
ng
nanogram
NHL
non-Hodgkin lymphoma
nM
nanomolar
NOAEL
no observable adverse effect level
OS
overall survival
ORR
overall 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
QD
once-daily
RA
refractory anemia
RBC
red blood cell
REB
research ethics board
RFS
relapse - free survival
RNA
ribonucleic acid
SADR
serious adverse drug reactions
SAE
serious adverse event
SCT
stem cell transplant
SD
stable disease
SD
standard deviation
SDD
spray dried dispersion
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
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.
Background
Acute myeloid leukemia (AML) is a biologically heterogeneous disease of the hematopoietic 
system characterized by clonal accumulation and expansion of immature myeloid cells in the 
bone marrow {Lowenberg 1999}. A number of clinical factors including age, hyperleukocytosis, 
prior chemotherapy, and extramedullary or CNS 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 {Mrozek 2008}. 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 {Mrozek 2008}. This predictive value is used to direct initial treatment strategies, 
including allogeneic transplantation in first CR. 
Traditional therapy for AML has remained unchanged over 5 decades and usually consists of a 
standard chemotherapy regimen of 7 days of cytarabine plus 3 days of an anthracycline (7+3). 
CR rates to induction chemotherapy range from 20% to 85% with higher CR rates noted in 
patients younger than 60 years of age and those with good-risk karyotype. Patients with poor-risk 
karyotype and certain molecular mutations (eg, FLT3-ITD) are typically referred for an 
allogeneic stem cell transplantation in first CR. Unfortunately, with current treatment strategies, 
only approximately 40% of the subjects achieve long-term remission. Of those subjects who 
relapse, only a fraction undergo successful salvage treatment followed by allogeneic 
hematopoietic stem cell transplant (HSCT) with curative intent. Outcomes for older subjects are 
far worse and this is related to host and disease related factors. Many older adults may not be 
candidates for intensive induction chemotherapy with 7+3 or HSCT due to co-morbid illness, 
poor performance status, and others refuse standard therapy due to concerns of high toxicity and 
low efficacy. Increasingly, elderly AML patients are being treated with hypomethylating agents 
like decitabine and azacitidine with CR rates of 20% to 25%. However, even with adaptation of 
cytogenetically risk-stratified therapies, 20% to 30% of subjects with AML never achieve CR, 
and greater than 50% of subjects who achieve CR subsequently experience very early disease 
relapse. 
Important factors predictive of prognosis in AML include age, white blood cell count at 
presentation, the presence of secondary AML (ie, arising after prior chemotherapy or a prior 
myelodysplastic or myeloproliferative disorder), extramedullary or central nervous system 
disease, and chromosomal abnormalities {Steelman 2004}. Non-random chromosomal 
abnormalities, which are identified in approximately 50% to 70% of adult patients with primary 
acute leukemia, have long been recognized as one of the most important independent prognostic 
indicators for achievement of CR, duration of first CR, and survival following intensive 
chemotherapy treatment {Steelman 2004, Stone 2004}. There are several molecular mutations
(eg, FLT3-ITD, NPMI, IHD1/2, DNMT3A, MLL-PTD) and overexpression of genes 
(eg, ERG, BAALC) that have a prognostic role in AML disease outcomes {Marcucci 2011}.


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Genetic alterations not only represent independent prognosticators, but also may constitute 
targets for specific therapeutic intervention, including the use of allogeneic transplantation in 
first CR. The lack of significant advancements in the treatment of AML in adults in the last 
40 years highlights the need for development of novel therapeutic strategies.
1.2.
Spleen Tyrosine Kinase Biology in AML
SYK is a non-receptor cytoplasmic 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, result in SYK recruitment to the receptor complex and 
activation 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 
{Geahlen 2014, Ruzza 2009}. 
SYK has been shown to play an important role as a potential pro-survival factor in hematological 
malignancies {Geahlen 2014}. SYK activates an array of B-cell responses, including 
proliferation, survival, differentiation, and apoptosis through key signal transduction pathways 
downstream of the B-cell receptor (BCR) such as phospholipase C-gamma (PLCγ), 
phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK). Additionally, 
the BCR can deliver antigen-independent signals that have also been postulated to require SYK 
activity. Antigen-dependent and independent signals have been implicated in the pathogenesis of 
several B-cell malignancies {Efremov 2011}.
In AML, SYK has been shown to regulate leukemic cell survival and proliferation (Figure 1-1).
SYK is expressed in 90% of AML samples and is constitutively activated (pSYK-Y526/6) in 
AML blasts {Hahn 2009}. 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}. In FLT3 mutant AML, SYK is 
constitutively activated and has been shown to phosphorylate FLT3-ITD and result in up 
regulation of FLT3 signaling pathways including downstream activation of the signal transducer 
and activator of transcription 3 and 5 (STAT3 and STAT5) proteins, which are responsible for 
the proliferation and survival of AML leukemic blasts 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}.
Activation of the SYK signaling pathways in AML occurs through several receptors including 
stimulation of Fc-γ chain and the β integrins, Mac-1 and Integrin 3. Further, activation of 
STAT3 and STAT5, which are responsible for the proliferation and survival of AML has been 
demonstrated to be SYK-dependent {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 CD61/Itgb3 (Integrin B3) impaired homing 
of primary leukemia cells and induced myeloid differentiation in murine models and in human 


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leukemia cell lines causing decreased levels of p-SYK in MLL mutated primary cells. 
Ultimately, integrin signaling through SYK leads to SYK activation affecting transcription, 
differentiation, and leukemic stem cell survival {Oellerich 2013}.
In an exceptionally high risk group of AML with HOXA9/MEIS1, SYK is critical to leukemic 
cell survival {Mohr 2016}. HOXA9 and MEIS1 have been found to be over expressed in 
approximately 30% to 40% of AML cases and expression correlates with poor prognosis 
{Drabkin 2002, Gao 2016, Heuser 2009, Zangenberg 2009}. High co-expression of HOXA9 and 
MEIS1 were shown to result in increased SYK protein levels in AML. Non-clinical investigation 
of this finding in a murine model of HOXA9/MEIS1-induced leukemia demonstrated that 
genetic knockdown or pharmacologic inhibition of SYK with fostamatinib resulted in a dramatic 
survival benefit {Mohr 2016}.
Figure 1-1.
SYK Regulation of AML Cell Survival and Proliferation
1.3.
Entospletinib
Entospletinib (ENTO; GS-9973), a new chemical entity, is a potent and highly selective inhibitor 
of SYK, being developed by Gilead Sciences, Inc. (Gilead) for oral administration in the 
treatment of AML. In vitro studies and emerging clinical data suggest that inhibition of SYK 
may be beneficial in the treatment of certain cancers where SYK-dependent signaling is 
important for the maintenance and proliferation of malignant cells, including those of AML.
Bone Marrow 
Stromal Cell 
~2 lntegrin 
or 
FcyRs 
~
SYK 
Survival and Prolife 
+-------------------------- miR-146a 
---, 
' 
~
OXM 
. 
AML Blast 


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1.3.1.
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 (Figure 1-2).
Figure 1-2.
ENTO 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, 


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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 IC50 for 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 
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.
1.3.2.
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.
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.
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, dogs and 
monkeys was recovered in urine.
ENTO showed good metabolic stability with human hepatic material in vitro. In humans, 
clearance through metabolism is therefore expected to be slow. 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. These results are consistent with clinical drug interaction studies with potent inhibitors 
and inducers of CYP3A and CYP2C9.
ENTO is 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%).


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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. This was confirmed in vivo where ENTO affected the pharmacokinetics of 
rosuvastatin, a substrate for OATP and BCRP transporters. ENTO is a weak inhibitor of OCT2 
and BSEP (IC50 10 µM for each) but does not inhibit MRP1, OAT1, OAT3 or OCT1. 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.
ENTO was a weak inhibitor of intestinal Pgp in vivo. It is not a substrate of OATP1B1, 
OATP1B3 or Pgp in vitro but is transported by BCRP.
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.
1.3.3.
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 


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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. No carcinogenicity studies have 
been conducted to date.  
Further information on the nonclinical toxicology of ENTO is available in the 
Investigator’s Brochure.
1.3.4.
Clinical Trials of ENTO
As of July 2016, a total of 930 subjects (476 healthy subjects, 7 subjects with rheumatoid 
arthritis [RA], 10 subjects with impaired hepatic function, 171 subjects with chronic 
lymphocytic leukemia [CLL], 11 subjects with acute lymphocytic leukemia [ALL], 31 subjects 
with AML, 223 subjects with non-Hodgkin lymphoma [NHL], and 1 subject with chronic 
graft-versus-host-disease [cGVHD]) have participated in Phase 1 and Phase 2 clinical studies of 
ENTO. Of these, 904 subjects were treated with ENTO (450 healthy subjects, 7 subjects with 
RA, 10 subjects with impaired hepatic function, 171 subjects with CLL, 11 subjects with ALL, 
31 subjects with AML, 223 subjects with NHL, and 1 subject with cGVHD). 
Study GS-US-339-0102, entitled “A Phase 2, Open Label Study Evaluating the Efficacy, Safety, 
Tolerability, and PD of ENTO in Subjects with Relapsed or Refractory Hematologic 
Malignancies” is ongoing and as of the data cutoff date (31 May 2016) had enrolled and treated 
265 subjects with either the original ENTO 800 mg Mono-MSA formulation (n=213) or the 
ENTO 400 mg Bis-MSA SDD formulation (n=52). The Bis-MSA SDD ENTO formulation was 
introduced later in the course of the study. Consequently, a smaller proportion of subjects had 
been treated with the Bis-MSA SDD ENTO formulation for more than 12 months compared to 
the Mono-MSA formulation (9.6%, 5 subjects versus 19.2%, 41 subjects). The Bis-MSA SDD 
ENTO formulation of ENTO will be used in ongoing and planned clinical trials. AEs ≥ Grade 3 
in severity were reported in 185 of 265 subjects (69.8%), and SAEs occurred in 94 subjects 
(35.5%). Overall, the 3 most common AEs were fatigue (55.8%, 148 subjects), nausea (43.0%, 
114 subjects), and diarrhea (41.5%, 110 subjects) and the 3 most common AEs with a worst 
severity of ≥ Grade 3 were anemia (11.3%, 30 subjects; 4 Grade 4), ALT increased (9.8%, 
26 subjects; 8 Grade 4), and neutropenia (9.4%, 25 subjects; 14 Grade 4). The most commonly 
reported AEs of any grade in the Bis-MSA SDD ENTO treatment group were fatigue (50.0%, 
26 subjects); diarrhea (32.7%, 17 subjects); and anemia, cough, nausea (23.1%, 12 subjects each) 
and the 3 most common AEs with a worst severity of ≥ Grade 3 were anemia (9.6%, 5 subjects; 
all Grade 3), neutropenia (7.7%, 4 subjects; 2 Grade 4), and sepsis (7.7%, 4 subjects; 2 Grade 4).
For additional information, please refer to the current investigator brochure.


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Study GS-US-339-1559, entitled “A Phase 1b/2 Study of Entospletinib (GS-9973) Monotherapy 
and in Combination with Chemotherapy in Patients with Acute Myeloid Leukemia (AML)” is an 
ongoing Phase 1b/2 open-label study evaluating the efficacy, safety, tolerability, and 
pharmacodynamics of ENTO administered at doses of 200 and 400 mg twice daily (BID) in 
combination with chemotherapy in previously untreated AML subjects who are candidates for 
standard 7+3 chemotherapy (Group A), in combination with decitabine or azacitidine in 
previously untreated subjects who are not candidates for standard chemotherapy (Group B), and 
as monotherapy in subjects with previously untreated AML who are not candidates for 
chemotherapy or in subjects with relapsed or refractory AML (Group C). A total of 
approximately 205 subjects with previously untreated or relapsed/refractory AML will be dosed 
in the 3 groups (A, B, and C) in Study GS-US-339-1559, each including a Phase 1b dose 
escalation phase (3+3) and a Phase 2 dose expansion phase. Based on the evaluation of ENTO in 
Groups A and C of the Phase 1b portion of the study, the dose level planned for further 
evaluation in the Phase 2 portion of the study as well as planned studies of ENTO in AML has 
been determined to be 400 mg BID. 
1.3.4.1.
GS-US-339-1559 Initial Study Results
Initial Phase 1b results as of 12 Oct 2016 are available from 12 AML subjects enrolled in 
Study GS-US-339-1559 Group A. Subjects in Group A received ENTO monotherapy BID 
during a 2-week lead-in period, which continued to be given daily in combination with IV 
chemotherapy (cytarabine and daunorubicin [7+3]) for up to 2 cycles of induction chemotherapy. 
All 3 subjects receiving ENTO 200 mg BID and 7 of 9 subjects receiving ENTO 400 mg BID
were evaluable for efficacy. 10 of the 12 subjects treated with ENTO had a CR/CRi.  The overall 
CR rate among evaluable subjects was 83% (including CR, cytogenetic complete remission 
[CRc], or CRi).
A plot of bone marrow blasts over time for all enrolled subjects is provided in Figure 1-3 and a 
plot of circulating blasts over time is provided in Figure 1-4. ENTO was well tolerated during the 
2-week monotherapy lead-in period as evidenced by the lack of dose reductions or interruptions. 
1 subject in Group A required hydroxyurea to control blast count. Most subjects showed an 
improvement in blast count during the ENTO lead-in period (Figure 1-3). One subject (Subject 
 had evidence of increasing circulating blast count through the end of ENTO 
monotherapy, which may have been due to margination and myeloid differentiation of blasts. 
This subject obtained a CRi at the end of the first cycle of induction and CR at the end of 
treatment. 
PPD


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Figure 1-3.
GS-US-339-1559: Group A Bone Marrow Blasts Trajectory Through 
Induction Treatment (Full Analysis Set)
Figure 1-4.
GS-US-339-1559: Group A Circulating Blasts Through Induction 
Treatment (Full Analysis Set)
PPD
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End of Induction 
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• 


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1.3.4.2.
Treatment-Emergent Adverse Events in GS-US-339-1559
In Study GS-US-339-1559, treatment-emergent AEs that occurred in Group A are those that 
have been previously recognized in subjects with AML during chemotherapy induction 
treatment.  
As of 12 October 2016, the most commonly reported treatment-emergent AEs in Group A 
(ENTO with cytarabine and daunorubicin) occurring in at least 4 subjects across dose levels were 
as follows: febrile neutropenia (75.0%, 9 subjects), nausea (66.7%, 8 subjects), diarrhea (58.3%, 
7 subjects), edema peripheral (75.0%, 6 subjects), and headache (33.3%, 4 subjects).
As of 07 November 2016, the most commonly reported treatment-emergent AEs in Groups B 
(ENTO with decitabine) and C (ENTO monotherapy) occurring in at least 4 subjects across dose 
levels were as follows:

Group B — febrile neutropenia (72.7%, 8 subjects), , nausea (54.5%, 6 subjects), and 
constipation, device related infection, lung infection(36.4%, 4 subjects each)

Group C —diarrhea, nausea, and anaemia (28.6%, 4 subjects each)
For additional information, please refer to the current investigator brochure.
1.4.
Information about Cytarabine
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 uM, above which the transport is by passive diffusion. To become an active 
compound ARA-C is converted to ARA-C triphosphate (ARA-CTP) by 3 sequential enzymes, 
deoxycitidine kinase, deoxycitidine monophosphate kinase, and nucleotide-disphosphate kinase. 
Competing with these enzymes, there are 2 other enzymes, cytidine deaminize and dCMP 
deaminase that inactivate ARA-C and ARA-CMP, respectively, to the corresponding 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 
the DNA polymerases resulting in termination of the 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 (HiDAC) 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 
20 years and is commonly used for AML consolidation.
1.5.
Information about 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 


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complexes with DNA by intercalating between base pairs. It inhibits topoisomerase II activity by 
stabilizing the DNA-topoisomerase II complex, preventing the relegation portion of the 
ligation-religation reaction that topoisomerase II catalyzes. Single strand and double strand DNA 
breaks results. 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. Dose limiting 
toxicities for daunorubicin are myelosuppression and cardiotoxicity. Other AEs include 
mucositis, diarrhea, rash, reversible alopecia, and contact dermatitis. Daunorubicin is also a 
backbone of AML therapy, commonly delivered by IV bolus for three days during the cytarabine 
infusion.
1.6.
Rationale for This Study
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 vitro and has anti-leukemia activity in AML mouse 
models. SYK has been shown to be part of the neoplastic progress in AML, as well as in several 
B-cell malignancies such as NHL and CLL. SYK may also have a role in other hematologic 
malignancies, such as multiple myeloma {Koerber 2015} and chronic myeloid leukemia 
{Gioia 2011}. Therefore, it is reasonable to administer ENTO to a wide variety of hematologic 
malignancies where patients have failed standard therapies. Based on this and the compelling 
initial findings from Study GS-US-339-1559, Gilead is planning to conduct this Phase 1 clinical 
trial to evaluate the safety, tolerability, and PK of ENTO monotherapy for Japanese subjects with 
relapsed or refractory hematologic malignancies and ENTO in combination with cytarabine and 
daunorubicin for Japanese subjects with previously untreated AML who are candidates for 
chemotherapy. Data from this study will support the development of ENTO in Japanese subjects.
1.6.1.
Rationale for Dose Selection
As of July 2016, a total of 9 evaluable subjects in Group A and 6 evaluable subjects in Group B
have received ENTO in the dose escalation phase of Study GS-US-339-1559 at dose levels of 
200 mg and 400 mg, and 9 evaluable subjects in Group C have received ENTO at dose levels of 
400 mg (n=3) and 800 mg (n=6). To date, no new safety findings have emerged during the 
course of the study to impact the current safety profile of ENTO. 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. ENTO clinical activity was noted as a single agent at 
200 mg and 400 mg and in combination with 7+3 chemotherapy. The time to CR and depth of 
response (CRc vs. CR vs. CRi) was improved at 400 mg vs. 200 mg in previously untreated 
subjects. Based on these data, ENTO will be administered at a starting dose of 400 mg BID (PO) 
in a fasted state in this study.


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1.7.
Risk/Benefit Assessment for the Study
1.7.1.
Potential Risks Based on Nonclinical Safety Data with ENTO
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. In rats treated with 500 mg/kg/day ENTO for 4 weeks, 
slight villus alteration in the duodenum was noted; this finding was not observed following 
administration of up to 100 mg/kg/day to rats for 26 weeks. In rabbits and dogs, the predominant 
organs affected were the GI tract and lymphoid tissues including spleen, lymph nodes, and/or the 
thymus. At high doses, evidence of lymphoid tissue depletion was noted in rabbits and dogs. 
Oral administration of ENTO to rats for up to 26 weeks or cynomolgus monkeys for up to 
39 weeks showed no evidence of GI toxicity or lymphoid changes at exposures which 
overlapped with or exceeded those in dogs. 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 increased in any ENTO-treated 
species. Clinical assessments will monitor for signs and symptoms of infection, hemorrhage, GI 
disturbances, 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. At dose levels associated with maternal toxicity (reduced body weights 
and food consumption), decreased fetal weights and delayed ossification were noted in these 
studies. No gross 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 
30 days (Group A ENTO monotherapy) or 6 months (Group B ENTO + cytarabine + 
daunorubicin) following last treatment administration. Male subjects with female partners of 
childbearing potential must use condoms during treatment and until 90 days (Group A) or 
6 months (Group B) from the last dose of study drug. 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 (Group A) or 6 months 
(Group B) from the last dose of study drug.


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1.7.2.
Potential Risks Based on Clinical Safety Data with ENTO
To date, ENTO has been well tolerated. Treatment-emergent AEs commonly reported across the 
studies involving healthy subjects include headache, somnolence, rash, and GI symptoms 
(nausea and abdominal pain), all of which were mild and reversible. Increased transaminase 
levels were noted in some subjects, and these changes were also found to be reversible.
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.
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 
and daunorubicin. To mitigate the risk of bone marrow suppression, hematology monitoring will 
be performed. 
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.
The available nonclinical and clinical data support the evaluation of ENTO in eligible subjects 
with relapsed or refractory hematologic malignancies or previously untreated AML. Given the 
seriousness of these conditions, the aggregate potential benefits considered in the context of 
potential risk, support further development of ENTO in Japanese subjects in this Phase 1b study.
1.8.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objectives of this study are:

To evaluate the safety and tolerability of ENTO monotherapy in Japanese subjects with 
relapsed or refractory hematologic malignancies

To evaluate the safety and tolerability of ENTO in combination with cytarabine and 
daunorubicin (7+3) in Japanese subjects with previously untreated AML who are candidates 
for chemotherapy
The secondary objectives of this study are: 

To evaluate the PK of ENTO in Japanese subjects with relapsed or refractory hematologic 
malignancies

To evaluate the PK of ENTO in Japanese subjects with previously untreated AML who are 
candidates for chemotherapy

To evaluate the safety and tolerability of ENTO in combination with age-adjusted HiDAC in 
Japanese subjects with previously untreated AML who are candidates for chemotherapy  
The exploratory objectives of this study are:
CCI


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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoints of this study are:
Safety Endpoints:

Occurrence of AEs and laboratory abnormalities defined as DLTs for ENTO monotherapy in 
subjects with relapsed or refractory hematologic malignancies

Occurrence of AEs and laboratory abnormalities defined as DLTs for ENTO in combination 
with cytarabine and daunorubicin in subjects with previously untreated AML who are 
candidates for chemotherapy
The secondary endpoints of this study are:
Safety

Occurrence of AEs, laboratory findings and findings on physical exam not defined as DLTs 
Pharmacokinetics

Determination of the PK parameters of ENTO based on plasma concentrations
The exploratory endpoints of this study are:
CCI


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3.2.
Study Design
A Phase 1b, open-label, multicenter study evaluating the safety, tolerability, and PK of ENTO
monotherapy in Japanese subjects with relapsed or refractory hematologic malignancies
(Group A) and ENTO in combination with 7 + 3 in Japanese subjects with previously untreated 
AML (Group B). Approximately 12 subjects will be enrolled to receive ENTO BID as 
monotherapy or in combination with cytarabine and daunorubicin. 
The starting ENTO dose level of 400 mg BID is defined as dose level 0. This dose was chosen 
from the Phase 1b dose escalation portion of Study GS-US-339-1559 based on clinical activity 
and tolerability and is currently being explored in the Phase 2 portion of Study GS-US-339-1559
as well as Studies GS-US-339-0102 and GS-US-339-1560.  The first 6 subjects will be enrolled 
in Group A at dose level 0. The safety and tolerability of dose level 0 will be assessed in 
Group A before proceeding with Group B.
Dose Level
ENTO
-1
200 mg BID
0
400 mg BID
3.2.1.
Dose Limiting Toxicities
The DLT assessment window for Group A begins on Cycle 1 Day 1 and ends on Cycle 1 Day 28 
and for Group B begins on lead-in Cycle 0 Day 1 and ends 28 days from Cycle 1 Day 1 of 
induction chemotherapy. The subjects in this study should be in hospital during the DLT 
assessment window, and the window for Group B may be expanded for bone marrow recovery as 
noted below. During the DLT assessment window, subjects who fail to complete a total of 
21 days of ENTO (or in Group B, miss any doses of cytarabine and daunorubicin) for reasons 
CCI


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other than DLT will not be evaluable for DLT assessment and additional (replacement) subjects 
may be enrolled in a timely manner to that dose level in order to provide adequate safety data, as 
determined by the Gilead Medical Monitor, the Japanese CRO Medical Monitor, and the 
Principal Investigator. 
A Grade 4 non-hematologic toxicity attributable to ENTO will be considered a DLT with the 
exception of alopecia, nausea and vomiting controllable with anti-emetic therapy, line associated 
venous thrombosis, line associated infection and fatigue.
In subjects without bone marrow evidence of hematologic malignancy (eg, leukemia, lymphoma, or 
myeloma) by pathological examination, hematologic toxicity will be defined as failure to recover 
neutrophil count (ANC>500/uL) or platelet count (>25000/uL) within 28 days for Group A and 
within 8 weeks from chemotherapy initiation for Group B.
Subjects with transient Grade 4 electrolyte abnormalities that are not clinically significant and 
are correctable within 24 hours will not be considered DLTs.
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 DLTs.
In general, infection will not constitute 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 DLTs unless the toxicity does not resolve to ≤ Grade 2 
within 10 days.  Subjects in whom ENTO was suspended or dose reduced for a period of more 
than 10 days will be considered as having a DLT.  
Once the sixth evaluable subject has completed the DLT assessment window, the safety review 
team will evaluate the safety data from all enrolled subjects..

If 0 or 1 out of the 6 subjects experiences a DLT, Group B will open and 6 subjects will be 
enrolled in Group B at dose level 0.

If ≥ 2 out of the 6 subjects experience a DLT, 6 additional subjects will be enrolled in 
Group A at the reduced dose level -1 (200 mg BID) and Group B will not open.
3.2.2.
Group A (ENTO monotherapy)
Eligible subjects with relapsed or refractory hematologic malignancies will receive ENTO BID 
on Days 1-28 of every 28-day cycle and will continue on study treatment as long as the subject is 
experiencing benefit and does not meet criteria for study treatment discontinuation.
Disease assessments will be performed at the end of Cycle 1 on Day 28, as clinically indicated 
after Cycle 1, at remission/relapse, and at EOT. A bone marrow biopsy and aspirate sample will 
be collected for disease assessment for subjects with AML. Subjects with hematologic 
malignancies other than AML will undergo disease assessment using the appropriate clinical, 
radiographic, and laboratory procedures per the standard of care or institutional practice.


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3.2.3.
Group B (ENTO + cytarabine + daunorubicin)
Figure 3-1.
Group B Dosing Schema
Lead-in (Cycle 0): Eligible subjects with previously untreated AML will receive ENTO BID on 
Days 1-14 as a single agent. However, cytarabine and daunorubicin (7+3) treatment (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:
Examples of such situations may include but are not limited to:

White blood cell count is increasing and is greater than 20,000/uL

Leukemic related complications that, in the opinion of the treating physician, requires 
initiation of cytotoxic chemotherapy 
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.  
I 
-
Post-Remission 
CR/CRi 
chemotherapy 
Stem Cell 
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s 
-
Induct ion 
ENTO + HiDAC 
Transplant 
C 
Lead-in 
(2-4 cycles) 
R 
(Cycle 0) 
ENTO + 
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E 
7+3 
ENTO 
Non-
E 
14 days 
(up to 2 
CR/ 
N 
cycles) 
CRi 
Treat ment 
-
Failure 
(if completed 2 
induction cycles) 
-


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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 Treatment). 
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.
Induction (up to 2 cycles): Following the lead-in cycle, ENTO will continue to be administered 
BID on Days 1-28 in combination with IV daunorubicin 60 mg/m2 on Days 1- 3 and IV 
cytarabine 100 mg/m2 on Days 1-7 for up to 2 cycles.
Chemotherapy
Dose
Days
IV daunorubicin
60 mg/m2
1-3
IV cytarabine
100 mg/m2
1-7
If the Cycle 1 Day 14 bone marrow evaluation has unequivocal evidence of persistent AML, 
subjects will immediately proceed with Cycle 2. If the bone marrow is hypocellular without 
evidence of residual leukemia on Day 14, a bone marrow evaluation should be repeated on Day 
28 or within 21 days as blood counts recover. Subjects are to continue receiving ENTO BID as 
they are awaiting disease assessment results and until the completion of induction therapy as 
determined by bone marrow response. The start of Cycle 2 will depend on the timing of the 
disease assessment results. Cycle 2 is to be omitted if CR or CRi status is obtained after 
1 induction cycle.
If CR/CRi is achieved at the end of Cycle 1 or 2, the subject may proceed to stem cell transplant 
(SCT) if eligible. Otherwise, the subject will receive post-remission chemotherapy. 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 endpoint criteria, and will be discontinued from the study.
Post-remission chemotherapy (at least 2 cycles, up to 4 cycles): Therapy will be offered to 
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.  ENTO will be administered 
BID on Days 1-28 of each 28-day cycle combined with 3g/m2 high dose cytarabine (HiDAC)
administered IV BID on Days 1, 3, and 5 (≤60 years of age) or 1g/m2 HiDAC administered IV 
once daily on Days 1-5 (> 60 years of age). Careful attention should be paid to the subject’s 
neurological status, particularly cerebellar function prior to each HiDAC dose. The HiDAC
doses are the same doses that have been implemented across ENTO clinical studies. Subjects 
may proceed to allogeneic SCT based on donor availability during post-remission chemotherapy 
and following completion of post-remission chemotherapy.  


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Chemotherapy
Subject Age
Dose
Days
HiDAC
≤ 60 years
3g/m2 BID
1, 3, 5
HiDAC
> 60 years 
1g/m2 once daily
1-5
3.3.
Study Treatments
The investigational study drugs (ENTO, daunorubicin, and cytarabine) will be supplied by 
Gilead Sciences. ENTO 200 mg strength tablets will be self-administered by the subjects 
enrolled in the trial. Daunorubicin and cytarabine will be administered as described in 
Section 5.3.2.
3.4.
Duration of Treatment
Subjects may continue receiving ENTO until treatment failure, planned completion of treatment, 
start of new therapy, unacceptable toxicity, withdrawal of consent, or other reasons specified in 
Section 3.5.1.
3.5.
Discontinuation Criteria
3.5.1.
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 A: If there is disease progression or if there has not been an improvement in 
cytopenias, blast count, peripheral blood or marrow that would suggest clinical benefit, the 
subject should be removed from study treatment per Investigator discretion. Decisions 
regarding continuation of ENTO monotherapy in subjects should be determined by the 
Investigator.

Group A: Requires continued treatment with hydroxyurea after Cycle 1

Group B: If a CR or CRi is not achieved by the end of induction Cycle 2, the subject will be 
considered to have refractory leukemia, to meet the definition of treatment failure and study 
endpoint criteria, and will be discontinued from the study treatment


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
Subjects may be removed in the case of new CNS disease or other new sites of 
extramedullary involvement

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 the last 
study visit (see Section 6.8.3, Long term follow up)

Subjects with noncompliance to study treatment administration, study procedures, or study 
requirements that increase risk or substantially compromise the interpretation of study results
should be withdrawn from study treatment.

Pregnancy or breastfeeding begins during the study 

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. 

Initiation of non-study specific anti-cancer therapy 

Discontinuation of the study treatment at the request of Gilead, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC)
3.5.2.
Discontinuation of Study
Discontinuation from the study may occur in the following instances:

If, in the investigator’s opinion and in consultation with Gilead, it is determined not to be in 
the subject’s best interest to continue

Pregnancy or breastfeeding begins during the study

Death

Discontinuation of the study at the request of Gilead, a regulatory agency, or an 
institutional review board or independent ethics committee (IRB/IEC) occurs

Withdrawal of consent

Lost to follow-up
3.6.
End of Treatment
Subjects will be removed from study treatment when any of the criteria listed in Section 3.5.1
apply. The End of Treatment (EOT) visit should be completed when a subject discontinues study 
treatment and prior to initiating a new therapy.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 12 Japanese subjects with relapsed or refractory hematologic malignancies or
previously untreated AML who meet the eligibility criteria will be enrolled to receive ENTO 
BID as monotherapy or in combination with cytarabine and daunorubicin. 
4.2.
Inclusion Criteria
Subjects must meet all of the following applicable inclusion criteria to be eligible for 
participation in this study.
1) Group A: Subjects age > 18 with relapsed or refractory hematologic malignancies by 
WHO criteria and who are not eligible to receive standard of care 
2) Group B: Subjects age > 18 with previously untreated AML by WHO criteria, who are 
deemed fit for cytarabine and daunorubicin (7+3) induction chemotherapy and are able to 
undergo up to 2 cycles of induction chemotherapy, as determined by the treating physician
3) Subjects must have been born in Japan and must not have lived outside of Japan for a period 
> 1 year in the 5 years prior to Day 1 of study treatment
4) Subjects must be able to confirm the Japanese origin of their maternal and paternal ancestry 
5) ECOG performance status less than or equal to 2
6) Life expectancy of at least 3 months
7) Meet required screening laboratory criteria unless disease related, as shown below 


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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 or 
Estimated creatinine 
clearance
< 1.5 x ULN or
CrCl ≥ 30 ml/min as calculated by the Cockroft-Gault method
Hematology
Hemoglobin
≥ 8.0 g/dL 
(without transfusion support, except if due to disease marrow involvement)
Coagulation
INRa
< 1.7
Pregnancy
-HCGb
Negative
Infection
HIV
Negative HIV antibody
HBV
Negative HBsAg and negative HBc antibody or 
positive HBc and negative HBV DNA by quantitative PCR
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 post-menopausal). Female 
subjects with medically documented ovarian failure must also have serum FSH levels within the institutional 
post-menopausal range.
8) Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO or MUGA and no 
clinical evidence of congestive heart failure 
9) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in
Appendix 4
10) Lactating females must agree to discontinue nursing from screening until 30 days (Group A 
ENTO monotherapy) or 6 months (Group B ENTO + cytarabine + daunorubicin) following 
the end of relevant systemic exposure
11) Willingness to comply with scheduled visits, drug administration plan, imaging studies, 
laboratory tests, other study procedures, and study restrictions 
12) Have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of study procedures


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not eligible for study participation:
1) Subjects with previously untreated AML with recurrent genetic abnormalities involving 
chromosomal translocation t(15;17) (q22;q12) and/or the fusion gene PML/RARA
(FAB classification M3)
2) Known or suspected 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) Current therapy with proton pump inhibitors. Note: H2 receptor antagonists and antacids will 
be allowed for use during the protocol.
4) Current therapy with medicines that are strong CYP3A or CYP2C9 inducers, or moderate 
CYP2C9 inducers. See Section 5.5 Excluded Medication.
5) History of active malignancy except for hematologic malignancies and 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, early gastric 
cancer cured by endoscopic mucosal resection (EMR) or endoscopic submucosal dissection 
(ESD), or any other cancer that has been in complete remission without treatment for 
≥5 years prior to enrollment
6) Evidence of ongoing uncontrolled 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.
7) Ongoing 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.
8) Ongoing (within the past 6 weeks) hepatic encephalopathy
9) Ongoing pneumonitis
10) Ongoing inflammatory bowel disease
11) Ongoing alcohol or drug addiction as determined by investigator
12) Pregnancy or breastfeeding
13) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation


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14) Group A: Ongoing therapy for the treatment of hematologic malignancies (including 
radiotherapy, chemotherapy, tyrosine-kinase inhibitors [TKIs], immunotherapy, or 
investigational therapy).
Group B: AML directed therapy prior to enrollment other than hydroxyurea or leukapheresis, 
if indicated for rapidly rising white blood cell count.
For Group A, ongoing therapy must be discontinued prior to study drug initiation as follows:
a) Prior anti-cancer therapy must be discontinued at least 1 week or 5 half-lives (whichever 
is longer) prior to the initiation of study therapy
b) Exceptions or modifications to the above are as follows: Medications that are typically 
part of a maintenance therapy may be administered up to 3 days prior to the first dose 
(eg, mercaptopurine, methotrexate, steroids for acute lymphoblastic leukemia (ALL)).  
Tyrosine kinase inhibitors are not permitted to be continued at screening (eg Imatinib) 
and should be discontinued 3 days prior to first dose of ENTO.
c) CNS prophylaxis in subjects with relapsed ALL should be discontinued at least 1 week 
prior to first dose of study treatment
d) For biologics (eg, monoclonal antibodies), a washout period of at least 4 weeks or 
5 half-lives (whichever is shorter) since the last dose
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
15) Concurrent participation in an investigational drug trial with therapeutic intent defined as 
prior study therapy within 14 days prior to study treatment
16) 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
17) 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
18) Prior treatment with SYK inhibitors


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19) 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
20) Known hypersensitivity to ENTO. Also for Group B subjects, known hypersensitivity to
cytarabine or daunorubicin, their metabolites, or formulation excipients


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Description and Handling
5.1.1.
Formulation
ENTO tablets, 200 mg strength, are 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.
Daunorubicin is administered by IV infusion or IV bolus during Group B induction therapy and
is supplied in vials of 20 mg. Each vial contains a red freeze-dried powder of 20 mg (titer) 
daunorubicin hydrochloride and 100 mg D-mannitol. .
Cytarabine is administered by IV infusion during Group B induction and post-remission
chemotherapy. For induction therapy, cytarabine may be supplied in vials of 20 mg, 40 mg, 
60 mg, 100 mg or 200 mg solution for injection or concentrate solution for infusion.   The 
pharmacy manual should be referenced for information on the actual vial sizes that will be 
supplied.  If the 100 mg vials are supplied, each vial will contain a 5 ml solution for injection 
with a concentrate for solution for infusion containing 100 mg cytarabine (20 mg/ml).  Each 
100 mg vial will also contain a sodium-S-lactate solution (50%), sodium chloride, and water for 
injections. For post-remission therapy, cytarabine is supplied in vials of 1 g solution for infusion
with 20 mL solution that contains 1000 mg cytarabine (50 mg/mL). Each 1 g vial contains 
sodium-S-lactate solution (50%) and water for injections as a clear, colorless to yellowish 
solution free of particles. 
5.1.2.
Packaging and Labeling
Study drug (ENTO [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.
Gilead will supply daunorubicin and/or cytarabine to each site as study drug and details 
regarding the packaging and labeling will be provided separately in the pharmacy manual. 
Study drugs to be distributed to centers in Japan shall be labeled to meet applicable requirements 
of the Pharmaceuticals and Medical Devices Agency (PMDA) and/or other local regulations.


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5.1.3.
Storage and Handling
Study drug (ENTO) 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 through inhalation when handling.
Daunorubicin and cytarabine will be supplied as study drug and the site should handle and store
them in accordance with the pharmacy manual. 
5.2.
Premedication
No specific premedications or supporting medications are required in conjunction with ENTO
administration. All subjects should receive anti-microbial, anti-fungal, and anti-viral prophylaxis 
per institutional guidelines.
For cytarabine and daunorubicin, the site should reference the pharmacy manual.
5.3.
Dosage and Administration
5.3.1.
Entospletinib
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.  Subjects should also be instructed to contact the site 
staff or investigators if the incorrect dose of ENTO is taken.
ENTO will be administered orally (PO) BID approximately every 12 hours while in a fasted 
state. Ideally, ENTO should be taken at approximately the same times each day. 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.
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.


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Vomited doses should be retaken, but only if the tablets are visible in the vomitus.
5.3.1.1.
Guidelines for ENTO Dose Modifications
Recommendations for dose modifications based on the type and severity of AEs or laboratory 
abnormalities are provided in Table 5-1. The dose adjustment recommendations are based on the 
CTCAE grade of specific toxicities. However, exceptions are expected for subjects who initiate 
study treatment with low blood counts. Clinical judgement should apply, and in cases of 
uncertainty, the study medical monitor should be contacted.
The dose modification instructions focus on the types of events most commonly attributed to 
ENTO or other drugs that target B-cell receptor signaling pathways. The recommendations 
provided in Table 5-1 comprise only guidelines; variations from these recommendations may be 
warranted based on an investigator’s individual judgement in considering potential risks, 
benefits, and therapeutic alternatives available to each subject.


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Table 5-1.
ENTO Dose Modification Guidelines
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Neutropenia
Maintain current dose level and schedule.
Continue dosing at same 
or lower dose level at 
investigator discretion.
Thrombocytopenia
Maintain current dose level and schedule.
Continue dosing at same 
or lower dose level at 
investigator discretion.
Dermatological
Maintain current dose level and schedule.
Withhold dosing until 
≤Grade 1. Resume 
dosing at current dose 
level.
Withhold dosing until 
Grade ≤1.
If re-challenge at current 
dose level results in 
recurrence, may resume 
dosing at same or lower 
dose level at investigator 
discretion.
May resume at lower 
dose level or 
discontinue dosing at 
investigator discretion
Hepatic
(elevations in ALT, 
AST, or bilirubin)
Note: If subject has 
febrile neutropenia, 
rule out infectious 
cholecystitis and 
other infectious 
causes.
(ALT/AST3xULN)
(Direct Bilirubin 
1.5xULN)
(ALT/AST>3-5xULN)
(Direct Bilirubin 
>1.5-3xULN)
(ALT/AST>5-20xULN)
(Direct Bilirubin 
>3-10xULN)
(ALT/AST>20xULN)
(Direct Bilirubin 
>10xULN)
Maintain current dose 
level and schedule.
Maintain current dose 
level and schedule. 
Monitor ALT, AST, 
ALP, and direct
bilirubin at least 
1x per week.
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.
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.
Pneumonitis 
(dyspnea, cough, 
hypoxia and/or 
diffuse interstitial 
pattern or 
ground-glass 
opacities on chest 
CT and no obvious 
infectious cause)
Note: If subject has 
febrile neutropenia, 
rule out bacterial 
/fungal pneumonia.
Maintain current dose 
level and schedule. 
Withhold dosing until 
Grade ≤1.
May resume at initial 
or lower dose level at 
investigator discretion.
Withhold dosing until Grade ≤1.
May resume at lower dose level or discontinue 
dosing at investigator discretion.
Other Study Drug 
Related, 
Non-hematological 
AEs
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.


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5.3.2.
Cytarabine and Daunorubicin
During induction chemotherapy, IV cytarabine 100 mg/m2 will be administered on Days 1-7 of 
each cycle. During post-remission chemotherapy, age-adjusted HiDAC will be administered. 
Subjects ≤60 years of age will receive 3 g/m2 HiDAC BID on Days 1, 3, and 5 of each cycle and 
subjects > 60 years of age will receive 1 g/m2 HiDAC once daily on Days 1 to 5 of each cycle.
IV daunorubicin 60 mg/m2 will be administered on Days 1-3 of each cycle of induction 
chemotherapy.
The site should administer cytarabine and daunorubicin in accordance with the pharmacy manual. 
5.4.
Prior and Concomitant Medications
Subjects should receive full supportive care including transfusions of blood and blood products, 
antibiotics, antiemetics, antifungals, allopurinol, etc., when appropriate.  
Nausea and/or vomiting should be treated with maximal medical therapy, which should include a 
5HT3 receptor antagonist, unless otherwise contraindicated.  
Strong consideration should be given to transfusing subjects with markedly compromised 
hemoglobin levels (< 8 g/dL) unless contraindicated.  
The use of myeloid growth factors during induction chemotherapy is not permitted but during 
post-remission chemotherapy may be used per guidelines for use in AML.  During the DLT 
assessment period, primary prophylaxis with granulocyte-colony stimulating factor (G-CSF) is 
not permitted.
5.5.
Excluded 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.
Subjects who initiate therapy with excluded medications will be discontinued from the trial. The 
following therapies are not permitted at any point during the trial beginning with the first dose of 
study treatment.

rEPO is not permitted at any time on the study.

No other direct anti-leukemia therapy is permitted.

Palliative radiation therapy may not be administered while the subject is on study.

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.


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
Proton Pump Inhibitors since they are likely to decrease exposure to ENTO. Use of a proton 
pump inhibitor should be avoided for 7 days prior to study drug administration.
Note: H2 blockers and antacids will be allowed for use during the protocol

Co-administration of strong CYP3A and CYP2C9 inducers, and moderate CYP2C9 inducers
are contraindicated 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 5-2.
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. 
Table 5-2.
Contraindicated 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,
vonoprazan
*
Not yet approved in Japan
In a study in healthy volunteers, ENTO 400 mg BID increased rosuvastatin exposure by 
approximately 3.8-fold, which may theoretically increase the risk of AEs. The following 
restrictions apply to the use of HMG-CoA reductase inhibitors with ENTO:
HMG-CoA reductase inhibitor
Dose Adjustment Required
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
*
Not yet approved in Japan


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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.
5.6.
Accountability for IMP
The investigator is responsible for ensuring adequate accountability of all used and unused IMP.
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
Study drug (ENTO, cytarabine and daunorubicin) accountability records will be provided to each 
study site to:

Record the date received and quantity of IMP

Record the date, subject number, subject initials, the IMP number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
5.6.1.
Investigational Medicinal Products Return or 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 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment
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.
6.2.
Study Procedure Descriptions
6.2.1.
Informed Consent
All subjects must sign and date the most recent Independent Ethics Committee (IEC) approved 
informed consent form before any study procedures are performed.  For subjects < 20 years of 
age, both the subject and the subject’s legal representative must sign and date the informed 
consent form before any study procedures are performed.  
Subjects who screen fail must re-sign the informed consent, in the event any screening 
procedures will be performed outside of the screening window from the time of the first 
informed consent.
6.2.2.
Medical History
A complete medical history will be obtained by the investigator or qualified designee at 
screening and recorded on the eCRF. Medical history will include information on the subject’s
significant past medical events (eg, prior hospitalizations or surgeries), a review of the disease 
under study, prior anti-cancer therapies, and any concurrent illnesses. 
6.2.3.
Prior and Concomitant Medications
All medications taken up to 30 days prior to the screening visit will be recorded on the eCRF. In 
addition, supportive therapies given during the course of the study (eg, blood transfusion, growth 
factor) should be collected and recorded on the eCRF.
At each study visit, the site will capture any and all medications taken by the subject since the 
last visit or during the visit (as applicable). Concomitant medications include prescription and 
non-prescription medications, pre-infusion medications (eg, anti-emetics), and vitamins and 
minerals.


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6.2.4.
Physical Examination
The investigator or qualified designee will perform a complete physical examination at 
designated time points during the study (Refer to Appendix 2). Pre-dose abnormal findings will 
be reported on the medical history page of the eCRF. Any changes from the pre-dose baseline 
physical examination that represent a clinically significant deterioration will be documented on 
the AE page of the eCRF. The Screening physical examination will be complete physical 
examinations, thereafter, a modified physical examination will be performed to monitor for any 
changes, and will also include weight and assessment of disease-related clinical signs and 
symptoms. 
6.2.5.
Vital Signs
Vital signs will include blood pressure, respiratory rate, pulse, temperature and oxygen 
saturation. All measurements will be recorded on the appropriate eCRF page with appropriate 
source documentation. Any abnormal measurements may be repeated and reported as AEs if 
appropriate. All measures of blood pressure will be performed using standard 
sphygmomanometry. Measurements of blood pressure should be taken per institutional 
guidelines.
6.2.6.
Electrocardiogram
12-lead electrocardiograms (ECGs) reporting ventricular rate, PR, QRS, QT, and QTc intervals 
will be obtained at the applicable study visits (Appendix 2).
Subjects should be resting quietly and free of distraction (eg, television, conversation) for 
10 minutes prior to ECG collection and ECGs should be collected over a 5 minute window at 
each time point.
The investigator or qualified designee will review all ECGs. The ECG tracings will be 
maintained in the source documentation of each subject and the appropriate data reported on the 
eCRF. 
6.2.7.
Echocardiogram
Echocardiograms will be performed at the time points listed in the Study Procedures Table 
(Appendix 2). Multigated acquisition (MUGA) scans are also acceptable. However, the same 
modality must be used throughout study participation.
Abnormal echocardiogram findings that are considered clinically significant by the investigator 
should be reported as AEs and recorded in the AE eCRF if the finding meets the definition of an 
AE.


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6.2.8.
ECOG Performance Status
ECOG Performance Status is an investigator assessment of the impact of the disease on the 
subject’s activities of daily living. ECOG assessments will be performed at the time points listed 
in the Study Procedures Table (Appendix 2 and Appendix 3). ECOG will be scored using the 
scale index in Appendix 5.
6.2.9.
Adverse Events
Subjects will be assessed for AEs per guidelines in the National Cancer Institute (NCI) CTCAE 
(see Section 8.6.2) at the time points outlined in Appendix 2. Any AEs reported after informed 
consent is obtained and throughout the study will be recorded on the eCRF with appropriate 
source documentation. The subject will be assessed for AEs until approximately 30 days after the 
last dose of study treatment.
Please refer to Section 7 for additional information on AE reporting.
6.2.10.
Laboratory Assessments
Screening laboratory samples should be obtained within 14 days prior to the Cycle 1 Day 1 
(Group A) or Cycle 0 Day 1 (Group B) ENTO dose. Local laboratory complete blood count 
(CBC) assessments may be collected as required for dose adjustments and medical management 
throughout the study. Local laboratory assessments resulting in a dose change will be reported on 
the eCRF.
The central laboratory will be responsible for chemistry, hematology, coagulation, urinalysis, 
and serum pregnancy testing per Table 6-1 and the Study Procedures Tables (Appendix 2 and 
Appendix 3) and storage of other study samples. If central laboratory results are not available, 
local laboratories may be used for dosing decisions. Other tests listed in Table 6-1 may be 
performed by a designated laboratory, and the virology and urine pregnancy testing may be 
performed by the local laboratory. Any sample collected per the Study Procedures Tables
(Appendix 2 and Appendix 3) may be analyzed for any tests necessary to ensure subject safety. 
Specific instructions for processing, labeling, and shipping samples will be provided in the 
central laboratory manual. The date and time of sample collection will be recorded in the 
subject’s source documentation and reported to the central laboratory.
The date and time of previous ENTO dose will be recorded in the subject’s source 
documentation on days where PK is collected. WBC differentials will be reported as absolute 
counts. All laboratory tests must be reviewed for clinical significance by the investigator or 
qualified designee. The analytes listed in Table 6-1 will be tested.


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Table 6-1.
Analytes
Serum Chemistry
Hematology
Other
Sodium
Potassium
Chloride
Lipase
Amylase
Bicarbonate
Creatinine
BUN
Phosphorus
LDHa
Uric acid a
Magnesiuma
Total bilirubin 
Direct bilirubin
Indirect bilirubin
ALT 
AST
Alkaline phosphatase
Total CPKb
Hemoglobin
Hematocrit
Red Blood Cell (RBC) count
White Blood Cell (WBC) Count 
Neutrophils 
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Pharmacokinetic Sampling
Coagulation
Prothrombin time
APTT
INR
Pregnancy Testing
Virology
Serum Qualitative β-HCG and FSHa
Urine pregnancy test
Hep B
Hep C
HIV  
a
Screening only. Serum FSH also required for female subjects with medically documented ovarian failure.
b
Screening for Groups A and B. See Appendix 2 for additional Group A timepoints and Appendix 3 for additional Group B 
timepoints.
All female subjects of childbearing potential (as defined in Appendix 4) will have serum 
pregnancy and FSH testing (for female subjects with medically documented ovarian failure) at 
screening. The results must be confirmed as negative for pregnancy prior to administration of the 
first dose of study drug.
Female subjects of childbearing potential urine pregnancy tests will be performed monthly and at 
EOT.
6.2.11.
Pharmacokinetic Samples
PK samples will be collected at the time points listed below for each group. ENTO plasma 
concentrations will be determined using a validated assay. The date and time of ENTO dosing 
will be collected prior to and on the day of PK sampling. 
6.2.12.
Chest X-ray
A chest x-ray to screen for infiltrates or other evidence of infection must be completed prior to 
initiating study treatment. 


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6.2.13.
Bone Marrow Biopsy and Aspirate 
Bone marrow aspirate/biopsy samples will be assessed by a local hematopathologist for disease 
assessment.  For subjects with AML, bone marrow aspirate samples for molecular mutational 
testing of leukemia will be shipped to a central lab. Results of the molecular mutational testing 
will be disclosed to the investigator but these results will not be used for clinical decision making
in the conduct of this study.  Biopsy will be used in the event the aspirate cannot be collected or 
analyzed (eg, dry-tap, hemodiluted specimen, or lack of spicules). 
6.2.14.
Biological Sample Storage
PK samples and bone marrow aspirate samples (for mutational testing of leukemia) at the 
conclusion of this study may be retained in storage by the Sponsor for a period of up to 10 years 
for purposes of this study before being destroyed.  Samples will be destroyed by internationally 
accepted means (eg, incineration).  The sample storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form.  Samples other than the PK samples and bone 
marrow aspirate samples (for mutational testing of leukemia) will not be retained.    
6.3.
Screening Visit
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 (and other 
clinical, radiographic, and laboratory procedures required for subjects with hematologic 
malignancies other than AML) 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

Performance status

12-lead ECG

ECHO or MUGA 


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
Obtain blood samples for:
Chemistry
Hematology 
Coagulation 
Serum pregnancy test (female subjects of childbearing only) and FSH (for female 
subjects with medically documented ovarian failure)
HIV/HBV/HCV

Urinalysis

Chest X-ray 

Subjects with AML will undergo a bone marrow aspirate and biopsy  for disease assessment
within 21 days before the first administration of study treatment Cytogenetic testing will be 
locally performed and molecular mutation testing of leukemia for FLT3, NPM1, and CEBPA 
will be centrally performed.

Subjects with hematologic malignancies other than AML will undergo the appropriate 
clinical, radiographic, and laboratory procedures per the standard of care or institutional 
practice for disease assessment within 21 days before the first administration of study 
treatment

Record any serious adverse events (SAEs) and all AEs related to protocol mandated 
procedures occurring after signing of the consent form
Subjects meeting all of the applicable 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 SAEs, as well as any AEs related to protocol-mandated procedures 
on the AE case report form (eCRF). All other untoward medical occurrences observed during the 
screening period, including exacerbation or changes in medical history are to be captured on the 
medical history eCRF. See Section 7 for additional details.
6.4.
Treatment Assessments – Group A (ENTO Monotherapy)
Subjects with relapsed or refractory hematologic malignancies who have met all eligibility 
criteria will come to the clinic on Cycle 1 Day 1 to perform study required procedures prior to 
dosing. Review prior/ concomitant medications and record AEs at each clinic visit.


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6.4.1.
Cycle 1

ENTO will be administered BID on Days 1-28 as a single agent

Obtain current smoking status (Day 1)

Physical examination (Days 1 and 14)

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level (Days 1, 8, 14, and 28)

Weight (Day 1)

Performance status (Days 1 and 14)

Urine pregnancy test (prior to dose on Day 1; female subjects of childbearing potential only) 

Obtain blood samples for: 
Chemistry (Days 1 (pre-dose), 8, 14, and 28)
Hematology (Days 1 (pre-dose), 8, 14, and 28)
Coagulation (Days 14 and 28)
Sparse PK (Days 1, 14, and 28 at pre-dose and 2 hours post-dose of ENTO) 
Intensive PK (Day 8 at pre-dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose of ENTO)
Note: ENTO should be held until the pre-dose blood samples have been drawn. Record the 
approximate time of the last two doses of ENTO on PK collection days and the time the PK 
blood samples are obtained

Subjects with AML will undergo a bone marrow biopsy and aspirate for disease assessment 
(histopathological evaluation) (~8mL) at the end of Cycle 1 on Day 28.  Subjects with 
cytogenetic and molecular mutations at screening must have cytogenetic and molecular 
mutation testing repeated.  

Subjects with hematologic malignancies other than AML will undergo the appropriate 
clinical, radiographic, and laboratory procedures per the standard of care or institutional 
practice for disease assessment at the end of Cycle 1 on Day 28
6.4.2.
Subsequent Cycles

ENTO will be administered BID on Days 1-28 as a single agent


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
Obtain current smoking status (Day 1 of each cycle)

Physical examination (Day 1 of each cycle)

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level (Day 1 of each cycle)

Weight (Day 1 of each cycle)

Performance status (Day 1 of each cycle)

Urine pregnancy test (prior to dose on Day 1 of each cycle; female subjects of childbearing 
potential only) 

Obtain blood samples for: 
Chemistry (Day 28 of each cycle)
Hematology (Day 28 of each cycle)
Coagulation (Day 28 of each cycle)
Sparse PK (Day 28 of each cycle at pre-dose and 2 hours post-dose of ENTO) 
Note: ENTO should be held until the pre-dose blood samples have been drawn. Record the 
approximate time of the last two doses of ENTO on PK collection days and the time the PK 
blood samples are obtained 

Subjects with AML will undergo a bone marrow biopsy and aspirate for disease assessment 
(histopathological evaluation) (~8mL) as clinically indicated

Subjects with hematologic malignancies other than AML will undergo the appropriate 
clinical, radiographic, and laboratory procedures per the standard of care or institutional 
practice for disease assessment as clinically indicated
6.5.
Treatment Assessments – Group B (ENTO + cytarabine + daunorubicin)
Subjects with previously untreated AML who have met all eligibility criteria will come to the 
clinic on Cycle 0 Day 1 to perform study required procedures prior to dosing. Review 
prior/ concomitant medications and record AEs at each clinic visit.
6.5.1.
Lead-in (Cycle 0)

ENTO will be administered BID on Days 1-14 as a single agent

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level 


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
Physical examination (Day 1)

Obtain current smoking status (Day 1)

Performance status (Day 1)

Urine pregnancy test (prior to dose on Day 1; female subjects of childbearing potential only)

Obtain blood samples for: 
Chemistry (Days 1 (pre-dose), 8, and 14)
Hematology (Days 1 (pre-dose), 8, and 14)
Coagulation (Day 14)
Sparse PK (Days 1, 14 at pre-dose and 2 hours post-dose of ENTO) 
Intensive PK (Day 8 at pre-dose, 1, 2, 3, 4, 6, 8, and 12 hours post-dose of ENTO)
Note: ENTO should be held until the pre-dose blood samples have been drawn. Record the 
approximate time of the last two doses of ENTO on PK collection days and the time the PK 
blood samples are obtained

A bone marrow aspirate sample for disease assessment (histopathological evaluation)
(~8mL) will be collected at completion of the lead-in cycle, which is anticipated to occur on 
Cycle 0 Day 14. The bone marrow aspirate sample must be collected prior to starting 
7+3 treatment (Cycle 1).  Subjects with cytogenetic and molecular mutations at screening 
must have cytogenetic and molecular mutation testing repeated.  
6.5.2.
Induction

ENTO will continue to be administered BID on Days 1-28 in combination with IV cytarabine 
100 mg/m2 daily on Days 1-7 and IV daunorubicin 60 mg/m2 daily on Days 1-3 of each 
28-day cycle. Subjects will receive at least 1 cycle of induction chemotherapy but no more 
than 2 cycles.

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level (Days 1, 3, and 7 of each cycle)

Weight (Day 1 of each cycle) 

Performance status (Day 28 of each cycle)

Physical exam (Day 1 of each cycle)


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
Obtain smoking status (Day 1 of each cycle) 

Urine pregnancy test (Day 1 of each cycle; female subjects of childbearing potential only)

Obtain blood samples for: 
Chemistry (Days 7, 14, and 28 of each cycle)
Hematology (Days 7, 14, and 28 of each cycle; local hematology (complete blood count)
daily from Day 15 until count recovery for subjects with hypocellular bone marrow and 
no evidence of residual leukemia on Day 14) 
Coagulation (Days 7, 14, and 28 of each cycle)
Sparse PK (Day 3 of each cycle at pre-dose, 2, and 4 hours post-dose of ENTO; 
Days 14 and 28 of each cycle at pre-dose and 2 hours post-dose of ENTO)
Intensive PK (Day 7 [Cycle 1 only] at pre-dose, 1, 2, 3, 4, 6, 8, and 12 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 two 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 (and Cycle 2 Day 14 if 
needed) for disease assessment (~8mL).  Subjects with cytogenetic and molecular mutations 
at screening must have cytogenetic and molecular mutation testing repeated on Cycle 1 Day 
14 (or at count recovery).
If the Cycle 1 Day 14 bone marrow evaluation has unequivocal evidence of persistent 
AML, subjects will immediately proceed with Cycle 2
If the bone marrow is hypocellular (≤ 20% cellularity) without evidence of residual 
leukemia on Day 14, a bone marrow evaluation must be repeated on Day 28 or within 
21 days (eg, no later than Day 35) as blood counts recover prior to proceeding to SCT or 
post-remission chemotherapy. Subjects are to continue receiving ENTO BID as they are 
awaiting disease assessment results and until the completion of induction chemotherapy 
as determined by bone marrow response. Cycle 2 is to be omitted if CR or CRi status is 
achieved after 1 induction cycle.  
If CR/CRi is achieved at the end of Cycle 1 or 2 as demonstrated on the bone marrow 
aspirate and biopsy, the subject may proceed to SCT if eligible. Otherwise, the subject 
will receive post-remission chemotherapy.


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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 endpoint criteria, and will be discontinued from 
study treatment
6.5.3.
Post-remission chemotherapy

ENTO will continue to be administered BID on Days 1-28 in combination with age-adjusted 
HiDAC for at least 2 cycles and up to 4 cycles
For subjects ≤ 60 years of age, 3 g/m2 HiDAC will be administered BID on 
Days 1, 3, and 5 of each 28-day cycle
For subjects > 60 years of age, 1 g/m2 HiDAC will be administered once daily on 
Days 1-5 of each 28-day cycle

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level (Day 1 of each cycle)

Weight (Day 1 of each cycle) 

Performance status (Day 28 of each cycle)

Physical exam (Day 1 of each cycle)

Obtain smoking status (Day 1 of each cycle) 

Urine pregnancy test (on Day 1 of each cycle; female subjects of childbearing potential only)

Obtain blood samples for: 
Chemistry (Day 28 of each cycle)
Hematology (Day 28 of each cycle)
Coagulation (Day 28 of each cycle)
Sparse PK (Days 5 and 28 of each cycle at 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 two doses of ENTO on PK collection days and the time the PK 
blood samples are obtained

Obtain bone marrow aspirate at Cycle 2 Day 28 and Cycle 4 Day 28, or as clinically 
indicated for disease assessment (~8mL)
During and following completion of post-remission chemotherapy, subjects may proceed to SCT 
based on donor availability.


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6.6.
Assessments for Premature Discontinuation from Study
If a subject prematurely discontinues study treatment (see Section 3.5.1, Discontinuation of 
Study Treatment), every attempt should be made to keep the subject in the study and continue to 
perform the required study-related follow-up and procedures (see Sections 6.8). If this is not 
possible or acceptable to the subject or investigator, the subject may be withdrawn from the 
study and no further study-related follow-up and procedures will be performed.
6.7.
End of Treatment
Subjects will be removed from study treatment when any of the criteria listed in Section 3.5.1
apply. The following procedures will be conducted when a subject discontinues study treatment 
and prior to initiating a new therapy. 

Review concomitant medications 

Review any AEs

Performance status 

Physical exam 

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

Weight

Obtain blood samples for: 
Chemistry 
Hematology (with differential)
Coagulation 

Urine Pregnancy Test (for females of childbearing potential)

Subjects with AML will undergo a bone marrow aspirate and biopsy for disease assessment
(~8mL) (if not performed within the last 2 weeks).  Subjects with cytogenetic and molecular 
mutations at screening must have cytogenetic and molecular mutation testing repeated.

Subjects with hematologic malignancies other than AML will undergo the appropriate 
clinical, radiographic, and laboratory procedures per the standard of care or institutional 
practice for disease assessment (if not performed within the last 2 weeks)


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6.8.
Follow-up
6.8.1.
Remission/Relapse
Subjects with AML who achieve remission or relapse should undergo a bone marrow aspirate 
and biopsy for disease assessment (~8mL) and have a blood sample obtained for hematology.  
Subjects with cytogenetic and molecular mutations at screening must have cytogenetic and 
molecular mutation testing repeated.
Subjects with hematologic malignancies other than AML will undergo the appropriate clinical, 
radiographic, and laboratory procedures per the standard of care or institutional practice for 
disease assessment. 
6.8.2.
30-day Follow-up
Subjects will be contacted by telephone 30 days (± 7 days) after the last dose of ENTO to assess 
AEs and review concomitant medications. The 30-day follow-up visit may be substituted by a 
scheduled study visit if it occurs within the same window.
6.8.3.
Long Term Follow-up
Long term follow-up (LTFU) for OS begins after EOT or the last study visit if EOT does not 
occur. Subjects will be contacted by telephone or during a routine clinic visit every 6 months 
(± 4 weeks) to gather leukemia treatments, other malignancies, and survival for up to 3 years 
after EOT or the last study visit. Every attempt should be made to keep the subject in LTFU for 
OS.


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


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.2.1.
Protocol-Specific Serious Adverse Event Instructions
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 may be profoundly anemic and 
thrombocytopenic secondary to bone marrow involvement by their AML or from the 
myelosuppressive effects of chemotherapy. These subjects will thus require transfusional support 
with red cells and platelets per institutional guidelines and therefore may require hospitalization 
for transfusions.  
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 


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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 Section 7.1. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result 
(ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.1.3.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the IMP. For SAEs, an alternative 
causality must be provided (eg, pre-existing condition, underlying disease, intercurrent 
illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE occurred as a result of protocol procedures (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the CTCAE, Version 4.03 (see Section 8.6.2). 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 drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (eCRF): all SAEs and AEs related to protocol-
mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH and Gilead Japan DSPH within 24 hours of the investigator’s 
knowledge of the event. Detailed instructions can be found in the eCRF completion 
guidelines.

If for any reason it is not possible to record the SAE information electronically (ie, the eCRF 
database is not functioning) record the SAE on the paper SAE reporting form and submit 
within 24 hours to Gilead DSPH. Fax:
or email:

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the 
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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.
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, 
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 Section 7.1. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result 
(ie, decreased hemoglobin).
7.6.
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. See Section 8.6.2.
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of AEs associated with product complaints, and pregnancy reports regardless of an associated 
AE.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
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 
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An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
7.7.2.
Instructions for Reporting Special Situations
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead DSPH (Fax: 
 or email: 
 using the 
pregnancy report form within 24 hours of becoming aware of the pregnancy.
Refer to the eCRF completion guidelines for full instructions on the mechanism of pregnancy 
reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email:
 and Fax: 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to or Gilead DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH. Fax number:
or email:
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
PPD
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7.7.3.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.7 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are:

To evaluate the safety and tolerability of ENTO monotherapy in Japanese subjects with 
relapsed or refractory hematologic malignancies

To evaluate the safety and tolerability of ENTO in combination with cytarabine and 
daunorubicin (7+3) in Japanese subjects with previously untreated AML who are candidates 
for chemotherapy
The secondary objectives of this study are: 

To evaluate the PK of ENTO in Japanese subjects with relapsed or refractory hematologic 
malignancies 

To evaluate the PK of ENTO in Japanese subjects with previously untreated AML who are 
candidates for chemotherapy

To evaluate the safety and tolerability of ENTO in combination with age-adjusted HiDAC in 
Japanese subjects with previously untreated AML who are candidates for chemotherapy
The exploratory objectives of this study are: 
8.1.2.
Primary Endpoints
The primary endpoints of this study are:
Safety Endpoints:

Occurrence of AEs and laboratory abnormalities defined as DLTs for ENTO monotherapy in 
subjects with relapsed or refractory hematologic malignancies

Occurrence of AEs and laboratory abnormalities defined as DLTs for ENTO in combination 
with cytarabine and daunorubicin in subjects with previously untreated AML who are 
candidates for chemotherapy
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8.1.3.
Secondary Endpoints
The secondary endpoints of this study are:
Safety

Occurrence of AEs, laboratory findings and findings on physical exam not defined as DLTs
Pharmacokinetics

Determination of the PK parameters of ENTO based on plasma concentrations
8.1.4.
Other Endpoints of Interest
The exploratory endpoints of this study are:
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8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Full-Analysis Set (FAS)
Full-Analysis Set (FAS) includes all subjects who receive at least 1 dose of study drug (ENTO). 
This analysis set will be used in the analyses of subject characteristic, drug exposure, safety, and 
efficacy. 
8.2.1.2.
DLT Analysis Set
DLT Analysis Set includes all subjects in FAS who receive sufficient drug exposure 
(Section 3.2) or experience a DLT during the DLT assessment window.
8.2.1.3.
Pharmacokinetic Analysis Sets
Pharmacokinetic Analysis Sets include all subjects in FAS who have necessary baseline and 
post-treatment assessments in order to provide interpretable results for the specific parameters of 
interest.
8.3.
Data Handling Conventions
By-subject listings will be created for important variables from each eCRF module. Summary
tables for continuous variables will contain the following statistics: N (the number of subject in 
group), n (the number of subjects with assessment), 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.
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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, dose level, duration of study treatment, reasons of study 
treatment discontinuation, and reasons of study discontinuation. Available information on 
subjects who are screened but are not treated may be listed separately.
Subject demographic and baseline characteristics will be listed and summarized by dose level 
based on Full Analysis set.
8.5.
Efficacy Analysis
Assessment of clinical response in subjects with hematologic malignancies other than AML will 
be according to the latest set of published response criteria. Assessment of clinical response in 
subjects with AML will be according to the modified International Working Group criteria and 
will include findings on examination of blood, bone marrow and physical examination.
Complete Remission Rate and Composite Complete Remission Rate and other response rate 
variables will be described. In the analyses of Complete Remission Rate and Composite 
Complete Remission Rate by induction completion, subjects who do not have evaluable post-
treatment assessment to characterize response will be counted as non-responder. For all analyses, 
the corresponding 95% exact CIs will be presented.
Time-to-Event Endpoints
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. In addition, the estimated rate at 6- month, 
12-month, 2-year, and 3-year will be reported.
The following censoring rules will be applied:
RFS: For subjects who are not known to have relapsed or died by the end of the study or data 
cutoff, RFS is censored on the date of the last available disease assessment.
EFS: For subjects with none of the events defined in EFS before the end of the study or data 
cutoff, EFS is censored at the date of the last available disease assessment.
OS: For subjects who are not known to have died by the end of the study or data cutoff, OS is 
censored on the last dates on which the subjects are known to be alive.
Analysis of Complete Remission Duration and Composite Complete Remission Duration will be 
analyzed using cumulative incidence by considering death without relapse as competing risks. 
The estimate of the cumulative incidence of relapse (CIR) will be reported with the associated 


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95% CI. For subjects who die without report of relapse, Complete Remission Duration and 
Composite Complete Remission Duration are censored on the date of death, regardless of cause. 
For subjects with no report of relapse by the end of the study or data cutoff date, the Remissions 
are censored on the date of the last available disease assessment.
Continuous Endpoints
TTR will be summarized using descriptive statistics.
Categorical Endpoints
For the analysis of Proportion of bridging to SCT, subjects who do not have evaluable 
post-treatment assessment to characterize response will be counted as non-responder. For this 
analysis, the corresponding 95% exact CIs will be provided.
8.6.
Safety Analysis
All safety data collected on or after the date that ENTO is first dosed up to 30 days after the 
permanent discontinuation of study treatment will be summarized by dose level.
8.6.1.
Extent of Exposure
Descriptive information will be provided by phase and dose level regarding the number of doses 
of study treatment prescribed the total number of doses taken, duration of treatment, and the 
number 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 AEs will be listed. The AE summarization will focus on treatment-emergent AEs. 
Treatment-emergent AEs are defined as AEs that onset in the period from the first dose of study 
treatment to 30 days after the permanent discontinuation of study treatment or that lead to 
permanent study treatment discontinuation.
AEs that occur before the first dose of study treatment or >30 days after study treatment 
discontinuation will be included in data listings.
AEs will be classified using Medical Dictionary for Regulatory Activities (MedDRA) with
descriptions by System Organ Class, High-Level Group Term, High Level Term, Preferred
Term, and Lower-Level Term. The severity of AEs will be graded by the investigator according 
to the CTCAE, Version 4.03 (http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-
%20DMCC.pdf), whenever possible. If a CTCAE criterion does not exist for a specific type of 
AE, the grade corresponding to the appropriate adjective will be used by the investigator to 
describe the maximum intensity of the AE: Grade 1 (mild), Grade 2 (moderate), Grade 3 
(severe), Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the AE to study 
treatment will be categorized as related or unrelated.


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Treatment-emergent AEs will be summarized by presenting the number and percentage of 
subjects with treatment-emergent AEs by severity grade. Subjects who report multiple 
treatment-emergent AEs under the same Preferred Term (or System Organ Class) are counted 
only once under the worst severity grade. The summary will be presented in decreasing 
frequency of System Organ Class and Preferred Term of the ‘Total’ column. Within the same 
frequency, the AEs are ordered in the alphabetical order of System Organ Class and
Preferred Term. Separate listings and summaries will be provided for the following types of 
treatment-emergent AEs:

Study treatment related AEs

AEs with severity ≥ Grade 3

s leading to study treatment interruption and/or dose modification

AEs leading to study treatment discontinuation

Study treatment related SAEs

DLT

DLT rates and their 90% CI
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 laboratory data summarization will focus on
treatment-emergent laboratory abnormalities. Treatment-emergent laboratory abnormalities are 
defined as abnormalities that, compared to baseline, worsens by >=1 grade in the period from the 
first dose of study treatment to 30 days after the permanent discontinuation of study treatment. If 
baseline data are missing, any graded abnormality will be considered as treatment-emergent. 
Laboratory abnormalities that occur before the first dose of study treatment or >30 days after the 
permanent discontinuation of study treatment will be included in data listings.
Hematological, serum chemistry, coagulation, and urinalysis 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 based on subjects’ age, sex, etc.
Hematological, serum chemistry, coagulation assessments and their changes from baseline will 
be summarized by presenting the number and percentage of subjects by severity grade. For 
laboratory tests without CTCAE scale, the summary will present the number and percentage of 
subjects below, within, and above the normal ranges. Subjects will be counted only once for a 
given laboratory test under the worst severity grade during a period of interest (eg, during the 
study or from baseline to a particular visit).


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Separate listings and summaries will be prepared for laboratory abnormalities that are ≥ Grade 3.
8.7.
Pharmacokinetic Analysis
Concentrations of ENTO and its metabolites (if applicable) in plasma will be determined using a 
validated bioanalytical assay. Calculated pharmacokinetic parameters will include AUCtau, Cmax, 
Tmax, t1/2, and Ctau (if applicable). Pharmacokinetic parameters will be listed and summarized for 
ENTO and its metabolites (if applicable) using descriptive statistics (eg, sample size, arithmetic 
mean, geometric mean, % coefficient of variation, standard deviation, median, minimum, and 
maximum). Plasma concentrations of ENTO and its metabolites (if applicable) over time will be 
plotted in semi logarithmic and linear formats as mean ± standard deviation.
8.8.
Sample Size
The first 6 subjects will be enrolled at dose level 0 in Group A. During the DLT assessment 
window, if 0 or 1 out of these 6 subjects experience DLTs in Group A, Group B will open and 
6 subjects will be enrolled at dose level 0 in Group B. However, if 2 or more subjects experience 
DLTs in Group A, 6 additional subjects will be enrolled at dose level -1 in Group A and Group B 
will not open. Subjects who discontinue early for a non-DLT defined reason during the DLT 
assessment window will not be evaluable for DLT and may be replaced. The aforementioned 
subjects are DLT evaluable subjects.
With consideration for subject replacement, up to 24 subjects will be enrolled to the study.
8.9.
Timing of Analyses
8.9.1.
Interim Analyses
No formal interim analyses are planned in this study. The Gilead study team and the 
investigators will collectively discuss study conduct and accumulating safety and other data.
8.9.2.
Final Analysis
Final analysis is expected to occur after all subjects have discontinued from the study.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Independent Ethics Committee (IEC) Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent). The investigator will not begin any study subject activities until approval 
from the IEC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IEC if any modifications are made to the protocol or any accompanying material to be 
provided to the subject after initial approval, with the exception of those necessary to reduce 
immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IEC-approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 


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


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


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described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (eg data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IEC, 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 IEC in 
accordance with local requirements and receive documented IEC approval before modifications 
can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory 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 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
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 
complex-mediated inflammation. J Pharmacol Exp Ther 2006;319 (3):998-1008.
Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, et al. Pretreatment 
cytogenetic abnormalities are predictive of induction success, cumulative 
incidence of relapse, and overall survival in adult patients with de novo acute 
myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). 
Blood 2002;100 (13):4325-36.
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.
Drabkin HA, Parsy C, Ferguson K, Guilhot F, Lacotte L, Roy L, et al. Quantitative HOX 
expression in chromosomally defined subsets of acute myelogenous leukemia. 
Leukemia 2002;16 (2):186-95.
Efremov DG, Laurenti L. The Syk kinase as a therapeutic target in leukemia and lymphoma. 
Expert opinion on investigational drugs 2011;20 (5):623-36.
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 
myeloid leukemia. OncoTargets and therapy 2016;9:711-22.
Geahlen RL. Getting Syk: spleen tyrosine kinase as a therapeutic target. Trends Pharmacol Sci 
2014;35 (8):414-22.
Gioia R, Leroy C, Drullion C, Lagarde V, Etienne G, Dulucq S, et al. Quantitative 
phosphoproteomics revealed interplay between Syk and Lyn in the resistance to 
nilotinib in chronic myeloid leukemia cells. Blood 2011;118 (8):2211-21.
Hahn CK, Berchuck JE, Ross KN, Kakoza RM, Clauser K, Schinzel AC, et al. Proteomic and 
genetic approaches identify Syk as an AML target. Cancer cell 2009;16 (4):281-
94.


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Heuser M, Sly LM, Argiropoulos B, Kuchenbauer F, Lai C, Weng A, et al. Modeling the 
functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem 
cell self-renewal. Blood 2009;114 (19):3983-93.
Koerber RM, Held SA, Heine A, Kotthoff P, Daecke SN, Bringmann A, et al. Analysis of the 
anti-proliferative and the pro-apoptotic efficacy of Syk inhibition in multiple 
myeloma. Exp Hematol Oncol 2015;4:21.
Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med 1999;341 
(14):1051-62.
Marcucci G, Haferlach T, Dohner H. Molecular genetics of adult acute myeloid leukemia: 
prognostic and therapeutic implications. J Clin Oncol 2011;29 (5):475-86.
Mohr S, Doebele C, Berg T, Comoglio F, Beck J, Alexe G, et al. Hoxa9 and Meis1 
Cooperatively Induce Addiction to Syk Signaling By Suppression of Mir-146a in 
Acute Myeloid Leukemia [Abstract 1533]. American Society of Hematology 
(ASH); 2016 03-06 December; San Diego, CA. 
Mrozek K. Acute Myeloid Leukemia with a Complex Karyotype [Author Manuscript]. Semin 
Oncol 2008;35 (4):365-77.
Oellerich T, Oellerich MF, Engelke M, Munch S, Mohr S, Nimz M, et al. beta2 integrin-derived 
signals induce cell survival and proliferation of AML blasts by activating a 
Syk/STAT signaling axis. Blood 2013;121 (19):3889-99, S1-66.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5 (6):649-55.
Puissant A, Fenouille N, Alexe G, Pikman Y, Bassil CF, Mehta S, et al. SYK is a critical 
regulator of FLT3 in acute myeloid leukemia. Cancer cell 2014;25 (2):226-42.
Ruzza P, Biondi B, Calderan A. Therapeutic prospect of Syk inhibitors. Expert Opin Ther Pat 
2009;19 (10):1361-76.
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.
Stone RM, O'Donnell MR, Sekeres MA. Acute myeloid leukemia. Hematology / the Education 
Program of the American Society of Hematology. American Society of 
Hematology 2004:98-117.


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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 Table: Group A (ENTO Monotherapy)
Appendix 3.
Study Procedures Table: Group B (ENTO + cytarabine + daunorubicin)
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 5.
Performance Scales: Karnofsky & ECOG Scores {Oken 1982}
Appendix 6.
Modified International Working Group Criteria for AML


PPD
PPD
Entospletinib 
Protocol GS-US-429-4104 
Final 
Gilead Sciences lnc. 
Amendment 3 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase lb Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Entospletinib 
(ENTO) as Monotherapy in Japanese Subjects with Relapsed or Refractory Hematologic 
Malignancies and in Combination with Chemotherapy in Japanese Subjects with Previously 
Untreated Acute Myeloid Leukemia (AML) 
GS-US-429-4104, Amendment 3, 23 August 2017 
Signature 
oru or 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
jnformation provided by Gilead Sciences, Inc. l will discuss this material with them to ensure 
that they are fully infonned about the drugs and the study. 
Principal Investigator ame (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 92 
23 August 2017 


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Appendix 2.
Study Procedures Table: Group A (ENTO Monotherapy)
Study Phase
Screening
Cycle 1
Subsequent Cycles
Remission/Relapse
End of 
Treatment 
(EOT)
30-day 
Follow-Up
Long Term
Follow-up
Study Day
Screening
1
8
14
28
1
28
Window (day)
-14
NA
±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
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/MUGA
X
Performance Status
X
X
X
X
X
Chest X-ray
X
Overall survival, treatments, 
and other malignancies
X
(every 6 months)
Study Treatment
ENTO Administrationd
X
X
X
X
X
X
Laboratory Assessments
Chemistrye
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 FSHf
X
Urine Pregnancy Testg
X
X
X
HIV/HBV/HCV
X
Sparse PKh
X
X
X
X
Intensive PKi
X
Disease Assessmentj
X
X
X
X
I 
I I I 
I 
I 


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Study Phase
Screening
Cycle 1
Subsequent Cycles
Remission/Relapse
End of 
Treatment 
(EOT)
30-day 
Follow-Up
Long Term
Follow-up
Study Day
Screening
1
8
14
28
1
28
Window (day)
-14
NA
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
Bone Marrow Assessments
Biopsyk
X
X
X
X
Aspiratek
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 EOT.
d
ENTO will be administered BID 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. The subject may continue on ENTO monotherapy 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 EOT. 
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. 
g
For females of childbearing potential, urine pregnancy tests will be done on Day 1 of each cycle and at EOT.
h
Peripheral blood samples for sparse PK will be obtained on Cycle 1 Days 1, 14 and 28, and Day 28 of subsequent cycles at pre-dose and 2hrs post-dose of ENTO. 
i
Peripheral blood samples for intensive PK will be obtained on Cycle 1 Day 8 at 0 (pre-dose), 1, 2, 3, 4, 6, 8, and 12 hours post-dose of ENTO.
j
Subjects with hematologic malignancies other than AML will undergo the appropriate clinical, radiographic, laboratory procedures for disease assessment per the standard of 
care/institutional practice at screening (within 21 days before the first administration of study treatment), at the end of Cycle 1 on Day 28, as clinically indicated after Cycle 1, 
remission/relapse, and EOT (if not performed within the last 2 weeks).
k
Subjects with AML will undergo a bone marrow biopsy and aspirate (~8mL) for disease assessment at screening (within 21 days before the first administration of study 
treatment), at the end of Cycle 1 on Day 28, as clinically indicated after Cycle 1, remission/relapse, and EOT (if not collected within the last 2 weeks). Biopsy will be used in 
the event the aspirate cannot be collected or analyzed. Subjects with AML with cytogenetic and molecular mutations at screening must have cytogenetic and molecular 
mutation testing repeated at Cycle 1 Day 28, remission/relapse, and EOT.


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Appendix 3.
Study Procedures Table: Group B (ENTO + cytarabine + daunorubicin)
Study Phase
Screening
Lead-in
Cycle 0
Induction Cycle 1
(if needed Cycle 2)
Post-remission 
chemotherapy
(up to Cycle 4)
Relapse
End of 
Treatment
(EOT)
30-day 
Follow-up
Long 
Term 
Follow-
up
Study Day
Screening
1
8
14
1
3
7
14
15 to 
count 
recovery
28
1
3
5
28
NA
NA
NA
NA
Window (day)
-14
NA
±2
±2
±2
±2
±2
±2
NA
±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
Smoking statusa
X
X
X
X
Physical Examb
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
Height and Weightd
X
X
X
X
ECGe
X
ECHO/MUGAf
X
X
X
Performance Statusg
X
X
X
X
X
X
Overall survival, leukemia 
treatments, and other 
malignancies
X
(every
6 months)
Chest X-ray 
X
Study Treatment
ENTO Administrationh,i, 
X
X
X
X
X
X
X
X
X
X
X
X
IV daunorubicinj
X
X
IV cytarabineh,i, 
X
X
X
X
X
X
I I I I I I I I 
I I I I I I 
I 


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Study Phase
Screening
Lead-in
Cycle 0
Induction Cycle 1
(if needed Cycle 2)
Post-remission 
chemotherapy
(up to Cycle 4)
Relapse
End of 
Treatment
(EOT)
30-day 
Follow-up
Long 
Term 
Follow-
up
Study Day
Screening
1
8
14
1
3
7
14
15 to 
count 
recovery
28
1
3
5
28
NA
NA
NA
NA
Window (day)
-14
NA
±2
±2
±2
±2
±2
±2
NA
±2
±2
±2
±2
±2
±2
±7
±7
± 4 
weeks
Laboratory Assessments
Chemistryj,k
X
X
X
X
X
X
X
X
X
Hematologyk, r
X
X
X
X
X
X
X
X
X
X
X
Coagulationk
X
X
X
X
X
X
X
Urinalysis
X
Serum Pregnancy Test and FSHl
X
Urine Pregnancy Testm
X
X
X
X
HIV/HBV/HCV
X
Sparse PKn
X
X
X
X
X
X
X
Intensive PKo
X
X
Bone Marrow Assessments
Biopsyp
X
X
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 chemotherapy, a physical exam is to be 
completed on Cycle 1 Day 1 and Cycle 3 Day 1.
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.
d
Height and weight will be measured at screening. Only weight will be measured on Day 1 of each induction cycle, Day 1 of each post-remission chemotherapy cycle, and at 
EOT.
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 if applicable, prior to starting induction Cycle 2 (on Cycle 1 Day 14 or 28).
g
During post-remission chemotherapy, performance status to be completed on Cycle 2 Day 28 and Cycle 4 Day 28.
h
ENTO will be administered BID 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 28-day cycle (Cycle 1 and up to Cycle 2). Subjects are to continue receiving ENTO BID as they are awaiting disease assessment results.
I I I I I I I I 
I I I I I I 


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i
During post-remission chemotherapy, subjects will receive 2-4 cycles of 3g/m2 HiDAC administered every 12 hours on Days 1, 3, and 5 (≤ 60 years of age) or 1g/m2 HiDAC
administered once daily on Days 1-5 (> 60 years of age) in combination with ENTO BID on Days 1-28.
j
Include Total CPK at screening, Day 14 of induction Cycle 1 (and Cycle 2, if applicable), Day 28 of post-remission chemotherapy Cycles 1 and 3, and EOT. 
k
During post-remission chemotherapy, collect Chemistry, Hematology, and Coagulation on Day 28 of Cycles 1 and 3 only.
l
A negative serum pregnancy test is required for female subjects (unless surgically sterile or post-menopausal). Female subjects with medically documented ovarian failure 
must also have serum FSH levels within the institutional post-menopausal range.
m
For females of childbearing potential, urine pregnancy tests will be done on Day 1 of each cycle and at EOT.
n
Peripheral blood samples for sparse PK will be collected at pre-dose and 2hrs post-dose of ENTO on Cycle 0 Days 1 and 14, Days 14 and 28 of each induction cycle, and 
Days 5 and 28 of each post-remission chemotherapy cycle. Sparse PK will also be collected at pre-dose, 2, and 4 hours post-dose of ENTO on Day 3 of each induction cycle.
o
Peripheral blood samples for intensive PK will be collected on Cycle 0 Day 8 and induction Cycle 1 Day 7 at 0 (pre-dose), 1, 2, 3, 4, 6, 8, and 12 hours post-dose of ENTO. 
p
A bone marrow biopsy will be performed at screening (within 21 days before the first administration of study treatment), Cycle 0 Day 14, Day 14 of each induction cycle
(if hypocellular on Day 14, must repeat on Day 28 or within 21 days as blood counts recover prior to proceeding to post-remission chemotherapy or SCT), relapse, and EOT
(if not performed within the last 2 weeks) for disease assessment. Subjects with cytogenetic and molecular mutations at screening must have cytogenetic and molecular 
mutation testing repeated at Cycle 0 Day 14, Cycle 1 Day 14 (or at count recovery), relapse, and EOT.
q
A bone marrow aspirate (~8mL) will also be collected for disease assessment at the bone marrow biopsy time-points noted above as well as post-remission chemotherapy
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.
r
For subjects without evidence of residual leukemia on Day 14 of induction chemotherapy, local hematology (complete blood count) to be collected daily from Day 15 of 
induction chemotherapy until complete blood count demonstrates recovery.


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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy and are without 
an alternative medical cause for amenorrhea.
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 a malformation effect is unknown, taking into 
consideration class effects, genotoxic potential, or a strong suspicion of human 
teratogenicity/fetotoxicity in early pregnancy based on non-clinical data. ENTO has insufficient 
data to exclude the possibility of a clinically relevant interaction with hormonal contraception 
that results in reduced contraception efficacy. 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 have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on the Baseline/Day 1 visit prior to enrollment. Pregnancy tests 
will be performed at monthly intervals thereafter. Female subjects must agree to one of the 
following methods from Screening until 30 days (Group A ENTO monotherapy) or 6 months 
(Group B ENTO + cytarabine + daunorubicin) following the end of relevant systemic exposure.


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Individual Methods
Combination Methods
Hormone Methods
(choose one and use with a
barrier method)
Barrier Methods
(use both OR choose one and use 
with a hormone method)
Intrauterine Devices (IUDs)

Copper T 380A IUD*,**

LNg 20 IUD*, ***
Tubal Sterilization*
Estrogen and Progesterone

Oral contraceptives*

Transdermal patch

Vaginal ring
Progesterone

Injection

Implant*

Diaphragm with spermicide*
OR
Cervical cap with spermicide

Male condom (with* or without 
spermicide*)
Partner’s vasectomy must be used with a hormone or barrier method.
Abbreviation: IUD = intrauterine device
*
Approved in Japan
**
Sold in Japan as Copper T 380 IUD
*** Sold in Japan as Minera 52mg
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days (Group A) or 6 months (Group B) after the end of relevant systemic 
exposure.
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid. Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 90 days 
(Group A) or 6 months (Group B) after the end of relevant systemic exposure. Additional 
contraception recommendations should also be considered if the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
(Group A) or 6 months (Group B) after the end of relevant systemic exposure.
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 (Group A) or 6 months (Group B) of last 
study drug dose. Subjects who become pregnant or who suspect that they are pregnant during the 
study must report the information to the investigator and discontinue study drug immediately. 
Subjects whose partner has become pregnant or suspects she is pregnant during the study must 
report the information to the investigator. Instructions for reporting pregnancy, partner 
pregnancy, and pregnancy outcome are outlined in Section 7.7.


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Appendix 5.
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
Severely 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 6.
Modified International Working Group Criteria for AML
Assessment of clinical response in Group B 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 (i.e. Cycle 1 Day 14)

Guides subsequent treatment (eg, need for or timing of second induction course)
Morphologic Complete Remission (CR)
CR requires all of the following:

< 5% blasts in bone marrow aspirate

Neutrophils ≥1,000/uL

Platelets ≥ 100,000/uL

No extramedullary disease

No blasts with Auer rods detected
Cytogenetic Complete Remission (CRc)
CRc requires all of the following:

< 5% blasts in bone marrow aspirate

Neutrophils ≥ 1,000/UL

Platelets ≥ 100,000/UL

No extramedullary disease

No blasts with Auer rods detected

Reversion to a normal karyotype with an abnormal karytype at the time of diagnosis


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Morphologic CR with incomplete blood count recovery (CRi)
CRi requires all of the following:

< 5% blasts in bone marrow aspirate

Neutrophils < 1,000/uL or Platelets < 100,000/uL 

No extramedullary disease

No blasts with Auer rods detected
Partial Remission (PR)
PR requires all of the following:

≥ 50% decrease in blasts in bone marrow aspirate to a range of 5-25%

Neutrophils ≥ 500/uL

Platelets ≥ 50,000/uL
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. Subjects who survive ≥ 7 days following completion of initial treatment, with 
evidence of persistent leukemia by blood and/or bone marrow examination.

Death in Aplasia: Subjects who survive ≥ 7 days following completion of initial treatment, 
but dies while cytopenic, with an aplastic or hypoplastic marrow obtained within 7 days of 
death, without evidence of persistent leukemia

Death from Indeterminate cause: Subjects who die before completion of treatment or 
< 7 days following completion of initial treatment; subjects who die ≥7 days following 
completion of initial treatment with no peripheral blood blasts, but no bone marrow 
examination is available; subjects who fail to complete the first cycle of therapy


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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.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 1b Study to Investigate the Safety, Tolerability, and
Pharmacokinetics of Entospletinib (ENTO) as Monotherapy in 
Japanese Subjects with Relapsed or Refractory Hematologic 
Malignancies and in Combination with Chemotherapy in Japanese 
Subjects with Previously Untreated Acute Myeloid Leukemia 
(AML)
Name of Test Drug:
Entospletinib (ENTO)
Study Number:
GS-US-429-4104
Protocol Version (Date):
Amendment 3 (23 August 2017)
Analysis Type:
Final
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
24 May 2018 
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF ABBREVIATIONS........................................................................................................................................4
1.
INTRODUCTION ................................................................................................................................................6
1.1.
Study Objectives ......................................................................................................................................6
1.1.1.
Primary Objectives.................................................................................................................6
1.1.2.
Secondary Objectives.............................................................................................................6
1.2.
Study Design............................................................................................................................................6
1.3.
Sample Size and Power............................................................................................................................7
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................9
2.1.
Interim Analysis.......................................................................................................................................9
2.2.
Final Analysis ..........................................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................10
3.1.
Analysis Sets..........................................................................................................................................10
3.1.1.
Full Analysis Set ..................................................................................................................10
3.1.2.
Dose-Limiting Toxicity (DLT) Analysis Set........................................................................10
3.1.3.
Pharmacokinetic Analysis Sets.............................................................................................10
3.2.
Subject Grouping ...................................................................................................................................10
3.3.
Strata and Covariates..............................................................................................................................10
3.4.
Examination of Subject Subgroups........................................................................................................10
3.5.
Multiple Comparisons............................................................................................................................11
3.6.
Missing Data and Outliers......................................................................................................................11
3.6.1.
Missing Data ........................................................................................................................11
3.6.2.
Outliers.................................................................................................................................11
3.7.
Data Handling Conventions and Transformations .................................................................................11
3.8.
Analysis Visit Windows.........................................................................................................................12
3.8.1.
Definition of Study Day .......................................................................................................12
3.8.2.
Analysis Windows................................................................................................................12
4.
SUBJECT DISPOSITION ..................................................................................................................................13
4.1.
Subject Enrollment and Disposition.......................................................................................................13
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................13
4.2.1.
Exposure to Study Drug .......................................................................................................13
4.2.2.
Adherence to Study Drug.....................................................................................................14
4.3.
Protocol Deviations................................................................................................................................14
5.
BASELINE CHARACTERISTICS....................................................................................................................15
5.1.
Demographics ........................................................................................................................................15
5.2.
Other Baseline Characteristics ...............................................................................................................15
5.3.
Medical History......................................................................................................................................15
5.4.
Prior Anti-Cancer Therapy.....................................................................................................................15
6.
EFFICACY ANALYSES ...................................................................................................................................16
6.1.
Primary Efficacy Endpoints ...................................................................................................................16
6.2.
Secondary Efficacy Endpoints ...............................................................................................................16
6.3.
Exploratory Efficacy Endpoints.............................................................................................................16
6.3.1.
Definition of Exploratory Efficacy Endpoints......................................................................16
6.3.2.
Analysis Methods of Exploratory Efficacy Endpoints .........................................................17
6.3.3.
Changes from Protocol-Specified Efficacy Analyses...........................................................17


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7.
SAFETY ANALYSES........................................................................................................................................18
7.1.
Adverse Events and Deaths....................................................................................................................18
7.1.1.
Adverse Event Dictionary ....................................................................................................18
7.1.2.
Adverse Event Severity........................................................................................................18
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................18
7.1.4.
Serious Adverse Events........................................................................................................18
7.1.5.
Treatment-Emergent Adverse Events...................................................................................18
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................19
7.1.7.
Dose Limiting Toxicity ........................................................................................................20
7.2.
Laboratory Evaluations ..........................................................................................................................20
7.2.1.
Graded Laboratory Values ...................................................................................................21
7.2.2.
Shifts Relative to the Baseline Value ...................................................................................21
7.3.
Body Weight and Vital Signs.................................................................................................................21
7.4.
Prior and Concomitant Medications.......................................................................................................21
7.4.1.
Prior Medications .................................................................................................................22
7.4.2.
Concomitant Medications.....................................................................................................22
7.5.
Electrocardiogram and MUGA Scan .....................................................................................................22
7.6.
Other Safety Measures ...........................................................................................................................22
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................22
8.
PHARMACOKINETIC ANALYSES ................................................................................................................23
8.1.
PK Sample Collection............................................................................................................................23
8.2.
Statistical Analysis Methods ..................................................................................................................23
8.2.1.
Plasma Concentration...........................................................................................................23
9.
REFERENCES ...................................................................................................................................................24
10.
SOFTWARE.......................................................................................................................................................25
11.
SAP REVISION..................................................................................................................................................26
12.
APPENDICES ....................................................................................................................................................27
Appendix 1.
Study Procedures Table: Group A (ENTO Monotherapy) .....................................................28


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LIST OF ABBREVIATIONS
AE
adverse event
AML
acute myeloid leukemia
ATC
Anatomical-Therapeutic-Chemical classification
BID
bis in die (twice a day)
BLQ
below the limit of quantitation
cm
centimeter
CR
complete remission
CRc
cytogenetic complete remission
CRi
morphologic CR with incomplete blood count recovery
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DBP
diastolic blood pressure
DLT
dose limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form(s)
EFS
event free survival
ENTO
Entospletinib
EOS
end of study
EOT
end of treatment
ETA
early treatment assessment
FAB
French-American-British
FAS
full analysis set
FDA
(United States) Food and Drug Administration
HiDAC
high-dose cytarabine
g
gram
GCP
Good Clinical Practice (Guidelines)
Gilead
Gilead Sciences, Inc.
h, hr
hour
HLGT
high-level group term
HLT
high-level term
HSCT
hematopoietic stem cell transplant
ID
identification
ICH
international conference on harmonisation
IV
intravenous
kg
kilogram


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LFS
leukemia free survival
LLT
lower-level term
LOQ
lower limit of quantitation
mg
milligram
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NIH
National Institutes of Health
NE
not evaluable
ORR
objective response rate
OS
overall survival
PD
progressive disease
PK
pharmacokinetic(s)
PR
partial remission
PT
preferred term
Q1
first quartile
Q3
third quartile
StD
standard deviation
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SE
standard error
SOC
system organ class
SOP
standard operating procedure
TEAE
treatment emergent adverse event
TF
Treatment failure
TFL
tables, figures and listings
TTR
time to response
uL
microliter
ULN
upper limit of the normal range
US
United States
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 a synoptic study report (CSR) 
for Study GS-US-429-4104. This SAP is based on Protocol GS-US-429-4104 Amendment 3
dated 23 August 2017 and the electronic case report form (eCRF). The SAP will be finalized 
before database finalization. Any changes made after the finalization of the SAP will be 
documented in the CSR.
The study was originally designed to evaluate the safety, tolerability, and pharmacokinetics of 
entospletinib (ENTO) in 2 stages: (1) ENTO monotherapy (Group A) for relapsed or refractory 
hematologic malignancies; (2) ENTO in combination with cytarabine and daunorubicin (Group 
B) for AML. However, per the Sponsor’s decision, only the monotherapy stage is conducted
with full enrollment of Group A, and the study will be terminated early without opening 
enrollment in Group B. The decision to terminate the study was not due to any safety concerns. 
Therefore, a synoptic CSR will be generated, and this SAP describes the analyses for the 
monotherapy part (Group A) only. 
1.1.
Study Objectives
1.1.1.
Primary Objectives

To evaluate the safety and tolerability of ENTO monotherapy in Japanese subjects with 
relapsed or refractory hematologic malignancies

To evaluate the safety and tolerability of ENTO in combination with cytarabine and 
daunorubicin (7+3) in Japanese subjects with previously untreated AML who are candidates 
for chemotherapy
1.1.2.
Secondary Objectives

To evaluate the pharmacokinetics (PK) of ENTO in Japanese subjects with relapsed or 
refractory hematologic malignancies

To evaluate the PK of ENTO in Japanese subjects with previously untreated AML who are 
candidates for chemotherapy

To evaluate the safety and tolerability of ENTO in combination with age-adjusted high-dose 
cytarabine (HiDAC) in Japanese subjects with previously untreated AML who are candidates 
for chemotherapy
1.2.
Study Design
This is a Phase 1b, open-label, multicenter study evaluating the safety, tolerability, and PK of 
ENTO as monotherapy in Japanese subjects with relapsed or refractory hematologic 
malignancies and in combination with cytarabine and daunorubicin (7+3) in Japanese subjects 


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with previously untreated AML. The study was originally designed for 2 stages sequentially: 
(1) ENTO monotherapy in subjects with relapsed or refractory hematologic malignancies 
(Group A); (2) ENTO in combination with cytarabine and daunorubicin (7 + 3) in subjects with
untreated AML (Group B). Up to 24 subjects will be dosed in 2 groups using a rolling 6 design
to evaluate 12 subjects for DLT assessment. However, per the Sponsor’s decision, it was decided 
to only enroll subjects into Group A. The planned dose levels for Group A are:
Dose Level
Entospletinib
-1
200 mg twice daily
0
400 mg twice daily
The first 6 subjects in Group A will be enrolled at dose level 0 (400 mg twice daily BID). 
Subjects will receive ENTO BID on Days 1-28 of every 28-day cycle and will continue on study 
treatment as long as the subject is experiencing clinical benefit and does not meet criteria for
study treatment discontinuation. When the sixth evaluable subject has completed the DLT 
assessment window (begins on Cycle 1 Day 1 and ends on Cycle 1 Day 28), the safety review 
team will evaluate the safety data from all enrolled subjects. During the DLT assessment 
window, subjects who fail to complete a total of 21 days of ENTO for reasons other than a DLT 
will not be evaluable for DLT assessment and may be replaced in a timely manner as determined 
by the Gilead Medical Monitor, the Japanese CRO Medical Monitor, and the Principal 
Investigator.

If 0 or 1 out of the 6 subjects experiences a DLT, Group B will open and 6 subjects will be 
enrolled in Group B at dose level 0

If ≥ 2 out of the 6 subjects experience a DLT, 6 additional subjects will be enrolled in 
Group A at the reduced dose level -1 (200 mg BID) and Group B will not open.
The schedules of study procedure are provided in Appendix 1.
1.3.
Sample Size and Power
There is no formal efficacy or safety hypothesis to be tested in this study, and therefore no 
formal size calculation was performed.
The rolling 6 design is implemented for the study. The first 6 subjects will be enrolled at dose 
level 0 in Group A. During the DLT assessment window, if 0 or 1 out of these 6 subjects 
experience DLTs in Group A, Group B will open and 6 subjects will be enrolled at dose level 0 
in Group B. However, if 2 or more subjects experience DLTs in Group A, 6 additional subjects 
will be enrolled at dose level -1 in Group A and Group B will not open. Subjects who 
discontinue early for a non-DLT defined reason during the DLT assessment window will not be 
evaluable for DLT and may be replaced. The aforementioned subjects are DLT evaluable 
subjects.


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With consideration for subject replacement, up to 24 subjects will be enrolled to the study.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analysis
No formal interim analyses are planned in this Phase 1b study.
2.2.
Final Analysis
Final study reporting is expected to occur after all subjects have discontinued from the study.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
As the study was terminated early with only 9 subjects enrolled, the synoptic CSR will only 
include listings for efficacy analyses. Both summarized tables and listings will be provided for 
safety analyses.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. The analysis set will be identified
and included as a subtitle of each table, figure, and listing.
3.1.1.
Full Analysis Set
Full Analysis Set (FAS) includes all subjects who took at least 1 dose of study drug (ENTO). 
This analysis set will be used in the analyses of subject characteristics, drug exposure, safety, and 
efficacy.
3.1.2.
Dose-Limiting Toxicity (DLT) Analysis Set
DLT Analysis Set includes all subjects in the FAS who meet at least one of the following 
criteria:

Receive at least 21 days of ENTO during the DLT assessment window (refer to Section 1.2).

Experience a DLT during the DLT assessment window.
This analysis set will be used for analyses related to DLT.
3.1.3.
Pharmacokinetic Analysis Sets
The Pharmacokinetic (PK) Analysis Sets include all subjects in the FAS who have necessary 
baseline and at least 1 non-missing post-treatment assessments. 
3.2.
Subject Grouping
Due to the early termination of the study, only one dose is evaluated. Subjects will be presented 
under ‘400 mg BID’ dose level for FAS, DLT Analysis Set, and PK Analysis Sets. 
3.3.
Strata and Covariates
Not applicable.
3.4.
Examination of Subject Subgroups
Not applicable.


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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. 
The handling of missing or incomplete date for AE onset is described in Section 7.1.5.2, and for 
prior medication and concomitant medication 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
In general, age (in years) on the first dosing date of study drug will be used for analyses and 
presentation in listings. For enrolled subjects who are not dosed with any study drug, the 
enrollment date will be used instead of the first dosing date of study drug. For screen failures, the 
date the informed consent was signed will be used for age calculation. If only the birth year is 
collected on the CRF, “01 July” will be used for the unknown birth day and month for the 
purpose of age calculation. If only birth year and month are collected, “01” will be used for the 
unknown birth day.
Non-PK laboratory data that are continuous in nature but are less than the lower limit of 
quantitation (LOQ) or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used 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).


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Plasma concentration values that are below the limit of quantitation (BLQ) will be presented as 
“BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 at pre-dose time 
points, and one-half the value of the LOQ at post-baseline time points.
The following conventions will be used for the presentation of summary and order statistics: 

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug and derived as follows:

For post-treatment study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date
Therefore, Study Day 1 is the day of first dose of study drug administration. 
Baseline is defined as the last non-missing record on or prior to the date of Study Day 1, unless
otherwise specified.
3.8.2.
Analysis Windows
The nominal visit as recorded on the CRF will be used when data are summarized by visit and no 
analysis window will be derived. 


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject disposition will be provided by dose level based on FAS. This summary 
will present the number and percentage of subjects in the following categories: 

ENTO discontinuation
Reasons of ENTO discontinuation

Included in the DLT analysis set

Study discontinuation
Reasons of Study discontinuation
The denominator for the percentage calculation will be the total number of subjects in FAS
corresponding to that column.
A data listing of subject enrollment to describe the site, subject number, date of first and last
dose and dose level of ENTO, analysis set inclusion (FAS and DLT analysis sets), reasons for
ENTO discontinuation, and reasons for study discontinuation will be provided.
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 
study drug and the level of adherence to the study drug specified in the protocol. The summaries 
will be based on FAS.
4.2.1.
Exposure to Study Drug
Total duration of exposure to study drug will be defined as last dosing date minus first dosing 
date plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.5 weeks).
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, 28 days, and 
2, 3, 6, 9 months, etc. 
The number of cycles subjects were exposed to study drug will be summarized using descriptive 
statistics, as well as the number and percentage of subjects exposed to a given cycle category
(eg, Cycle X).
The number and percentage of subjects, who had dose reduction or interruption, and the reason,
will also be summarized.


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4.2.2.
Adherence to Study Drug
A by-subject listing of study drug accountability (dispenses and returns) and dose modification
will be provided by subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations
Subjects who did not meet the eligibility criteria for study entry, but enrolled in the study will be 
identified regardless of whether they were exempted by the sponsor or not. 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. 
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. A by-subject listing will be provided for those subjects with important protocol 
deviation. 


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5.
BASELINE CHARACTERISTICS
The baseline characteristics will be presented by treatment group based on 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, and 
ethnicity. 
Age will be calculated by the formula: 
Age (in years) = (date of first dose – date of birth+1) / 365.25 (round down to an integer)
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include body weight (in kg), height (in cm), body mass index 
(BMI; in kg/m2), ECOG status, cytogenetics, genetic risk group classification, and type of 
hematologic malignancy. BMI will be calculated by the formula: 
BMI (kg/m2) = weight / (height2) (round to 1 decimal point).
Other baseline characteristics will be summarized using descriptive statistics. 
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
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). General medical history data will not be 
coded.
A by-subject listing of disease-specific (including hematologic malignancy type, date of initial 
diagnosis, and detailed diagnosis) and general medical history will be provided by subject ID 
number in ascending order. 
5.4.
Prior Anti-Cancer Therapy
A by-subject listing of prior anti-cancer therapy and prior radiation therapy will be provided by 
subject ID number in ascending order. 


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6.
EFFICACY ANALYSES
Assessment of clinical response in subjects with hematologic malignancies other than AML will 
be according to the latest set of published response criteria. Assessment of clinical response in 
subjects with AML will be according to the modified International Working Group criteria and 
will include findings on examination of blood, bone marrow and physical examination.
Clinical response will be evaluated by investigator assessments. All efficacy endpoints will be 
analyzed by treatment group using FAS.
6.1.
Primary Efficacy Endpoints
Not applicable.
6.2.
Secondary Efficacy Endpoints
Not applicable.
6.3.
Exploratory Efficacy Endpoints
6.3.1.
Definition of Exploratory Efficacy Endpoints
CCI


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6.3.2.
Analysis Methods of Exploratory Efficacy Endpoints
 
6.3.3.
Changes from Protocol-Specified Efficacy Analyses
 
 
 
CCI
CCI
CCI


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7.
SAFETY ANALYSES
Safety analyses are conducted using FAS, unless otherwise specified.
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 
(ie, Version 21.0) 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
{U.S. Department of Health and Human Services 2010}. The severity grade of events for which 
the investigator did not record severity will be categorized as “missing” for tabular summaries
and data listings and 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 Entospletinib”. 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 the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from then Gilead Drug Safety and 
Public Health Department before data finalization.
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


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug
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.
In case when the AE onset date is incomplete and needs to be imputed, the following algorithm 
will be followed:

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 first dosing date if they have the same month and year, whichever is 
later.

If 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.
7.1.6.
Summaries of Adverse Events and Deaths
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, PT, and maximum severity as follows:

All TEAEs

Grade 3 or higher TEAEs

ENTO-related TEAEs

ENTO-related Grade 3 or higher TEAEs

Serious TEAEs

ENTO-related Serious TEAEs

TEAEs leading to ENTO discontinuation


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
TEAEs leading to ENTO reductions 

TEAEs leading to ENTO interruptions

TEAEs leading to death

TEAEs leading to study discontinuations
A brief, high-level summary of AEs described above will be provided by the number and 
percentage of subjects who experienced the above AEs. All deaths occurred in the study will also 
be included.
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 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, data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

All SAEs

Deaths

TEAEs leading to ENTO discontinuation
7.1.7.
Dose Limiting Toxicity
Dose limiting toxicity (DLT) will be analyzed based on the DLT analysis set. 
A listing of the DLT AEs will be provided by dose level, subject identification, actual dose 
amount prior to or on the start date of the AE, DLT terms from the investigators, CTCAE terms, 
and associated severity grade, if available.
7.2.
Laboratory Evaluations
Central laboratory assessment will be used for safety analysis. Laboratory data collected during 
the study will be analyzed and summarized using both quantitative and qualitative methods. 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.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on CTCAE 
severity grade will be flagged in the data listings, as appropriate.


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7.2.1.
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.
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.
7.2.1.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any post-baseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug, or the 
last available date in the database snapshot for subjects who were still on treatment at the time of 
an interim analysis. 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 to be treatment 
emergent.
7.2.1.2.
Summaries of Laboratory Abnormalities
Summary (number and percentage of subjects) of baseline and worst post-baseline 
treatment-emergent laboratory abnormalities will be provided by lab test. Subjects will be 
categorized according to the most severe post-baseline abnormality grade for a given lab test.
A by-subject listing will include all laboratory results with flags to indicate treatment emergent 
laboratory abnormalities.
7.2.2.
Shifts Relative to the Baseline Value
Shift tables will be presented by showing change in severity grade from baseline to the worst 
post-baseline grade.
7.3.
Body Weight and Vital Signs
A by-subject listing of body weight and vital signs will be provided by subject ID number and 
visit in chronological order. High or low values for vital signs will be flagged.
7.4.
Prior and Concomitant Medications
Prior and concomitant medications will be coded based on World Health Organization Drug 
Dictionary (WHO DRUG) Version Q32017 into Anatomical-Therapeutic-Chemical 
classification (ATC) codes. 


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7.4.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first dose of 
study drug. For the purposes of analysis, any medication with a start date prior to the first dosing 
date of study drug will be considered as prior medication 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 considered as prior 
medication, unless otherwise specified.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. 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 
to the date of first dosing date of study drug or a start date after the last dosing date of study drug 
will not be considered as concomitant. 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 not be considered as concomitant medication. 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 not be considered as concomitant medication. 
Medications with completely missing start and stop dates will be considered as concomitant 
medication, unless otherwise specified.
The incomplete dates handling method used for AE summaries will be used for concomitant 
medication summaries (Section 7.1.5.2). 
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 
based on FAS analysis set.
7.5.
Electrocardiogram and MUGA Scan
Electrocardiogram (ECG) and MUGA data will not be presented in the synoptic CSR since 
ECGs and MUGA scan were not assessed in this study other than as part of the screening process 
for potential new subjects.
7.6.
Other Safety Measures
No additional safety measures are specified in the protocol.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
8.1.
PK Sample Collection
Intensive PK samples are collected on Day 8 of Cycle 1 at 0 (pre-dose), 1, 2, 3, 4, 6, 8, and 
12 hours post-dose of ENTO.
Sparse PK samples are collected at pre-dose and 2 hours post-dose of ENTO on (1) Days 1, 14, 
and 28 of Cycle 1; (2) Day 28 of Cycle 2 and subsequent cycles.
Concentrations of ENTO in plasma will be determined using a validated bioanalytical assay. 
8.2.
Statistical Analysis Methods
8.2.1.
Plasma Concentration
Plasma PK sampling details by subject including nominal collection time, actual dosing time and 
actual collection time, calculated time postdose of sample collection, differences in scheduled 
and actual draw times, sample age, and sample ENTO concentration will be provided in the 
listing.


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9.
REFERENCES
U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse 
Events (CTCAE). Version 4.0 (Published: May 28, 2009). v4.03 (Published: June 
14, 2010)  NIH Publication No. 09-5410.  2010.


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10.
SOFTWARE
SAS® Software Version 9.4 or higher, SAS Institute Inc., Cary, NC, USA. 


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11.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Appendix 1.
Study Procedures Table: Group A (ENTO Monotherapy)


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Appendix 1.
Study Procedures Table: Group A (ENTO Monotherapy)
Study Phase
Screening
Cycle 1
Subsequent Cycles
Remission/Relapse
End of 
Treatment 
(EOT)
30-day 
Follow-Up
Long Term
Follow-up
Study Day
Screening
1
8
14
28
1
28
Window (day)
-14
NA
±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
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/MUGA
X
Performance Status
X
X
X
X
X
Chest X-ray
X
Overall survival, treatments, 
and other malignancies
X
(every 6 months)
Study Treatment
ENTO Administrationd
X
X
X
X
X
X
Laboratory Assessments
Chemistrye
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 FSHf
X
Urine Pregnancy Testg
X
X
X
HIV/HBV/HCV
X
Sparse PKh
X
X
X
X
Intensive PKi
X
Disease Assessmentj
X
X
X
X
I 
I I I 
I 
I 


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Study Phase
Screening
Cycle 1
Subsequent Cycles
Remission/Relapse
End of 
Treatment 
(EOT)
30-day 
Follow-Up
Long Term
Follow-up
Study Day
Screening
1
8
14
28
1
28
Window (day)
-14
NA
±2
±2
±2
±2
±2
±2
±7
±7
± 4 weeks
Bone Marrow Assessments
Biopsyk
X
X
X
X
Aspiratek
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 EOT.
d
ENTO will be administered BID 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. The subject may continue on ENTO monotherapy 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 EOT. 
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. 
g
For females of childbearing potential, urine pregnancy tests will be done on Day 1 of each cycle and at EOT.
h
Peripheral blood samples for sparse PK will be obtained on Cycle 1 Days 1, 14 and 28, and Day 28 of subsequent cycles at pre-dose and 2hrs post-dose of ENTO. 
i
Peripheral blood samples for intensive PK will be obtained on Cycle 1 Day 8 at 0 (pre-dose), 1, 2, 3, 4, 6, 8, and 12 hours post-dose of ENTO.
j
Subjects with hematologic malignancies other than AML will undergo the appropriate clinical, radiographic, laboratory procedures for disease assessment per the standard of 
care/institutional practice at screening (within 21 days before the first administration of study treatment), at the end of Cycle 1 on Day 28, as clinically indicated after Cycle 1, 
remission/relapse, and EOT (if not performed within the last 2 weeks).
k
Subjects with AML will undergo a bone marrow biopsy and aspirate (~8mL) for disease assessment at screening (within 21 days before the first administration of study 
treatment), at the end of Cycle 1 on Day 28, as clinically indicated after Cycle 1, remission/relapse, and EOT (if not collected within the last 2 weeks). Biopsy will be used in 
the event the aspirate cannot be collected or analyzed. Subjects with AML with cytogenetic and molecular mutations at screening must have cytogenetic and molecular 
mutation testing repeated at Cycle 1 Day 28, remission/relapse, and EOT.


SAP GS-US-429-4104_v1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
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yyyy hh:mm:ss)
Clinical Pharmacology
eSigned
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Clinical Research eSigned
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Biostatistics eSigned
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PPD
PPD
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