Conditions: Acute Lymphoblastic Leukemia
Keywords: Syk inhibitor Blood malignancy Leukemia
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 30
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the safety of entospletinib in combination with vincristine (VCR), and dexamethasone (DEX) in adults with previously treated relapsed or refractory B-cell lineage acute lymphoblastic leukemia (ALL).

This is a dose escalation study in which after 2 induction cycles participants may be put on maintenance for up to 36 cycles if they have obtained clinical benefit from the treatment.

Detailed description:

Arms:
arm 1: Monotherapy Lead-In (Day -7 to Day -1): Entospletinib (ENTO) 200 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 200 mg twice daily continuously in combination with vincristine (VCR) 0.5 mg intravenously (IV) on Days 1, 8, 15, and 22 of each cycle; dexamethasone (DEX) 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and central nervous system (CNS) prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a complete remission (CR) received stem cell transplant (SCT) (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a partial response \[PR\]) after induction were offered maintenance therapy with ENTO 200 mg twice daily continuously in combination with VCR 0.5 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle. arm 2: Monotherapy Lead-In (Day -7 to Day -1): ENTO 400 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 400 mg twice daily continuously in combination with VCR 0.5 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 400 mg twice daily continuously in combination with VCR 0.5 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle. arm 3: Monotherapy Lead-In (Day -7 to Day -1): ENTO 400 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 400 mg twice daily continuously in combination with VCR 1.0 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 400 mg twice daily continuously in combination with VCR 1.0 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle. arm 4: Monotherapy Lead-In (Day -7 to Day -1): ENTO 400 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 400 mg twice daily continuously in combination with VCR 2.0 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 400 mg twice daily continuously in combination with VCR 2.0 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle.

Interventions: intervention 1: Entospletinib intervention 2: Vincristine intervention 3: Dexamethasone intervention 4: CNS Prophylaxis
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_001.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1b/2 Open-Label, Dose Escalation and Expansion Study 
Evaluating the Safety and Efficacy of Entospletinib (GS-9973)
with Vincristine and Dexamethasone in Adult Subjects with 
Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
NCT:
116416
2015-002768-18
02404220
Indication:
Acute Lymphoblastic Leukemia
Protocol ID:
GS-US-339-1560
Gilead Clinical Program 
Manager:
Name:
Telephone:
Email:
 
Gilead Medical Monitor:
Name:
Telephone:
Email:
Protocol Version/Date:
Original:
18 December 2014
Amendment 1:
18 June 2015
Amendment 2:
09 December 2015
Amendment 3:
21 November 2016
Amendment 4:
31 August 2017
Amendment 5:
13 April 2018
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................16
1.
INTRODUCTION ..............................................................................................................................................20
1.1.
Acute Lymphoblastic Leukemia ............................................................................................................20
1.2.
Spleen Tyrosine Kinase..........................................................................................................................21
1.2.1.
Spleen Tyrosine Kinase in Hematologic Malignancies........................................................21
1.2.2.
Clinical Experience in Hematologic Malignancies treated with Syk 
Inhibitors ..............................................................................................................................22
1.3.
Entospletinib (ENTO [GS-9973]) ..........................................................................................................23
1.3.1.
Nonclinical Pharmacology ...................................................................................................23
1.3.2.
Nonclinical Drug Metabolism and Pharmacokinetics ..........................................................24
1.3.3.
Nonclinical Toxicology........................................................................................................25
1.3.4.
Monotherapy Clinical Trials of GS-9973.............................................................................27
1.3.5.
GS-9973 Target Drug Concentrations..................................................................................28
1.3.6.
Use of Concomitant Medications with GS-9973..................................................................29
1.4.
Rationale for This Study ........................................................................................................................30
1.4.1.
Rationale for the GS-9973 Dose Selection...........................................................................31
1.5.
Information about Chemotherapy Agents ..............................................................................................31
1.5.1.
Vincristine............................................................................................................................31
1.5.2.
Dexamethasone ....................................................................................................................32
1.6.
OVERALL RISK AND BENEFIT ASSESSMENT..............................................................................32
1.7.
Compliance ............................................................................................................................................34
2.
OBJECTIVES AND ENDPOINTS ....................................................................................................................35
2.1.
Objectives...............................................................................................................................................35
3.
STUDY DESIGN................................................................................................................................................36
3.1.
Endpoints ...............................................................................................................................................36
3.2.
Study Design..........................................................................................................................................36
3.3.
Study Treatment.....................................................................................................................................36
3.3.1.
Dose Escalation....................................................................................................................36
3.3.2.
Dose Expansion....................................................................................................................37
3.3.3.
Maintenance .........................................................................................................................38
3.4.
Duration of Treatment............................................................................................................................38
3.5.
Dose-Limiting Toxicity..........................................................................................................................38
3.5.1.
Management of Dose Limiting Toxicities............................................................................40
3.5.2.
Guidelines for Dose Modifications ......................................................................................40
3.5.3.
Dose Modifications for Hematologic Toxicity for GS-9973, VCR, and 
dexamethasone.....................................................................................................................41
3.5.4.
Management of Low Grade Chronic Toxicities...................................................................41
3.5.5.
Specific Considerations for Managing Hyperbilirubinemia.................................................42
3.6.
End of Study...........................................................................................................................................42
3.7.
Post Study Care......................................................................................................................................42
4.
SUBJECT POPULATION..................................................................................................................................43
4.1.
Number of Subjects and Subject Selection ............................................................................................43
4.2.
Inclusion Criteria....................................................................................................................................43


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4.3.
Exclusion Criteria...................................................................................................................................45
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................48
5.1.
Description and Handling of Entospletinib (ENTO [GS-9973])............................................................48
5.1.1.
Formulation..........................................................................................................................48
5.1.2.
Source...................................................................................................................................48
5.1.3.
Packaging and Labeling .......................................................................................................48
5.1.4.
Storage and Handling...........................................................................................................48
5.1.5.
Study Drug Accountability...................................................................................................49
5.2.
Treatment Plan .......................................................................................................................................49
5.2.1.
Pre-medication .....................................................................................................................49
5.2.2.
Administration Instructions..................................................................................................49
5.2.3.
Dosing Schedule...................................................................................................................49
5.2.4.
Dose Schedule Interruptions and Vomited Doses ................................................................49
5.2.5.
Concomitant and Supportive Therapy..................................................................................50
5.3.
Excluded Medication .............................................................................................................................50
5.4.
Study Drug Disposal ..............................................................................................................................51
6.
STUDY PROCEDURES ....................................................................................................................................53
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................53
6.2.
Subject Enrollment and Treatment Assignment.....................................................................................53
6.2.1.
Obtain Written Informed Consent........................................................................................53
6.2.2.
Recording Medical History ..................................................................................................53
6.2.3.
Medication History...............................................................................................................53
6.2.4.
Physical Examination...........................................................................................................53
6.2.5.
Vital Signs............................................................................................................................53
6.2.6.
Laboratory Assessments.......................................................................................................54
6.2.7.
Bone Marrow Aspirate and Biopsy ......................................................................................54
6.2.8.
Eastern Cooperative Oncology (ECOG) Performance Status ..............................................55
6.3.
Biomarker Testing..................................................................................................................................55
6.3.1.
Biomarker Samples to Address the Study Objectives:.........................................................55
6.3.2.
Biomarker Samples for Optional Future Research...............................................................55
6.3.3.
56
6.4.
Pretreatment Assessments......................................................................................................................57
6.4.1.
Screening Visit .....................................................................................................................57
6.5.
Treatment Assessments..........................................................................................................................57
6.5.1.
Lead-in Phase:......................................................................................................................57
6.5.2.
Cycle 1 .................................................................................................................................58
6.5.3.
Cycle 2 .................................................................................................................................61
6.6.
Maintenance...........................................................................................................................................64
6.7.
End of Study Treatment Assessments....................................................................................................64
6.7.1.
30-Day Follow-up ................................................................................................................65
6.7.2.
Long Term Follow-Up .........................................................................................................66
6.8.
Criteria for Discontinuation of Study Treatment....................................................................................66
6.9.
End of Study...........................................................................................................................................66
6.10.
Post Study Care......................................................................................................................................66
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................67
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................67
7.1.1.
Adverse Events.....................................................................................................................67
7.1.2.
Serious Adverse Events........................................................................................................67
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................68
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................69
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................69
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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
7.7.
Special Situations Reports......................................................................................................................73
7.7.1.
Definitions of Special Situations..........................................................................................73
7.7.2.
Instructions for Reporting Special Situations.......................................................................73
8.
STATISTICAL CONSIDERATIONS................................................................................................................75
8.1.
Analysis Objectives and Endpoints........................................................................................................75
8.1.1.
Analysis Objectives..............................................................................................................75
8.1.2.
Primary Endpoint .................................................................................................................75
8.1.3.
Secondary Endpoint .............................................................................................................76
8.1.4.
Exploratory endpoints ..........................................................................................................76
8.2.
Analysis Sets..........................................................................................................................................77
8.2.1.
All Enrolled Analysis Set.....................................................................................................77
8.2.2.
Full Analysis Set ..................................................................................................................77
8.2.3.
DLT Analysis Set.................................................................................................................77
8.2.4.
Pharmacokinetic Analysis Set..............................................................................................77
8.3.
Data Handling Conventions ...................................................................................................................77
8.4.
Demographic Data and Baseline Characteristics ...................................................................................78
8.5.
Efficacy Analysis ...................................................................................................................................78
8.5.1.
Primary 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.
Biomarker Analysis................................................................................................................................81
8.9.
Sample Size............................................................................................................................................81
8.10.
Timing of Analyses................................................................................................................................82
8.10.1.
Interim Analyses ..................................................................................................................82
8.10.2.
Final Analysis.......................................................................................................................82
9.
RESPONSIBILITIES..........................................................................................................................................83
9.1.
Investigator Responsibilities ..................................................................................................................83
9.1.1.
Good Clinical Practice..........................................................................................................83
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................83
9.1.3.
Informed Consent.................................................................................................................83
9.1.4.
Confidentiality......................................................................................................................84
9.1.5.
Study Files and Retention of Records ..................................................................................84
9.1.6.
Case Report Forms...............................................................................................................85
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................86
9.1.8.
Inspections............................................................................................................................86
9.1.9.
Protocol Compliance............................................................................................................86
9.2.
Sponsor Responsibilities ........................................................................................................................86
9.2.1.
Protocol Modifications.........................................................................................................86
9.2.2.
Study Report and Publications .............................................................................................87
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................87
9.3.1.
Payment Reporting...............................................................................................................87
9.3.2.
Access to Information for Monitoring..................................................................................87


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9.3.3.
Access to Information for Auditing or Inspections ..............................................................88
9.3.4.
Study Discontinuation..........................................................................................................88
10.
REFERENCES ...................................................................................................................................................89
11.
APPENDICES ....................................................................................................................................................91
Appendix 1.
Investigator Signature Page....................................................................................................92
Appendix 2.
Study Procedures Table..........................................................................................................93
Appendix 3.
Management of Clinical and Laboratory Adverse Events......................................................95
Appendix 4.
Response assessment in ALL .................................................................................................97
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................99
Appendix 6.
ECOG status.........................................................................................................................101
Appendix 7.
NCCN Guidelines (version 2.2016) .....................................................................................102
LIST OF IN-TEXT TABLES
Table 3-1.
GS-9973/VCR Dose Escalation..............................................................................................36
Table 3-2.
Dose Escalation/DLT Guidelines ...........................................................................................39
Table 4-1.
Required Screening Laboratory Values..................................................................................44
Table 5-1.
Examples of Contraindicated Medication Requiring GSI Medical Monitor Approval ..........51
Table 6-1.
Analytes..................................................................................................................................54
Table 7-1.
Grading of Adverse Event Severity........................................................................................70
Table 8-1.
Probability of Dose Escalation (N=3+3) ................................................................................81
LIST OF IN-TEXT FIGURES
Figure 1-1.
Positive and Negative Regulators of Antigen-dependent BCR Signaling..............................22
Figure 1-2.
GS-9973 Kinome Scan...........................................................................................................23
Figure 1-3.
GS-9973 AUCtau at Steady State ............................................................................................27
Figure 1-4.
GS-9973 Cmax at Steady State.................................................................................................28
Figure 1-5.
Inhibition of Basophil Activation...........................................................................................29
Figure 1-6.
Inhibition of pSyk...................................................................................................................29


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 1b/2, Open-Label, Dose Escalation and Expansion Study Evaluating 
the Safety and Efficacy of Entospletinib (GS-9973) with Vincristine and 
Dexamethasone in Adult Subjects with Relapsed or Refractory Acute 
Lymphoblastic Leukemia (ALL)
IND Number:
116416
EudraCT 
Number:
2015-002768-18
Study Centers 
Planned:
Approximately 20 sites in North America and Europe
Objectives:
The primary objective of this study is:

To evaluate safety of entospletinib (GS-9973) in combination with 
vincristine (VCR) and dexamethasone in adult subjects with previously 
treated relapsed or refractory B-cell lineage ALL
The secondary objectives of this study are: 

To determine the recommended dose of GS-9973 in combination with
VCR and dexamethasone in adult subjects with previously treated 
relapsed or refractory B-cell lineage ALL

To evaluate the therapeutic response of GS-9973 in combination with
VCR and dexamethasone in adult subjects with previously treated 
relapsed or refractory B-cell lineage ALL
The exploratory objectives of this study are: 
 
 
 
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Study Design:
This is an open-label, Phase 1b dose-escalation and Phase 2 expansion study 
evaluating the safety, efficacy, tolerability, and pharmacokinetics of GS-9973 
in combination with VCR and dexamethasone. 
There will be four dose levels in the dose escalation phase where cohorts of
3 to 6 subjects will sequentially enroll into one of the dose levels using a 
3+3 dose escalation design.  The starting dose level for the first cohort is 
defined as Dose Level 1. 
Dose Level
GS-9973 
Vincristine (VCR)
1
200 mg BID
0.5 mg per dose
2
400 mg BID
0.5 mg per dose
3
400 mg BID
1 mg per dose
4
400 mg BID
2 mg per dose
Dose Escalation: Induction (Lead-in, Cycle 1 and Cycle 2)
Lead-in (GS-9973 Monotherapy): Beginning on Day -7 of Lead-in, 
GS-9973 will be administered orally twice daily (BID) for 7 days as a single 
agent.  
Cycle 1 and Cycle 2 (GS-9973, VCR, dexamethasone, CNS Prophylaxis):
GS-9973 will be continuously administered orally BID in combination with 
chemotherapy for the duration of the study treatment.  
VCR will be administered on Days 1, 8, 15 and 22 of each 28-day cycle for 
Cycle 1 and Cycle 2 only. 
Dexamethasone (20 mg twice daily for 4 days) will be administered orally
during Cycle 1 on Days 8-11 and Days 22-25 and during Cycle 2 on Days 1-4 
and Days 15-18. 
CNS prophylaxis per institutional standard will be given on Day 28 (±3 days)
of Cycle 1 and Cycle 2.
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Bone marrow (BM) aspirate/biopsy will be performed during screening 
(within 28 days prior to the start of study treatment), Cycle 1 on Day 8 and 
during both Cycle 1 and Cycle 2 on Day 28.
Imaging (computerized tomography [CT] with contrast or Positron Emission 
Tomography (PET) scan should be performed for subjects with 
extramedullary disease (EMD) if these are the only sites of evaluable disease 
(no BM involvement) to evaluate disease status and response, at screening, 
Cycle 1 Day 8 and Day 28, and Cycle 2 Day 28. Imaging will be evaluated 
using the NCCN guidelines version 2.2016 (Patients with no BM involvement 
and only EMD will not require BM aspirate/biopsy on cycle 1 day 8 and day 
28, and cycle 2 day 28).
Subjects will continue on their assigned dose level throughout all cycles and 
through maintenance. Intra-subject dose escalations are not permitted. Dose 
modifications are not permitted during the GS-9973 Lead-in or Cycle 1 as this 
is used to assess dose limiting toxicities (DLT).  Following the completion of 
Cycle 1, if a GS-9973 related AE of Grade ≥ 3 occurs, the subject will have 
GS-9973 held until the AE improves to Grade ≤ 1 and then may resume study 
therapy at the prior dose (or decreased by 1 dose level after discussion with 
Sponsor). For subjects assigned to Dose Level 1, the decreased dose of 
GS-9973 will be defined as 100 mg orally twice daily.  
Dose Escalation treatment schedule is outlined in the schema below:
Dose Expansion:
At the time of this amendment, there have been no DLTs in the Phase 1
portion of the study.  However, due to the low response rate to ENTO + 
vincristine + dexamethasone in relapsed/refractory ALL patients, it has been 
decided not to proceed with the dose expansion (Phase 2) portion of this trial.  
Prior to this amendment, dose expansion had been initiated at 400 mg BID,
but was subsequently closed with no subjects enrolled.


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Maintenance:
It is anticipated that most subjects who are transplant eligible will receive 
hematopoietic stem cell transplant (HSCT) or therapy with curative intent if a 
complete remission (CR) is reached. In the absence of a suitable alternative 
therapeutic option, subjects who obtain clinical benefit (at least partial 
response [PR]) after completing both cycles of induction therapy in dose 
escalation may continue GS-9973 at the assigned dose level during 
maintenance for up to 36 cycles.  Subjects will continue GS-9973 and VCR at 
their assigned dose.  GS-9973 will continue to be taken orally twice daily with 
VCR to be administered on Day 1 of each 28-day cycle and dexamethasone 
20 mg total dose daily for 4 days (either 10 mg twice daily or 20 mg once 
daily) on Days 1-4 and Days 15-18 of each 28-day cycle.
Bone marrow evaluations and additional central nervous system (CNS) 
directed therapy can be performed as clinically indicated during maintenance.
Number of 
Subjects 
Planned:
Approximately 30
Target 
Population:
Adult subjects with relapsed or refractory B-cell lineage ALL
Duration of 
Treatment:
Subjects may continue receiving GS-9973 until refractory disease at the end 
of induction, relapsed disease, start of new therapy, unacceptable toxicity, 
withdrawal of consent by subject, or withdrawal from study by investigator.
Diagnosis 
and Main 
Eligibility 
Criteria:
(see 
Protocol for 
Details)
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for 
participation in this study:
1) ≥18 years of age 
2) Previously treated ALL including Philadelphia chromosome (BCR-Abl) 
positive ALL who meet all of the following criteria:
a) Diagnosis of precursor B-cell ALL based on flow cytometry and 
histology
b) Previously treated subjects with primary refractory disease OR after 
first or subsequent relapse
c) Subjects with >10% lymphoblasts in bone marrow or extramedullary 
disease (EMD) that is radiographically measureable and amenable to 
imaging studies and repeat biopsies
d) Patients with Ph+ ALL  must have failed treatment with at least one 
2nd generation (eg. dasatanib) or 3rd generation (eg. ponatinib)
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3) Eastern Cooperative Oncology Group (ECOG) performance status ≤2
4) Adequate organ function defined by the screening laboratory value 
inclusion and absence of known cardiac dysfunction
5) Required screening laboratory data (within 7 days prior to administration 
of GS-9973) (Table 4-1)
6) Discontinuation of all therapy (including radiotherapy, chemotherapy, 
tyrosine-kinase inhibitors [TKIs], immunotherapy, or investigational 
therapy) for the treatment of cancer as follows: 
a) At least 1 week or 5 half-lives (whichever is longer) from the last dose 
of prior anti-cancer therapy and the initiation of study therapy
b) Exceptions or modifications to the above are as follows: Medications 
that are typically part of a maintenance therapy for ALL, such as 
glucocorticoids or mercaptopurine, may be administered up to 3 days 
prior to the first dose, except vinca alkaloids which must be 
discontinued at least 14 days prior to the start of study treatment. TKIs
are not permitted to be continued at screening (eg, Gleevec). Subjects 
may receive hydroxyurea or leukapheresis if indicated for rapidly 
rising white blood cell count 
c) CNS prophylaxis should be dosed up at least one week prior to first 
dose of GS-9973 
d) For biologics (eg, monoclonal antibodies), washout period of at least 
4 weeks or 5 half-lives (whichever is shorter) since the last dose
e) If prior stem cell transplant, subject must be at least 100 days from 
stem cell infusion and off all systemic anti-graft versus host disease 
(GVHD) medications
f)
If prior donor lymphocyte infusion (DLI), subject must be at least 
4 weeks from DLI and off all systemic anti-graft versus host disease 
(GVHD) medications and have no evidence of any infection
g) If prior Chimeric Antigen Receptor (CAR) T-Cell Therapy, subject 
must be at least 4 weeks from CART infusion
7) All acute toxic effects of any prior antitumor therapy must be resolved to 
Grade ≤ 1 before enrollment, with the exception of alopecia (any grade 
permitted), or bone marrow parameters (any grades permitted)
8) For female subjects of childbearing potential, willingness to abstain from 
heterosexual intercourse or use a recommended method of contraception 
from the screening visit (Visit 1) throughout the study treatment period
and to 30 days from the last dose of GS-9973 (See Appendix 5)  


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9) For male subjects having intercourse with females of childbearing 
potential, willingness to abstain from heterosexual intercourse or use a 
protocol-recommended method of contraception from the start of 
GS-9973 throughout the study treatment period and for 90 days following 
the last dose of GS-9973. Also, male subjects should refrain from sperm 
donation from the start of the GS-9973 throughout the study treatment 
period and for 3 months following the last dose of GS-9973
10) In the judgment of the investigator, participation in the protocol offers an 
acceptable benefit-to-risk ratio when considering current disease status, 
medical condition, and the potential benefits and risks of alternative 
treatments for the subject’s ALL
11) Willingness to comply with scheduled visits, drug administration plan, 
imaging studies, laboratory tests, other study procedures, and study 
restrictions
Note: Psychological, social, familial, or geographical factors that might 
preclude adequate study participation should be considered
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) Diagnosis of mature B-cell ALL (Burkitt’s leukemia), or lymphoid blast 
crisis of chronic myelogenous leukemia (CML)
2) A life threatening illness, medical condition or organ system dysfunction 
which, in the investigator’s opinion, could compromise the subject’s 
safety or interfere with the absorption or metabolism of GS-9973
3) Active or symptomatic central nervous system (CNS) disease
For study purposes a subject will NOT be considered as having active 
CNS disease if the subject has documentation of prior CNS disease and 
has received treatment (IT or radiation) and are:
a) asymptomatic  for the last 28 days prior to screening, and 
b) has documented at least 2 negative cerebrospinal fluid (CSF) cytology  
(which must include 1 lumbar puncture [LP] within the study 
screening window)
4) Uncontrolled intercurrent illness including, but not limited to, unstable 
angina pectoris or psychiatric illness/social situations that would limit 
compliance with study requirements. Subjects with active infection are 
permitted to enroll provided that the infection is documented to be under 
control and after discussion with study Sponsor
5) History of myelodysplastic syndrome or solid organ transplantation


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6) History of a non-lymphoid malignancy except for the following: 
adequately treated local basal cell or squamous cell carcinoma of the skin, 
cervical carcinoma in situ, superficial bladder cancer, asymptomatic 
prostate cancer without known metastatic disease and with no requirement 
for therapy or requiring only hormonal therapy and with normal prostate 
specific antigen for > 1 year prior to the start of GS-9973, or any other 
cancer that has been in complete remission without treatment for ≥ 5 years 
prior to enrollment
7) Known hypersensitivity or intolerance to any of the active substances or 
excipients in the formulations for GS-9973
8) Evidence of uncontrolled systemic bacterial, fungal, or viral infection at 
the start of GS-9973
Note: Subjects with localized fungal infections of skin or nails are 
eligible. Subjects may be receiving prophylactic antiviral, antifungal, or 
antibacterial regimens (eg, anti-pneumocystis prophylaxis at the 
discretion of the investigator per institutional guidelines. If azoles are 
used for antifungal prophylaxis, subjects must be monitored for possible 
DDI with VCR)
9) Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), 
chronic active hepatitis B (HBV), HIV, alcoholic liver disease, 
non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic 
obstruction caused by cholelithiasis, cirrhosis of the liver, or portal 
hypertension
10) Prior allogeneic bone marrow progenitor cell transplant within 100 days 
or on active systemic immunosuppression for graft versus host disease 
(GVHD) treatment or prophylaxis within 28 days prior to enrollment
11) Active (symptomatic or requiring current medical treatment within 
28 days prior to the start of study treatment) for GVHD
12) Ongoing immunosuppressive therapy other than corticosteroids
(corticosteroids being used for GVHD treatment are not permitted). 
Note: Subjects may use topical, enteric, inhaled, or systemic 
corticosteroids as therapy for manifestations of comorbid conditions
13) Current therapy with proton pump inhibitors (PPI) must be avoided 
(as there is the potential to interfere with GS-9973 absorption)
Note: H2 blockers and antacids will be allowed for the use during the 
study
14) Pregnancy or breastfeeding
15) Ongoing active pneumonitis
16) Concurrent participation in an investigational drug trial with therapeutic 
intent defined as prior study therapy within 28 days prior to GS-9973 
administration
17) Ongoing or recent treatment with an excluded medication, as defined in 
Section 5.3, Excluded Medication


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Test Product, 
Dose, and 
Mode of 
Administration:
Study drug, GS-9973 is available as 200 mg strength tablets.  200 mg or 
400 mg of GS-9973 will be administered orally twice daily (BID) while in a 
fasted state.  
Intravenous administration of up to 2 mg Vincristine (VCR) per protocol 
schedule.
Oral administration of 20 mg dexamethasone twice daily, taken for  up to 
two courses of 4 days each in both Cycle 1 and Cycle 2 and per protocol 
during Maintenance.
CNS prophylaxis regimen per institutional standard, given once at the end of 
each cycle during Induction period.
Please refer to the package inserts for standard of care products for more 
information.
Criteria for 
Evaluation:
Safety:
The primary endpoint is safety. Safety will be evaluated by the occurrence of 
adverse events and laboratory abnormalities defined as dose limiting toxicities 
(DLTs) and also the Occurrence of AEs and laboratory abnormalities not 
defined as DLTs.
Efficacy:
Efficacy endpoints are considered secondary and will include:

Overall Remission (CR or CRi) rate at end of induction - defined as the 
proportion of subjects who achieve a complete remission (CR) or 
complete remission with incomplete hematologic recovery (CRi) at end of 
induction

Complete remission (CR) rate at end of induction

Partial response (PR) rate at end of induction - defined as the proportion 
of subjects who achieve a partial response of marrow (as defined in 
Appendix 4 of the protocol) or by imaging criteria for patients with 
extramedullary disease (NCCN guidelines version 2.2016) as the best 
response.

Overall Response (CR, CRi, or PR) rate at end of induction - defined as 
the proportion of subjects who achieve a complete remission (CR), 
complete remission with incomplete hematologic recovery (CRi) or partial 
response (PR) at end of induction
Exploratory Endpoints
 
 
 
PPD


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Pharmacokinetics
Plasma drug concentrations will be analyzed to evaluate pharmacokinetics of 
GS-9973
Statistical 
Methods:
Appropriate data analysis sets will be defined. The full-analysis set will 
include data from all subjects who receive at least 1 dose of study treatment. 
DLT analysis set includes subjects in Full Analysis Set (FAS) with sufficient 
drug exposure (Section 3.3.1) or who experience a DLT during the DLT 
assessment window.
Subject characteristics and study results will be described and summarized by  
dose level and overall for the relevant analysis sets. Descriptive summaries 
will be prepared to show sample size, mean, standard deviation (StD), 
95% confidence intervals (CIs) on the mean, median, minimum, and 
maximum for continuous variables and counts, percentages, and 95% 
exact CIs on the percentage for categorical variables.
Based on the FAS, information regarding study treatment administration, 
study drug compliance, safety variables, and post-study therapies will be 
described and summarized. Study drug plasma concentrations, and will also 
be described and summarized using pharmacokinetics set. 
PPD


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Sample Size Calculation
Sequential dose-escalation is consistent with usual oncologic paradigms for 
dose ranging. The intent is to limit the number of subjects who are exposed to 
excessively toxic doses of a drug in an early phase evaluation of an anticancer 
agent. The trial employs the standard National Cancer Institute (NCI) 
definition of MTD (starting dose associated with DLT in < 33.3% of subjects 
during the DLT assessment window) to determine dose escalation. The cohort 
size and dose-escalation rules establish a low probability of increasing the 
dose if the true rate of DLT is high while there is a high likelihood of 
escalating or proceeding to the next cohort of the study if the true underlying 
probability of DLT is low. For example, if the true underlying probability of 
DLT is low (e.g, < 10%) at the current dose level, there is a high probability 
(> 0.91) of dose escalation to the next dose level. Conversely, if the true 
underlying proportion of DLT is high (e.g, > 60%) at the current dose level, 
there is a low probability (< 0.08) of escalation to the next dose level.
Assuming that 4 planned dose levels are tested for escalation and 3, 3, 6 and 
6 subjects are tested at each dose level, respectively (18 subjects for 
escalation), and assuming 10% subjects are not evaluable during dose 
escalation, 20 subjects will be enrolled during dose escalation.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
AM
Morning
ANC
absolute neutrophil count
ARA-C
Cytarabine-(Cytosine arabinoside)
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)
BCR
B-cell receptor
BID
bis in die (twice a day)
BM
bone marrow
BUN
blood urea nitrogen
Cmax
maximum observed concentration of drug
CFR
(United States) Code of Federal Regulations
CI
confidence interval
CLL
chronic lymphocytic leukemia
cm/s
centimeter per second
CNS
central nervous system
CR
complete remission
CRi
Morphologic CR with incomplete blood count recovery
CRO
contract research organization
CSF
cerebrospinal fluid
CT
computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLBCL
diffuse large B-cell lymphoma
dL
Deciliter
DLT
Dose limiting toxicities
DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Drug Safety and Public Health
EC
ethics committee
EC50
50% effective inhibitory concentration
ECG
Electrocardiogram


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ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form(s)
EFS
event-free survival
EDC
electronic data capture
EOS
end of study
EU
European
EMD
extramedullary disease
ENTO
entospletinib (GS-9973)
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FL
follicular lymphoma
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.
GVHD
Graft versus host disease
h, hr
Hour
HBc
hepatitis B core
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
-HCG
beta human chorionic gonadotropin
HSCT
hematopoietic stem cell transplant
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HL
Hodgkin lymphoma
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
IND
Investigational New Drug (Application)
iNHL
indolent non-Hodgkin lymphoma
IRB
institutional review board
ITAM
immunoreceptor tyrosine-based activation motifs
IXRS
Interactive Voice/Web Response System
kg
Kilogram
L
Liter


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LD
longest diameter
LDH
lactate dehydrogenase
LP
lumbar puncture
MAPK
mitogen-activated protein kinase
MCL
mantle cell lymphoma
mg
Milligram
mL
Milliliter
mm
Millimeter
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MZL
marginal zone lymphoma
NCI
National Cancer Institute
ND
no disease
NE
not evaluable
ng
Nanogram
NHL
non-Hodgkin lymphoma
nM
Nanomolar
OS
overall survival
ORR
objective response rate
PBMC
peripheral blood mononuclear cells
PD
progressive disease
PFS
progression-free survival
Ph+
Philadelphia chromosome positive
PI
prescribing information
PI3K
phosphatidylinositol 3-kinase
PK
pharmacokinetic(s)
PM
Evening
PPD
product of the perpendicular diameters
PPI
proton pump inhibitor
PR
partial response
pSyk
phospho-spleen tyrosine kinase
QD
once-daily
REB
research ethics board
RFS
relapse-free survival
RNA
ribonucleic acid
SD
stable disease
SDD
Spray-dried dispersion
StD
standard deviation
SADR
serious adverse drug reactions
SAE
serious adverse event
SLL
small lymphocytic lymphoma


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SOP
standard operating procedure
SPD
sum of the products
SPEP
serum protein electrophoresis
SUSAR
Suspected Unexpected Serious Adverse Reaction
Syk
spleen tyrosine kinase
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)
TKI
Tyrosine-kinase inhibitors
TTC
time to peripheral blast clearance
TNF
tumour necrosis factor
TNF-α
tumour necrosis factor-α
TTR
time to response
ULN
upper limit of the normal range
US
United States
VCR
Vincrsitine
WHO
World Health Organization
WM
Waldenström macroglobulinemia
αIgM
anti-IgM
β
population mean slope
z
terminal elimination rate constant, estimated by linear regression of the terminal 
elimination phase of the concentration of drug versus time curve


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1.
INTRODUCTION
1.1.
Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is a biologically heterogeneous disease of the 
hematopoietic system characterized by clonal accumulation and expansion of immature 
lymphoid cells (B or T cells) either in the bone marrow (ALL) or presenting as a mass lesion 
(lymphoblastic lymphoma, LBL).  There are an estimated 6,000 new cases of ALL diagnosed 
annually in the USA {American Cancer Society 2014}.  While the majority of cases of ALL 
occur in children, the majority of deaths (approximately 4/5) occur in adults {American Society 
of Clinical Oncology (ASCO) 2014}.  Survival in childhood ALL currently approaches 90%, but 
results of therapy in adults remains unsatisfactory {Bassan 2011, Hunger 2012}.  The long-term 
survival of adults with ALL who are intensively treated is about 40%.  However, despite 
hematologic remissions being obtained in up to 90% of subjects, after further consolidation 
therapy and maintenance chemotherapy, less than half will have long-term leukemia-free 
survival; the majority of adults with ALL will ultimately relapse. In addition, up to 20 % will 
have primary resistant disease {Goldstone 2008}.
Treatment for ALL typically spans 2 to 2.5 years, and comprises of three phases: induction of 
remission, intensification/consolidation, and maintenance/continuation therapy {Pui 2008}.  
Most of the drugs currently used in the treatment of ALL were developed before 1970 and while 
few of the individual components of therapy have been evaluated rigorously in randomized trials, 
their dosages and schedule in combination have been empirically optimized over time based on 
risk assessment, biological features, response to treatment, and pharmacodynamic and 
pharmacogenomics findings in subjects {Inaba 2013}.  The primary goal of induction therapy is 
to achieve an initial complete remission (CR), defined as eradication of all detectable leukemia 
cells (< 5%blasts) from the bone marrow and blood and the restoration of normal hematopoiesis 
(> 25% percent cellularity and normal peripheral blood counts) {National Comprehensive 
Cancer Network (NCCN) 2014}.  Subjects with BCR-Ab1-positive disease have poor prognoses 
but benefit from early treatment with tyrosine-kinase inhibitors (imatinib, dasatinib), which 
improve complete remission rates and event-free survival when added to combination 
chemotherapy regimens {Schultz 2009}.  Subjects who do not achieve a CR with initial 
induction therapy are considered to have resistant disease.  Consolidation and 
maintenance/continuation therapy are meant to eradicate residual leukemic cells without 
additional cytotoxic therapy, virtually all subjects will relapse within weeks or months.
Because further intensification of existing chemotherapy regimens is unlikely to substantially 
improve survival, new agents and treatment regimens should be investigated.  In addition, 
treatment for relapsed disease, defined as the reappearance of leukemia cells in the bone marrow 
or peripheral blood any time after the attainment of a complete remission, remains generally 
unsuccessful.  Emerging evidence suggests that chemoresistance is frequently driven by 
subpopulations of cells harboring specific genetic alterations that confer resistance.  This 
highlights the need for novel therapeutic strategies either alone or in combination with existing 
treatment regimens to improve on the currently dismal prognosis for relapsed/refractory ALL 
subjects, particularly in the adult age group.


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1.2.
Spleen Tyrosine Kinase 
1.2.1.
Spleen Tyrosine Kinase in Hematologic Malignancies
Spleen tyrosine kinase (Syk) is a non-receptor cytoplasmic tyrosine kinase that is primarily 
expressed in cells of hematopoietic lineage. It is an important mediator of immunoreceptor 
signaling in macrophages, neutrophils, mast cells, and B cells. Syk contains 2 adjacent SH2 
domains that bind to immunoreceptor tyrosine-based activation motifs (ITAMs) to 
autophosphorylate and activate the enzyme. This allows Syk to phosphorylate its specific 
substrates including other enzymes and adaptor proteins, orchestrating a complex series of 
cellular responses such as cell proliferation, differentiation, survival, and phagocytosis.
Recent studies have suggested a role for the dysregulation of the tyrosine kinase Syk in B-cell 
malignancies. Syk is expressed in B-cells and is essentially involved in multiple signal 
transduction pathways downstream of the B-cell receptor (BCR). In this process, Syk
trans-autophosphorylates, and activates effector molecules such as PLCy, PI3K, and 
mitogen-activated protein kinase (MAPK) and their associated signaling pathways, to induce a 
variety of responses including: proliferation, survival, differentiation, anergy, and apoptosis 
(Figure 1-1). In B-cells, the Syk inhibitor GS-9973 effectively blocks BCR-mediated activation 
and proliferation (data on file). Additionally, the BCR can deliver antigen-independent signals 
that have also been postulated to require Syk activity. Both antigen-dependent and independent 
signals have been implicated in the pathogenesis of several common B-cell malignancies, 
including chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), 
follicular lymphoma (FL), mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL).
Importantly, signaling through the Syk-dependent pre-BCR and pre-BCR-independent pathways 
are required for the survival of pre-B lymphocytes and may contribute to the pathogenesis of 
B-cell lineage acute lymphoblastic leukemia (B-ALL) {Efremov 2011, Perova 2014}. As a 
result, inhibitors of Syk activity are an attractive therapeutic option for hematopoietic B-cell 
lymphomas and other Non-Hodgkin lymphoma (NHL) histologies where Syk inhibition would 
prevent B-cell receptor-mediated signaling and therefore the uncontrolled growth of lymphoma 
cells.


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Figure 1-1.
Positive and Negative Regulators of Antigen-dependent BCR 
Signaling
Source: {Efremov 2011}
1.2.2.
Clinical Experience in Hematologic Malignancies treated with Syk Inhibitors
Positive results have been reported from a Phase 2 clinical trial with the putative Syk inhibitor 
fostamatinib showing objective anti-tumor responses in CLL and DLBCL subjects {Friedberg 
2010}. These responses occurred despite off target toxicities that limited drug exposure. 
GS-9973 is a highly selective inhibitor of Syk and hence has the potential for an improved 
efficacy and tolerability profile in subjects with hematologic malignancies.
GS-9973 is currently in a Phase 2 clinical trial in subjects with relapsed or refractory CLL/NHL. 
Subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n = 41) or 
non-Hodgkin’s lymphoma (NHL; n = 104) were enrolled in a monotherapy trial of GS-9973. 
Subjects received 800 mg of GS-9973 twice daily. Initial data analysis has been completed for 
the CLL cohort and is ongoing in the MCL and FL cohorts. Efficacy outcomes have been 
reported in the CLL cohort (n = 41) and safety outcomes in all cohorts (N = 145). The primary 
end point was progression-free survival (PFS) rate at 24 weeks in subjects with CLL. PFS rate at 
24 weeks is 69.8% (95% confidence interval [CI]: 50.9%, 82.6%). The objective response rate 
(ORR) was 56.1% (95% CI: 39.7%, 71.5%). Two subjects (4.9%) with stable disease achieved 
nodal response with persistent lymphocytosis. Forty-five subjects (31.0%) had serious adverse 
events (AEs). The most common treatment-emergent serious AEs included dyspnea, pneumonia, 
febrile neutropenia, and pyrexia. Common grade 3/4 lab abnormalities included neutropenia 
(14.5%) and reversible alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
elevations (14.5%). GS-9973 demonstrates clinical activity in subjects with relapsed or 
refractory CLL with acceptable toxicity.


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1.3.
Entospletinib (ENTO [GS-9973])
1.3.1.
Nonclinical Pharmacology
GS-9973 is an adenosine triphosphate (ATP) competitive inhibitor of Syk with an IC50 of
8.5 ± 3.6 nM. GS-9973 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 GS-9973 
for Syk versus 359 nonmutant kinases. Furthermore, there was < 50% binding of GS-9973 at 
1 uM to any of a panel of 67 ion channels, transporters, and receptors. Therefore, GS-9973 
demonstrated at least 14-fold selectivity against a total of 426 biological targets tested 
(See Figure 1-2).
Figure 1-2.
GS-9973 Kinome Scan
The cellular activity of GS-9973 was evaluated in 2 anti-IgM (αIgM)-stimulated CD86 
expression assays in human peripheral and mouse splenic B-cells. GS 9973 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, GS 9973 was evaluated 
in vitro in an FcεRI-triggered αIgE stimulated β-hexosaminidase release assay in mouse bone 
marrow derived mast cell (BMMC) cultures. GS-9973 inhibited the FcεRI-stimulated 
hexosaminidase release into the media with a mean EC50 of 159.3 ± 14.8 nM. GS-9973 was 
evaluated in vitro in an immune-complex (IC) stimulated TNFα release assay in primary human 
monocytes. GS-9973 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.


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The potency of GS-9973 was evaluated in human whole blood by a αIgE-stimulated CD63 
expression assay in human basophils. GS-9973 inhibited the αIgE-stimulated CD63 expression 
on CD123+/HLADR- human basophils with a mean EC50 ± SD of 0.387 ± 0.220 nM. 
Additionally, GS-9973 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.
GS-9973 was evaluated in a battery of safety pharmacology studies. The IC50 for the inhibitory 
effect of GS-9973 on human ether-à-go-go-related gene (hERG) potassium current in vitro was 
estimated to be greater than 1 μM. Because GS-9973 is 97.3% protein bound in human plasma 
and the total plasma concentrations of GS-9973 are in the 1 to 3 micromolar range, with a 
corresponding range of free GS-9973 of 27 to 81 nM, it is unlikely that a clinically relevant 
effect on QT interval would occur. No GS-9973 SS-related effects were noted on neurological or 
respiratory function in rats at doses up to 1000 mg/kg, the highest dose tested. In dogs, GS-9973 
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.
GS-9973 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 GS-9973 is available in the 
Investigator’s Brochure.
1.3.2.
Nonclinical Drug Metabolism and Pharmacokinetics
Despite high plasma protein binding, GS-9973 had a moderate volume of distribution, close to 
that of total body water.  The systemic clearance was low in rats, moderate in dogs, and moderate 
to high in monkeys.
Single-day dose escalation of GS-9973 administered orally to rats, dogs, and monkeys showed a 
less than dose proportional increase in GS-9973 systemic exposure in all species over the dose 
ranges tested.
Consistent with the moderate to high bioavailability seen in nonclinical species, GS-9973 
showed high forward permeability across Caco-2 monolayers and low potential for efflux.
GS-9973 showed good metabolic stability with human hepatic material in vitro. In humans, 
clearance through metabolism is therefore expected to be low.  The primary routes of 
metabolism of GS-9973 involved oxidative opening of the morpholine ring as well as further 
oxidation or conjugation.  In humans, CYP2C9, CYP3A, and CYP1A2 were shown to oxidize 
GS-9973.


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Metabolism followed by biliary excretion is likely to be the major route of elimination of 
GS-9973 and its metabolites, as < 5% of the radiolabeled dose administered orally to rats was 
recovered in urine.
GS-9973 will be unlikely to cause clinical drug interactions through inhibition of CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. GS-9973 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 GS-9973 
(> 97%).
GS-9973 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.  GS-9973 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 GS-9973 (> 97%) may mitigate some of the potential drug-drug 
interactions at clinically relevant doses.
GS-9973 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 GS-9973 is 
available in the Investigator’s Brochure.
1.3.3.
Nonclinical Toxicology
GS-9973 was well tolerated in single-dose studies at doses of 1000 mg/kg in dogs and 
cynomolgus monkeys. GS-9973 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, GS-9973 was well tolerated for 7 days at 50 mg/kg/day 
and at 10 mg/kg/day for 4 weeks. GS-9973 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. Additional organs potentially affected in individual dogs at higher 
doses included gallbladder, pancreas (rabbits and dogs), urinary bladder, and epididymis. The 
gastrointestinal tract toxicity presented as enteropathy in the duodenum in rats, and hemorrhage 
and/or inflammation in rabbits and dogs. Gastrointestinal tract toxicity in rats, rabbits, and dogs 
was associated with decreased food consumption and/or decreased body weight or body weight 
gain. However, decreased food consumption and body weight changes also occurred in rabbits 
and dogs at doses below those which caused histological evidence of gastrointestinal toxicity. 


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Assessments in the clinical program will include monitoring for signs and symptoms of 
gastrointestinal distress and changes in clinical pathology parameters (changes in red cell mass, 
neutrophils, lymphocytes, liver enzymes, and total and indirect bilirubin) that could occur after 
GS-9973 administration. Because evidence of lymphoid tissue depletion was noted in rabbits and 
dogs at high doses, clinical assessments will also include monitoring for signs and symptoms of 
infection.
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. GS-9973 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 GS 9973 treated rats or 
dogs, and GS-9973 levels above the IC50 for UGT1A1 were achieved in serum, this seems a 
plausible mechanism for the noted increases in bilirubin.
Hemorrhage and/or sinus erythrocytosis in lymph nodes with decreases in red cell mass in 
individual animals was noted in rabbits and dogs, but not rats or cynomolgus monkeys. Although 
the mechanism for these changes is not clear, Syk deficiency in rodents and rodents with Syk
deficient bone marrow have been associated with hemorrhage, the latter in the presence of 
normal bleeding times and therefore suggesting normal platelet function {Turner 2000}. No 
evidence of altered coagulation parameters were noted at any dose level in the GS-9973
nonclinical studies and no biologically relevant effects were noted in an in vitro study of platelet 
aggregation. Other inhibitors of Syk have been found to have no effect on platelet function at 
efficacious dose levels in subjects 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}. Evidence of hemorrhage and/or decreases in red cell mass will be monitored during 
clinical studies.
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. Recently published data demonstrated that species specific 
lymphoid changes can occur in dogs but not rats, cynomolgus monkeys, or humans treated with 
small molecule kinase inhibitors that inhibit pathways that overlap with Syk signaling pathways; 
rabbits were not evaluated {Morris 2010}. Lymphoid toxicity occurs in dogs treated with p38α 
MAPK inhibitors, but not in rats or cynomolgus monkeys despite higher exposure levels 
achieved in these species. There has not been evidence of significant immunotoxicity in 
numerous clinical trials with p38α mitogen-activated protein kinase (MAPK) inhibitors. The 
relevance of the findings in rabbits and dogs to humans is unknown.
GS-9973 was negative in the bacterial mutation, in vitro chromosomal aberration, and rat 
micronucleus assays. GS-9973 can be considered non-genotoxic.  Dose range finding embryo 
fetal developmental toxicity studies have been completed in the rat and rabbit. Maternal toxicity 
was demonstrated by dose-dependent decreases in the body weight gains of the dams. 
Dose-dependent developmental findings included increased incidence of early and late fetal 
resorptions at 500 mg/kg/day (rat only) and reduced fetal weights (500 and ≥ 15 mg/kg/day; rat 
and rabbit, respectively) which correlated with the maternal toxicity.


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Further information on the nonclinical toxicology of GS-9973 is available in the Investigator’s 
Brochure.
1.3.4.
Monotherapy Clinical Trials of GS-9973
As of March, 2017, GS-9973 has been studied in single and multiple ascending dose studies in 
470 healthy subjects (16 subjects with hepatic impairment), 464 subjects with hematologic 
malignancies, 7 subjects with cGVHD, and 7 subjects with RA have participated. Of these 
subjects, 948 received ENTO and 26 received placebo. Refer to the latest IB Edition for the most 
recent information.  
In pharmacokinetics studies at steady state in healthy subjects, GS-9973 was well tolerated when 
given in a fasted state for 7 days at doses of 25, 75, 200, 600, 900, and 1200 mg twice daily
(GS-US-245-0101) and when given in a fed state for 6 days at doses of 100 and 900 mg twice 
daily (GS-US-245-0106), for 4 days at doses of 200 and 600 mg twice daily (GS-US-339-0101), 
and at 1200 mg twice daily for 5 days (GS-US-339-0109).Exposure, as measured by AUC and 
maximum concentration Cmax, did not increase appreciably at doses of 600 mg and above under 
fasted condition. See Figure 1-3 and Figure 1-4.
Figure 1-3.
GS-9973 AUCtau at Steady State


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Figure 1-4.
GS-9973 Cmax at Steady State
To provide a margin for inter-patient variability, a dose of 900 mg twice daily was chosen for the 
study of subjects with rheumatoid arthritis receiving stable doses of methotrexate in Study 
GS-US-245-0101.  A dose of 900 mg GS-9973 twice daily was given in a fasted state for 26 days 
in 7 subjects.  The median AUCtau in these subjects was similar to that of the healthy subjects.  In 
general, this dose was well tolerated.   One subject developed reversible, Grade 2 alkaline 
phosphatase and transaminase elevations starting 7 days after her last dose of GS-9973, 
concurrent with new onset of a bronchopneumonia.  One other subject reported not feeling well 
and experienced hot flashes, fever, shivers, rash, headache, dizziness, and fainting 1 day after her 
last dose of GS-9973 with reversible Grade 1 alkaline phosphatase and Grade 3 transaminase 
elevations which peaked 1 week later.  While these events are potentially confounded by 
concurrent illnesses, hepatic enzymes will be closely monitored during this study.
Consistent with the known inhibition of UGT1A1 by GS-9973, 8 of the 178 healthy subjects 
developed asymptomatic indirect bilirubin elevations (6 Grade 1, 1 Grade 2 and 1 Grade 3) that 
resolved following discontinuation of the drug.  Three of the 7 subjects with rheumatoid arthritis 
who received GS-9973 for 26 days developed asymptomatic indirect bilirubin elevations 
(2 Grade 1, 1 Grade 3) which improved despite continued dosing.
1.3.5.
GS-9973 Target Drug Concentrations
In healthy subjects, Syk inhibition, as measured by the ability to inhibit CD63 basophil activation 
and pSyk activation was evaluated in peripheral blood mononuclear cells (PBMCs) at multiple 
doses and schedules of GS-9973.  Plasma GS-9973 exposures were correlated with the degree of 
Syk inhibition.  GS-9973 inhibited Syk as measured by ex-vivo basophil activation (Figure 1-5) 
and pSyk (Figure 1-6) assays with EC70s of 923 and 275 ng/mL respectively.
fasted
fed
fasted
fed
fasted
fed
fasted
fed
no MTX
w MTX
0
2000
4000
6000
8000
200 mg
  BID
600 mg
 BID
900 mg
  BID
1200 mg
 BID
median (Q1,Q3)
900 mg
  BID
GS-9973 Cmax (ng/ml)


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Figure 1-5.
Inhibition of Basophil Activation
Figure 1-6.
Inhibition of pSyk
1.3.6.
Use of Concomitant Medications with GS-9973
In vivo and in vitro data indicates that Entospletinib is a substrate of CYP2C9 and CYP3A. 
Co-administration of CYP2C9 inhibitors or inducers may increase or decrease Entospletinib 
exposure, respectively. As such, co-administration of moderate and strong CYP3A and CYP2C9 
inducers, and moderate CYP2C9 inducers are prohibited in this study. Caution should be 
exercised when co-administering drugs that are moderate or strong inhibitors of CYP2C9 
(eg fluconazole, voriconazole or amiodarone) as they may increase Entospletinib exposure. 
Administration of strong CYP3A and CYP2C9 inducers, and moderate CYP2C9 inducers, 
should be avoided for 2 weeks prior to study drug administration. 


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Studies in healthy volunteers have demonstrated a significant reduction in Entospletinib 
exposure when proton pump inhibitors are co-administered. Therefore, proton pump inhibitors 
are prohibited in combination with Entospletinib. Use of a proton pump inhibitor should be 
avoided for 1 week prior to study drug administration. Examples of, strong CYP3A and CYP2C9 
inducers, moderate CYP2C9 inducers and proton pump inhibitors that are prohibited in this study 
are provided in Section 5.3 (see Table 5-1).
In vitro data indicates that Entospletinib has the potential to inhibit several transporters and the 
metabolizing enzyme UGT1A1, which may affect the plasma concentrations of substrates of 
these transporters and/or enzyme. Caution should be exercised when co-administering 
medications that are transported by OATP1B1, OATP1B3, MATE1, P-gp and BCRP or 
metabolized by UGT1A1; dose adjustment or switching to an alternative medication may be 
necessary if clinically indicated.
In a study in healthy volunteers, Entospletinib 400 mg twice daily increased rosuvastatin 
exposure by approximately 4-fold, which may theoretically increase the risk of rhabdomyolysis. 
In reviewing the safety of subjects whom have received a statin with Entospletinib there have 
been no reports of rhabdomyolysis nor a different adverse events profile, but in the interest of 
caution, restrictions apply to the use of HMG-CoA reductase inhibitors with Entospletinib in this 
study. These restrictions are included in Section 5.3.
1.4.
Rationale for This Study
Despite progress made in understanding the biology and improvements in the treatment of ALL, 
the majority of adults with ALL will ultimately relapse after initial complete remission (CR) and 
up to 25 percent will have primary resistant disease.  Retreatment of such subjects is generally 
unsuccessful, and most will die of their disease, underscoring the need for novel therapeutic 
approaches.  Allogeneic hematopoietic stem cell transplantation (HSCT) after initial 
cytoreduction or in second CR offers a chance of cure in a small, highly selected group of 
subjects.  As such, induction of a second CR is the first step in the treatment of relapsed disease.  
Increased activity of Syk in ALL cells may play a role in leukemia cell survival and 
proliferation, and inhibition of Syk has shown to attenuate the growth of B-cell ALL in vitro and 
in vivo in mouse models {Perova 2014}.  Thus, Syk activation sustains the growth of multiple 
B-ALL subtypes, suggesting that Syk inhibitors may improve outcomes for high risk and 
relapsed B-ALL.  
The potential for enhanced antiproliferative activity of the combination of GS-9973 and VCR 
was investigated in vitro. At concentrations of each agent that were minimally growth 
inhibitory, combination of doses of GS-9973 that approximated trough concentrations with doses 
of VCR (< 10um) resulted in strong growth inhibition in human ALL cell lines in vitro. These 
data suggest that the combination of GS-9973 and VCR may have increased anti-tumor activity 
and warrants clinical investigation. We therefore propose this early phase clinical trial of dose 
escalated GS-9973 in combination with chemotherapy for fit subjects with relapsed or refractory 
ALL.


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GS-9973 is an adenosine triphosphate (ATP) competitive inhibitor that disrupts the kinase 
activity of purified Syk protein with a concentration that results in 50% inhibition 
(IC50) ± standard deviation (StD) of 8.6 ± 3.6 nM (Study PC-245-2006).
1.4.1.
Rationale for the GS-9973 Dose Selection
GS-9973 administered twice daily in previous studies was well tolerated up to 1200 mg (7 days 
in the fasted state) in healthy subjects and 900 mg (6 days in the fed state) in rheumatoid arthritis 
(RA) subjects. A GS-9973 dose of 800 mg twice daily is being evaluated in the Phase 2 program 
in subjects with CLL, indolent NHL, mantle cell lymphoma, diffuse large B-cell lymphoma, 
follicular lymphoma, and non-FL iNHL. Pharmacodynamic evaluation at exposures equivalent to 
an 800 mg twice daily dose, resulted in trough concentrations that inhibited 70-80% of Syk 
activity in normal healthy volunteers.   In CLL patients, this level of target suppression resulted 
in clinical benefit.  
In the current protocol, a new spray-dried dispersion (SDD) formulation will be used.  With this 
formulation, a 400 mg dose resulted in exposures similar to the 800 mg dose of the original 
formulation.  Among the subjects treated with GS-9973 SDD formulation (N = 28), there were 
no SAEs reported.  In the study, 3 subjects (10.7%) had AEs resulting in study drug 
discontinuation. Overall, 19 subjects (67.9%) reported an AE. The most common AEs included: 
headache (11 subjects, 39.3%); back pain and nausea (6 subjects each, 21.4%); ALT increased, 
rash, and pruritus (4 subjects each, 14.3%); and (3 subjects each, 10.7%) reported AST increased 
and constipation. No Grade 3 or 4 AEs were reported. 
Subjects enrolled in the first cohort will receive 200 mg of GS-9973 and 0.5 mg of VCR.  These 
conservative doses were selected to minimize the potential safety risk to subjects.  Nonclinical 
studies suggest that these low doses in combination can have anti-proliferative activity.  
The doses of GS-9973 SDD proposed in the current study, from 200 mg twice daily to 400 mg 
twice daily, provides a wide range of daily doses (2-fold between 200 mg twice daily vs. 400 mg 
twice daily) to evaluate the dose/exposure/PD relationship which may be helpful in dose 
selection for ongoing/future GS-9973 SDD ALL studies. Vincristine will be dose escalated up to 
2 mg, which is the commonly used dose cap for VCR, in combination with 400 mg of GS-9973.  
1.5.
Information about Chemotherapy Agents
1.5.1.
Vincristine
Vincristine (VCR) is a vinca alkaloid mitotic inhibitor used in the treatment of leukemia and 
lymphoma.  The compound is delivered via intravenous infusion, and binds to tubulin dimers, 
inhibiting assembly of microtubule structures and arresting mitosis in metaphase.  Because 
vincristine's mechanism of action targets all rapidly dividing cell types, it not only inhibits 
cancerous cells but can also affect the intestinal epithelium and bone marrow.  Side effects 
include peripheral neuropathy, hyponatremia, constipation, and hair loss.  Please see package 
insert/label for product details.


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1.5.2.
Dexamethasone
Dexamethasone is a corticosteroid with anti-inflammatory and immunosuppressant effects used 
in the treatment of a variety of diseases.  It is 25 times more potent than cortisol in its 
glucocorticoid effect, while having minimal mineralocorticoid effect.  Dexamethasone is 
commonly used as part of combination chemotherapy regimens for the treatment of leukemia 
and lymphoma.  Side effects include increased risk of infection, osteonecrosis, and increased risk 
of bone fractures, psychosis, and myopathy.   Please see package insert/label for product details.
1.6.
OVERALL RISK AND BENEFIT ASSESSMENT
Potential Risks Based On Nonclinical Safety Data with GS-9973
Spleen tyrosine kinase deficiency and SYK-deficient bone marrow in rodents have been 
associated with hemorrhage. In an ex vivo platelet function assay, GS-9973 showed no 
biologically relevant inhibition or activation of platelets at concentrations up to 12.3 μM. No 
evidence of altered coagulation parameters was noted at any dose level in the GS-9973
nonclinical studies. 
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. 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. Oral 
administration of GS-9973 to rats for up to 26 weeks or cynomolgus monkeys for up to 39 weeks 
showed no evidence of GI toxicity or lymphoid changes at exposures which overlapped with or 
exceeded those in dogs. Clinical assessments will monitor for signs and symptoms of infection, 
hemorrhage, GI distress, and changes in clinical pathology parameters (changes in hemoglobin, 
neutrophils, lymphocytes, liver enzymes, and total and indirect bilirubin) that could occur after 
GS-9973 administration. Because evidence of lymphoid tissue depletion was noted in rabbits and 
dogs at high doses, clinical assessments will also include monitoring for signs and symptoms of 
infection. 
Coadministration of ENTO with vincristine (VCR) did not exacerbate VCR-related 
hematological toxicity in male rats. Addition of GS-9973 to low dose VCR resulted in a mild 
slowing of caudal nerve conduction velocity compared with low dose VCR; no contributive 
effects of GS-9973 to nerve conduction velocity at high dose VCR were observed. The effect 
may be mitigated by the high plasma protein binding of ENTO (> 97%).
Administration of ENTO to pregnant female rats and rabbits resulted in dose-dependent 
developmental findings. The 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 to 
30 days from the last dose of ENTO. For male subjects having intercourse with females of 
childbearing potential, must be willing to abstain from heterosexual intercourse or use a 
protocol-recommended method of contraception from the start of ENTO throughout the study 
treatment period and for 90 days following the last dose of ENTO.  


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Also, male subjects should refrain from sperm donation from the start of the ENTO throughout 
the study treatment period and for 90 days from the last dose of ENTO.
Potential Risks Based On Clinical Safety Data with Entospletinib (ENTO [GS-9973])
As of March 2017, 18 clinical studies have been conducted in which 470 healthy subjects 
(including16 subjects with hepatic impairment), 464 subjects with hematologic malignancies, 
7 subjects with cGVHD, and 7 subjects with RA have participated. Of these subjects, 
948 received ENTO and 26 received placebo. Overall, ENTO was generally well tolerated when 
administered as a single dose or as multiple doses. Treatment emergent AEs commonly reported 
across the studies involving healthy volunteer subjects include headache, somnolence, and GI 
symptoms (nausea and abdominal pain), all of which were mild and reversible.
Increased transaminases levels were noted in some subjects which is reversible. 
ENTO is an inhibitor of UGT1A1 and may transiently inhibit UGT1A1 activity in vivo at the 
expected clinical concentrations. Administrations of drugs such as ENTO that inhibit UGT1A1
are expected to increase total bilirubin due to decreased conjugation rather than liver 
dysfunction. The elevations in indirect bilirubin observed in clinical trials with ENTO were 
generally self-limited and did not result in discontinuation of ENTO.  In the absence of 
symptoms or other hepatic laboratory abnormalities, ENTO dose modification is not required for 
elevated indirect bilirubin levels.
The bis-MSA spray-dried dispersion (SDD) formulation will be used in this study and was 
chosen because it had less interaction with acid reducing agents. Administration of the bis-MSA 
formulation in studies GS-US-339-0111 and GS-US-245-1222, demonstrated that the change in 
ENTO exposure upon coadministration with omeprazole was less than the reduction in exposure 
observed in Study GS-US-245-0106 using the original formulation. The new formulation did not 
completely annul the DDI effect of a coadministered PPI agent, however the interaction of 
ENTO new formulation with an H2 receptor antagonist (H2RA) (eg famotidine) is not 
considered clinically meaningful.
In study GS-US-245-1222, the administration of food with the bis-MSA formulation of ENTO 
resulted in a reduction in ENTO exposure compared to fasted conditions. Due to this, ENTO 
should be taken under fasted conditions, as described in the administration instructions in this 
protocol.
Peripheral neuropathy has been reported with the use of vincristine. Subjects that have current or 
ongoing neuropathy (sensory or motor) Grade > 1 or any history of Grade ≥ 3 neuropathy with 
prior VCR or chemotherapy exposure are excluded from the study.
Based on the clinical experience with ENTO and VCR administered as single agents, and the 
absence of notable additive effects with the combination in nonclinical studies, ENTO alone or 
in combination with VCR demonstrates an acceptable benefit/risk profile for the proposed 
treatment of hematological malignancies in adults.


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The available nonclinical and clinical data support the evaluation of ENTO in eligible subjects 
with relapsed or refractory ALL.
Refer to the IB for complete details of the compound including completed and ongoing 
preclinical and clinical studies including summary safety and response data.
1.7.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES AND ENDPOINTS
2.1.
Objectives
The primary objective of this study is:

To evaluate safety of entospletinib (GS-9973) in combination with vincristine (VCR) and 
dexamethasone in adult subjects with previously treated relapsed or refractory B-cell lineage 
ALL
The secondary objectives of this study are: 

To determine the recommended dose of GS-9973 in combination with VCR and 
dexamethasone in adult subjects with previously treated relapsed or refractory B-cell lineage 
ALL

To evaluate the therapeutic response of GS-9973 in combination with VCR and 
dexamethasone in adult subjects with previously treated relapsed or refractory B-cell lineage 
ALL
The exploratory objectives of this study are: 
 
 
 
 
 
 
PPD


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3.
STUDY DESIGN
3.1.
Endpoints 
The endpoints for this study are described in Section 8.1.2.
3.2.
Study Design
This is an open-label, Phase 1b dose-escalation and Phase 2 expansion study evaluating the 
safety, efficacy, tolerability, and pharmacokinetics of GS-9973 in combination with VCR, and 
dexamethasone.
3.3.
Study Treatment
This study consists of two parts: dose escalation and dose expansion. The dose escalation begins 
with a 7-day lead-in of GS-9973 monotherapy where subjects are enrolled into dose level cohorts 
as outlined in Table 3-1.  For the dose expansion, the 7-day GS-9973 monotherapy Lead-in is 
omitted and the dosage is based on the maximum tolerated dose (MTD) or recommended dose 
determined from dose escalation results. However, after completion of dose escalation, it was 
decided not to move forward with dose expansion.  
3.3.1.
Dose Escalation 
During dose escalation, there will be four dose levels (outlined in Table 3-1) investigated in dose 
escalation where subjects in cohorts of 3 to 6 will sequentially enroll into one of the dose levels 
using the 3+3 dose escalation design.  The starting dose level for the first cohort is defined as 
Dose Level 1.
Table 3-1.
GS-9973/VCR Dose Escalation
Dose Level
GS-9973 
Vincristine (VCR)
1
200 mg BID
0.5 mg per dose
2
400 mg BID
0.5 mg per dose
3
400 mg BID
1 mg per dose
4
400 mg BID
2 mg per dose
Subjects in Dose Level 1 will receive 200 mg GS-9973 taken orally twice daily (BID).  Subjects 
in Dose levels 2 to 4 will receive 400 mg GS-9973 orally BID. Subjects in all dose levels will 
receive dexamethasone 20 mg BID for four days during Cycle 1 on Days 8-11 and Days 22-25 
and during Cycle 2 on Days 1-4 and Days 15-18. Each treatment cycle is 28 days in length.
In the absence of toxicity requiring a drug interruption (as defined in Section 3.5.2.1), dosing of 
GS-9973 will be taken continuously without interruption.


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Subjects will have evaluations for safety and provide blood for drug levels prior to starting 
Lead-in and 1.5 hours after the first dose of GS-9973. 
Additional PK blood samples will be collected at (applies to both escalation and expansion): 

Pre-dose during Cycle 1 on Day 1 and 1.5 hours (± 30 minutes) post-dose of GS-9973

Pre-dose during Cycle 1 on Day 8, and 1.5 hours (± 30 minutes) post-dose of GS-9973

Pre-dose during Cycle 1 on Day 28 and Cycle 2 on Day 28, and 1.5 hour (± 30 minutes)
post-dose of GS-9973

A sample of cerebrospinal fluid (CSF) for PK analysis will be taken during Cycle 1 on 
Day 28 and Cycle 2 on Day 28 (untimed sample) prior to CNS prophylaxis administration
3.3.1.1.
Treatment Plan in Dose Escalation
Subjects will be enrolled and dosed in accordance with the 3+3 dose escalation design 
(Table 3-1). Intra-subject dose escalation is not allowed. Up to 6 subjects will be dosed per dose 
level. Dose escalation will be performed based on assessments of DLTs and other adverse events 
data obtained within the DLT window (GS-9973 Lead-in and Cycle 1; study day 1 through
day 35). Subjects with CR, CRi, or PR on Day 28 of Cycle 1 bone marrow, and /or subjects who 
in the investigator’s opinion have obtained clinical benefit from Cycle 1 induction, will continue 
to Cycle 2 of induction.
During the DLT assessment window, subjects who fail to complete 21 days of GS-9973 or fail to 
receive sufficient exposure (> 50% of planned total dose) to VCR and dexamethasone for 
reasons other than treatment-related toxicity will not be evaluable for DLT assessment and an 
additional (replacement) subjects may be enrolled to that dose level in order to provide adequate 
safety data for dose escalation decisions.
Decision to open the next higher dose level to enrollment or expand the current cohort will be 
determined by the sponsor in consultation with study Principal Investigators (PIs).
The maximum tolerated dose (MTD) is defined as the highest tested dose associated with an 
observed DLT rate of < 33% during the DLT window. 
A minimum of 6 subjects need to be treated at a dose level before this dose level can be 
determined as MTD or recommended dose.
3.3.2.
Dose Expansion 
At the time of this amendment, there have been no DLTs in the Phase 1 portion of the study.  
However, due to the low response rate to ENTO + vincristine + dexamethasone in
relapsed/refractory ALL patients, it has been decided not to proceed with the dose expansion 
(Phase 2) portion of this trial.  Prior to this amendment, dose expansion had been initiated at 
400 mg BID, but was subsequently closed with no subjects enrolled.


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3.3.3.
Maintenance 
It is anticipated that most subjects will receive hematopoietic stem cell transplant (HSCT) 
therapy with curative intent if a complete remission (CR) is reached. In the absence of suitable 
alternative therapeutic options, subjects who obtain clinical benefit (at least PR) after completing 
both cycles of induction therapy in dose escalation may continue GS-9973 at the assigned dose 
level in the maintenance phase for up to 36 cycles.  Subjects will continue GS-9973 and VCR at 
their assigned dose.  GS-9973 will continue to be taken orally twice daily with VCR given on 
Day 1 of each 28-day cycle. Dexamethasone may be administered as a single dose of 20 mg once 
daily or a divided dose of 10 mg twice daily on Days 1-4 and Days 15-18 of each 28-day cycle.
Bone marrow evaluations and additional central nervous system (CNS) directed therapy can be 
performed as clinically indicated in the maintenance phase. 
3.4.
Duration of Treatment
Dose escalation consists of a 7 day lead-in followed by 2 induction cycles (1 cycle=28 days).  
Subjects may be put on maintenance for up to 36 cycles with VCR on Day 1 of each cycle, if
they have obtained clinical benefit from the assigned dose level. There may be up to a 7 day 
interval between Cycle 1 and Cycle 2.
3.5.
Dose-Limiting Toxicity
The evaluation period for dose-limiting toxicity (DLT) will occur from the start of treatment 
through the end of Cycle 1 in the escalation phase. Subjects who fail to complete 21 days of 
GS-9973 or fail to receive sufficient exposure (> 50% of planned total dose) to VCR and 
dexamethasone for reasons other than treatment-related toxicity will be considered not evaluable 
for DLT assessment and additional (replacement) subjects may be enrolled to that dose level in 
order to provide adequate safety data on which to base dose escalation decisions.  All toxicities 
will be graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03 (Appendix 3).
The occurrence of any of the following toxicities during Lead-in/Cycle 1 will be considered a 
DLT if judged by the Investigator to be possibly, probably, or definitely related to the 
administration of any drug in the treatment regimen (GS-9973, VCR, dexamethasone, 
institutional standard CNS prophylaxis):

Grade 4 (or higher) non-hematologic toxicity

Grade 3 non-hematologic toxicity lasting ≥7 days despite optimal supportive care

Any Grade 3 non-hematologic laboratory value if: 
Medical intervention is required to treat the patient, or
The abnormality leads to hospitalization, or
The abnormality persists for >1 week


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
Grade 4 Neutropenia (ANC < 500 /μl) persistent for greater than 14 days or associated with 
febrile neutropenia 

Grade 4 thrombocytopenia (platelets < 25,000/μl) persisting for greater than 14 days 
(or greater than 25,000 /μl, but requiring prophylactic platelet transfusion to maintain this 
level)
The following will NOT be considered as a DLT for the purposes of this study, regardless of 
grade:

Alopecia

Fatigue

Nausea or vomiting controllable with anti-emetic therapy

Catheter-associated venous thrombosis

Infection (or infection-related toxicities such as fever/sepsis, unless it is felt that the infection 
resulted from unexpectedly complicated myelosuppression due to study medication)

Transient electrolyte abnormalities (any grade) that are not clinically significant and are 
correctable within 24 hours

Transient liver function test abnormalities (AST, ALT, bilirubin, or alkaline phosphatase) 
that resolve to ≤Grade 2 within 7 days
Table 3-2.
Dose Escalation/DLT Guidelines
Number of subjects with 
DLT at a given level
Escalation Decision Rule
0 out of 3
Enroll 3 subjects at the next higher dose level.
If this dose level is the highest dose level, it will be declared the maximally 
administered dose, and enroll 3 additional subjects at this dose level.
1 out of 3
Enter 3 additional subjects at this dose level.

If 0 of these 3 subjects experience DLT, proceed to the next higher dose level.

If 1 or more of them experience DLT, then dose escalation is stopped, and this 
dose is declared the maximally administered dose. Three additional subjects will 
be entered at the next lower dose level if only 3 subjects were treated previously 
at that dose.
≥2 out of 3
Dose escalation will be stopped. This dose level will be declared the maximally 
administered dose (highest dose administered). Three additional subjects will be 
entered at the next lower dose level if only 3 subjects were treated previously at that 
dose.
≤1 out of 6 at highest dose 
level at or below the 
maximally administered 
dose
This is the maximum tolerated dose (MTD) and generally the recommended dose. 
At least 6 subjects must be enrolled at MTD or the recommended dose.


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3.5.1.
Management of Dose Limiting Toxicities
It is recognized that drug-related toxicity in this population may be difficult to ascertain given 
the nature of hematologic disease. Investigators will attempt to assign attribution of toxicities to 
each drug if possible. The Cancer Therapy Evaluation Program (CTEP) Active Version of the 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized 
for AE reporting.
3.5.2.
Guidelines for Dose Modifications
3.5.2.1.
Dosing Delays/Dose Modifications Attributed to GS-9973 (beyond Cycle 1)
If the following signs or symptoms are medically manageable, they are not to be a consideration 
with respect to the subject’s dosing or continuation on study: nausea/mild vomiting/diarrhea, 
drug-related fever or chills, transient and correctable laboratory test abnormalities, line 
associated thrombosis, or alopecia. See Appendix 3.
There will be no dose modifications during Lead-in or Cycle 1 for GS-9973, VCR, or 
dexamethasone. Subjects experiencing toxicity attributed to these agents during Cycle 1 
requiring discontinuation of any drug shall be removed from study and will be considered a 
DLT. 
Dose modification of GS-9973 in subsequent cycles is permitted following guidelines provided
in Appendix 3. Subjects who experience a non-hematologic toxicity assessed as GS-9973 related 
that is Grade 3 or higher will hold dosing of GS-9973 until the toxicity resolves to ≤ Grade 1, 
and then may resume study therapy at the prior dose through the end of the cycle (or decreased 
by 1 dose level after discussion with Sponsor). For subjects assigned to Dose Level 1, the 
decreased dose of GS-9973 will be defined as 100 mg orally twice daily. Missed doses are not to 
be made up.
Adverse events and laboratory abnormalities will be graded using the CTCAE, Version 4.03.
3.5.2.2.
Dose Modifications for Non-Hematologic Toxicity for VCR, and dexamethasone
If the subject experiences any non-hematologic clinically significant Grade 3 or greater toxicity 
felt to “possibly” be related to any agent, hold the protocol therapy until it resolves to ≤ Grade 2.  
If related to VCR, reduce the dose of VCR to by one dose level (per Table 3-1); if at lowest dose 
level, resuming treatment with VCR will be at Investigator’s discretion after discussion with 
Sponsor.  Refer to product label information for specific toxicity management.  If related to 
dexamethasone, resuming treatment with dexamethasone will be at the discretion of the 
Investigators. If the toxicity recurs, subject will be removed from study. If protocol therapy is 
withheld for more than 2 weeks for toxicity possibly, probably, or definitely related to 
protocol-based therapy or up to 4 weeks for any other reason, subjects will be removed from 
protocol. 


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Subjects who have been dose-reduced cannot be returned to a higher dose level.
Toxicities in an individual subject must resolve to Grade 2 or to baseline levels before 
proceeding with the next cycle of treatment.  
3.5.3.
Dose Modifications for Hematologic Toxicity for GS-9973, VCR, and 
dexamethasone
It is recognized that drug-related hematologic toxicity in this population may be difficult to 
ascertain given the aggressive hematologic disease and the fact that multiple cycles of therapy 
may need to be administered for maximal clinical response. Therefore, there will be no dose 
modifications for hematologic toxicity due to GS-9973, VCR, or dexamethasone during Cycle 1.  
However, after the first cycle is administered, subjects suspected to have protocol therapy related 
ANC and/or platelet count toxicity (i.e. fail to recover to at least 50% of the prior cycle’s 
baseline value), will have the dose of VCR reduced by one dose level (or 50% if at lowest dose 
level) dexamethasone and the dose of GS-9973 will be decreased one dose level.  Dose 
modifications because of concern for drug induced cytopenias will be discussed with the study 
PIs.  Dose modifications for hematologic toxicity for subjects who have achieved a CR or CRi 
are detailed below.
3.5.3.1.
Neutropenia 
In the event of Grade 4 neutropenia (ANC < 500/μL) that occurs after Cycle 1 and persists for 
14 days or more or is associated with febrile neutropenia, further cycles of GS-9973/VCR will be 
decreased by 1 dose level. For subjects assigned to Dose Level 1, the decreased dose of GS-9973 
will be defined as 100 mg twice daily.  If Grade 4 neutropenia that persists for 14 days or more 
(or Grade 4 neutropenia associated with fever) recurs for the third time, 
GS-9973/VCR/dexamethasone should be discontinued.  Refer to VCR product label for specific 
guidance.
3.5.3.2.
Thrombocytopenia 
In the event of Grade 4 thrombocytopenia (platelets < 25,000/μL) that occurs with the second or 
subsequent cycles of maintenance and persists for more than 14 days (or >25,000/uL but 
requiring prophylactic platelet transfusions to maintain this over the 14 day period), further 
cycles of GS-9973/VCR shall be decreased by 1 dose level. For subjects assigned to Dose 
Level 1, the decreased dose will be defined as 100 mg twice daily. If Grade 4 thrombocytopenia 
persisting for more than 14 days (or patient requires prophylactic platelet transfusions to 
maintain >25,000/μL over the 14 day period) recurs for the third time, discontinue the 
GS-9973/VCR/dexamethasone.  Refer to VCR product label for specific guidance.
3.5.4.
Management of Low Grade Chronic Toxicities
Since subjects will be receiving the GS-9973 daily, low grade chronic side effects such as 
nausea, fatigue and diarrhea, while not meeting the above definition for dose limiting toxicities, 
may not be tolerable when experienced for long periods of time. Following discussion with the 
Gilead Medical Monitor, dose reduction may be permitted if low grade chronic side effects 
cannot be managed effectively with supportive care.


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3.5.5.
Specific Considerations for Managing Hyperbilirubinemia
3.5.5.1.
Unconjugated (Indirect) Bilirubin Elevations
GS-9973 is an inhibitor of UGT1A1 and reversible increases in unconjugated (indirect) bilirubin 
values occurred in healthy subjects receiving GS-9973. In the absence of symptoms or other 
hepatic laboratory abnormalities, GS-9973 dose modification is not required for elevated indirect 
bilirubin levels.
3.6.
End of Study
End of study will be defined as when all patients complete long term follow-up or discontinue 
their participation in the study due to death, withdrawal of consent or lost to follow up, or the 
time at which the Sponsor closes the study.
3.7.
Post Study Care
Does not apply.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) ≥18 years of age 
2) Previously treated ALL including Philadelphia chromosome (BCR-Abl) positive ALL who 
meet all of the following criteria:
a) Diagnosis of precursor B-cell ALL based on flow cytometry and histology
b) Previously treated subjects with primary refractory disease OR after first or subsequent 
relapse
c) Subjects with >10% lymphoblasts in bone marrow (BM) or extramedullary disease 
(EMD) that is radiographically measureable and amenable to imaging studies and repeat 
biopsies  
d) Patients with Ph+ ALL  must have failed treatment with at least one 2nd generation
(ex. dasatanib) or 3rd generation (ex. ponatinib) tyrosine kinase inhibitor
3) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
4) Adequate organ function defined by the screening laboratory inclusion values (Table 4-1) 
and absence of known cardiac dysfunction 
5) Required screening laboratory data (within 7 days prior to administration of GS-9973) as 
shown in (Table 4-1)
Note: Confirmation should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within the screening period and 
should be the most recent measurement obtained


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Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total 
bilirubin
<2.0mg/dL or 1.5 x ULN (unless elevated due to Gilbert’s syndrome)
AST (SGOT)
2.5 x institutional ULN (unless due to disease then < 5 x ULN)
ALT (SGPT)
Renal
Creatinine
<2.0mg/dL
Pregnancy
-HCGa
Negative
Infectionc
HIVb
Negative HIV antibody/PCR
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 women of childbearing potential only; serum -HCG must be negative during screening and serum -HCG or urine 
dipstick pregnancy test must be negative at start of study drug
b
If screening test is positive, a negative confirmatory test will be required for eligibility
c
Screening for infection can be done up to 30 days prior to administration of study drug 
Abbreviations: ULN=upper limit of normal, -HCG=beta human chorionic gonadotropin, DNA=deoxyribonucleic acid, 
HBc antibody=anti-hepatitis B core antibody, HBsAg=hepatitis B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C 
virus, HIV=human immunodeficiency virus, Ig=immunoglobulin, PCR=polymerase chain reaction, RNA=ribonucleic acid. 
6) Discontinuation of all therapy (including radiotherapy, chemotherapy, tyrosine-kinase 
inhibitors [TKIs], immunotherapy, or investigational therapy) for the treatment of cancer as 
follows: 
a) At least 1 week or 5 half-lives (whichever is longer) from the last dose of prior 
anti-cancer therapy and the initiation of study therapy
b) Exceptions or modifications to the above are as follows:
Medications that are typically part of a maintenance therapy for ALL, such as 
glucocorticoids or mercaptopurine, may be administered up to 3 days prior to the 
first dose, except vinca alkaloids which must be discontinued at least 14 Days prior to the 
start of study treatment. TKIs are not permitted to be continued at screening 
(eg, Gleevec). Subjects may receive hydroxyurea or apheresis if indicated for rapidly 
rising white blood cell count 
c) CNS prophylaxis up to at least one week prior to first dose of GS-9973
d) For biologics (eg, monoclonal antibodies), washout period of 1 month beyond the 
recommended dosing interval and at least 4 weeks or 5 half-lives (whichever is shorter) 
since the last dose
e) If prior stem cell transplant, subject must be at least 100 days from stem cell infusion and 
off all systemic anti-graft versus host disease  (GVHD) medications


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f)
If prior donor lymphocyte infusion (DLI), subject must be at least 4 weeks from DLI and 
off all systemic anti-graft versus host disease (GVHD) medications and have no evidence 
of any infection
g)
If  prior Chimeric Antigen Receptor (CAR) T-Cell Therapy, subject must be at least 
4 weeks from CART infusion
7) All acute toxic effects of any prior antitumor therapy must be resolved to Grade ≤ 1 before 
enrollment, with the exception of alopecia (any grade permitted), or bone marrow parameters 
(any grades permitted)
8) For female subjects of childbearing potential, willingness to abstain from heterosexual 
intercourse or use a protocol recommended method of contraception from the screening visit 
(Visit 1) throughout the study treatment period and to 30 days from the last dose of GS-9973.
A negative serum pregnancy test is required for female subjects at screening.  Lactating 
females must agree to discontinue nursing before GS-9973 is administered. See Appendix 5
9) For male subjects having intercourse with females of childbearing potential, willingness to 
abstain from heterosexual intercourse or use a protocol-recommended method of 
contraception from the start of GS-9973 throughout the study treatment period and for 
90 days following the last dose of GS-9973. Also, male subjects should refrain from sperm 
donation from the start of the GS-9973 throughout the study treatment period and for 
3 months following the last dose of GS-9973. See Appendix 5.
10) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current disease status, medical condition, and the
potential benefits and risks of alternative treatments for the subject’s ALL
11) Willingness to comply with scheduled visits, drug administration plan, imaging studies, 
laboratory tests, other study procedures, and study restrictions  
Note: Psychological, social, familial, or geographical factors that might preclude adequate 
study participation should be considered
12) Have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of study procedures
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Diagnosis of mature B-cell ALL (Burkitt’s leukemia), or lymphoid blast crisis of chronic 
myelogenous leukemia (CML)
2) A life threatening illness, medical condition or organ system dysfunction which, in the 
investigator’s opinion, could compromise the subject’s safety or interfere with the absorption 
or metabolism of GS-9973


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3) Active or symptomatic central nervous system (CNS) disease
For study purposes a subject will NOT be considered as having active CNS disease if the 
subject has documentation of prior CNS disease and has received treatment (IT or radiation) 
and are:
a) asymptomatic  for the last 28 days prior to screening, and 
b) has documented at least 2 negative cerebrospinal fluid (CSF) cytology (which must 
include 1 lumbar puncture [LP] within the study screening window)
4) Uncontrolled intercurrent illness including, but not limited to, unstable angina pectoris or 
psychiatric illness/social situations that would limit compliance with study requirements. 
Subjects with active infection are permitted to enroll provided that the infection is 
documented to be under control and after discussion with study Sponsor
5) History of myelodysplastic syndrome or solid organ transplantation
6) History of a non-lymphoid malignancy except for the following: 
adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma 
in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic 
disease and with no requirement for therapy or requiring only hormonal therapy and with 
normal prostate specific antigen for > 1 year prior to the start of GS-9973, or any other 
cancer that has been in complete remission without treatment for ≥ 5 years prior to 
enrollment
7) Known hypersensitivity or intolerance to any of the active substances or excipients in the 
formulations for GS-9973 
8) Evidence of uncontrolled systemic bacterial, fungal, or viral infection at the start of GS-9973
Note: Subjects with localized fungal infections of skin or nails are eligible. Subjects may be 
receiving prophylactic antiviral, antifungal, or antibacterial regimens (eg, anti-pneumocystis 
prophylaxis at the discretion of the investigator per institutional guidelines. If azoles are 
used for antifungal prophylaxis, subjects must be monitored for possible DDI with VCR)
9) Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis 
B (HBV), HIV, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary 
cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal 
hypertension
10) Prior allogeneic bone marrow progenitor cell transplant within 100 days or on active 
systemic immunosuppression for graft versus host disease (GVHD) treatment or prophylaxis 
within 28 days prior to enrollment
11) Active (symptomatic or requiring current medical treatment within 28 days prior to the start 
of study treatment) for GVHD


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12) Ongoing immunosuppressive therapy other than corticosteroids (corticosteroids being used 
for GVHD treatment are not permitted)
Note: Subjects may use topical, enteric, inhaled, or systemic corticosteroids as therapy for 
manifestations of comorbid conditions
13) Current therapy with proton pump inhibitors (PPI) must be avoided (as there is the potential 
to interfere with GS-9973 absorption).
Note: H2 blockers and antacids will be allowed for the use during the study
14) Pregnancy or breastfeeding
15) Ongoing active pneumonitis
16) Concurrent participation in an investigational drug trial with therapeutic intent defined as 
prior study therapy within 28 days prior to start of GS-9973 administration
17) Ongoing or recent treatment with an excluded medication, as defined in Section 5.3, 
Excluded Medication


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Description and Handling of Entospletinib (ENTO [GS-9973])
5.1.1.
Formulation 
Entospletinib 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, entospletinib tablets contain the following inactive ingredients: methanesulfonic acid, 
hydroxypropyl methylcellulose (hypromellose), mannitol, microcrystalline cellulose, 
crospovidone, poloxamer 188, silicon dioxide, magnesium stearate, polyethylene glycol, 
polyvinyl alcohol, talc, titanium dioxide, ferrosoferric oxide/black iron oxide, iron oxide red, and 
iron oxide yellow.
5.1.2.
Source
GS-9973 will be supplied free of charge by Gilead Sciences, Inc, (GSI). Any questions or 
concerns regarding study treatment supply should be referred to your site monitor.
5.1.3.
Packaging and Labeling
Study drug (Entospletinib [GS-9973] 100 mg and 200 mg tablets) are packaged in white, 
high-density polyethylene (HDPE) bottles. Each bottle contains 60 tablets, a silica gel desiccant 
and polyester packing material. Each bottle is enclosed with a white, continuous thread, 
child-resistant, polypropylene screw cap fitted with an induction-sealed, aluminum-faced liner. 
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
5.1.4.
Storage and Handling
Study drug (Entospletinib) should be stored at controlled room temperature of 25°C (77°F); 
excursions are permitted between 15°C and 30°C (59°F and 86°F). Storage conditions are 
specified on the label. Until dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel. 
To ensure the stability and proper identification, study drug should not be stored in a container 
other than the container in which they were supplied. Keep the bottle tightly closed to protect 
from moisture.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling. 


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5.1.5.
Study Drug Accountability
The investigator or designee (eg, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug bottles during the study. This includes acknowledgement of 
receipt of each shipment of study drug (quantity and condition) and tracking of bottles 
assigned/utilized for subject dosing. All used and unused study drug bottles must be returned to 
the site by the subjects.
Investigational Drug Accountability records will be provided to each study site to:

Record the date received, quantity of GS-9973, and lot number

Record the date, subject number, subject initials, the GS-9973 lot number dispensed

Record the date, quantity of used and unused GS-9973 returned, along with the initials of the 
person recording the information
5.2.
Treatment Plan
5.2.1.
Pre-medication
No specific pre-medications or supporting medications are required in conjunction with GS-9973 
administration. For VCR, dexamethasone, and CNS prophylaxis please follow the most recent 
version of the package insert and institutional guidelines when administrating.
5.2.2.
Administration Instructions
GS-9973 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.
5.2.3.
Dosing Schedule 
GS-9973 should be taken at approximately the same times each day. Ideally, doses should be 
taken at approximately 12-hour intervals, while in a fasted state. While it is understood that 
variations in the dosing schedule may occur, the prescribed regimen should be followed as 
closely as possible. Compliance with the protocol dosing schedule will be documented in the 
subject’s chart and the electronic data capture (EDC) at each scheduled visit.  Counseling 
regarding subject compliance may be required.
5.2.4.
Dose Schedule Interruptions and Vomited Doses
Subjects who have a delay in administration of a dose of GS-9973 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 GS-9973 of 6 hours, the dose should not be taken. GS-9973 
administration may continue but the missed dose should not be made up and the planned timing 
of subsequent GS-9973 dosing should not be altered.
Vomited doses should be retaken, but only if the tablets are visible in the vomitus.


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5.2.5.
Concomitant and Supportive Therapy
Subjects should receive full supportive care including transfusions of blood and blood products, 
antibiotics, antiemetics, allopurinol, etc., when appropriate.
No other direct anti-leukemia therapy is permitted.
Growth Factor (eg. G-CSF or GM-CSF) use in Cycle 1 is not permitted as it may impact the 
determination of DLT. Beyond cycle 1 the use of myeloid growth factors is permitted according 
to American Society of Clinical Oncology (ASCO) guidelines for use in ALL.
rEPO is not permitted at any time on the study.
Palliative radiation therapy may not be administered while the subject is on study unless 
discussed and approved by the Sponsor.  
5.3.
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:

Any non-study anti-cancer chemotherapy or non-study immunotherapy (approved or 
investigational), except steroids used as anti-emetics

Co-administration of strong CYP3A and CYP2C9 inducers, and moderate CYP2C9 inducers
are prohibited in this study. Administration of these medications should also be avoided for 
2 weeks prior to study drug administration. Examples of these medicines, and other 
medications that are prohibited in this study are provided in Table 5-1

Caution should be exercised when co-administering drugs that are moderate or strong
inhibitors of CYP2C9 (eg fluconazole, voriconazole or amiodarone) as they may increase 
Entospletinib exposure

Proton Pump Inhibitors are prohibited in combination with Entospletinib. Use of a proton 
pump inhibitor should be avoided for 1 week prior to study drug administration and for the 
duration of treatment with study drug. H2 blockers and antacids will be allowed for use 
during the protocol. 


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Table 5-1.
Examples of Contraindicated Medication Requiring GSI Medical 
Monitor 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

Caution should be exercised when co-administering medications that are transported by 
OATP1B1, OATP1B3, MATE1, P-gp and BCRP or metabolized by UGT1A1; dose 
adjustment or switching to an alternative medication may be necessary if clinically indicated.

The following restrictions apply to the use of HMG-CoA reductase inhibitors with 
Entospletinib:
HMG-CoA reductase inhibitor
Dose Adjustment Required
Atorvastatin
Maximum dose 20 mg QD
Rosuvastatin
Maximum dose 10 mg QD
Pravastatin
Maximum dose 40 mg QD
Simvastatin
Maximum dose 20 mg QD
Lovastatin
Maximum dose 20 mg QD
Fluvastatin
Maximum dose 20 mg BID or 40 mg QD
Pitavastatin
Maximum dose 1 mg QD
The management of subjects who are benefiting from the protocol treatment and who 
subsequently require treatment with the above medications should be discussed with the Gilead 
Medical Monitor. 

Granulocyte-colony stimulating factors (GCSF) are not permitted during Cycle 1 for all 
subjects
5.4.
Study Drug Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has a process instruction (eg, Standard Operating Procedures [SOPs]) for 
on-site drug destruction which is reviewed by the study monitor, then the site should destroy 
used (empty bottles) and unused study drug supplies in accordance with the site’s 


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(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 GSI (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.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or the Clinical Research Associate (CRA). 
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study. Once consent is obtained, all screening tests 
and procedures are assessed, and study eligibility is confirmed, subjects will be enrolled to 
receive GS-9973.
6.2.
Subject Enrollment and Treatment Assignment
A subject will be considered enrolled once enrolled in IWRS. It is the responsibility of the 
investigator to ensure each subject is eligible for the study before enrollment.
6.2.1.
Obtain Written Informed Consent
All subjects must personally sign and date the institutional review board / independent ethics 
committee (IRB/IEC) approved informed consent form before any study procedures are 
performed (Section 9.1.3)
6.2.2.
Recording Medical History
A complete medical, surgical and smoking history will be obtained prior to enrollment.
6.2.3.
Medication History
A history of smoking and medications taken within 30 days prior to screening and during the 
screening period will be obtained prior to enrollment.
6.2.4.
Physical Examination 
A complete physical examination will be performed at the screening visit and a modified exam at
all other study visits. Physical examination will be performed to monitor for any changes and 
will include vital signs, weight and height. Weight should be collected with the subject standing 
without shoes. Physical examination findings during the screening period will be reported as 
medical history.
6.2.5.
Vital Signs
Vital signs will include pulse, respiratory rate, systolic and diastolic blood pressure, oxygen 
saturation level, and body temperature. They should be collected per institutional guidelines.


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6.2.6.
Laboratory Assessments
All samples collected in this study for laboratory assessments will be sent to the central 
laboratory with the exception of urine pregnancy test which will be completed at the site.  
Screening laboratory samples should be obtained within 7 days prior to the first dose of study 
drug. If the samples were obtained more than 7 days prior to first dose of study drug, only the 
hematology and chemistry lab samples must be repeated. Local laboratory results may be used 
for eligibility evaluation while pending central laboratory results.
The central laboratory will be responsible for chemistry, CBC, coagulation, urinalysis, and serum 
pregnancy testing per Table 6-1. Any samples collected per the Study Procedure Table
(Appendix 2) may be analyzed for any tests necessary to ensure subject safety. Specific 
instructions for processing, labeling, and shipping samples will be provided in a central 
laboratory manual. The date and time of sample collection will be reported to the central 
laboratory.
Table 6-1.
Analytes
Serum Chemistry
Hematology
Other
Sodium
Potassium
Chloride
Lipase
Amylase
Bicarbonate
Creatinine
BUN
Phosphorus
LDH a
Uric acid a
Magnesium a
Total bilirubin 
Indirect Bilirubin
Direct Bilirubin
ALT 
AST
Alkaline phosphatase
CPKb
Hemoglobin
Hematocrit
Red Blood Cell (RBC) count
White Blood Cell (WBC) Count 
Neutrophils 
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Pharmacokinetic Sampling
Biomarker Sampling

Syk and relevant down-stream signaling 
pathways 

mechanisms of resistance

PBMC

Bone Marrow Aspirate

Bone Marrow Biopsy
Urinalysis
Coagulation
Prothrombin Time
APTT
INR
Pregnancy Testing
Virology
Serum Qualitative -HCG 
or FSH a
Urine pregnancy test
Hep B
Hep C
HIV
a
Screening only 
b
At Screening, Day 1 of each cycle and End of Treatment
6.2.7.
Bone Marrow Aspirate and Biopsy
Bone marrow aspirate/biopsy samples will be assessed by a local hematopathologist.  Unstained 
slides should be made available to the sponsor for central review. Results from assessment of 
bone marrow aspirate/biopsy samples obtained as part of the subject’s routine medical care may 
be used if the documentation is available.
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6.2.8.
Eastern Cooperative Oncology (ECOG) Performance Status
The ECOG performance status is an investigator assessment of the impact of the disease on the 
subject’s activities of daily living. It is assessed on a 6-point scale as described in Appendix 6
{Oken 1982}.
6.3.
Biomarker Testing
6.3.1.
Biomarker Samples to Address the Study Objectives:
The following biological specimens will be collected in this study and will be used to evaluate 
the association of exploratory systemic and/or tissue specific biomarkers with study drug 
response including efficacy and/or adverse events, as well as to increase knowledge and 
understanding of the biology of related diseases. The specific analyses will include, but will not 
be limited to, the biomarkers and assays listed below. Because biomarker science is a rapidly 
evolving area of investigation, and adverse events in particular are difficult to predict, it is not 
possible to specify prospectively all tests that will be done on the specimens provided. The 
testing outlined below is based upon the current state of scientific knowledge. It may be modified 
during or after the end of the study to remove tests no longer indicated and/or to add new tests 
based upon the growing state of the art knowledge. Specimens will be collected from all subjects 
which may allow for individualized drug therapy for subjects in the future. Blood samples will 
be collected from all subjects at baseline and after treatment to assess changes in the Syk 
pathway, relevant downstream pathways and Syk associated pathways in blasts. The testing may 
include assessing phosphorylation of Syk and other downstream mediators, cytokines and 
chemokines. Specimens will be collected from all subjects.
 
Blood and bone marrow samples will be collected to study:

Mechanisms of resistance to GS-9973 by analysis of DNA and genes, and/or proteins that 
change between baseline and at disease progression. These studies will allow us to identify 
new and improved therapies for ALL

Effects of GS-9973 on signaling and minimal residual disease to better understand the effects 
of GS-9973 on disease burden
6.3.2.
Biomarker Samples for Optional Future Research 
 
 
 
 
 
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6.4.
Pretreatment Assessments
6.4.1.
Screening Visit
Subjects will be screened within 28 days of their first administration of study treatment to 
determine eligibility for participation in the study. The following will be performed and 
documented at screening:

Obtain written informed consent

Obtain medical history

Obtain smoking status

Complete physical examination including, vital signs, body weight, and height

Obtain blood samples 

Bone marrow aspirate/biopsy (if not done within 28 days of the first dose of GS-9973)

CT scan or PET-CT of affected site/s for subjects with EMD only and without measureable 
BM involvement

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 28 days of screening for enrollment into the study.
From the time of obtaining informed consent through the first administration of study drug 
(GS-9973), record all serious adverse events (SAEs), as well as any adverse events related to 
protocol-mandated procedures on the adverse events case report form (CRF/eCRF).  All other 
untoward medical occurrences observed during the screening period, including exacerbation or 
changes in medical history are to be captured on the medical history CRF/eCRF.  See Section 7.6
Adverse Events and Toxicity Management for additional details.
6.5.
Treatment Assessments
Subjects who have met all eligibility criteria will come to the clinic to start the Lead-in phase of 
the study and to perform study required procedures prior to dosing.  Review prior/ concomitant 
medications and record adverse events at each clinic visit.
For study purposes, the GS-9973 Lead-in is 7 days.
6.5.1.
Lead-in Phase:

Review prior/concomitant medication 


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
Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation

Performance status (ECOG)

Modified physical exam including weight 

Smoking Status

Laboratory assessments (Section 6.2.6): 
Hematology
Chemistry
Coagulation
Pharmacokinetic sampling at pre-dose and 1.5 hours post-dose of 
GS-9973 (± 30 minutes)
Biomarker sampling (pre-dose)
Urine pregnancy test for females of child bearing potential

Study drug dispensation
6.5.2.
Cycle 1
After completing the 7 day Lead-in phase, the subjects will start Cycle 1 for 28 days.
6.5.2.1.
Cycle 1: Day 1

Review prior/concomitant medication 

Record any adverse events

Obtain smoking status

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation
level

Performance status (ECOG)

Modified physical exam including weight

Laboratory assessments (Section 6.2.6.): 
Hematology 
Chemistry 


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Coagulation
Pharmacokinetic peripheral blood sampling at pre-dose and 1.5 hours post-dose of 
GS-9973 (± 30 minutes) 
Biomarker sampling

Study drug dispensation

VCR administration

Urine pregnancy test for females of child bearing potential 
6.5.2.2.
Cycle 1: Day 8

Review prior/concomitant medication 

Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

Performance status (ECOG)

Modified physical exam 

Laboratory assessments (Section 6.2.6.): 
Hematology 
Chemistry 
Coagulation
Pharmacokinetic peripheral blood sampling pre-dose and 1.5 hours post-dose of GS-9973
(± 30 minutes)
Biomarker sampling (pre-dose)

VCR administration

Dexamethasone dispensation

Bone marrow aspirate/biopsy

CT scan or PET-CT of affected site/s for subjects with EMD only and without measureable 
BM involvement (Patients with no BM involvement and only EMD will not require BM 
aspirate/biopsy on cycle 1 day 8).
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6.5.2.3.
Cycle 1: Day 15

Review prior/concomitant medication 

Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

Performance status (ECOG)

Modified physical exam 

Laboratory assessments (Section 6.2.6.): 
Hematology 
Chemistry 
Coagulation

VCR administration
6.5.2.4.
Cycle 1: Day 22

Review prior/concomitant medication 

Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

Performance status (ECOG)

Modified physical exam 

Laboratory assessments (Section 6.2.6.): 
Hematology 
Chemistry 
Coagulation

VCR administration

Dexamethasone dispensation
6.5.2.5.
Cycle 1: Day 28

Review prior/concomitant medication 


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
Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

Performance status (ECOG)

Modified physical exam including weight

Laboratory assessments:
Hematology 
Chemistry 
Pharmacokinetic peripheral blood sampling at pre-dose and 1.5 hours post-dose of 
GS-9973 (± 30 minutes)
Biomarker sampling (pre-dose)

CNS Prophylaxis (per institutional standard)

Bone marrow aspirate/biopsy

Cerebrospinal fluid (CSF) for PK analysis (prior to CNS prophylaxis administration)

CT scan or PET-CT of affected site/s for subjects with EMD only and without measureable 
BM involvement (Patients with no BM involvement and only EMD will not require BM 
aspirate/biopsy on cycle 1 day 28)

Study drug dispensation; if needed for cycle break coverage
6.5.3.
Cycle 2
Subjects may continue to Cycle 2 within 7 days of completing Cycle 1.
6.5.3.1.
Cycle 2: Day 1

Review prior/concomitant medication 

Record any adverse events

Obtain smoking status

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

Performance status (ECOG)


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
Modified physical exam including weight

Laboratory assessments (Section 6.2.6.): 
Hematology 
Chemistry 
Coagulation

Urine pregnancy test for females of child bearing potential

Study drug dispensation

VCR administration

Dexamethasone dispensation
6.5.3.2.
Cycle 2: Day 8 

Review prior/concomitant medication 

Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

Performance status (ECOG)

Modified physical exam 

Laboratory assessments (Section 6.2.6.): 
Hematology 
Chemistry 
Coagulation

VCR administration
6.5.3.3.
Cycle 2: Day 15

Review prior/concomitant medication 

Record any adverse events


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
Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

Performance status (ECOG)

Modified physical exam 

Laboratory assessments (Section 6.2.6.): 
Hematology 
Chemistry 
Coagulation

VCR administration

Dexamethasone dispensation
6.5.3.4.
Cycle 2: Day 22

Review prior/concomitant medication 

Record any adverse events

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

Performance status (ECOG)

Modified physical exam 

Laboratory assessments (Section 6.2.6.): 
Hematology 
Chemistry 
Coagulation

VCR administration
6.5.3.5.
Cycle 2: Day 28

Review prior/concomitant medication 

Record any adverse events


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
Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

Performance status (ECOG)

Modified physical exam 

Laboratory assessments : 
Hematology 
Chemistry 
Pharmacokinetic peripheral blood sampling at pre-dose and 1.5 hours post-dose of 
GS-9973 (± 30 minutes)
Biomarker sampling (pre-dose)

Study drug dispensation, if needed for cycle break coverage

CNS prophylaxis (per institutional standard)

Bone marrow aspirate/biopsy

Cerebral fluid (CSF) for PK analysis (prior to CNS prophylaxis administration)

CT scan or PET-CT of affected site/s for subjects with EMD only and without measureable 
BM involvement, unless imaging was performed within 30 days of end of treatment (Patients 
with no BM involvement and only EMD will not require BM aspirate/biopsy on cycle 2 day 28).
6.6.
Maintenance
Subjects who obtain clinical benefit in the opinion of the treating physician may continue 
GS-9973 at the assigned dose level during maintenance for up to 36 cycles. VCR will be 
administered on Day 1 of each 28-day cycle. Dexamethasone (20 mg total dose daily for 4 days, 
either 10 mg twice daily or 20 mg once daily) will be taken on Days 1-4 and 15-18 of each 
28-day cycle.
Refer to Appendix 2 for procedures performed during maintenance. Study drug (GS-9973) will
be dispensed at Day 1 of each cycle during maintenance.
Bone marrow evaluations and additional central nervous system (CNS) prophylaxis can be 
performed as clinically indicated per institutional standards in the maintenance.
6.7.
End of Study Treatment Assessments
Subjects will be removed from study treatment when any of the criteria listed in Section 6.8
apply.


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The following procedures will be conducted when a subject goes off study treatment and prior to 
initiating a new regimen.
If the subject chooses not to continue participation on the study, the procedures listed below are 
to be conducted within 14 days of the last dose of study treatment or prior to initiating a new 
therapy. 

Review prior/concomitant medication 

Record any adverse events

Performance status (ECOG)

Modified physical exam including weight

Vital signs; including blood pressure, respiratory rate, pulse, temperature, oxygen saturation 
level

Laboratory assessments (Section 6.2.6.):
Chemistry 
Hematology 
Coagulation
Biomarker sampling

Obtain bone marrow aspirate/biopsy samples for disease assessment and Biomarker testing

CT scan or PET-CT of affected site/s for subjects with EMD only and without measureable 
BM involvement unless imaging was performed within 30 days of end of treatment (Patients 
with no BM involvement and only EMD will not require BM aspirate/biopsy) 
6.7.1.
30-Day Follow-up
After the last dose of study drug, subjects should be followed for any drug-related AEs and/or 
ongoing serious adverse events (SAEs) until those events have resolved or become stable, 
whichever occurs later. The site will contact the study subject regardless of AE/SAE status 
approximately 30 days after the subject’s last dose of study drug to assess adverse events since 
the last study visit and review concomitant medications. Subject should be contacted by phone 
(or in person, if necessary) to assess the subject’s condition and record any adverse events 
reported during the follow-up contact. Phone call or visit should be documented.


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6.7.2.
Long Term Follow-Up
Long term follow-up for survival will be conducted every 3 months (± 4 weeks) after the 
discontinuation of treatment visit until end of study. Information to be gathered includes ALL 
treatments, other malignancies, and survival which could be collected during a routine clinic 
visit, other contact with the subject, or via telephone. Gilead reserves the right to discontinue or 
shorten the duration of participation in the long term follow-up period at any time.
6.8.
Criteria for Discontinuation of Study Treatment
Study medication must 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 not to be in the subject’s best 
interest

The investigator, in consultation with the Gilead 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

Subject request to discontinue for any reason. Any subject has the right to withdraw from the 
study at any time

Subject noncompliance with study treatment administration, study procedures, or study 
requirements should be withdrawn from study treatment in circumstances that increase risk 
or substantially compromise the interpretation of study results

Any subject who becomes pregnant or begins breastfeeding should be withdrawn from study 
drug; refer to Appendix 5

Discontinuation of the study at the request of GSI, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)
6.9.
End of Study
End of study will be defined as when all patients complete long term follow-up or discontinue 
their participation in the study due to death, withdrawal of consent or lost to follow up, or the 
time at which the Sponsor closes the study.
6.10.
Post Study Care
Does not apply.


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported

Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be preexisting and should be documented on the medical history CRF
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) or serious adverse drug reaction (SADR) is defined as an event 
that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

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:
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 Acute Lymphoblastic Leukemia (ALL) being studied

Death due to Acute Lymphoblastic Leukemia (ALL) being studied
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the study drugs caused or contributed to the disease 
progression (i.e., by a means other than lack of effect). Unrelated disease progression should be 
captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.


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7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study drug. For 
SAEs, an alternative causality must be provided (eg, preexisting 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 (study drug GS-9973).
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity 
The severity of adverse events will be graded using the CTCAE, Version 4.03. For each episode, 
the highest severity grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to 
describe the maximum intensity of the adverse event. For purposes of consistency with the 
CTCAE, these intensity grades are defined in Table 7-1.


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Table 7-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, and 
may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up.
Grade 4
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events listed in Section 7.3.
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 (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication until 30 days after last administration of study 
medication AEs, regardless of cause or relationship, must be reported to the CRF/eCRF database 
as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the
CRF/eCRF database and Gilead 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 drug, 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 study drug, he/she should promptly document and 
report the event to Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to: Email: 
 and 
Fax:

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. For fatal or life-threatening events, copies of hospital case reports, 
autopsy reports, and other documents are also to be submitted by e-mail or fax when 
requested and applicable. Transmission of such documents should occur without personal 
subject identification, maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
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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 drug. 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 are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (eg, clinical chemistry, hematology, and urinalysis) that require medical or surgical 
intervention or lead to investigational medicinal product interruption 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 7.1.1 and 7.1.2, respectively. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (ie, anemia) not the laboratory result (ie, decreased 
hemoglobin).
Severity should be recorded and graded according to the CTCAE (version 4.03).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
7.6.
Toxicity Management 
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead Medical Monitor or designee. Whether or not considered treatment-related, all 
subjects experiencing AEs must be monitored periodically until symptoms subside, any 
abnormal laboratory values have resolved or returned to baseline levels or they are considered 
irreversible, or until there is a satisfactory explanation for the changes observed.
Grade 3 or 4 clinically significant laboratory abnormalities should be confirmed by repeat testing 
as soon as practical to do so, and preferably within 3 calendar days after receipt of the original 
test results.
Any questions regarding toxicity management should be directed to the Gilead Sciences Medical 
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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 adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the or Gilead DSPH using the pregnancy report form within 24 hours of becoming 
aware of the pregnancy. 
Refer to Section 9.1.6 and the CRF/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 
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A spontaneous abortion is always considered to be an SAE and will be reported within 24 hours
(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 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 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
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 drug 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 CRF/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 CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
Primary objectives

To evaluate safety of entospletinib (GS-9973) in combination with vincristine (VCR) and 
dexamethasone in adult subjects with previously treated relapsed or refractory B-cell lineage 
ALL
Secondary objectives

To determine the recommended dose of GS-9973 in combination with VCR and 
dexamethasone in adult subjects with previously treated relapsed or refractory B-cell lineage 
ALL

To evaluate the therapeutic response of GS-9973 in combination with VCR and 
dexamethasone in adult subjects with previously treated relapsed or refractory B-cell lineage 
ALL
The exploratory objectives of this study are: 
 
 
 
 
 
 
8.1.2.
Primary Endpoint
The primary endpoint is safety. Safety will be evaluated by:

Occurrence of adverse events and laboratory abnormalities defined as dose limiting toxicities 
(DLTs)
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8.1.3.
Secondary Endpoint

Overall Remission (CR or CRi) rate at end of induction - defined as the proportion of 
subjects who achieve a complete remission (CR) or complete remission with incomplete 
hematologic recovery (CRi) at end of induction

Complete remission (CR) rate at end of induction

Partial response (PR) rate at end of induction - defined as the proportion of subjects who 
achieve a partial response of marrow (as defined in Appendix 4) or by imaging criteria for 
patients with extramedullary disease (NCCN guidelines version 2.2016) as the best response.

Overall Response (CR, CRi, or PR) rate at end of induction - defined as the proportion of 
subjects who achieve a complete remission (CR), complete remission with incomplete 
hematologic recovery (CRi) or partial response (PR) at end of induction
8.1.4.
Exploratory endpoints
 
 
 
 
 
 
 
 
 
  
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8.2.
Analysis Sets
8.2.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all subjects who received a study subject identification 
number in the study after screening.
8.2.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who receive at least 1 dose of study treatment. 
This analysis set will be used in the analyses of subject characteristics, exposure, safety, and 
efficacy.  Subjects will be grouped by dose level and overall. 
8.2.3.
DLT Analysis Set
The DLT Analysis Set includes subjects in FAS with sufficient drug exposure (Section 3.3.1) or 
experience a DLT during the DLT assessment window. Subjects will be grouped by dose level 
and overall.    
8.2.4.
Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis sets include subjects in FAS who have the necessary baseline and 
post-treatment measurements to provide interpretable results for the specific parameters of 
interest. This analysis set will be used in the analysis of GS-9973 plasma pharmacokinetic.
8.3.
Data Handling Conventions
By-subject listings will be created for important variables from each eCRF module. Summary 
tables for continuous variables will contain the following statistics: N (number in population), 
n (number with data), mean, standard deviation, 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 time point if applicable. 
As appropriate, changes from baseline to each subsequent time point 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 drug treatment, and the reason 
for discontinuing study treatment. Available information on subjects who were screened but not 
treated may be listed separately.
Subject demographic and baseline characteristics will be listed and summarized by dose level for 
the full analysis set.
8.5.
Efficacy Analysis
The efficacy will be evaluated per the response criteria in NCCN guidelines on ALL 
(Appendix 4).
8.5.1.
Primary Analysis
Categorical Endpoints 
Overall remission rate and other response rate variables will be described. In the analyses of 
overall remission rate at induction completion, subjects who do not have sufficient baseline or on 
study tumor assessment to characterize response will be counted as failures. 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 a subject who is not known to have relapsed or died by the end of the study follow-up 
or data cutoff, RFS is censored on the date of the last available disease assessment of the subject.  
EFS: For subjects with none of the events defined in EFS before the end of the study follow-up 
or data cutoff, EFS is censored at the date of the last available disease assessment of the subject. 
OS: For a subject who is not known to have died by the end of study follow-up or data cutoff, 
OS is censored on the date the subject is last known to be alive.
Analysis of 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 95% CI. For a subject with no report of relapse by the end of 
the study follow-up or data cutoff date, observation is censored on the date of the last available 
assessment of the subject. 


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Continuous Endpoints
Continuous endpoints (e.g. TTR and TTC) will be summarized using descriptive statistics.
8.6.
Safety Analysis
All safety data collected on or after the date that study treatment was first dosed up to 30 days 
after the date of last dose of study treatment will be summarized by dose level. 
8.6.1.
Extent of Exposure
Descriptive information will be provided by dose level regarding the number of doses of study 
treatment prescribed, the total number of doses taken, duration of treatment, and the number and 
timing of prescribed dose reductions and interruptions.
GS-9973 compliance will be described in terms of the proportion of study treatment actually 
taken based on returned pill count relative to the amount that was dispensed (taking into account 
physician-prescribed reductions and interruptions).
8.6.2.
Adverse Events
All adverse events will be listed. The focus of adverse event summarization will be on treatment 
emergent adverse events. A treatment-emergent adverse event is defined as an adverse event that  
onset in the period from the first dose of study treatment to 30 days after the permanent 
discontinuation of study treatment or that leads to permanent discontinuation of study treatment. 
Adverse events that occur before the first dose of study treatment or >30 days after the subject 
has been discontinued from study treatment will be included in data listings.
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High Level Term, Preferred 
Term, and Lower-Level Term. The severity of adverse events will be graded by the investigator 
according to the CTCAE, Version 4.03 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-
06-14_QuickReference_5x7.pdf), whenever possible. If a CTCAE criterion does not exist for a 
specific type of adverse event, the grade corresponding to the appropriate adjective will be used 
by the investigator to describe the maximum intensity of the adverse event: Grade 1 (mild), 
Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal). The 
relationship of the adverse event to the study treatment will be categorized as related or 
unrelated.
Treatment-emergent adverse events will be summarized. Summary tables will be presented to 
show the number of subjects reporting treatment-emergent adverse events by severity grade and 
corresponding percentages. A subject who reports multiple treatment-emergent adverse events 
within the same Preferred Term (or System Organ Class) is counted only once for that Preferred 
Term (or System Organ Class) using the worst severity grade. 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 
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Separate listings and summaries will be prepared for the following types of treatment emergent 
adverse events:

Study-drug-related adverse events

Adverse events that are Grade ≥3 in severity

Adverse events leading to study treatment interruption and/or dose modification

Adverse events leading to study treatment discontinuation

Serious adverse events 

DLT will be listed and summarized; DLT rate will be presented by dose level and the 
corresponding 90% CIs will be presented
8.6.3.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data 
and will be reported using conventional units. The focus of laboratory data summarization will 
be on treatment-emergent laboratory abnormalities. A treatment emergent laboratory abnormality 
is defined as an abnormality that, compared to baseline, worsens by >=1 grade in the period from 
the first dose of study treatment to 30 days after the last dose of study treatment. If baseline data 
are missing, then any graded abnormality (ie, an abnormality that is Grade >=1 in severity) will 
be considered treatment emergent. Laboratory abnormalities that occur before the first dose of 
study treatment or >30 days after the subject has been discontinued from 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 for the subject’s age, sex, etc.
Hematological and serum chemistry and their changes from baseline will be summarized. 
Summary tables will be presented for each relevant assay to show the number of subjects by 
CTCAE severity grade with corresponding percentages. For parameters for which a CTCAE 
scale does not exist, the frequency of subjects with values below, within, and above the normal 
ranges will be summarized. Subjects will be characterized only once for a given assay, based on
their worst severity grade observed during a period of interest (eg, during the study or from 
baseline to a particular visit).
Shift tables for hematology and serum chemistry will also be presented by showing change in 
CTCAE severity grade from baseline to each visit. For parameters for which a CTCAE scale 
does not exist, shift tables will be presented showing change in results from baseline (normal, 
low and high [or abnormal] to each visit (normal, low and high [or abnormal]). 


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Separate listings and summaries will be prepared for laboratory abnormalities that are Grade ≥3 
in severity.
8.7.
Pharmacokinetic Analysis
Concentrations of each agent of the treatment in plasma will be determined using a validated 
bioanalytical assay. Plasma concentrations will be displayed as individual concentration vs. time 
using scheduled sampling times. Concentrations will be listed by subject and summarized using 
descriptive statistics (eg, n, arithmetic mean, geometric mean, % coefficient of variation [CV], 
StD, median, Q1, Q3, min, and max). Mean (±StD) plasma concentration-time curves will be 
plotted in both semi-logarithmic and linear formats. 
8.8.
Biomarker Analysis
Changes in biomarkers will be evaluated descriptively. Data explorations may be performed to 
evaluate potential associations between subject characteristics and outcome measures. 
Explorations may also be performed to assess the potential associations between different 
outcomes measures (eg, relationships between biomarkers and clinical endpoints of response).
8.9.
Sample Size
Assuming that 4 planned dose levels are tested for escalation and 3, 3, 6 and 6 subjects are tested 
at each dose level, respectively (18 subjects for Dose Escalation),  and assuming 10% subjects 
are unevaluable during Dose Escalation, 20 subjects will be enrolled during Dose Escalation.
A total of 3 to 6 subjects will be treated at each of the proposed dose levels. Based on the 
3+3 dose-escalation scheme, Table 8-1 shows the probability of escalating to the next dose level 
or proceeding to the next stage, based on the true rate of DLT at the current dose level.
Table 8-1.
Probability of Dose Escalation (N=3+3)
True Incidence of DLT
Probability of Escalating
10%
0.91
20%
0.71
30%
0.49
40%
0.31
50%
0.17
60%
0.08
Thus, if the true underlying proportion of DLT is low (eg, ≤10% at the current dose level, there 
is a high probability (≥0.91) of dose escalation to the next dose level. Conversely, if the true 
underlying proportion of DLT is high (eg, ≥60%) at the current dose level, there is a low 
probability (≤0.08) of escalation to the next dose level.


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The trial employs the standard NCI definition of MTD (starting dose associated with DLT in 
< 33.3% of subjects during the DLT assessment window).
8.10.
Timing of Analyses
8.10.1.
Interim Analyses 
No formal interim analyses are planned in this study. The GSI study team and the investigators 
will collectively discuss study conduct and accumulating safety and other data.
8.10.2.
Final Analysis
Final study reporting is expected to occur after all subjects have discontinued 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.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the Sponsor been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB/IEC approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 


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and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by 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, or laboratory. Laboratory specimens must 
be labeled in such a way as to protect subject identity while allowing the results to be recorded to 
the proper subject. Refer to specific laboratory instructions NOTE: The investigator must keep a 
screening log showing codes, names, and addresses for all subjects screened and for all subjects 
enrolled in the trial. Subject data will be processed in accordance with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the study drug, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);
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
Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 
as described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 


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the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (e.g. data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Used and unused study drug supplies should be destroyed on site if the site has an appropriate 
standard operating procedure (SOP) for drug destruction as determined by Gilead. The site may 
destroy used (empty or partially empty) and unused study drug supplies in accordance with that 
site’s approved SOP. A copy of the site’s approved SOP will be obtained for central files. 
The study monitor will evaluate each study center’s study drug disposal procedures and provide 
appropriate instruction for destruction of unused study drug supplies on site. The investigator 
must maintain accurate records for all study drug destroyed at the site. Records must show the 
identification and quantity of each unit destroyed, the method of destruction, and the person who 
disposed of the study drug. Upon study completion, copies of the study drug accountability 
records must be filed at the site. Another copy will be returned to Gilead. 
If destruction of study drug on site is not possible, the study drug is to be returned to the shipping 
facility for eventual destruction. The monitor will provide further instructions for the return.
The study monitor will review study drug supplies and associated records at study monitoring 
visits.
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 IRBs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB in 
accordance with local requirements and receive documented IRB approval before modifications 
can be implemented.


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


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


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10.
REFERENCES
American Cancer Society. What are the key statistics about acute lymphocytic leukemia? 
Available at: http://www.cancer.org/cancer/leukemia-
acutelymphycyticallinadults/detailedguide/leuke... Accessed: 13 November 2014.
American Society of Clinical Oncology (ASCO). Leukemia - Acute Lymphocytic - ALL -
Statistics.  Avalailable at http://www.cancer.net/cancer-types/leukemia-acute-
lymphocytic-all/statistics. Accessed: 13 November 2014.
Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol 2011;29 
(5):532-43.
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.
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.
Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al. Inhibition of 
Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin 
lymphoma and chronic lymphocytic leukemia. Blood 2010;115 (13):2578-85.
Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, et al. In adults 
with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved 
from a matched sibling allogeneic transplantation in first complete remission, and 
an autologous transplantation is less effective than conventional 
consolidation/maintenance chemotherapy in all patients: final results of the 
International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008;111 
(4):1827-33.
Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, et al. Improved survival for 
children and adolescents with acute lymphoblastic leukemia between 1990 and 
2005: a report from the children's oncology group. J Clin Oncol 2012;30 
(14):1663-9.
Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet 2013;381 
(9881):1943-55.
Morris DL, O'Neil SP, Devraj RV, Portanova JP, Gilles RW, Gross CJ, et al. Acute lymphoid 
and gastrointestinal toxicity induced by selective p38alpha map kinase and map 
kinase-activated protein kinase-2 (MK2) inhibitors in the dog. Toxicol Pathol 
2010;38 (4):606-18.


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Amendment 5
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National Comprehensive Cancer Network (NCCN). Acute Lymphoblastic Leukemia: NCCN 
Clinical Practice Guidelines in Oncology. Version 1.2014.  June, 2014.
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.
Perova T, Grandal I, Nutter LM, Papp E, Matei IR, Beyene J, et al. Therapeutic potential of 
spleen tyrosine kinase inhibition for treating high-risk precursor B cell acute 
lymphoblastic leukemia. Science translational medicine 2014;6 (236):236ra62.
Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet 2008;371 (9617):1030-
43.
Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, et al. Improved early 
event-free survival with imatinib in Philadelphia chromosome-positive acute 
lymphoblastic leukemia: a children's oncology group study. J Clin Oncol 2009;27 
(31):5175-81.
Turner M, Schweighoffer E, Colucci F, Di Santo JP, Tybulewicz VL. Tyrosine kinase SYK: 
essential functions for immunoreceptor signalling. Immunology today 2000;21 
(3):148-54.
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
Appendix 3.
Management of Clinical and Laboratory Adverse Events
Appendix 4.
Response assessment in ALL
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 6.
ECOG status
Appendix 7.
NCCN Guidelines (version 2.2016)


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Amendment 5 
Appendix l. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 1 b/2, Open-Label, Dose Escalation and Expansion Study Evaluating the Safety 
and Efficacy of Entospletinib (GS-9973) with Vincristine and Dexamethasone in Adult 
Subjects with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL) 
GS-US-339-1560, Amendment 5, 13April 201 8 
This protocol has been approved by Gilead Sciences, Inc. The followi 
this approval. 
Date 
INVESTIGATOR STATEMENT 
1 have read the protocol, including all appendices, and 1 agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I wiJI discuss this material with them to ensure 
that they are fully infonned about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFLDENTIAL 
Page 92 
13 April 2018 


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Appendix 2.
Study Procedures Table
Study Phase
Screening 
(-28 days)
GS-9973 
Lead-in*
Cycle 1
Cycle 2
Maintenance**
End of 
Treatment
30 Day 
Follow-Up
Cycle Day
Screening
-7
1
8
15
22
28
1
8
15
22
28
1
8
15
22
28
Study Day
1
8
15
22
29
35
Study Assessments
Informed Consent
X
General and Safety Assessments
Physical Exam and 
weighta
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE/Concomitant Medsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical History
X
HBV, HCV, and HIV 
Virology
X
Smoking status
X
X
X
X
X
Disease Assessments
ECOG
X
X
X
X
X
X
Laboratory Assessments
Bone marrow aspirate 
and biopsyd
X
X
X
X
X
Hematologye
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Chemistry & 
Liver Function Testing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Urine or Serum 
Pregnancy Test or FSHf
X
X
X
X
X
X
Pharmacokinetic 
Samplingg
X
X
X
X
X
CSF (for PK sampling)h
X
X
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Study Phase
Screening 
(-28 days)
GS-9973 
Lead-in*
Cycle 1
Cycle 2
Maintenance**
End of 
Treatment
30 Day 
Follow-Up
Imaging
CT or PETk
(Investigator’s 
discretion, for EMD 
subjects only)
X
X
X
X
Investigational Product and Auxiliary  
GS-9973l
X
X
X
X
X
X
X
IV Vincristinem
X
X
X
X
X
X
X
X
X
Dexamethasonen
X
X
X
X
X
X
CNS Prophylaxis per
institutional standardo
X
X
*
For Dose Escalation only
**
During Maintenance Cycle 1, all visits are required. Starting from Maintenance Cycle 2, Day 1 is required and Day 8/15/22/28 visits are per the Investigator’s discretion.
a
Complete physical examination will be performed at Screening which includes height.  A modified physical examination capturing changes from prior exams will be 
performed at other visits. 
b
Vital signs (including blood pressure, respiratory rate, pulse, oxygen saturation by pulse oximetry and temperature) should be taken after the subject has been sitting for at 
least 5 minutes.
c
Following consent, adverse events will be assessed pre-and post-dose during each clinic visit, and 30 (±7) days following completion of the subject’s last dose of study drug.  
Subjects should be contacted by phone (or in person, if necessary) 30 days (±7 days) after the subject’s last dose of study drug to assess AEs.  Subjects should be asked
specifically if there are any AEs since stopping the study.    
d
Bone marrow aspirate/biopsy will be taken during Screening; Cycle 1 on Day 8 and Day 28; Cycle 2 on Day 28.
 
e
CBC with differential including PT/INR and PTT.  
f
For female subjects of childbearing potential, serum testing performed at screening only.  Urine pregnancy test will be performed at Lead-in on Day -7 of (escalation) or
during Cycle 1 on Day 1 (expansion). Pregnancy tests will be performed on a Day 1 of each cycle thereafter.
g
Pharmacokinetic peripheral blood samples will be obtained pre-dose during Lead-in on Day -7; Cycle 1 on Day 1, 8, 28 and Cycle 2 on Day 28. PK blood samples will also be 
collected 1.5 hours post-dose of GS-9973 (±30 minutes) during Lead-in on Day -7; Cycle 1 on Days 1, 8, 28 and Cycle 2 on Day 28. CNS prophylaxis administration is 
independent of PK time point.
h
CSF samples will be collected for pharmacokinetic analysis during Cycles 1 and Cycle 2 on Day 28 (prior to CNS prophylaxis administration). 
 
k
Subjects with EMD only, with no BM involvement will not require BM aspirate/biopsy
l
Treatment with GS-9973 will be continuous. GS-9973 should be dispensed on Day 28 to include cycle break drug coverage, if necessary. 
m
Vincristine will be administered during Cycles 1 and Cycle 2 on Days 1, 8, 15, 22 and during Maintenance on Day 1 of each cycle.
n
Dexamethasone (20 mg BID; dosed for 4 days) will be dispensed during Cycle 1 on Day 8 and Day 22 and during Cycle 2 on Day 1 and  Day 15. During Maintenance, 
dexamethasone (20 mg QD or 10 mg BID; dosed for 4 days) will be dispensed on Day 1 and Day 15 of each cycle.
o
CNS prophylaxis per institutional standard during Cycle 1 and Cycle 2 on Day 28 (± 3 days).
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Appendix 3.
Management of Clinical and Laboratory Adverse Events
Dosing Delays/Dose Modifications for AEs Attributed to GS-9973 (beyond Cycle 1)
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Dermatological
Maintain current dose level and 
schedule.
Maintain current dose level and 
schedule.
Withhold dosing until ≤ Grade 1 or 
return to baseline.  
Resume dosing at current dose 
level. If re-challenge at current dose 
level results in recurrence, may 
resume dosing at same or lower 
dose level at investigator discretion.
Withhold dosing until Grade ≤1 
or return to baseline.
May resume at lower dose level 
or discontinue dosing at 
investigator discretion.
Gastrointestinal Inflammation-
Diarrhea
Provide anti-diarrheal 
(e.g., loperamide) and maintain 
current dose level and schedule
Provide anti-diarrheal 
(e.g., loperamide). Withhold 
dosing until Grade <1. Resume 
dosing at current dose level.
If re-challenge results in 
recurrence, may resume at 
initial or lower dose level at 
investigator discretion.
Consider addition of 
anti-inflammatory 
(e.g., sulfasalazine, 
budesonide).
Provide anti-diarrheal 
(e.g., loperamide). Withhold dosing 
until Grade ≤1 or return to baseline. 
Resume at lower dose level.
Consider addition of 
anti-inflammatory 
(e.g., sulfasalazine, budesonide).
Provide anti-diarrheal 
(e.g., loperamide). Withhold 
dosing until Grade ≤1 or return 
to baseline. 
May resume at lower dose level 
or discontinue dosing at 
investigator discretion.
Consider addition of 
anti-inflammatory 
(e.g., sulfasalazine, budesonide).
Hepatic
(elevations in ALT, AST, or 
bilirubin) 
ALT/AST<3xULN)
(Direct Bilirubin<1.5xULN)
(ALT/AST>3-5xULN)
(Direct Bilirubin>1.5-<3xULN)
Withhold dosing. Monitor ALT, 
AST, ALP, and direct bilirubin at 
least 1x per week until all 
abnormalities are Grade ≤1 or 
return to baseline.
Withhold dosing. Monitor ALT, 
AST, ALP, and direct bilirubin 
at least 1x per week until all 
abnormalities are Grade ≤1 or 
return to baseline.
Maintain current dose level and 
schedule
Maintain current dose level and 
schedule
If direct bilirubin was Grade <3, 
resume dosing at same dose level. 
If direct bilirubin was Grade >3, 
resume at lower dose level.
If direct bilirubin was Grade <4, 
resume dosing at lower dose 
level. If direct bilirubin was 
Grade 4, discontinue dosing.


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Dosing Delays/Dose Modifications for AEs Attributed to GS-9973 (beyond Cycle 1)
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Pneumonitis (dyspnea, cough, 
hypoxia and/or diffuse interstitial 
pattern or ground-glass opacities 
on chest CT and no obvious 
infectious cause)
Maintain current dose level and 
schedule. Consider 
Pneumocystis therapy
Withhold dosing until Grade 
<1.
Consider systemic 
corticosteroids and 
Pneumocystis treatment.
May resume at initial or lower 
dose level at investigator 
discretion.
Withhold dosing until Grade ≤ 1 or 
return to baseline.
May resume dosing at initial or 
lower dose level or discontinue 
dosing at investigator discretion.
Withhold dosing until Grade ≤1 
or return to baseline.
May resume dosing at initial or 
lower dose level or discontinue 
dosing at investigator discretion.
Other Study Drug Related, Non 
hematological Adverse Events
Maintain current dose level and 
schedule
Maintain current dose level and 
schedule
Withhold dosing until Grade ≤ 1 or 
return to baseline.
May resume dosing at initial or 
lower dose level or discontinue 
dosing at investigator discretion
Withhold dosing until Grade ≤1 
or return to baseline.
May resume dosing at initial or 
lower dose level or discontinue 
dosing at investigator discretion
Dosing Delays/Dose Modifications for Non-hematologic AEs Attributed to VCR (beyond Cycle 1) 
Grade 1
Grade 2
Grade 3
Grade 4
Maintain current dose level and 
schedule
Consider withholding dose until AE 
resolves to  Grade ≤ 1 or baseline. 
May resume dosing at same dose level 
(or dose-reduced by 50%)
Withhold dosing until AE resolves to 
Grade ≤ 1 or baseline.
May resume dosing at same dose level or 
dose-reduced by 50%.
Withhold dosing until AE resolves to Grade ≤ 1 
or baseline.
May resume dosing at 50% dose-reduction or 
discontinue per investigator discretion.
For unacceptable neuropathy, consider permanent 
discontinuation.
Dosing Delays/Dose Modifications for Non-hematologic AEs Attributed to dexamethasone (beyond Cycle 1)
Grade 1
Grade 2
Grade 3
Grade 4
Maintain current dose level and 
schedule
Consider withholding dose  until AE 
resolves to  Grade ≤ 1 or baseline.
May resume at same dose level/frequency 
(or dose-reduced by 50%)
Consider withholding dosing until AE 
resolves to Grade ≤ 1 or baseline.
May resume dosing at same dose 
level/frequency or dose-reduced by 50%.
Withhold dosing until AE resolves to Grade ≤ 1 
or baseline.
May resume dosing at 50% dose-reduction or 
discontinue per investigator discretion.
For unacceptable myopathy, consider permanent 
discontinuation.


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Appendix 4.
Response assessment in ALL
Assessment of clinical response will be made according to NCCN guidelines on ALL Version 2. 
2016 with the exception of Partial Remission, Overall Response Rate, Refractory Disease, and 
Relapsed Disease. 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.
Response criteria for blood and bone marrow
Complete Remission (CR)
CR requires all of the following:

No circulating  blasts  or extramedullary disease (no lymphadenopathy, splenomegaly, 
skin/gum infiltration/testicular mass/CNS involvement

Trilineage hematopoiesis (TLH) and < 5% blasts in bone marrow aspirate.

Absolute Neutrophil Count (ANC) > 1,000/uL.

Platelets > 100,000/uL.
CR with incomplete blood count recovery (CRi)
CRi meets all criteria for CR except platelet count and/or ANC:

Platelets ≤ 100, 000/ uL and/or ANC is ≤1,000/uL
Overall response rate (ORR=CR+CRi+PR)
Partial Remission (PR)
Note: PR is not defined per NCCN guidelines but defined in this protocol. PR requires all of the 
following: Meets all criteria for CR except for BM blasts:

bone marrow may contain ≥ 5% but less than 25% blast morphology 
Refractory disease: Failure to achieve CR, CRi or PR at the end of induction
Progressive disease (PD): increase of at least 25% in the absolute number of circulating or bone 
marrow blasts or development of extramedullary disease
Relapsed disease: reappearance of blasts in the blood or bone marrow (> 5%) or in any 
extramedullary site after a CR / CRi/PR.


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Response criteria for mediastinal/extramedullary disease:
CR: Complete resolution of mediastinal enlargement or extramedullary mass/es by CT. For 
patients with a previous positive PET scan, a post-treatment residual mass of any size is 
considered as CRE as long as it is PET negative.
PR: > 50% decrease in the SPD of the mediastinal enlargement or extramedullary mass/es from 
baseline. For patients with a previous positive PET scan, post-treatment PET must be positive in 
at least one previously involved site.
PD: > 25% increase in the SPD of the mediastinal enlargement or extramedullary mass/es from 
nadir or development new mediastinal/extramedullary mass/es. For patients with a previous 
positive PET scan, post-treatment PET must be positive in at least one previously involved site.
No Response (NR): failure to quantify for CR, PR or PD
Relapse: Recurrence of mediastinal enlargement after achieving CR. For patients with a previous 
positive PET scan, post-treatment PET must be positive in at least one previously involved site.


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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential 
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless
permanently sterile or with medically documented ovarian failure. Women are considered to be 
in a postmenopausal state when they are > 54 years of age with cessation of previously occurring 
menses for > 12 months without an alternative cause. In addition, women of any age with 
amenorrhea of > 12 months may also be considered postmenopausal if their follicle stimulating 
hormone (FSH) level is in the postmenopausal range and they are not using hormonal 
contraception or hormonal replacement therapy. Permanent sterilization includes hysterectomy, 
bilateral oophorectomy, or bilateral salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered to be fertile after the initiation 
of puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraceptive Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
GS-9973 is contraindicated in pregnancy as there is a strong suspicion of human 
teratogenicity/fetotoxicity in early pregnancy based on non-clinical data. In addition, GS-9973
has insufficient data to exclude the possibility of a clinically relevant interaction with hormonal 
contraception that results in reduced contraception efficacy; therefore, contraceptive steroids are 
not recommended as a contraceptive method either solely or as a part of a contraceptive regimen. 
Please refer to the latest version of the investigator’s brochure for additional information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must also not rely on hormone-containing contraceptives as a 
form of birth control during the study.  They must have a negative serum pregnancy test at 
screening and a negative pregnancy test on the Baseline visit (lead-in).  Pregnancy tests will be 
performed on a monthly basis thereafter.  Female subjects must agree to one of the following 
methods to avoid pregnancy from Screening until 30 days from the last dose of GS-9973.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or


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
Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days from the last dose of GS-9973.
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 90 days from the 
last dose of GS-9973.  Additional contraception recommendations should also be considered if 
the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
from the last dose of GS-9973.
4) Unacceptable Birth Control methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar,
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides
only, and lactational amenorrhea method (LAM). Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days from the last dose of GS-9973. 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.


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Appendix 6.
ECOG status
Grade
ECOG 
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
{Oken 1982}


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Appendix 7.
NCCN Guidelines (version 2.2016)
Response assessment
Response Criteria for Blood and Bone Marrow:

Complete Response (CR):
No circulating blasts or extramedullary disease
No Lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS 
involvement
Trilineage hematopoiesis (TLH) and <5% blasts
Absolute neutrophil count (ANC) >1000/microL
Platelets >100,000/micro/L
No recurrence for 4 weeks

Complete Response with incomplete blood count recovery (CRi):
Meets all criteria for CR except platelet count and/or ANC

Overall response rate (ORR = CR + CRi)

Refractory disease
Failure to achieve CR at the end of induction

Progressive disease (PD)
Increase of at least 25% in the absolute number of circulating or bone marrow blasts 
or development of extramedullary disease

Relapsed disease
Reappearance of blasts in the blood or bone marrow (>5%) or in any extramedullary 
site after a CR
Response Criteria for Mediastinal Disease

CT of chest with IV contrast and PET imaging should be performed to assess response

CR: Complete resolution of mediastinal enlargement by CT. For patients with a previous 
positive PET scan, a post-treatment residual mass of any size is considered a CR as long 
as it is PET negative

PR: >50% decrease in the sum of the product of the greatest perpendicular diameters 
(SPD) of the mediastinal enlargement. For patients with a previous positive PET scan, 
post-treatment PET must be positive in at least one previously involved site

PD: >25% increase in the SPD of the mediastinal enlargement. For patients with a 
previous positive PET scan, post-treatment PET must be positive in at least one
previously involved site

No Response (NR): failure to qualify for PR or PD

Relapse: recurrence of mediastinal enlargement after achieving CR. For patients with a 
previous positive PET scan, post-treatment PET must be positive in at least one 
previously involved site

SAP_000.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 1b/2 Open-Label, Dose Escalation and Expansion 
Study Evaluating the Safety and Efficacy of Entospletinib 
(GS-9973) with Vincristine and Dexamethasone in Adult 
Subjects with Relapsed or Refractory Acute Lymphoblastic
Leukemia (ALL)
Name of Test Drug:
Entospletinib (ENTO)
Study Number:
GS-US-339-1560
Protocol Version (Date):
Amendement 5
Protocol Date:
13 April 2018
Analysis Type:
Final
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
03 December 2018
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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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
1.1.3.
Exploratory Objectives...........................................................................................................6
1.2.
Study Design............................................................................................................................................7
1.3.
Sample Size and Power............................................................................................................................9
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................11
2.1.
Interim Analysis.....................................................................................................................................11
2.2.
Final Analysis ........................................................................................................................................11
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................12
3.1.
Analysis Sets..........................................................................................................................................12
3.1.1.
All Enrolled Analysis Set.....................................................................................................12
3.1.2.
Full Analysis Set ..................................................................................................................12
3.1.3.
Safety Analysis Set...............................................................................................................12
3.1.4.
Dose-Limiting Toxicity Analysis Set...................................................................................12
3.1.5.
Pharmacokinetic (PK) Analysis Sets....................................................................................13
3.2.
Subject Grouping ...................................................................................................................................13
3.3.
Strata and Covariates..............................................................................................................................13
3.4.
Examination of Subject Subsets.............................................................................................................13
3.5.
Multiple Comparisons............................................................................................................................13
3.6.
Missing Data and Outliers......................................................................................................................13
3.6.1.
Missing Data ........................................................................................................................13
3.6.2.
Outliers.................................................................................................................................13
3.7.
Data Handling Conventions and Transformations .................................................................................13
3.8.
Analysis Visit Windows.........................................................................................................................14
3.8.1.
Definition of Study Day .......................................................................................................14
3.8.2.
Analysis Windows................................................................................................................15
4.
SUBJECT DISPOSITION ..................................................................................................................................16
4.1.
Subject Enrollment and Disposition.......................................................................................................16
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................17
4.2.1.
Duration of Exposure to Study Drugs ..................................................................................17
4.2.2.
Adherence (Compliance) with Study Drugs.........................................................................17
4.3.
Protocol deviations.................................................................................................................................17
5.
BASELINE CHARACTERISTICS....................................................................................................................18
5.1.
Demographics ........................................................................................................................................18
5.2.
Other Baseline characteristics ................................................................................................................18
5.3.
Medical History......................................................................................................................................18
5.4.
Prior Anticancer Therapy.......................................................................................................................18
6.
EFFICACY ANALYSES ...................................................................................................................................19
6.1.
Primary Efficacy Endpoints ...................................................................................................................19
6.2.
Secondary Efficacy Endpoints ...............................................................................................................19
6.2.1.
Definition of the Secondary Efficacy Endpoints..................................................................19
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................19


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7.
SAFETY ANALYSES........................................................................................................................................20
7.1.
Adverse Events and Deaths....................................................................................................................20
7.1.1.
Adverse Event Dictionary ....................................................................................................20
7.1.2.
Adverse Event Severity........................................................................................................20
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................20
7.1.4.
Serious Adverse Events (SAEs)...........................................................................................20
7.1.5.
Treatment-Emergent Adverse Events...................................................................................20
7.1.5.1.
Definition of Treatment-Emergent Adverse Events .......................................20
7.1.5.2.
Incomplete Dates ............................................................................................21
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................21
7.1.6.1.
Summaries of AE Incidence by Severity........................................................21
7.1.6.2.
Summary of Deaths ........................................................................................22
7.1.7.
Dose Limiting Toxicity ........................................................................................................22
7.2.
Laboratory Evaluations ..........................................................................................................................23
7.2.1.
Graded Laboratory Values ...................................................................................................23
7.2.1.1.
Treatment-Emergent Laboratory Abnormalities.............................................23
7.2.1.2.
Summaries of Laboratory Abnormalities........................................................23
7.2.2.
Shift in CTCAE Grade Relative to Baseline ........................................................................24
7.3.
Body Weight and Vital Signs.................................................................................................................24
7.4.
Prior and Concomitant Medications.......................................................................................................24
7.4.1.
Prior Medications .................................................................................................................24
7.4.2.
Concomitant Medications.....................................................................................................24
7.5.
Electrocardiogram Results .....................................................................................................................25
7.6.
Other Safety Measures ...........................................................................................................................25
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................25
8.
PHARMACOKINETIC ANALYSES ................................................................................................................26
8.1.
Statistical Analysis Methods ..................................................................................................................26
8.1.1.
Plasma Concentration...........................................................................................................26
9.
REFERENCES ...................................................................................................................................................27
10.
SOFTWARE.......................................................................................................................................................28
11.
SAP REVISION..................................................................................................................................................29
12.
APPENDICES ....................................................................................................................................................30
Appendix 1
Schedule of Assessments........................................................................................................31


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LIST OF ABBREVIATIONS
AE
adverse event
ALL
acute lymphoblastic leukemia
ATC
Anatomical-Therapeutic-Chemical classification
BID
bis in die (twice a day)
BLQ
below the limit of quantitation
BMI
body mass index
CBC
complete blood count
CLL
chronic lymphocytic leukemia
cm
centimeter
CNS
central nervous system
CR
complete remission
CRi
Morphologic CR with incomplete blood count recovery
CRO
contract research organization
CRF
case report form
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DDI
drug-drug interaction
DLT
Dose limiting toxicities
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form(s)
EFS
event-free survival
EMD
extramedullary disease
ENTO
entospletinib
EOS
end of study
EOT
end of treatment
FAB
French-American-British
FAS
full analysis set
FDA
(United States) Food and Drug Administration
g
gram
GCP
Good Clinical Practice (Guidelines)
Gilead
Gilead Sciences, Inc.
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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LLT
lower-level term
LOQ
lower limit of quantitation
mg
milligram
MedDRA
Medical Dictionary for Regulatory Activities
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NIH
National Institutes of Health
OS
overall survival
PK
pharmacokinetic(s)
PR
partial remission
PT
preferred term
PVE
Pharmacovigilance and Epidemiology
Q1
first quartile
Q3
third quartile
RFS
relapse-free survival
SAE
serious adverse event
SAP
statistical analysis plan
SE
standard error
SOC
system organ class
SOP
standard operating procedure
StD
standard deviation
Syk
Spleen tyrosine kinase
TEAE
treatment emergent adverse event
TFL
tables, figures and listings
uL
microliter
ULN
upper limit of the normal range
US
United States
VCR
vincristine
WHO
World Health Organization


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-339-1560. This SAP is based on the study protocol GS-US-339-1560 
Amendment 5 dated 13 April 2018 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, efficacy, tolerability, and 
pharmacokinetics (PK) of entospletinib (ENTO) in combination with vincristine (VCR) and
dexamethasone in 2 stages: (1) Phase 1b dose-escalation; (2) Phase 2 expansion for relapsed or 
refractory Acute Lymphoblastic Leukemia (ALL). However, due to the low response rate to 
ENTO in combination with VCR and dexamethasone in Phase 1b portion, the Sponsor has 
decided to not proceed with the Phase 2 portion of this study. Subjects currently on study will 
continue to be treated and/or followed until the end of study criteria are met. A synoptic CSR 
will be generated, and this SAP describes the analyses for Phase 1b only. 
1.1.
Study Objectives
1.1.1.
Primary Objectives

To evaluate safety of ENTO in combination with VCR and dexamethasone in adult subjects 
with previously treated relapsed or refractory B-cell lineage ALL
1.1.2.
Secondary Objectives

To determine the recommended dose of ENTO in combination with VCR and 
dexamethasone in adult subjects with previously treated relapsed or refractory B-cell lineage 
ALL

To evaluate the therapeutic response of ENTO in combination with VCR and 
dexamethasone in adult subjects with previously treated relapsed or refractory B-cell lineage 
ALL
1.1.3.
Exploratory Objectives
 
 
 
PPD


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1.2.
Study Design
This is an open-label, Phase 1b dose-escalation and Phase 2 expansion study evaluating the 
safety, efficacy, tolerability, and PK of ENTO in combination with VCR and dexamethasone.
The study was originally designed for 2 stages sequentially: (1) Phase 1b dose escalation; 
(2) Phase 2 expansion. However, due to the low response rate to ENTO in combination with 
VCR and dexamethasone in Phase 1b portion, per the Sponsor’s decision, it has been decided not 
to proceed with the dose expansion (ie, Phase 2) portion of this study. 
There are four dose levels in the dose escalation phase (Table 1-1) where subjects in cohorts of 
3 to 6 are sequentially enrolled into one of the dose levels using a 3+3 dose escalation design 
(Table 1-2).  The starting dose level for the first cohort is defined as Dose Level 1.
Table 1-1
Entospletinib/Vincristine Dose Escalation
Dose Level
Entospletinib (ENTO)
Vincristine (VCR)
1
200 mg BID
0.5 mg per dose
2
400 mg BID
0.5 mg per dose
3
400 mg BID
1 mg per dose
4
400 mg BID
2 mg per dose
BID = twice per day
Dose Escalation: Induction (Lead-in, Cycle 1 and Cycle 2)
Lead-in (ENTO Monotherapy): Beginning on Day -7 of Lead-In, ENTO will be administered 
orally twice daily (BID) for 7 days as a single agent.
Cycle 1 and Cycle 2 (ENTO, VCR, dexamethasone, CNS prophylaxis)
ENTO will be continuously administered orally BID in combination with chemotherapy for the 
duration of the study treatment.  
VCR will be administered on Days 1, 8, 15 and 22 of each 28-day cycle for Cycle 1 and 2 only. 
Dexamethasone (20 mg twice daily for 4 days) will be administered orally during Cycle 1 on 
Days 8-11 and Days 22-25 and during Cycle 2 on Days 1-4 and Days 15-18.
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CNS prophylaxis per institutional standard will be given on Day 28 (±3 days) of Cycle 1 and 
Cycle 2.
Dose Escalation treatment schedule is outlined in the schema below:
Bone marrow (BM) aspirate/biopsy will be performed during screening (within 28 days prior to 
the start of study treatment), Cycle 1 on Day 8 and during both Cycle 1 and Cycle 2 on Day 28.
Imaging (computerized tomography [CT] with contrast or Positron Emission Tomography (PET) 
scan should be performed for subjects with extramedullary disease (EMD) if these are the only 
sites of evaluable disease (no BM involvement) to evaluate disease status and response, at 
screening, Cycle 1 Day 8 and Day 28, and Cycle 2 Day 28. Imaging will be evaluated using the 
NCCN guidelines version 2.2016 (Patients with no BM involvement and only EMD will not 
require BM aspirate/biopsy on cycle 1 day 8 and day 28, and cycle 2 day 28).
Up to 6 subjects will be dosed per dose level. Dose escalation will be performed based on 
assessments of Dose Limiting Toxicities (DLTs) and other adverse events data obtained within 
the DLT window (ENTO Lead-in and Cycle 1; study day 1 through day 35). Subjects with 
complete remission (CR), morphologic CR with incomplete blood count recovery (CRi), or 
partial remission (PR) on Day 28 of Cycle 1 bone marrow, and /or subjects who in the 
investigator’s opinion have obtained clinical benefit from Cycle 1 induction, will continue to 
Cycle 2 of induction.
During the DLT assessment window, subjects who fail to complete 21 days of GS-9973 or fail to 
receive sufficient exposure (> 50% of planned total dose) to VCR and dexamethasone for 
reasons other than treatment-related toxicity will not be evaluable for DLT assessment and an 
additional (replacement) subjects may be enrolled to that dose level in order to provide adequate 
safety data for dose escalation decisions.
Decision to open the next higher dose level to enrollment or expand the current cohort will be 
determined by the sponsor in consultation with study Principal Investigators (PIs).


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The maximum tolerated dose (MTD) is defined as the highest tested dose associated with an 
observed DLT rate of < 33% during the DLT window. A minimum of 6 subjects need to be 
treated at a dose level before this dose level can be determined as MTD or recommended dose.
Table 1-2
Dose Escalation/DLT Guidelines
Number of subjects with 
DLT at a given level
Escalation Decision Rule
0 out of 3
Enroll 3 subjects at the next higher dose level.
If this dose level is the highest dose level, it will be declared the maximally 
administered dose, and enroll 3 additional subjects at this dose level.
1 out of 3
Enter 3 additional subjects at this dose level.
If 0 of these 3 subjects experience DLT, proceed to the next higher dose level.
If 1 or more of them experience DLT, then dose escalation is stopped, and this dose is 
declared the maximally administered dose. Three additional subjects will be entered 
at the next lower dose level if only 3 subjects were treated previously at that dose.
≥ 2 out of 3
Dose escalation will be stopped. This dose level will be declared the maximally 
administered dose (highest dose administered). Three additional subjects will be 
entered at the next lower dose level if only 3 subjects were treated previously at that 
dose.
≤1 out of 6 at highest dose 
level below the maximally 
administered dose
This is the maximum tolerated dose (MTD) and generally the recommended dose. 
At least 6 subjects must be enrolled at MTD or the recommended dose.
Maintenance:
It is anticipated that most subjects who are transplant eligible will receive hematopoietic stem 
cell transplant (HSCT) therapy with curative intent if a CR is reached. In the absence of a 
suitable alternative therapeutic option, subjects who obtain clinical benefit (at least PR) after 
completing both cycles of induction therapy in dose escalation may continue ENTO at the 
assigned dose level during maintenance for up to 36 cycles. Subjects will continue ENTO and 
VCR at their assigned dose. ENTO will continue to be taken orally twice daily with VCR to be 
administered on Day 1 of each 28-day cycle and dexamethasone 20 mg total dose daily (either a 
divided dose of 10 mg twice daily or a single dose of 20 mg once daily) on Days 1-4 and 
Days 15-18 of each 28-day cycle.
Bone marrow evaluations and additional central nervous system (CNS) directed therapy can be 
performed as clinically indicated during maintenance.
1.3.
Sample Size and Power
The study implements 3+3 design. Sequential dose-escalation is consistent with usual oncologic 
paradigms for dose ranging. The intent is to limit the number of subjects who are exposed to 
excessively toxic doses of a drug in an early phase evaluation of an anticancer agent. The trial 
employs the standard National Cancer Institute (NCI) definition of MTD (starting dose 
associated with DLT in < 33.3% of subjects during the DLT assessment window) to determine 


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dose escalation. The cohort size and dose-escalation rules establish a low probability of 
increasing the dose if the true rate of DLT is high while there is a high likelihood of escalating or 
proceeding to the next cohort of the study if the true underlying probability of DLT is low. 
Table 1-3 shows the probability of escalating to the next dose level or proceeding to the next 
stage, based on the true rate of DLT at the current dose level. If the true underlying probability of 
DLT is low (eg, < 10%) at the current dose level, there is a high probability (> 0.91) of dose 
escalation to the next dose level. Conversely, if the true underlying proportion of DLT is high 
(eg, > 60%) at the current dose level, there is a low probability (< 0.08) of escalation to the next 
dose level.
Table 1-3
Probability of Dose Escalation (N=3+3)
True Incidence of DLT
Probability of Escalating
10%
0.91
20%
0.71
30%
0.49
40%
0.31
50%
0.17
60%
0.08
Assuming that 4 planned dose levels are tested for escalation and 3, 3, 6 and 6 subjects are tested 
at each dose level, respectively (18 subjects for escalation), and assuming 10% subjects are not 
evaluable during dose escalation, 20 subjects will be enrolled during dose escalation. 


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analysis
No formal interim analyses are planned in this study. The GSI study team and the investigators 
will collectively discuss study conduct and accumulating safety and other data.
2.2.
Final Analysis
Final study reporting is expected to occur after all subjects have discontinued the study.


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3.
GENERAL CONSIDERATIONS FOR DATAANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (StD) or standard error (SE), median, first 
quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the Full Analysis Set and sorted by 
subject identification (ID) number, visit date, and time (if applicable). Data collected on log 
forms, such as AEs, will be presented in chronological order within the subject. The treatment 
group to which subjects are initially assigned will be used in the listings. Age, sex at birth, race, 
and ethnicity will be included in the listings, as space permits.
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.
All Enrolled Analysis Set
The All Enrolled Analysis Set includes all subjects who receive a study identification number in 
the study after screening.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who receive at least 1 dose of study treatment. 
This analysis set will be used in the analyses of subject characteristics and efficacy.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who receive at least 1 dose of study treatment. 
This analysis set will be used in the drug exposure and safety analyses.
3.1.4.
Dose-Limiting Toxicity Analysis Set
Dose-Limiting Toxicity (DLT) Analysis Set includes all subjects in the Safety Analysis Set who 
meet at least one of the following criteria:

Receive at least 21 days of ENTO, >50% of planned total dose of VCR and dexamethasone
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.


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3.1.5.
Pharmacokinetic (PK) Analysis Sets
The Pharmacokinetic Analysis Sets include all enrolled subjects who took at least 1 dose of 
study drug and have at least 1 nonmissing postdose concentration value reported by the PK 
laboratory. This is the primary analysis set for all PK analyses. 
This analysis set will be used in the analysis of ENTO plasma pharmacokinetic.
3.2.
Subject Grouping
Unless otherwise specified, subjects will be grouped by dose level and overall for all analyses.
3.3.
Strata and Covariates
Not applicable.
3.4.
Examination of Subject Subsets
Not applicable.
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.


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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).
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


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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/time of the first dose of 
study treatment, 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 enrollment will be provided by dose level for each country and overall
based on all enrolled subjects. The summary will present the number and percentage of subjects 
enrolled. For each column, the denominator for the percentage calculation will be the total 
number of subjects analyzed for that column.
A 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

VCR discontinuation
Reasons of VCR discontinuation

Dexamethasone discontinuation
Reasons of dexamethasone discontinuation

CNS prophylaxis discontinuation
Reasons of CNS prophylaxis 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 all enrolled 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 all study drugs’ discontinuation, and reasons for study discontinuation will be 
provided.


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4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence to the study drug specified in the protocol. The summaries 
will be based on Safety Analysis Set.
4.2.1.
Duration of Exposure to Study Drugs
Total duration of exposure to study drugs 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 duration of exposure to ENTO, VCR, dexamethasone, and CNS prophylaxis will be 
summarized respectively using descriptive statistics. Besides, the number and percentage of 
subjects exposed to each drug will be presented as follows:

ENTO: at least 1 day, 14 days, 21 days, 28 days, and 2, 3, 6, 9 months, etc.

VCR: Cycle 1, Cycle 2, Maintenance Cycle 1, Maintenance Cycle 2, etc.

Dexamethasone: Cycle 1, Cycle 2, Maintenance Cycle 1, Maintenance Cycle 2, etc.

CNS prophylaxis: Cycle 1, Cycle 2
The number and percentage of subjects who have dose modification and dose interruption will 
also be summarized.
4.2.2.
Adherence (Compliance) with Study Drugs
By-subject listings of ENTO accountability (dispenses and returns), VCR administration, 
dexamethasone administration, CNS prophylaxis administration, dose interruption, 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 dose level and overall 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. 
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, and cytogenetics. 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 separately by 
subject ID number in ascending order.
5.4.
Prior Anticancer Therapy
A by-subject listing of prior anticancer therapy and prior radiation therapy will be provided 
separately by subject ID number in ascending order.


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6.
EFFICACY ANALYSES
Efficacy will be evaluated per the response criteria in NCCN guidelines on ALL Version 2, 
2016. 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. 
For subjects with extramedullary disease (EMD) if these are the only sites of evaluable disease 
(no BM involvement) to evaluate disease status and response, imaging (computerized 
tomography (CT) with contrast or positron emission tomography (PET)) should be performed. 
Imaging will be evaluated using NCCN guideline Version 2, 2016. 
Clinical response will be evaluated with investigator assessments. All efficacy endpoints will be 
analyzed by dose level using FAS. 
6.1.
Primary Efficacy Endpoints
Not applicable.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of the Secondary Efficacy Endpoints

Overall Remission (CR or CRi) rate at end of induction - defined as the proportion of 
subjects who achieve complete remission (CR) or complete remission with incomplete 
hematologic recovery (CRi) at the end of induction

Complete remission (CR) rate at the end of induction - defined as the proportion of subjects 
who achieve CR at the end of induction

Partial response (PR) rate at end of induction - defined as the proportion of subjects who 
achieve a partial response of marrow or by imaging criteria for patients with extramedullary 
disease (NCCN guidelines version 2.2016) as the best response

Overall Response (CR, CRi, or PR) rate at end of induction - defined as the proportion of 
subjects who achieve a complete remission (CR), complete remission with incomplete 
hematologic recovery (CRi) or partial response (PR) at end of induction
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
Overall Remission (CR/CRi) rate, CR rate, PR rate, and Overall Response rate (CR, CRi, or PR)
on or prior to other anticancer therapy and HSCT (if there is) at the end of induction will be 
summarized by dose level and overall. The number and percentage of subjects will be presented.
A by-subject listing of response assessment and EMD assessment will be provided by subject ID 
number (in ascending order) and visit (in chronological order).


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7.
SAFETY ANALYSES
Safety analyses will be conducted using Safety Analysis Set, 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 
20.1) 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 defined as AEs marked by investigators as ‘Related’ on the AE CRF to the 
questions of ‘Related to Study Treatment GS-9973 SDD’, ‘Related to Study Treatment 
Dexamethasone’, ‘Related to Study Treatment Vincristine’, ‘Related to Study Treatment 
Cytarabine Arabinoside’, and ‘Related to Study Treatment CNS Prophylaxis’. 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 treatment will be considered related to study 
treatment for summary purposes. However, by-subject data listings will show the relationship as 
missing. 
7.1.4.
Serious Adverse Events (SAEs)
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 Pharmacovigilance 
and Epidemiology (PVE) Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
AEs which meet at least one of the following criteria are defined as Treatment-Emergent
Adverse Events (TEAEs):

Any AEs with onset dates on or after the start of study treatment and up to 30 days after the 
permanent discontinuation of the study treatment

Any AEs leading to permanent discontinuation of study treatment


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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
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
7.1.6.1.
Summaries of AE Incidence by Severity 
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, HLT, PT, and treatment group. For other AEs described below, summaries 
will be provided by SOC, PT, and maximum severity:

TEAEs

TEAEs of Grade 3 or higher

Treatment-related TEAEs by study drugs (ie ENTO, VCR, dexamethasone, CNS 
prophylaxis)

Treatment-related Grade 3 or higher TEAEs by study drugs


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
TE SAEs

TE treatment-related SAEs by study drugs

TEAEs leading to treatment discontinuation by study drugs

TEAEs leading to treatment reductions or interruptions by study drugs

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.
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 AEs of Grade 3 or higher

All SAEs

Deaths

All AEs leading to study treatment discontinuation by study drugs
7.1.6.2.
Summary of Deaths
A summary (number and percentage of subjects) of deaths will be provided by treatment group. 
Summary will include the following categories:

All deaths

Deaths within 30 days of the last dosing of study drug

Deaths beyond 30 days of the last dosing of study drug
7.1.7.
Dose Limiting Toxicity
Dose limiting toxicity (DLT) will be analyzed using DLT analysis set. 


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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
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days. 
The analysis will be based on values reported in conventional units. When values are below the 
LOQ, they will be listed as such, and the closest imputed value will be used for the purpose of 
calculating summary statistics as specified in Section 3.7. Hemolized test results will not be 
included in the analysis, but they will be listed in by-subject laboratory listings.
A by-subject listing for laboratory test results will be provided by subject ID number and 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.
No formal statistical testing is planned.
7.2.1.
Graded Laboratory Values
CTCAE Version 4.03 will be used to assign 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. Local labs will be graded 
based on central lab normal ranges with in-house macro. In the event that both central and local 
lab results are collected in the clinical database, the worst toxicity grade will be used for the 
summary of lab toxicities. All central and local laboratory values will be listed.
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 postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days. If the relevant baseline laboratory value is missing, any 
abnormality of at least Grade 1 observed within the time frame specified above will be 
considered treatment emergent.
7.2.1.2.
Summaries of Laboratory Abnormalities
Summaries (number and percentage of subjects) of baseline and worst postbaseline treatment-
emergent laboratory abnormalities will be provided by lab test. Subjects will be categorized 
according to the most severe postbaseline abnormality grade for a given lab test.
A by-subject listing will include all laboratory results with flags to indicate treatment emergent 
laboratory abnormalities. 


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7.2.2.
Shift in CTCAE Grade Relative to Baseline
Shift tables will be presented by showing change in CTCAE severity grade from baseline to the 
worst grade postbaseline.
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.  
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 included in the prior medication summary regardless of when the stop date is. 
If a partial start date is entered the medication will be considered prior unless the month and year 
(if day is missing) or year (if day and month are missing) of the start date are after the first 
dosing date. Medications with a completely missing start date will be considered as prior 
medication, unless otherwise specified.
All prior medications will be provided in a by-subject listing sorted by subject ID number and 
administration date in chronological order based on FAS analysis set.
7.4.2.
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.


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The incomplete dates handling method used for AE summaries will be used for concomitant 
medication summaries (Section 7.1.5.2).
All 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 Results
Electrocardiogram is not planned to be assessed for the study.
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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03 December 2018
8.
PHARMACOKINETIC ANALYSES
Pharmacokinetic peripheral blood samples are obtained pre-dose during Lead-in on Day -7; 
Cycle 1 on Day 1, 8, 28 and Cycle 2 on Day 28. PK blood samples will also be collected 
1.5 hours post-dose of ENTO (±30 minutes) during Lead-in on Day -7; Cycle 1 on Days 1, 8, 28 
and Cycle 2 on Day 28. 
Concentrations of ENTO in plasma will be determined using a validated bioanalytical assay. 
8.1.
Statistical Analysis Methods
8.1.1.
Plasma Concentration
The listings of ENTO PK concentrations and pharmacokinetic sampling details by subject 
including deviations in scheduled and actual draw time and procedures will be provided.


Entospletinib (ENTO)
GS-US 339-1560 Statistical Analysis Plan
Final
CONFIDENTIAL
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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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GS-US 339-1560 Statistical Analysis Plan
Final
CONFIDENTIAL
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10.
SOFTWARE
SAS® Software Version 9.4 or higher, SAS Institute Inc., Cary, NC, USA.  


Entospletinib (ENTO)
GS-US 339-1560 Statistical Analysis Plan
Final
CONFIDENTIAL
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11.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision


Entospletinib (ENTO)
GS-US 339-1560 Statistical Analysis Plan
Final
CONFIDENTIAL
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12.
APPENDICES
Appendix 1
Schedule of Assessments........................................................................................................31


Entospletinib (ENTO)
GS-US-339-1560 Statistical Analysis Plan
Final
CONFIDENTIAL
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Appendix 1
Schedule of Assessments
Study Phase
Screening 
(-28 days)
ENTO
Lead-in*
Cycle 1
Cycle 2
Maintenance**
End of 
Treatment
30 Day 
Follow-Up
Cycle Day
Screening
-7
1
8
15
22
28
1
8
15
22
28
1
8
15
22
28
Study Day
1
8
15
22
29
35
Study Assessments
Informed Consent
X
General and Safety Assessments
Physical Exam and 
weighta
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE/Concomitant Medsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical History
X
HBV, HCV, and HIV 
Virology
X
Smoking status
X
X
X
X
X
Disease Assessments
ECOG
X
X
X
X
X
X
Laboratory Assessments
Bone marrow aspirate 
and biopsyd
X
X
X
X
X
Hematologye
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Chemistry & 
Liver Function Testing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Urine or Serum 
Pregnancy Test or FSHf
X
X
X
X
X
X
Pharmacokinetic 
Samplingg
X
X
X
X
X


Entospletinib (ENTO)
GS-US-339-1560 Statistical Analysis Plan
Final
CONFIDENTIAL
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Study Phase
Screening 
(-28 days)
ENTO
Lead-in*
Cycle 1
Cycle 2
Maintenance**
End of 
Treatment
30 Day 
Follow-Up
Cycle Day
Screening
-7
1
8
15
22
28
1
8
15
22
28
1
8
15
22
28
Study Day
1
8
15
22
29
35
CSF (for PK sampling)h
X
X
Imaging
CT or PETk
(Investigator’s 
discretion, for EMD 
subjects only)
X
X
X
X
Investigational Product and Auxiliary  
ENTOl
X
X
X
X
X
X
X
IV Vincristinem
X
X
X
X
X
X
X
X
X
Dexamethasonen
X
X
X
X
X
X
CNS Prophylaxis per 
institutional standardo
X
X
*
For Dose Escalation only
**
During Maintenance Cycle 1, all visits are required. Starting from Maintenance Cycle 2, Day 1 is required and Day 8/15/22/28 visits are per the Investigator’s discretion.
a
Complete physical examination will be performed at Screening which includes height.  A modified physical examination capturing changes from prior exams will be 
performed at other visits. 
b
Vital signs (including blood pressure, respiratory rate, pulse, oxygen saturation by pulse oximetry and temperature) should be taken after the subject has been sitting for at 
least 5 minutes.
c
Following consent, adverse events will be assessed pre-and post-dose during each clinic visit, and 30 (±7) days following completion of the subject’s last dose of study drug.  
Subjects should be contacted by phone (or in person, if necessary) 30 days (±7 days) after the subject’s last dose of study drug to assess AEs.  Subjects should be asked 
specifically if there are any AEs since stopping the study.    
d
Bone marrow aspirate/biopsy will be taken during Screening; Cycle 1 on Day 8 and Day 28; Cycle 2 on Day 28. 
 
e
CBC with differential including PT/INR and PTT.  
f
For female subjects of childbearing potential, serum testing performed at screening only.  Urine pregnancy test will be performed at Lead-in on Day -7 of (escalation) or 
during Cycle 1 on Day 1 (expansion). Pregnancy tests will be performed on a Day 1 of each cycle thereafter.
g
Pharmacokinetic peripheral blood samples will be obtained pre-dose during Lead-in on Day -7; Cycle 1 on Day 1, 8, 28 and Cycle 2 on Day 28. PK blood samples will also be 
collected 1.5 hours post-dose of ENTO (±30 minutes)  during Lead-in on Day -7; Cycle 1 on Days 1, 8, 28 and Cycle 2 on Day 28. CNS prophylaxis administration is 
independent of PK time point.
PPD
PPD


Entospletinib (ENTO)
GS-US-339-1560 Statistical Analysis Plan
Final
CONFIDENTIAL
Page 33
03 December 2018
h
CSF samples will be collected for pharmacokinetic analysis during Cycles 1 and Cycle 2 on Day 28 (prior to CNS prophylaxis administration). 
 
k
Subjects with EMD only, with no BM involvement will not require BM aspirate/biopsy
l
Treatment with ENTO will be continuous.  ENTO should be dispensed on Day 28 to include cycle break drug coverage, if necessary. 
m
Vincristine will be administered during Cycles 1 and Cycle 2 on Days 1, 8, 15, 22 and during Maintenance on Day 1 of each cycle. 
n
Dexamethasone (20 mg BID; dosed for 4 days)  will be dispensed during Cycle 1 on Day 8 and Day 22 and during  Cycle 2 on Day 1 and  Day 15. During Maintenance, 
dexamethasone (20 mg QD or 10 mg BID; dosed for 4 days) will be dispensed on Day 1 and Day 15 of each cycle. 
o
CNS prophylaxis per institutional standard during Cycle 1 and Cycle 2  on Day 28 (± 3 days). 
PPD
PPD


SAP CSR GS-US-339-1560_ v1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned 11-Jan-2019
00:43:50
Biostatistics eSigned
11-Jan-2019
01:19:08
PPD
PPD