Conditions: Advanced Solid Tumors
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 13
Healthy volunteers: no

Brief summary:
This study is planned to be conducted in 2 parts: Part 1: Dose Escalation and Part 2: Safety Run-In and Randomized Expansion.

The primary objectives of Part 1 are 1) To characterize the safety and tolerability of GS-3583 as monotherapy in participants with advanced solid tumors. 2) To determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of GS-3583 as monotherapy in participants with advanced solid tumors.

The primary objectives of Part 2 is to assess the safety and tolerability and to determine the RP2D of GS-3583 in combination with zimberelimab (ZIM) and platinum (cisplatin or carboplatin) + 5-fluorouracil (5-FU) chemotherapy in participants with head and neck squamous cell carcinoma (HNSCC) (Cohort A) or in combination with docetaxel in participants with non-small cell lung cancer (NSCLC) (Cohort B).

Detailed description:

Arms:
arm 1: Participants with advanced solid tumors will receive GS-3583 675 μg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 13 cycles (up to 52 weeks) or until the participant met study treatment discontinuation criteria. arm 2: Participants with advanced solid tumors will receive GS-3583 2000 μg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 13 cycles (up to 52 weeks) or until the participant met study treatment discontinuation criteria. arm 3: Participants with advanced solid tumors will receive GS-3583 6000 μg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 13 cycles (up to 52 weeks) or until the participant met study treatment discontinuation criteria. arm 4: Participants with advanced solid tumors will receive GS-3583 12000 μg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 13 cycles (up to 52 weeks) or until the participant met study treatment discontinuation criteria. arm 5: Participants with advanced solid tumors will receive GS-3583 20000 μg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 13 cycles (up to 52 weeks) or until the participant met study treatment discontinuation criteria. arm 6: Participants with head and neck squamous cell carcinoma (HNSCC) will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under the curve 5 mg/mL/min on Day 1 of each 28- day cycle up to 6 cycles + 5-5-flourouracil (5-FU) 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles. arm 7: Participants with non-small cell lung cancer (NSCLC) will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + docetaxel 75 mg/m\^2 on Day 1 of each 21-day cycle until 1 or more criteria for discontinuation are met. arm 8: Participants with HNSCC will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under the curve 5 mg/mL/min on Day 1 of each 21-day cycle up to 6 cycles + 5-FU 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles. arm 9: Participants with HNSCC will receive ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under th e curve 5 mg/mL/min on Day 1 of each 21-day cycle up to 6 cycles + 5-FU 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles. arm 10: Participants with NSCLC will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + docetaxel 75 mg/m\^2 on Day 1 of each 21-day cycle until 1 or more criteria for discontinuation are met. arm 11: Participants with NSCLC will receive docetaxel 75 mg/m\^2 on Day 1 of each 21-day cycle until 1 or more criteria for discontinuation are met.

Interventions: intervention 1: GS-3583 intervention 2: Zimberelimab intervention 3: Cisplatin intervention 4: Carboplatin intervention 5: 5-Fluorouracil intervention 6: Docetaxel
Intervention descriptions: intervention 1: Administered as an intravenous (IV) infusion intervention 2: Administered as an IV infusion intervention 3: Administered as an IV infusion intervention 4: Administered as an IV infusion intervention 5: Administered as an IV infusion intervention 6: Administered as an IV infusion

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1b Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Efficacy of GS-3583, a FLT3 
Agonist Fc Fusion Protein, as Monotherapy and in Combination 
With Anticancer Therapies in Subjects With Advanced Solid 
Tumors
Short Title:
Study to Assess the Effects of GS-3583 in Participants With 
Advanced Solid Tumors
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
145581
2022-000927-19
NCT04747470
Indication:
Advanced Solid Tumors 
Protocol ID:
GS-US-496-5657
Contact Information:
The medical monitor’s name and contact information will be 
provided on the Key Study Team Contact List.
Protocol Version/Date:
Original:
21 October 2020 
Amendment 1:
17 March 2022
Amendment 2: 
14 April 2022
This study will be conducted under United States Food and Drug Administration investigational 
new drug (IND) regulations (21 Code of Federal Regulations Part 312); however, sites located in 
the European Economic Area, the United Kingdom, and Switzerland are not included under the 
IND and are considered non-IND sites.
 
 


This study will be conducted in compliance with this protocol and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, and that are consistent with 
International Council for Harmonisation (ICH), Good Clinical Practice (GCP), and applicable 
regulatory requirements.
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
institutional review board or independent ethics committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in 
the protocol. You will not disclose any of the information to others without written 
authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered.


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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................3
LIST OF IN-TEXT TABLES .........................................................................................................................................6
LIST OF IN-TEXT FIGURES........................................................................................................................................7
PROTOCOL SYNOPSIS................................................................................................................................................8
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................................31
1.
INTRODUCTION................................................................................................................................................35
1.1.
Background..............................................................................................................................................35
1.1.1.
HNSCC..................................................................................................................................37
1.1.2.
NSCLC ..................................................................................................................................38
1.2.
Background on Study Interventions ........................................................................................................39
1.2.1.
GS-3583.................................................................................................................................39
1.2.2.
Information About Combination Therapies ..........................................................................41
1.3.
Rationale for This Study..........................................................................................................................42
1.3.1.
Rationale for GS-3583 + Chemotherapy Combination.........................................................43
1.3.2.
Rationale for GS-3583 + Immunotherapy Combination.......................................................45
1.4.
Rationale for Dose Selection of GS-3583 ...............................................................................................45
1.5.
Risk/Benefit Assessment for the Study ...................................................................................................46
1.6.
Compliance..............................................................................................................................................48
2.
OBJECTIVES.......................................................................................................................................................49
2.1.
Objectives: Part 1 ....................................................................................................................................49
2.2.
Objectives: Part 2 ....................................................................................................................................49
3.
STUDY DESIGN.................................................................................................................................................51
3.1.
Endpoints.................................................................................................................................................51
3.2.
Study Design ...........................................................................................................................................51
3.2.1.
Part 1: Dose Escalation of GS-3583 as Monotherapy...........................................................51
3.2.2.
DLT Definition......................................................................................................................53
3.2.3.
Part 2: Disease-specific Cohorts of GS-3583 in Combination With 
Anticancer Therapies.............................................................................................................55
3.2.4.
Safety Review Team..............................................................................................................59
3.3.
Study Treatments.....................................................................................................................................60
3.4.
Duration of Treatment .............................................................................................................................60
3.4.1.
Treatment Beyond Initial Progressive Disease......................................................................60
3.4.2.
Subsequent Anticancer Therapy............................................................................................61
3.5.
Study Discontinuation Criteria................................................................................................................61
3.6.
End of Study............................................................................................................................................62
3.7.
Poststudy Care.........................................................................................................................................62
3.8.
Source Data .............................................................................................................................................62
3.9.
Biomarker Testing...................................................................................................................................62
3.9.1.
Biomarker Samples to Address the Study Objectives...........................................................62
3.9.2.
Biomarker Samples for Optional Future Research................................................................64
3.9.3.
Biomarker Samples for Optional Genomic Research ...........................................................64
4.
SUBJECT POPULATION...................................................................................................................................65
4.1.
Number of Subjects and Subject Selection .............................................................................................65
4.1.1.
Target Population ..................................................................................................................65
4.1.2.
Subject Replacement .............................................................................................................65
4.2.
Inclusion Criteria.....................................................................................................................................65


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4.3.
Exclusion Criteria....................................................................................................................................69
4.3.1.
General Exclusion Criteria ....................................................................................................69
5.
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................................72
5.1.
Enrollment/Randomization......................................................................................................................72
5.2.
Blinding ...................................................................................................................................................72
5.3.
Description and Handling........................................................................................................................72
5.3.1.
GS-3583.................................................................................................................................72
5.3.2.
Zimberelimab ........................................................................................................................73
5.3.3.
Cisplatin.................................................................................................................................74
5.3.4.
Carboplatin ............................................................................................................................74
5.3.5.
5-Fluorouracil........................................................................................................................75
5.3.6.
Docetaxel...............................................................................................................................75
5.4.
Dosage and Administration .....................................................................................................................76
5.4.1.
GS-3583.................................................................................................................................76
5.4.2.
Combination Therapies .........................................................................................................77
5.5.
Dose Modifications and Treatment Delay...............................................................................................79
5.5.1.
GS-3583.................................................................................................................................80
5.5.2.
Zimberelimab ........................................................................................................................83
5.5.3.
Dose Modifications for Platinum (Cisplatin or Carboplatin)................................................92
5.5.4.
5-Fluorouracil........................................................................................................................94
5.5.5.
Docetaxel...............................................................................................................................96
5.6.
Prior and Concomitant Medications........................................................................................................97
5.6.1.
Acceptable Concomitant Medications...................................................................................97
5.6.2.
Prohibited and/or Restricted Treatments...............................................................................99
5.6.3.
Other Restrictions and Precautions .....................................................................................100
5.6.4.
Cisplatin, Carboplatin, 5-Fluorouracil, and Docetaxel........................................................100
5.6.5.
COVID-19 Vaccine and Prophylaxis ..................................................................................100
5.7.
Accountability for Investigational Medicinal Product ..........................................................................100
5.7.1.
Timing of Dose Administration...........................................................................................101
5.7.2.
Investigational Medicinal Product Return or Disposal .......................................................101
6.
STUDY PROCEDURES....................................................................................................................................103
6.1.
Subject Enrollment and Treatment Assignment....................................................................................103
6.2.
Pretreatment Assessments .....................................................................................................................103
6.2.1.
Screening Visit ....................................................................................................................103
6.2.2.
Rescreening Criteria ............................................................................................................105
6.2.3.
Medical History and Baseline Assessments........................................................................105
6.3.
Randomization.......................................................................................................................................106
6.4.
Treatment Assessments .........................................................................................................................106
6.4.1.
Baseline/Cycle 1 Day 1 Predose Assessments ....................................................................106
6.4.2.
Cycle 1 Day 1 Postdose Assessments .................................................................................108
6.4.3.
Vital Signs, Weight, and Height..........................................................................................108
6.4.4.
Physical Examination ..........................................................................................................109
6.4.5.
12-Lead Electrocardiogram (ECG) .....................................................................................109
6.4.6.
Echocardiogram (ECHO) or MUGA Scan..........................................................................109
6.4.7.
Prior and Concomitant Medications....................................................................................109
6.4.8.
Clinical Laboratory Assessments ........................................................................................110
6.4.9.
Tumor Biopsies ...................................................................................................................111
6.4.10.
Testing for HPV Status........................................................................................................113
6.5.
Pharmacokinetic, Biomarker, and Immunogenicity Assessments ........................................................113
6.5.1.
Pharmacokinetic Assessments.............................................................................................113
6.5.2.
Biomarker Assessments.......................................................................................................117
6.5.3.
Immunogenicity Assessments .............................................................................................121


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6.6.
Efficacy Assessments ............................................................................................................................122
6.6.1.
Response Assessment..........................................................................................................122
6.6.2.
Tumor Assessments.............................................................................................................123
6.7.
Sample Storage......................................................................................................................................124
6.8.
Unscheduled Visits................................................................................................................................124
6.8.1.
End of Treatment and Posttreatment Visits.........................................................................125
6.8.2.
Survival Follow-Up.............................................................................................................125
6.9.
Poststudy Care.......................................................................................................................................126
6.10.
Assessments for Early Discontinuation from Study Treatment or Study..............................................126
6.10.1.
Criteria for Discontinuation of Study Treatment.................................................................126
6.11.
End of Study..........................................................................................................................................127
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT..............................................................................128
7.1.
Definitions of Adverse Events and Serious Adverse Events.................................................................128
7.1.1.
Adverse Events....................................................................................................................128
7.1.2.
Serious Adverse Events.......................................................................................................128
7.1.3.
Study Drugs and Gilead Concomitant Therapy Special Situations Reports .......................130
7.2.
Assessment of Adverse Events and Serious Adverse Events................................................................130
7.2.1.
Assessment of Causality for Study Drugs and Procedures .................................................131
7.2.2.
Assessment of Severity........................................................................................................131
7.3.
Investigator Reporting Requirements and Instructions .........................................................................131
7.3.1.
Requirements for Collection Prior to Study Drug Initiation ...............................................131
7.3.2.
Adverse Events....................................................................................................................131
7.3.3.
Serious Adverse Events.......................................................................................................132
7.3.4.
Study Drug Special Situations Reports ...............................................................................132
7.3.5.
Concomitant Therapy Reports.............................................................................................132
7.4.
Reporting Process for Serious Adverse Events and Special Situation Reports.....................................133
7.4.1.
Serious Adverse Event Reporting Process ..........................................................................133
7.4.2.
Special Situations Reporting Process ..................................................................................134
7.5.
Gilead Reporting Requirements ............................................................................................................135
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events.........................................................................................................................136
7.7.
Toxicity Management............................................................................................................................136
8.
STATISTICAL CONSIDERATIONS...............................................................................................................137
8.1.
Analysis Objectives and Endpoints.......................................................................................................137
8.1.1.
Analysis Objectives.............................................................................................................137
8.1.2.
Endpoints: Part 1 .................................................................................................................137
8.1.3.
Endpoints: Part 2 .................................................................................................................138
8.2.
Planned Analyses...................................................................................................................................139
8.2.1.
Interim Analysis ..................................................................................................................139
8.2.2.
Final Analysis......................................................................................................................139
8.3.
Analysis Conventions............................................................................................................................139
8.3.1.
Analysis Sets .......................................................................................................................139
8.3.2.
Data Handling Conventions ................................................................................................140
8.4.
Demographic and Baseline Characteristics Analysis............................................................................141
8.5.
Efficacy Analysis...................................................................................................................................141
8.6.
Safety Analysis......................................................................................................................................141
8.6.1.
Extent of Exposure ..............................................................................................................142
8.6.2.
Adverse Events....................................................................................................................142
8.6.3.
Laboratory Evaluations .......................................................................................................142
8.6.4.
Other Safety Evaluations.....................................................................................................142
8.7.
Pharmacokinetic Analysis .....................................................................................................................142
8.8.
Biomarker Analysis...............................................................................................................................143


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8.9.
Immunogenicity Analysis......................................................................................................................143
8.10.
Sample Size ...........................................................................................................................................143
9.
RESPONSIBILITIES.........................................................................................................................................145
9.1.
Investigator Responsibilities .................................................................................................................145
9.1.1.
Good Clinical Practice.........................................................................................................145
9.1.2.
Financial Disclosure ............................................................................................................145
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval..............................................................................................................................145
9.1.4.
Informed Consent ................................................................................................................145
9.1.5.
Confidentiality.....................................................................................................................146
9.1.6.
Study Files and Retention of Records .................................................................................146
9.1.7.
Case Report .........................................................................................................................148
9.1.8.
Investigator Inspections.......................................................................................................148
9.1.9.
Protocol Compliance ...........................................................................................................148
9.2.
Sponsor Responsibilities .......................................................................................................................149
9.2.1.
Protocol Modifications ........................................................................................................149
9.2.2.
Study Report and Publications ............................................................................................149
9.3.
Joint Investigator/Sponsor Responsibilities ..........................................................................................149
9.3.1.
Payment Reporting ..............................................................................................................149
9.3.2.
Access to Information for Monitoring.................................................................................149
9.3.3.
Access to Information for Auditing or Inspections .............................................................149
9.3.4.
Study Discontinuation .........................................................................................................150
10.
REFERENCES...................................................................................................................................................151
11.
APPENDICES....................................................................................................................................................156
Appendix 1.
Investigator Signature Page...................................................................................................157
Appendix 2.
Pandemic Risk Assessment and Mitigation Plan ..................................................................158
Appendix 3.
American Society of Clinical Oncology (ASCO) Toxicity Management Guidelines...........161
Appendix 4.
Study Procedures Tables .......................................................................................................162
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements..................................................................................................177
Appendix 6.
NCI CTCAE v5.0 Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities ........................................................................................................................181
Appendix 7.
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) ................................182
LIST OF IN-TEXT TABLES
Table 3-1.
Part 1 Dose Escalation Dose Levels........................................................................................52
Table 3-2.
Safety Run-in Cohort A: Dose De-escalation..........................................................................58
Table 3-3.
Safety Run-in Cohort B: Dose De-escalation..........................................................................59
Table 5-1.
Proposed Schedule for GS-3583 in Part 1 and Part 2 of the Study .........................................76
Table 5-2.
Schedule for Measurement of Vital Signs in Part 1 and Part 2 of the Study...........................77
Table 5-3.
Proposed Dose Levels and Schedules of Combination Therapies for Randomized 
Disease-Specific Expansion Cohorts.......................................................................................78
Table 5-4.
GS-3583 Infusion-Related Reactions Management Guidelines..............................................82
Table 5-5.
Management of Infusion-related Reactions.............................................................................84
Table 5-6.
Toxicity Management Guidelines for Zimberelimab ..............................................................85
Table 5-7.
Treatment Management Guidelines for Dermatologic Toxicity Associated With 
Zimberelimab...........................................................................................................................90
Table 5-8.
Platinum Dose Modification Levels........................................................................................92


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Table 5-9.
Platinum Dose Modification Guidelines for Febrile Neutropenia or Documented 
Infection...................................................................................................................................92
Table 5-10.
Platinum Dose Modification Guidelines for Drug-Related Adverse Events...........................93
Table 5-11.
5-Fluorouracil Dose Modification Levels ...............................................................................94
Table 5-12.
5-Fluorouracil Dose Modification Guidelines for Febrile Neutropenia or 
Documented Infection .............................................................................................................94
Table 5-13.
5-Fluorouracil Dose Modification Guidelines for Drug-Related Adverse Events..................95
Table 6-1.
Analytes.................................................................................................................................111
Table 6-2.
Part 2 Tumor Biopsy Collection............................................................................................113
Table 6-3.
Part 1: Schedule of Intensive Pharmacokinetic Assessments................................................115
Table 6-4.
Schedule of GS-3583 Pharmacokinetic Sample Collection for Part 2 Cohort A and 
B (Safety Run-in and Randomized Expansion Cohorts [Treatment Arms]).........................116
Table 6-5.
Schedule of Zimberelimab Pharmacokinetic Sample Collection for Part 2 Cohort A 
(Safety Run-in and Randomized Expansion Cohorts [Control and Treatment Arms]).........117
Table 6-6.
Postbaseline Imaging Schedule .............................................................................................123
Table 8-1.
Exact 90% CI of ORR for a Sample Size of 30 in GS-3583 Combination Arm...................144
Table 8-2.
Exact 90% CI of Difference in ORR for a Sample Size of 45 with 2:1 
Randomization Ratio..............................................................................................................144
Table 11-1.
Time Point Response: Subjects with Target (+/- Non-target) Disease..................................185
Table 11-2.
Time Point Response: Subjects with Non-target Disease Only ............................................185
LIST OF IN-TEXT FIGURES
Figure 1-1.
Combination of Murine GS-3583 and Docetaxel Significantly Inhibits Tumor 
Growth in a Syngenic Murine Colon Carcinoma Cell Line (CT26) .......................................44
Figure 1-2.
Combination of Murine GS-3583 and Cisplatin Significantly Inhibits Tumor 
Growth in a Syngenic Murine Melanoma Cell Line (B16F10)...............................................44
Figure 1-3.
Combination of Murine GS-3583 With Anti-PD-1 Blockade Significantly Inhibits 
Tumor Growth in a Syngenic Murine Colon Carcinoma Cell Line (MC38) ..........................45
Figure 3-1.
Part 1 Study Schema................................................................................................................51
Figure 3-2.
3 + 3 Dose Escalation Scheme ................................................................................................53
Figure 3-3.
Part 2 Study Schema................................................................................................................56
Figure 3-4.
Part 2 Safety Run-in and Randomized Expansion Phases.......................................................57


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 1b Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Preliminary Efficacy of GS-3583, a 
FLT3 Agonist Fc Fusion Protein, as Monotherapy and in 
Combination with Anticancer Therapies in Subjects with 
Advanced Solid Tumors
Short Title:
Study to Assess the Effects of GS-3583 in Participants with 
Advanced Solid Tumors
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
145581 
2022-000927-19
NCT04747470
Study Centers Planned:
Approximately 30 centers overall in the United States, 
European Union, and Asia-Pacific.
Objectives:
Part 1:
The primary objectives of Part 1 are as follows:

To characterize the safety and tolerability of GS-3583 as 
monotherapy in subjects with advanced solid tumors

To determine the maximum tolerated dose (MTD) or 
recommended Phase 2 dose (RP2D) of GS-3583 as 
monotherapy in subjects with advanced solid tumors
The secondary objectives of Part 1 are as follows: 

To characterize the pharmacokinetics (PK) of GS-3583 in 
subjects with advanced solid tumors

To evaluate the immunogenicity of GS-3583 in subjects 
with advanced solid tumors


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The exploratory objectives of Part 1 are as follows: 
Part 2:
The primary objective of Part 2 is as follows:

To assess the safety and tolerability and to determine the 
RP2D of GS-3583 in combination with zimberelimab and 
platinum (cisplatin or carboplatin) + 5-fluorouracil (5-FU) 
chemotherapy in subjects with head and neck squamous cell 
carcinoma (HNSCC) (Cohort A) or in combination with 
docetaxel in subjects with non-small cell lung cancer 
(NSCLC) (Cohort B)
The secondary objectives of Part 2 are as follows:

To evaluate the investigator-assessed confirmed objective 
response rate (ORR) with GS-3583 in combination with 
zimberelimab and platinum (cisplatin or carboplatin) + 
5-FU chemotherapy in subjects with HNSCC (Cohort A) or 
in combination with docetaxel in subjects with NSCLC 
(Cohort B)

To assess the preliminary efficacy of GS-3583 in 
combination with zimberelimab and platinum (cisplatin or 
carboplatin) + 5-FU chemotherapy versus zimberelimab 
and platinum (cisplatin or carboplatin) + 5-FU 
chemotherapy alone in subjects with HNSCC (Cohort A) or 
in combination with docetaxel versus docetaxel alone in 
subjects with NSCLC (Cohort B) as determined by 
progression free survival (PFS), duration of response 
(DOR), and overall survival (OS)
CCI


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
To evaluate investigator-assessed disease control rate 
(DCR) with GS-3583 in combination with zimberelimab 
and platinum (cisplatin or carboplatin) + 5-FU 
chemotherapy in subjects with HNSCC (Cohort A) or in 
combination with docetaxel in subjects with NSCLC 
(Cohort B)

To evaluate the PK of GS-3583 administrated in 
combination with zimberelimab and platinum (cisplatin or 
carboplatin) + 5-FU chemotherapy in subjects with HNSCC 
(Cohort A) or in combination with docetaxel in subjects 
with NSCLC (Cohort B)

To evaluate the immunogenicity of GS-3583 administrated 
in combination with zimberelimab and platinum (cisplatin 
or carboplatin) + 5-FU chemotherapy in subjects with 
HNSCC (Cohort A) or in combination with docetaxel in 
subjects with NSCLC (Cohort B)
The exploratory objectives of Part 2 are as follows:
Study Design:
Part 1:
Part 1 is a Phase 1b, open-label, multicenter, sequential 
dose-escalation study to evaluate the safety, tolerability, PK, 
and preliminary efficacy of GS-3583 in subjects with advanced 
solid tumors.
CCI


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 11
14 April 2022
Dose Escalation
Subjects with advanced solid tumors will be enrolled in a 
standard 3 + 3 dose escalation study design to evaluate the 
safety, tolerability, PK, pharmacodynamics, and to determine 
the MTD or RP2D level of GS-3583 as monotherapy. 
GS-3583 will be administered on Days 1 and 15 of Cycle 1 and 
on Day 1 of each subsequent 4-week/28-day cycle for up to 
13 cycles or until the subject meets study treatment 
discontinuation criteria. The starting dose is 675 μg and may be 
modified if the results of the Phase 1a healthy volunteer (HV) 
study (Study GS-US-496-5619) are available prior to the 
initiation of this study. Approximately 33 subjects will be 
enrolled at up to 5 dose levels sequentially. The MTD will be a 
dose level with acceptable safety and tolerability. The RP2D 
will be a dose level with acceptable safety, tolerability, PK, and 
biomarker activities.
In Part 1, the dose-limiting toxicity (DLT) evaluation period is 
28 days in Cycle 1 and will start with the initial dose of 
GS-3583. A subject who fails to receive all GS-3583 treatments 
or fails to complete all safety assessments in the DLT period for 
reasons other than DLT will be replaced. The 
dose-escalation/stay/de-escalation decision will be made by the 
safety review team (SRT).
Dose escalation to the next cohort will occur if no subjects 
experience DLTs during the DLT evaluation period. If 1 subject 
within the initial cohort of 3 subjects experiences a DLT, an 
additional 3 subjects will be enrolled at the same dose level. If 
no DLTs are observed in the additional 3 subjects, dose 
escalation will occur. If ≥ 2 subjects experience DLTs at a dose 
level, dose de-escalation to a lower dose will occur. The MTD 
is the highest dose level with a subject incidence of DLTs of 
< 33% in 6 or more subjects during the first 28 days of study 
drug dosing. A minimum of 6 subjects need to be treated at a 
dose level before this dose level can be deemed as the MTD. 
Subjects who tolerate GS-3583 beyond the DLT evaluation 
period will have the option to receive stereotactic body 
radiation therapy (SBRT) starting at Cycle 2 per investigator’s 
discretion. Provision of SBRT will be according to the 
institution’s own protocol and in line with the local standard of 
care. 




GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 13
14 April 2022
Target Population:
Part 1:
Adult subjects aged ≥ 18 years with a histologically or 
cytologically confirmed locally advanced or metastatic 
malignant solid tumor that is refractory to or intolerant of 
standard therapy or for which no standard therapy is available.
Part 2 Cohort A:
Adult subjects aged ≥ 18 years with a histologically or 
cytologically confirmed diagnosis of metastatic HNSCC who 
have not previously received systemic therapy for metastatic 
disease or with recurrent disease who were considered 
incurable by local therapies.
Part 2 Cohort B:
Adult subjects aged ≥ 18 years with a histologically or 
cytologically confirmed locally advanced or metastatic NSCLC 
with documented progression on at least one anti-PD-1 or 
anti-PD-L1 mAb and platinum-based chemotherapy given 
individually or in combination.
Duration of Treatment:
Part 1:
GS-3583 will be administrated for a maximum of 13 cycles or 
until unacceptable toxicity, progressive disease, or other 
reasons for discontinuation listed in the protocol.
Part 2:
GS-3583 will be administered for a maximum of 8 cycles as 
follows:

In Cohort A (HNSCC), subjects will receive GS-3583 for 
an additional 2 cycles after the completion of 
chemotherapy. This will amount to a maximum of 8 cycles 
of GS-3583 since there will be a maximum of 6 cycles of 
chemotherapy. Should the chemotherapy be terminated 
prior to Cycle 6 (due to reasons other than disease 
progression), GS-3583 will be continued for an additional 
2 cycles. 

In Cohort B (NSCLC), docetaxel will be given until 1 or 
more criteria for discontinuation are met; and not limited by 
number of cycles. For these subjects, GS-3583 will be given 
for a maximum of 8 cycles. Should docetaxel be terminated 
prior to Cycle 6 (due to reasons other than disease 
progression), GS-3583 will be continued for an additional 
2 cycles.


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 14
14 April 2022
In Part 2, subjects who prematurely discontinue GS-3583 may 
be able to continue other study drugs and remain on the study if 
they are deemed to continue to derive benefit from those drugs. 
However, such cases must be discussed with and approved by 
the medical monitor.
Diagnosis and Main 
Eligibility Criteria:
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be 
eligible for participation in Part 1 or Part 2 of this study:
1) Voluntarily agree to participate by giving a signed written 
informed consent
2) Age ≥ 18 years
3) Have measurable disease on imaging based on response 
evaluation criteria in solid tumors Version 1.1 (RECIST 
V1.1) (Appendix 7). Tumor lesions situated in a previously 
irradiated area are considered measurable if progression has 
been demonstrated in such lesions. Historical images within 
28 days of the screening visit may be accepted as a 
screening image if deemed acceptable in the opinion of the 
investigator.
4) Eastern Cooperative Oncology Group (ECOG) performance 
status of ≤ 2 for Part 1 and ECOG of 0-1 for Part 2
5) Diagnosis
a) Part 1: Histologically or cytologically confirmed 
diagnosis of locally advanced or metastatic malignant 
solid tumor that is refractory to or intolerant of standard 
therapy or for which no standard therapy is available
b) Part 2 Cohort A (HNSCC): 
i)
Subjects must have histologically or 
cytologically-confirmed recurrent or metastatic 
HNSCC that is considered incurable by local 
therapies. 
ii) Subjects should not have had prior systemic therapy 
administered in the recurrent or metastatic setting. 
Systemic therapy which was completed more than 
6 months prior to signing consent if given as part of 
multimodal treatment for locally advanced disease is 
allowed. 
iii) The eligible primary tumor locations are 
oropharynx, oral cavity, hypopharynx, and larynx. 


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 15
14 April 2022
iv) Subjects with a primary tumor site of nasopharynx 
(any histology) are not allowed.
v) Subjects must provide adequate tissue for biomarker 
analysis at baseline (fine needle aspirate [FNA] is 
not adequate). Repeat samples may be required if 
adequate tissue is not provided. This specimen may 
be the diagnostic sample for subjects with a new 
diagnosis of metastatic HNSCC. If obtained for a 
subject with recurrent disease for locally advanced 
disease, then it must be obtained after completion of 
the previous initial management with no other 
treatment from the time of biopsy until the start of 
study treatment. Subjects must also have a combined 
positive score (CPS) at baseline using a locally 
available, validated test.
Note: In Randomized Expansion Cohort A, no more 
than 10 subjects with CPS < 1 will be enrolled in the 
Treatment Arm and no more than 5 subjects with 
CPS < 1 will be enrolled in the Control Arm.
vi) Subjects must have results from local testing of 
HPV for oropharyngeal cancer defined as p16 IHC 
testing using a locally available validated test.
Note: Subjects with oral cavity, hypopharynx, or 
larynx cancer are not required to undergo HPV 
testing by p16 IHC as by convention they are 
assumed to be HPV negative.
c) Part 2 Cohort B (NSCLC): 
i)
Subjects must have histologically or cytologically 
confirmed locally advanced, unresectable or 
metastatic NSCLC with documented progression on 
at least 1 anti-PD-1 or anti-PD-L1 mAb and 
platinum-based chemotherapy. Anti-PD-1 or anti-
PD-L1 mAb and platinum-based chemotherapy may 
have been given individually or in combination.
ii) Includes subjects who received prior platinum-based 
chemoradiotherapy (with or without maintenance 
anti-PD-L1 antibody) for Stage 3 disease. To be 
considered to have progressed during or after prior 
treatment with platinum-based chemotherapy, 
subjects should have either received prior 
platinum-based chemotherapy in the recurrent or 
metastatic setting or have experienced disease 


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 16
14 April 2022
progression within 6 months of last dose of 
platinum-based chemotherapy administered as part 
of concurrent chemoradiation for Stage 3 disease or 
as neoadjuvant or adjuvant therapy. To be 
considered to have progressed during or after prior 
treatment with an anti-PD-1 or anti-PD-L1 antibody, 
subjects should have either received this therapy in 
the recurrent or metastatic setting or have 
experienced disease progression during 
“maintenance” treatment following concurrent 
chemoradiation for Stage 3 disease.
These subjects must be tested for epidermal growth 
factor receptor (EGFR), anaplastic lymphoma kinase 
(ALK), ROS1, and PD-L1. Testing for other 
actionable genomic alterations is recommended and 
to be performed as per local standard of care.
iii) Subjects with EGFR, ALK, ROS1, or any other 
known actionable genomic alterations must have 
also received treatment with at least 1 approved 
therapy appropriate to the genomic alteration, unless 
these options are not available to the subjects.
1) Note: No additional treatments are allowed in 
the recurrent/metastatic setting for subjects with no 
actionable genomic alterations.
iv) Documented radiographic disease progression while 
on or after receiving the most recent treatment 
regimen for advanced or metastatic NSCLC.
v) Subjects with mixed small-cell lung cancer and 
NSCLC histology are not eligible.
vi) Subjects must provide adequate tissue for biomarker 
analysis at baseline (FNA is not adequate). Repeat 
samples may be required if adequate tissue is not 
provided. It must be obtained after completion of the 
previous line of therapy with no other treatment 
from the time of biopsy until the start of study 
treatment.
6) Life expectancy of ≥ 3 months, in the opinion of the 
investigator


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 17
14 April 2022
7) Adequate organ function as assessed by hematological, 
renal, and hepatic parameters and no clinically significant 
coagulopathy as indicated by the following laboratory 
values (Hematologic laboratory values must be met at 
screening visit and maintained without transfusional or 
growth factor support within 2 weeks of study drug 
initiation):
System
Laboratory Valuea
Hematologicalb
Absolute Neutrophil 
Count (ANC)
≥ 1.5  109/L 
Plateletsc
Part 1 and Part 2 Cohort B (NSCLC): 
≥ 100  109/L
Part 2 Cohort A (HNSCC): ≥ 75  109/L
Hemoglobinc
Part 1: ≥ 8 g/dL
(≥ 9.5 g/dL in subjects with cardiac disease)
Part 2: ≥ 9 g/dL
(≥ 9.5 g/dL in subjects with cardiac disease)
Renal
Creatinine Clearancec
Part 1 and Part 2 Cohort B (NSCLC): 
≥ 50 mL/min by the Cockcroft-Gault method
Part 2 Cohort A (HNSCC): ≥ 60 mL/min by 
the Cockcroft-Gault method 
Hepatic
Total Bilirubin
≤ 1.5  ULN
AST (SGOT) and ALT 
(SGPT)c
Part 1 and Part 2 Cohort A (HNSCC): 
≤ 3  ULN 
(≤ 5  ULN in subjects with liver metastases)
Part 2 Cohort B (NSCLC): ≤ 2.5  ULN
(≤ 5  ULN in subjects with liver metastases)
Serum albuminc
Part 2 Cohort B (NSCLC) only: > 3 g/dL
Coagulationd
International 
Normalized Ratio 
(INR) or Prothrombin 
Time (PT)
Activated Partial 
Thromboplastin Time 
(aPTT)
≤ 1.5  ULN unless the subject is receiving 
anticoagulant therapy
≤ 1.5  ULN unless the subject is receiving 
anticoagulant therapy
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SGOT = serum 
glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; 
ULN = upper limit of normal
a
All screening laboratory tests must be reviewed by the investigator and be 
acceptable prior to enrollment.


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 18
14 April 2022
b
Hematologic laboratory values must be met at screening visit and maintained 
without transfusional or growth factor support within 2 weeks of study drug 
initiation.
c
Adequate laboratory values differ by study part and/or cohort due to differences 
in anti-cancer agents used in Part 2.
d
Subjects on full-dose oral anticoagulation, must be on a stable dose (minimum 
duration 14 days prior to the screening visit). Subjects on low molecular weight 
heparin will be allowed. In subjects receiving warfarin, the recommended INR 
is ≤ 3.0 with no active bleeding (ie, no bleeding within 14 days prior to first 
dose of study drug).
8) A negative serum pregnancy test is required for female 
subjects (unless permanently sterile or greater than 2 years 
postmenopausal as described in Appendix 5).
9) Male subjects and female subjects of childbearing potential 
who engage in heterosexual intercourse must agree to use 
protocol-specified method(s) of contraception and refrain 
from egg or sperm donation as described in Appendix 5.
10) All acute toxic effects of prior antitumor therapy resolved to 
National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) Version 5.0 
Grade ≤ 1 before the first dose of study drug, with the 
exception of Grade 2 alopecia and peripheral neuropathy.
11) Lactating females must agree to discontinue nursing before 
the study drug is administered until 12 weeks after the last 
dose of study drug.
12) Able and willing to comply with the protocol requirements
Exclusion Criteria:
General Exclusion Criteria:
Subjects who meet any of the following exclusion criteria are 
not eligible to be enrolled in Part 1 or Part 2 of this study:
1) Is currently participating and receiving study therapy or has 
participated in a study of an investigational agent and 
received study therapy or used an investigation device 
within 3 weeks of the first dose of treatment
2) Has received prior systemic cytotoxic chemotherapy, 
biological therapy, radiotherapy, or major surgery within 
3 weeks of Cycle 1 Day 1; a 1-week washout is permitted 
for palliative radiation to non-central nervous system (CNS) 
disease with medical monitor approval


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 19
14 April 2022
3) Is expected to require any other form of systemic or 
localized anticancer therapy while on study (including 
maintenance therapy with another agent, and/or surgical 
resection); for subjects enrolled in Part 1 of the study, 
provision of SBRT per local standard of care is acceptable 
beyond the DLT evaluation period starting at Cycle 2. 
Hormonal/endocrine therapy for prostate cancer or breast 
cancer is permitted.
4) Has known severe hypersensitivity reactions (NCI CTCAE 
Grade ≥ 3) to fully human mAbs or fusion proteins, 
GS-3583 formulation excipients, or severe reaction to 
immuno-oncology agents, such as colitis or pneumonitis 
requiring treatment with corticosteroids, any history of 
anaphylaxis, or uncontrolled asthma
5) Is receiving systemic corticosteroid therapy 1 week prior to 
the first dose of study treatment or receiving any other form 
of systemic immunosuppressive medication
Note: The following corticosteroid uses are permitted: use 
as premedication for known hypersensitivity reactions 
(eg, IV contrast, IV drug infusions); intraocular, intranasal, 
inhaled, and/or topical corticosteroids; and/or prednisone at 
doses of up to 10 mg per day or equivalent. The use of 
physiologic doses of corticosteroids may be approved after 
consultation with the medical monitor.
6) Has concurrent active malignancy other than nonmelanoma 
skin cancer, carcinoma in situ of the cervix, or superficial 
bladder cancer who has undergone potentially curative 
therapy with no evidence of disease. Subjects with other 
previous malignancies are eligible if disease free for 
> 2 years.
7) Previous history of hematological malignancy, MGUS or 
other preleukemic states (Presence of CHIP/ ARCH is 
acceptable)
8) Has a known CNS metastasis(es), unless metastases are 
treated and stable and the subject does not require systemic 
corticosteroids for management of CNS symptoms at least 
1 week prior to study treatment. Subjects with history of 
carcinomatous meningitis are excluded regardless of 
clinical stability.


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 20
14 April 2022
9) Has active autoimmune disease that requires systemic 
treatment (ie, with use of disease-modifying agents, 
corticosteroids, or immunosuppressive drugs) 
Note: Subjects with diabetes type 1, vitiligo, psoriasis, 
hypothyroid disease, or hyperthyroid disease, not requiring 
immunosuppressive treatment are eligible.
10) Has had an allogeneic tissue/solid organ transplant
11) Has evidence of active pneumonitis
12) Has a serious systemic fungal, bacterial, viral, or other 
infection that is not controlled or requires IV antibiotics 
13) Previously known or existing FLT3 mutation of any kind
14) Has known active HBV and/or HCV, and/or HIV
a) Subjects must be negative for hepatitis B surface 
antigen and total anti-HBc. For subjects where total 
anti-HBc-positive, HBV DNA by quantitative 
polymerase chain reaction will be required. 
b) Subjects must be negative for HCV antibody. For 
subjects with positive HCV antibody, HCV RNA by 
quantitative polymerase chain reaction will be required. 
c) Subjects must also be negative for HIV at screening 
15) Subjects with cardiovascular disease/abnormalities will be 
excluded per the following criteria:
a) Has clinically significant (ie, active) cardiovascular 
disease: cerebral vascular accident/stroke or myocardial 
infarction within 6 months of enrollment, unstable 
angina, congestive heart failure (New York Heart 
Association class III or IV), or serious uncontrolled 
cardiac arrhythmia requiring medication
b) Has systolic dysfunction defined as ejection fraction 
< 45% measured by echocardiogram (ECHO) (or 
multigated acquisition [MUGA] scan). Results from 
ECHO or MUGA scan performed up to 30 days prior to 
enrollment are acceptable.
16) History or evidence of clinically significant disorder, 
condition, laboratory abnormality, or disease that, in the 
opinion of the investigator or medical monitor would pose a 
risk to subject safety or interfere with the study evaluations, 
procedures, or completion 




GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 22
14 April 2022
CPS and HPV testing (for those with cancer of oropharynx) 
performed by p16 immunohistochemistry (IHC) using a locally 
available validated assay. Subjects in Part 2 Cohort B (NSCLC) 
only will have baseline information on EGFR, ALK, ROS1, or 
any other known actionable genomic alterations. Subjects in 
Part 2 Randomized Expansion Cohorts shall undergo a 
mandatory tumor biopsy if the investigator considers that no 
undue risk is posed to the subjects due to biopsy related 
procedures; a fresh baseline biopsy is preferred, but a recent 
archival tumor biopsy obtained after the end of the last line of 
therapy and not older than 6 months may be substituted.
Treatment:
In Part 1, subjects will receive GS-3583 on Days 1 and 15 of 
Cycle 1 and on Day 1 of each subsequent 4-week/28-day cycle; 
up to a maximum of 13 cycles. 
In Part 2, subjects will receive GS-3583 on Day 1 of each 
3-week/21-day cycle up to a maximum of 8 cycles. 
Safety and efficacy assessments will occur on an outpatient 
basis, including assessment of tumor response, PE, vital signs, 
ECG, ECOG performance status, collection of blood samples 
(for routine safety labs, GS-3583 PK, immunogenicity, 
pharmacodynamic markers, and other biomarkers at applicable 
visits), stool samples, urine pregnancy test (at least every 4 weeks 
while receiving GS-3583 in females of childbearing potential), 
and assessment of AEs.
Subjects will undergo CT/MRI scans every 8 weeks during 
Part 1 of the study or every 6 weeks during Part 2 of the study. 
A subject who does not show evidence of disease progression 
by clinical assessment or by CT/MRI or other applicable scan 
may continue receiving GS-3583 for the maximum of cycles 
(52 weeks [13 cycles] in Part 1 and 24 weeks [8 cycles] in 
Part 2) or until disease progression (clinical or radiographic), 
unacceptable toxicity, withdrawal of consent, or other 
protocol-specified reasons for treatment discontinuation. 
Posttreatment:
After discontinuation of all study treatment, all subjects will be 
followed for safety for 60 days.


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 23
14 April 2022
Following discontinuation of GS-3583, subjects who do not 
present with progressive disease and/or start a new anticancer 
therapy will continue tumor imaging assessments every 
8 weeks (in Part 1) and every 6 weeks (± 7 days) from the first 
treatment dose until Week 24, then every 9 weeks thereafter 
starting at Week 33 (in Part 2) until documented progressive 
disease, initiation of a new anticancer therapy, or up to 1 year 
after the last dose of study drug, whichever occurs first. 
Thereafter, these subjects will move into survival follow-up and 
will be contacted via telephone call every 3 months for up to a 
year after the completion/discontinuation of tumor lesion 
assessments to report development of any new malignancies 
other than that which was being studied during treatment with 
GS-3583.
For subjects who permanently discontinue from the study in the 
absence of progressive disease/or start of a new line of 
anticancer therapy and will not be continuing tumor imaging 
during the posttreatment period, additional imaging is 
recommended at the EOT visit if the last imaging was 
performed more than 30 days prior.
Pharmacokinetic Assessments
Part 1: 
At Cycles 1 and 3, blood will be collected at predose 
(≤ 30 minutes before start of infusion), end of infusion 
(+ 5 minutes), and 2 hours (± 10 minutes), 6 hours 
(± 0.5 hours), Day 2 (24 hours [± 2 hours]), Day 3 (48 hours 
[± 4 hours]), Day 5 (96 hours [± 4 hours]), Day 8 (168 hours 
[± 12 hours]), Day 15 (for Cycle 1: pre-Day 15 dose 
[≤ 30 minutes before start of infusion], end of Day 15 infusion 
[+ 5 minutes), and 2 hours after start of Day 15 infusion 
[± 10 minutes]; for Cycle 3: 336 hours [± 12 hours]), and 
Day 24 (552 hours [± 12 hours]) after start of the Day 1 
infusion 
In addition, samples will be collected on Day 1 (predose) and 
Day 15 (336 hours) of Cycles 2, 4, and every subsequent even 
numbered cycle thereafter, and at the 60-day follow-up visit 
(approximately 60 days after last dose). An additional blood 
sample will be collected at the EOT visit if a subject terminates 
early from study treatment.
Serum concentrations of GS-3583 will be determined, and PK 
parameters will be estimated.


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 24
14 April 2022
Part 2: 
GS-3583 (Safety Run-in Cohorts): At Cycles 1 and 3, blood 
samples will be collected at predose (≤ 30 minutes before start 
of infusion), end of infusion (+ 5 minutes), and 2 hours 
(± 10 minutes), 6 hours (± 0.5 hours), Day 8 (168 hours 
[± 12 hours]), and Day 15 (336 hours [± 12 hours]) after start of 
the Day 1 infusion. 
In addition, blood samples will be collected on Day 1 (predose 
[≤ 30 minutes before start of infusion] and end of infusion 
[+ 5 minutes]) of Cycles 2, 5, and every subsequent odd 
numbered cycle thereafter, and at the 60-day follow-up visit 
(approximately 60 days after last dose). An additional blood 
sample will be collected at the EOT visit if a subject terminates 
early from study treatment.
GS-3583 (Randomized Expansion Cohorts Treatment 
Arms): Blood samples will be collected on Day 1 (predose 
[≤ 30 minutes before start of infusion] and end of infusion 
[+ 5 minutes]) of Cycles 1, 2, 3, and every subsequent odd 
numbered cycle thereafter, and at the 60-day follow-up visit 
(approximately 60 days after last dose). An additional blood 
sample will be collected at the EOT visit if a subject terminates 
early from study treatment.
Part 2 Cohort A:
Zimberelimab (Safety Run-in Cohort and Randomized 
Expansion Cohort Control and Treatment Arms): Blood 
samples will be collected on Day 1 (predose [≤ 30 minutes 
before start of infusion] and end of infusion [+ 5 minutes]) of 
Cycles 1, 2, 3, and every subsequent odd numbered cycle 
thereafter, and at the 60-day follow-up visit (approximately 
60 days after last dose). An additional blood sample will be 
collected at the EOT visit if a subject terminates early from 
study treatment.
Biomarker Assessments
Part 1: 
Whole blood biomarker samples will be collected and 
peripheral blood mononuclear cells (PBMCs) and plasma will 
be isolated to measure pharmacodynamic biomarkers for 
GS-3583 at the following time points relative to the start of 
infusion:


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 25
14 April 2022
Day 1 of Cycle 1 and Cycle 3 at predose, Day 8 (168 hours), 
Day 15 (336 hours, must be collected predose at Cycle 1), and 
Day 24 (552 hours) after start of the Day 1 infusion. The 
predose samples will be collected any time prior to the start of 
infusion at the Day 1 visit. However, for Cycle 1 Day 1 an 
additional set of predose samples should be collected up to 
72 hours prior to the Cycle 1 Day 1 visit, if feasible.
In addition, samples will be collected at predose on Day 1 and 
Day 15 (336 hours) of Cycles 2, 4, and every subsequent even 
numbered cycle thereafter, and at the 60-day follow-up visit 
(approximately 60 days after last dose). An additional sample 
will be collected at the EOT visit if a subject terminates early 
from study treatment.
A separate whole blood sample to determine blood cell counts 
will be drawn at the same time points as the above 
pharmacodynamic samples.
Additional biomarker samples will be collected per protocol 
Section 6.5.2.
Pharmacodynamic biomarkers will include, but are not limited 
to, analysis of dendritic cells (DCs) (type 1 and type 2 
conventional dendritic cells [cDC1s and cDC2s]) and 
plasmacytoid DCs, monocytes and CD135 (FMS-related 
tyrosine kinase 3).
Part 2:
Safety Run-in Cohorts:
Whole blood biomarker samples will be collected and PBMCs 
and plasma will be isolated to measure pharmacodynamic 
biomarkers for GS-3583 at the following time points relative to 
the start of infusion:
Predose at Day 1, and on Day 12 (264 hours [± 12 hours]), and 
Day 15 (336 hours [± 12 hours]) after start of the Day 1 
infusion of Cycles 1 and 3. In Cycle 1 and Cycle 3, the predose 
samples will be collected any time prior to the start of infusion 
at the Day 1 visit. However, for Cycle 1 Day 1, additional set of 
predose samples should be collected up to 72 hours prior to the 
Cycle 1 Day 1 visit, if feasible.


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 26
14 April 2022
In addition, samples will be collected at predose on Day 1 and 
Day 15 (336 hours) of Cycles 2, 4, and every subsequent even 
numbered cycle thereafter, and at the 60-day follow-up visit 
(approximately 60 days after last dose). An additional sample 
will be collected at the EOT visit if a subject terminates early 
from study treatment.
A separate whole blood sample to determine blood cell counts 
will be drawn at the same time points as the above 
pharmacodynamic samples.
Additional biomarker samples will be collected per protocol 
Section 6.5.2.
Pharmacodynamic biomarkers will include, but are not limited 
to, analysis of dendritic cells (DCs) (type 1 and type 2 
conventional dendritic cells [cDC1s and cDC2s]) and 
plasmacytoid DCs, monocytes and CD135 (FMS-related 
tyrosine kinase 3).
Randomized Expansion Cohorts:
Whole blood biomarker samples will be collected and PBMCs 
and plasma will be isolated to measure pharmacodynamic 
biomarkers for GS-3583 at the following time points relative to 
the start of infusion:
Predose on Day 1 and on Day 15 (336 hours [± 12 hours]) after 
start of the Day 1 infusion of Cycles 1, 2, 3, 4, and every 
subsequent even numbered cycle thereafter. However, for 
Cycle 1 Day 1, an additional set of predose samples should be 
collected up to 72 hours prior to the Cycle 1 Day 1 visit, if 
feasible.
In addition, samples will be collected at the 60-day follow-up 
visit (approximately 60 days after last dose). An additional 
sample will be collected at the EOT visit if a subject terminates 
early from study treatment.
A separate whole blood sample to determine blood cell counts 
will be drawn at the same time points as the above 
pharmacodynamic samples.
Additional biomarker samples will be collected per protocol 
Section 6.5.2.
Pharmacodynamic biomarkers will include, but are not limited 
to, analysis of dendritic cells (DCs) (type 1 and type 2 
conventional dendritic cells [cDC1s and cDC2s]) and 
plasmacytoid DCs, monocytes and CD135 (FMS-related 
tyrosine kinase 3).


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 27
14 April 2022
Immunogenicity Assessments
Part 1: Serum samples will be collected for immunogenicity 
assessments of GS-3583 at predose (≤ 30 minutes before start 
of infusion) on Day 1 of Cycles 1, 2, 3, 4, 7, and 13; and at the 
60-day follow-up visit (approximately 60 days after last dose). 
An additional blood sample will be collected at the EOT visit, if 
a subject terminates early from study treatment.
Part 2 (Safety Run-in Cohorts and Randomized Expansion 
Cohorts Treatment Arms): Subjects will have antidrug 
antibody (ADA) assessed at predose (≤ 30 minutes before start 
of infusion) on Day 1 of Cycle 1, 2, 3, 5, 9 and 17; and at 
60-day follow-up visit (approximately 60 days after last dose). 
An additional blood sample will be collected at the EOT visit if 
a subject terminates early from study treatment.
Part 2: Cohort A: 
Zimberelimab: Subjects will have ADA assessed at predose 
(≤ 30 minutes before start of infusion) on Day 1 of Cycle 1, 
2, 3, 5, 9, and 17; and at 60-day follow-up visit (60 days 
after last dose). An additional blood sample will be collected 
at the EOT visit if a subject terminates early from study 
treatment.
Test Product, Dose, and 
Mode of Administration:
Part 1: 
On Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 
4-week/28-day cycle, GS-3583 will be given as an IV infusion 
over 60 (± 10) minutes. The dose and the dosing frequency will 
be:
Cohort 1: Up to 675 μg (Dose Level 1) every 2 weeks for the 
first 3 doses; subsequent doses will be given every 4 weeks
Cohort 2: Up to 2000 μg (Dose Level 2) every 2 weeks for the 
first 3 doses; subsequent doses will be given every 4 weeks
Cohort 3: Up to 6000 μg (Dose Level 3) every 2 weeks for the 
first 3 doses; subsequent doses will be given every 4 weeks
Cohort 4: Up to 12,000 μg (Dose Level 4) every 2 weeks for 
the first 3 doses; subsequent doses will be given every 4 weeks
Cohort 5: Up to 20,000 μg (Dose Level 5) every 2 weeks for 
the first 3 doses; subsequent doses will be given every 4 weeks


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The dose levels and number of cohorts may be adjusted based 
on the available PK and pharmacodynamic data from the 
Phase 1a HV study (GS-US-496-5619).
Part 2 Safety Run-In Cohorts and Randomized Expansion 
Cohorts, Treatment Arms: 
The recommended GS-3583 dose for Part 2 will be determined 
based on the safety, PK, pharmacodynamics, and all other 
relevant data from Part 1 and will not exceed the MTD in 
Part 1.
Part 2 Cohort A:
Zimberelimab 360 mg IV infusion over 60 min ± 5 min on 
Day 1 of each cycle (up to 105 weeks)
Platinum (cisplatin or carboplatin):

Cisplatin 100 mg/m² of body surface area (BSA) IV 
infusion over 1 hour (or infusion duration per local practice) 
on Day 1 of each cycle (up to 6 cycles)
or

Carboplatin AUC of 5 mg/mL/min IV infusion over 1 hour 
(or infusion duration per local practice) on Day 1 of each 
cycle (up to 6 cycles)
5-FU 1000 mg/m2 of BSA/day continuous IV infusion over 
96 hours on Day 1 to Day 4 of each cycle (up to 6 cycles)
Part 2 Cohort B:
Docetaxel 75 mg/m2 of BSA IV infusion over 60 min ± 10 min 
on Day 1 of each cycle (until 1 or more discontinuation criteria 
are met)
Reference Therapy, Dose, 
and Mode of 
Administration:
Part 2 Randomized Expansion Cohort A, Control Arm:
Zimberelimab 360 mg IV infusion over 60 min ± 5 min on 
Day 1 of each cycle (up to 105 weeks)
Platinum (cisplatin or carboplatin):

Cisplatin 100 mg/m² of body surface area (BSA) IV 
infusion over 1 hour (or infusion duration per local practice) 
on Day 1 of each cycle (up to 6 cycles)
or


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
Carboplatin AUC of 5 mg/mL/min IV infusion over 1 hour 
(or infusion duration per local practice) on Day 1 of each 
cycle (up to 6 cycles)
5-FU 1000 mg/m2 of BSA/day continuous IV infusion over 
96 hours on Day 1 to Day 4 of each cycle (up to 6 cycles)
Part 2 Randomized Expansion Cohort B, Control Arm:
Docetaxel 75 mg/m2 of BSA IV infusion over 60 min ± 10 min 
on Day 1 of each cycle (until 1 or more discontinuation criteria 
are met)
Criteria for Evaluation:
Safety:
Safety will be evaluated by assessment of clinical laboratory 
tests, physical examination, 12-lead ECG, vital signs 
measurements, ECOG performance status, and the 
documentation of AEs. AEs will be graded using NCI CTCAE 
v5.0.
Efficacy:
Efficacy will be evaluated according to RECIST V1.1. In 
Part 1, imaging will be performed every 8 weeks. In Part 2, 
imaging will be performed every 6 weeks until Week 24, then 
every 9 weeks thereafter. 
Efficacy will be evaluated by ORR (complete response [CR] + 
partial response [PR], assessed as per RECIST V1.1), and PFS, 
defined as the interval from first dosing date of study drug to 
the earlier of the first documentation of definitive disease 
progression or death from any cause.
Pharmacokinetics:
Serum drug concentrations will be analyzed. The PK 
parameters to be estimated and reported may include, but may 
not be limited to, Cmax, AUCtau, Ctrough, Tmax and CL.
Pharmacodynamics:
Pharmacodynamics will be evaluated by monitoring 
longitudinal changes in the absolute number of DCs (cDC1s 
and cDC2s) and plasmacytoid DCs, monocytes, and CD135 
expression level on these cells, pretreatment and posttreatment.


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Statistical Methods:
Analysis sets are defined in Section 8.3.1.
Safety Analysis
DLTs will be summarized by dose level for subjects in the DLT 
analysis set. Safety data will be summarized by dose level 
and/or treatment for subject in the Safety Analysis Set. In 
general, categorical and ordinal data will be summarized by 
count and percentage of subjects. Continuous data will be 
summarized by descriptive summary statistics (mean, standard 
deviation, minimum, quartiles, median, and maximum).
Efficacy Analysis
Efficacy data will be summarized by treatment and/or tumor 
types, as appropriate, for subjects in the Full Analysis Set. 
Efficacy endpoints will include but may not be limited to ORR, 
DCR, PFS, DOR, and OS. Subjects who do not have sufficient 
baseline or on-study tumor assessments to characterize 
response will be counted as non-responders. Response rate and 
the corresponding 90% CIs based on the Clopper-Pearson exact 
method will be provided. Time to event endpoints such as PFS 
will be analyzed using Kaplan-Meier (KM) method. 
Pharmacokinetic Analysis
GS-3583 or zimberelimab serum concentrations and PK 
parameters will be described and summarized using descriptive 
statistics (eg, sample size, arithmetic mean, geometric mean, % 
coefficient of variations, standard deviation, median, minimum, 
and maximum) by dose level/cohort for subjects in the PK 
Analysis Set.
Sample Size
For Part 1, assuming up to 4 planned dose levels will be tested 
with up to 3 DLT-evaluable subjects for the first dose level and 
up to 6 DLT-evaluable subjects per subsequent dose level, 
21 DLT-evaluable subjects will be needed. Assuming 10% are 
not evaluable, approximately 24 subjects will be enrolled in 
Part 1. 
For Part 2, a maximum of 63 subjects will be enrolled for each 
cohort. Six to 18 subjects will be evaluated in Safety Run-In 
Cohorts, and 45 subjects will be enrolled in Randomization 
Expansion Cohorts with 2:1 randomization ratio. The total 
maximum sample size in Part 2 is approximately 126.
This study will be conducted in accordance with the guidelines of Good Clinical Practice 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
ADA
antidrug antibody
AE
adverse event
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
anti-HBc
antibody against hepatitis B core antigen
ARCH
age-related clonal hematopoiesis
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUCtau
area under the concentration versus time curve over the dosing interval
BSA
body surface area
CD
cluster determinant
cDC1
conventional type-1 dendritic cells
cDC2
conventional type-2 dendritic cells
CDDP
cis-diamminedichloroplatinum(II)
CHIP
clonal hematopoiesis of indeterminate potential
CI
confidence interval
CL
clearance 
Cmax
maximum observed concentration of drug
CNS
central nervous system
COVID-19
coronavirus disease 2019
CPS
combined positive score
CR
complete response
CRO
contract/clinical research organization
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
concentration at the end of the dosing interval 
CyTOF
cytometry by time-of-flight
DC
dendritic cell
DCR
disease control rate
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
EC50
half-maximal effective concentration
ECG
electrocardiogram


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ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EOT
end of treatment
EU
European Union
EudraCT
European Clinical Trials Database
Fc
fragment crystallizable
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FIH
first-in-human
FLT3
FMS-related tyrosine kinase 3
FLT3L
FMS-related tyrosine kinase 3 ligand
FNA
fine needle aspirate
5-FU
5-flourouracil
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
Gilead
Gilead Sciences
GLP
Good Laboratory Practice
GLPS
Gilead Global Patient Safety
GM-CSF
granulocyte macrophage colony-stimulating factor
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HNSCC
head and neck squamous cell carcinoma
HPV
human papillomavirus
HR
hazard ratio
HV
healthy volunteer
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation (of Technical Requirements for Pharmaceuticals 
for Human Use)
IEC
independent ethics committee
Ig
immunoglobulin
IHC
immunohistochemistry
IND
investigational new drug 
irAEs
immune related adverse events
IRB
institutional review board
IV
intravenous(ly)
IXRS
interactive voice/web response system


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Kd
affinity constant
KM
Kaplan-Meier
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MGUS
monoclonal gammopathy of unknown significance
MHC
major histocompatibility complex
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition (scan)
NCI
National Cancer Institute
NK
natural killer
NCCN
National Comprehensive Cancer Network
NOAEL
no observed adverse effect level
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PE
physical exam
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave, representing the time for both ventricular depolarization and repolarization to 
occur
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using the Fridericia formula 
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RT
radiotherapy
SAE
serious adverse event
SBRT
stereotactic body radiation therapy
SOP
standard operating procedure
SRT
safety review team
SSR
special situation report
SUSAR
suspected unexpected serious adverse reaction


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TCR
T-cell receptor
TEAE
treatment-emergent adverse event
TGI
tumor growth inhibition
TLR3
toll-like receptor 3
Tmax
time (observed time point) of Cmax
TME
tumor microenvironment
TTR
time to response
US
United States
w/v
weight-to-volume ratio


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1.
INTRODUCTION
1.1.
Background
Despite unprecedented clinical activity across multiple types of cancer with programmed cell 
death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade therapy, the majority 
of subjects do not respond (primary resistance) or develop resistance after initial tumor 
regression (acquired resistance) {Sharma 2017}. This is due, at least in part, to poor T-cell 
infiltration into the tumor, which is negatively correlated with treatment response {Tumeh 
2014}. Therefore, the development of novel approaches to increase T-cell infiltration within the 
tumor microenvironment (TME) is hypothesized to increase the number of subjects benefiting 
from immunotherapy. To this point, evidence indicates critical roles for tumor-residing 
Batf3-dependent conventional type-1 dendritic cells (cDC1s) (migratory CD103+ and lymphoid 
CD8a+ dendritic cells [DCs] in mice, and CD141+ DCs in humans) in priming and expansion of 
tumor-specific CD8+ T cells {Hildner 2008, Oba 2020, Roberts 2016} and their recruitment to 
the TME {Spranger 2017}. Unique among the various DC subsets, cDC1s display enhanced 
abilities to phagocytose dead cells, and to cross-present exogenous antigens onto major 
histocompatibility complex (MHC) class I molecules {Shortman 2010}. Although sparse in the 
TME, cDC1s can be recruited by systemic or intratumoral injection of FMS-like tyrosine kinase 
3 ligand (FLT3L) {Hammerich 2019, Hegde 2020}.
FMS-related tyrosine kinase 3 ligand (FLT3L) is a hematopoietic growth factor that binds to 
FMS-related tyrosine kinase 3 (FLT3) on myeloid and lymphoid progenitor cells in the bone 
marrow and terminally differentiated DCs {Lyman 1998}. FLT3 activation by FLT3L promotes 
receptor dimerization and phosphorylation leading to signaling events that promote proliferation 
and inhibit cell death {Parcells 2006}. Notably, FLT3L-mediated receptor signaling is required 
for the differentiation, expansion, and maintenance of DCs in peripheral and lymphoid organs. 
FLT3 or FLT3L-deficient mice have defective hematopoiesis, resulting in a profound reduction 
in the systemic DC compartment {Durai 2018}.
Dendritic cells are immune cells that effectively link the innate and adaptive arms of the immune 
system. Dendritic cells present antigens to naive and antigen-experienced (memory) T cells via 
major histocompatibility complex class I and II to regulate T-cell expansion and differentiation 
and the acquisition of effector functions {Merad 2013}. Productive antitumor immune responses 
in nonclinical models depend on a subtype of DCs termed cDC1 {Bottcher 2018}. In the context 
of cancer, cDC1s are prime tumor-reactive T cells in the regional draining lymph nodes through 
presentation of tumor-derived antigens {Broz 2014, Zelenay 2012}.
GS-3583 is a fusion protein composed of the extracellular domain of a recombinant human 
FLT3L fused to an engineered fragment crystallizable (Fc) region of a human immunoglobulin 
(Ig) G4. GS-3583 is designed to expand cDC1s in tumors and draining lymph nodes. The cDC1s 
capture and present tumor-derived antigens to T cells via major histocompatibility complex class 
I and II, leading to their subsequent activation and antitumor effector function. Nonclinical 
models and clinical trials using recombinant FLT3L (CDX-301, Celldex Therapeutics) have 
established the therapeutic potential of expanding cDC1s {Borges 1999, Hammerich 2019, 


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Salmon 2016}. However, the unfavorable pharmacokinetic (PK) properties of the recombinant 
FLT3L limit the duration of cDC1 expansion and thus its therapeutic potential 
{Anandasabapathy 2015}. GS-3583 is engineered to demonstrate superior PK properties 
compared to recombinant FLT3L, allowing for sustained cDC1 expansion in subjects and 
potential alignment with the dosing schedules for established immunotherapies. Treatment of 
cancer subjects with GS-3583 is expected to potentiate the activity of standard of care or 
immunomodulatory intervention therapeutics.
The safety, PK, and pharmacodynamics (as assessed by DC expansion) of multiple ascending 
doses of recombinant FLT3L (CDX-301) given subcutaneously for up to 10 days has previously 
been investigated in healthy volunteers (HVs) {Anandasabapathy 2015}. Overall, recombinant 
FLT3L was well tolerated. Likewise, GS-3583 was investigated in a first-in-human (FIH) study 
in HVs to evaluate the safety, tolerability, PK, and pharmacodynamics. Escalating single doses 
ranging from 75 μg to 2000 μg of GS-3583 were well tolerated and there were no serious or 
Grade 3 or higher adverse events (AEs) {Rajakumaraswamy 2021}.
Whereas mobilization of cDC1s alone is insufficient in generating antitumor T-cell responses in 
established tumors, systemic or intratumoral administration of a toll-like receptor 3 (TLR3) 
agonists as well as CD40 agonists activate cDC1s and enhances responses to anti-PD-1/PD-L1 
therapy {Salmon 2016, Sanchez-Paulete 2016}. Radiotherapy (RT) has been shown to cause 
immunogenic death of cancer cells, which can trigger DC activation, antigen presentation, and 
priming of tumor-specific CD8+ T cells {Demaria 2016}, and can be employed for enhancing 
FLT3L-induced cDC1 function in the tumor. Indeed, there is nonclinical and clinical data from 
T-cell-inflamed tumors showing that in situ vaccination with FLT3L, RT, and TLR3 agonist 
facilitates cross-priming of tumor-specific T cells, and synergizes with PD-1 blockade 
{Hammerich 2019}. Nonetheless, the vast majority of subjects with cancer do not present with 
tumor sites and/or lesions that are amenable to radiation which renders it a suboptimal mode for 
activating cDC1s. On the other hand, certain chemotherapeutic agents have the potential to 
trigger immunogenic death of cancer cells although their potential to activate the cDC1s 
expanded by FLT3L has not previously been investigated.
The current study, GS-US-496-5657, is designed to investigate the safety, tolerability, and 
preliminary efficacy of GS-3583 as monotherapy (Part 1) and in combination with other 
anticancer therapies (Part 2).
Part 1 of the study will investigate GS-3583 given intravenously (IV) as monotherapy to subjects 
with advanced solid tumors in dose-escalation cohorts in order to determine the maximum 
tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) as monotherapy.
Part 2 of the study will investigate GS-3583 in combination with other anticancer therapies. 
There will be 2 cohorts in Part 2:

Cohort A will consist of subjects with metastatic or unresectable, locally recurrent head and 
neck squamous cell carcinoma (HNSCC) who have not received previous systemic treatment 
for metastatic disease. GS-3583 will be combined with zimberelimab and platinum (cisplatin 
or carboplatin) + 5-fluorouracil (5-FU) chemotherapy.


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
Cohort B will consist of subjects with locally advanced, unresectable or metastatic non–
small-cell lung cancer (NSCLC) with documented progression on at least one anti-PD-1 or 
anti-PD-L1 monoclonal antibody (mAb) and platinum-based chemotherapy given 
individually or in combination. For these subjects, GS-3583 will be given in combination 
with docetaxel.
Part 2 of the study will test the hypothesis that the induction and activation of tumor-residing 
cDC1s will facilitate the priming, expansion, and infiltration of tumor-specific CD8+ T cells into 
the poorly T-cell inflamed TME, and improve responsiveness to anti-PD-L1 therapy (in 
HNSCC) and chemotherapy (in NSCLC). It is hypothesized that systemic administration of 
GS-3583 (FLT3L Fc fusion protein) will result in the mobilization of cDC1s to the TME 
whereas systemic administration of chemotherapy will induce immunogenic death of cancer 
cells, resulting in the maturation and activation of antigen-loaded cDC1s for priming and 
expansion of tumor-specific CD8+ T cells.
1.1.1.
HNSCC
Head and neck squamous cell carcinoma (HNSCC) is diagnosed in over 550,000 patients per 
year globally and is responsible for over 380,000 deaths {Global Burden of Disease Liver Cancer 
Collaboration 2017}.
According to the Global Burden of Disease study, lip and oral cavity cancers are the 15th most 
common cancers worldwide and are in the top 10 in South and Southeast Asia, Tropical Latin 
America, and Sub-Saharan Africa. The incidence has increased by 36.5% in the past decade 
{Global Burden of Disease Liver Cancer Collaboration 2017, Siegel 2017, Simard 2014}. 
Laryngeal cancers are the 20th most common and have increased by 23.1% in the past 10 years 
and other pharynx cancers are the 24th most common and have increased by 29.9% {Global 
Burden of Disease Liver Cancer Collaboration 2017, Siegel 2017, Simard 2014}.
In the United States (US), head and neck cancers account for approximately 4% of all cancers. 
The annual incidence in the US is approximately 60,000 new cases, with approximately 
14,000 deaths. Throughout all of the anatomical subtypes, males are more likely to be diagnosed 
with HNSCC than females at a 2:1 to 4:1 ratio {Bray 2008, Lambert 2011}. In some global 
regions, including areas of France, Hong Kong, India, Central and Eastern Europe, Spain, Italy, 
and Brazil, the incidence of HNSCC in males is over 20 per 100,000 people {Bray 2008, 
Lambert 2011}. In the USA, the incidence of laryngeal cancer is 50% higher in African 
American men compared with the rest of the population {DeSantis 2013}.
Several risk factors are associated with the incidence of head and neck cancers, including 
tobacco and alcohol consumption. In addition, human papillomavirus (HPV) infection is a 
causative agent for head and neck cancers. Squamous cell carcinomas account for over 90% of 
head and neck cancers arising in the oral cavity and larynx. Initial treatment of HNSCC is broken 
down by extent of disease (localized, locoregionally advanced, and metastatic). Subjects with 
localized disease (Stage I or II) have a 5-year overall survival (OS) of 70% to 90% and are 
treated with definitive surgery and/or radiation therapy. In contrast, subjects with metastatic 
disease have a poor prognosis, with a 5-year OS of approximately 4% {Beckham 2019}. 


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Systemic therapy with either chemotherapy and/or immune checkpoint inhibition is the standard 
of care for subjects with recurrent or metastatic disease in the frontline setting.
Recently, immune checkpoint inhibitors, specifically anti-PD-1 antibodies, have been approved 
for subjects with metastatic HNSCC. Notably, pembrolizumab was recently granted approval for 
the first-line treatment of metastatic or unresectable, recurrent HNSCC, as a monotherapy in 
subjects whose tumors express PD-L1 (combined positive score [CPS] ≥ 1) and in combination 
with 5-FU and platinum chemotherapy in subjects regardless of PD-L1 status. This approval was 
based on results from a Phase 3, randomized, open-label, active-controlled, multicenter study 
comparing pembrolizumab monotherapy, pembrolizumab + 5-FU + platinum, and cetuximab + 
5-FU + platinum (KEYNOTE-048). In the subgroup of subjects with a PD-L1 CPS ≥ 1, 
treatment with pembrolizumab monotherapy resulted in an improved median OS compared with 
cetuximab + 5-FU + platinum (12.3 months versus 10.3 months, respectively; hazard ratio 
[HR] = 0.78; p = 0.0086) {Burtness 2019}. In the overall study population, regardless of PD-L1 
status, treatment with pembrolizumab + 5-FU + platinum resulted in an improved median OS 
compared with cetuximab + 5-FU + platinum (13.0 months versus 10.7 months, respectively; 
HR = 0.77; p = 0.0034). Based on these results, pembrolizumab monotherapy for subjects whose 
tumors express PD-L1 and pembrolizumab + 5-FU + platinum for subjects regardless of PD-L1 
status have become standard-of-care options. However, novel agents that can improve OS in 
both groups are needed to enhance clinical benefit in this population that represents a high unmet 
medical need.
1.1.2.
NSCLC
Lung cancer is the leading cause of cancer-related mortality worldwide. It was estimated that in 
2020, there were over 2 million new cases of lung cancer and approximately 1.8 million deaths 
worldwide {International Agency for Research on Cancer (IARC) 2020}. In the US in 2021, it is 
estimated that there will be over 235,000 new cases of lung cancer and over 131,000 deaths 
{American Cancer Society 2021}. Approximately 80% to 85% of all lung cancers are NSCLC 
{Ettinger 2019} and more than half of these are identified at an advanced stage {Siegel 2019}.
Immune checkpoint inhibitor therapy has dramatically improved the prognosis of advanced lung 
cancer. Immune checkpoint inhibitor therapies, as monotherapy (PD-1 ≥ 50%) or in combination 
with platinum doublet chemotherapy (regardless of PD-L1 expression), are mainly used in the 
frontline metastatic setting based on results of Studies KN-024, KN-042, KN-189, and KN-407 
and similar studies for subjects who do not have actionable genomic alterations {KEYTRUDA 
2021}. Platinum doublet chemotherapy with or without PD-L1 inhibitor remains the standard 
treatment for subjects with actionable genomic alterations when they have failed treatment with 
targeted agents or such treatment is not available. After failure of immune checkpoint inhibitor 
therapy and platinum-based chemotherapy, there are limited treatment options for most subjects. 
According to the current National Comprehensive Cancer Network guidelines, the use of single 
agent chemotherapy (including taxanes) is the standard of care for subjects with recurrent or 
metastatic NSCLC after failure of platinum-based therapy and/or immune checkpoint therapy 
regardless of presence of genomic alterations and PD-L1 status. The main options for single 
agent chemotherapy in this setting generally include docetaxel (with or without ramucirumab) 


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and pemetrexed (for nonsquamous tumors, if not previously used). In a study of docetaxel versus 
best supportive care in relapsed NSCLC, the median progression-free survival (PFS) was 
approximately 3 months with a median OS of approximately 6 to 8 months {Shepherd 2000}. 
These numbers have been borne out in more contemporaneous studies with docetaxel following 
failure of platinum-based regimens in NSCLC {Horn 2017, Mazieres 2021}.
Although docetaxel is considered standard of care in subjects failing platinum-based regimens 
and checkpoint inhibitors, a significant unmet medical need remains in the treatment of patients 
who have progressed following anti-PD-1/anti-PD-L1 therapy.
1.2.
Background on Study Interventions
1.2.1.
GS-3583
1.2.1.1.
General Information
GS-3583 is a fusion protein composed of a recombinant human FLT3L extracellular domain 
fused to an engineered Fc region of a human IgG4. GS-3583 binds to human FLT3 with high 
affinity and potently activates signaling. GS-3583 has attenuated binding to activating Fc gamma 
receptors to avoid the depletion of FLT3 expressing progenitor cells and DCs and enhanced 
binding to the neonatal Fc receptor to increase its in vivo half-life. A murine surrogate of 
GS-3583 showed single dose antitumor activity in nonclinical tumor models, which correlated 
with peripheral and intratumoral DC expansion. Based on mechanism of action, GS-3583 has the 
potential to combine with a range of cancer therapies, including chemotherapy and immune 
checkpoint blockade.
For further information on GS-3583, refer to the current investigator’s brochure (IB), including 
information on the following:

Nonclinical PK and in vitro metabolism

Nonclinical pharmacology and toxicology
1.2.1.2.
Nonclinical Pharmacology and Toxicology
1.2.1.2.1.
Nonclinical Pharmacology
GS-3583 binds to recombinant human FLT3 with an estimated affinity constant (Kd) of 36 nM. 
It potently activates FLT3 signaling in cell-based assays, with a half-maximal effective 
concentration (EC50) of 0.053 nM, and induces expansion of primary human cDC1 in vitro with 
an EC50 of 0.25 nM. GS-3583 showed a dose-dependent and prolonged pharmacodynamic 
response in the peripheral blood of cynomolgus monkeys, as compared to recombinant FLT3L. 
In nonclinical tumor models, a murine surrogate of GS-3583 (GS-1062398) exhibited single 
agent efficacy that correlated with peripheral and intratumoral pharmacodynamic assessments. In 
addition, GS-1062398 combined effectively with PD-L1 pathway blockade to provide superior 
efficacy versus single agents alone. 


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1.2.1.2.2.
Nonclinical Toxicology
The cynomolgus monkey was selected as a suitable toxicology species based on a high sequence 
homology for the human FLT3L (95%) and the human Ig heavy constant gamma region (92%). 
In single dose and multidose non-Good Laboratory Practice (GLP) PK/pharmacodynamic IV 
studies in the cynomolgus monkey, GS-3583 was well tolerated up to a 10 mg/kg/dose given 
once weekly over 2 weeks, and 1000 μg/kg/dose given every 2 weeks over 4 weeks. A high 
incidence of antidrug antibodies (ADAs), with concurrent loss of systemic exposure, was 
observed at some of the lower doses, while higher doses (≥ 30 mg/kg once weekly) were not 
tolerated and necessitated unscheduled euthanasia of some animals. 
The nonclinical safety profile of GS-3583 has been characterized in a 4-week GLP IV 
repeat-dose toxicity study with 4-week recovery period in cynomolgus monkeys. GS-3583 was 
well tolerated when given IV at doses of up to 10 mg/kg/week for 4 weeks. GS-3583-related 
findings were noted at all doses and were generally consistent with FLT3 agonism and included 
the expansion of populations of peripheral monocytes especially, lymphocytes, total white blood 
cells, neutrophils, and eosinophils to a lesser degree. There was a minimal decrease in red blood 
cells and associated parameters in females. Immunophenotyping showed a notable expansion of 
cDC1 and cDC2 cell populations, and serum cytokine changes reflected these cell phenotypes. 
Also consistent with the pharmacological activity of GS-3583, histiocytic infiltrates detected 
microscopically in multiple tissues including lymphoid organs. In addition, bone marrow 
cellularity was increased, consistent with the noted increases in peripheral cell lineages. 
Enlargement of the spleen and lymph nodes were other findings correlating with the detected 
microscopic changes. All GS-3583-related findings were considered to be nonadverse. After a 
4-week recovery period, there was recovery, or a trend towards recovery in most of the 
GS-3583-related clinical pathology, gross, and histological changes detected in the terminal 
groups, although cDC1 and cDC2 subtypes and associated cytokines maintained elevated levels.
1.2.1.3.
Clinical Studies of GS-3583
Study GS-US-496-5619 was a Phase 1a, first-in-human, placebo-controlled study of GS-3583 in 
HVs to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of 
escalating single doses (ranging from 75 μg to 2000 μg) of GS-3583 {Rajakumaraswamy 2021}. 
The study was blinded to the subjects and the investigator. Each dose cohort enrolled 8-12 HVs 
who received GS-3583 or placebo as single IV infusion at 3:1 ratio. Subjects were observed in 
the Phase-1 unit for 15 days and then for 10 weeks as outpatients. As part of the 
pharmacodynamic evaluation, the changes in the number of cDC1 and conventional type-2 
dendritic cells (cDC2) cells were investigated.
As of 02 July 2021, selected safety, PK, and pharmacodynamic data from all 4 cohorts were 
available. GS-3583 was well tolerated and all subjects had been discharged. To date, there have 
been no serious or Grade 3 or higher AEs. Preliminary PK analysis suggested dose-dependent 
increase in GS-3583 exposure (AUC and Cmax). Preliminary pharmacodynamic analysis shows 
that administration of GS-3583 resulted in temporary, dose-dependent increases in cDC1/cDC2 
cells that peaked between Days 5 to 11 (higher doses resulted in later peaks) and returned to 
baseline within 3 weeks of drug administration.


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For further information on GS-3583, refer to the current IB.
1.2.2.
Information About Combination Therapies
1.2.2.1.
Information About Zimberelimab
Zimberelimab is a fully human IgG4 mAb targeting human PD-1. The PD-1 is a type I 
transmembrane protein that is part of the Ig gene superfamily and the CD28 family of cell 
surface receptors {Agata 1996}. PD-1 is expressed on T cells and functions as an immune 
checkpoint that negatively regulates T-cell activation and effector function when activated by its 
ligands PD-L1 (B7-H1, CD274) and programmed cell death ligand 2 (PD-L2); it plays an 
important role in tumor evasion from host immunity. Zimberelimab targets, binds to, and inhibits 
PD-1 and its downstream signaling pathways and hence restoring immune function through the 
activation of T cells and T-cell-mediated immune responses against tumor cells. Nonclinical data 
supports its binding to both PD-L1 and PD-L2 and release of the immunosuppressive inhibition 
of the T-cell effector function after exposure to zimberelimab. Zimberelimab is currently being 
evaluated for use in cancer patients in both monotherapy and combination studies with approved 
agents or other experimental regimens. Clinical data from monotherapy treatment in heavily 
pretreated patients with various advanced solid tumors has established tolerable and 
pharmacokinetically-stable dosing regimens of zimberelimab IV every 2 and every 3 weeks. 
Refer to the current zimberelimab IB for clinical studies conducted with zimberelimab.
1.2.2.2.
Information About Cisplatin
Cisplatin (cis-diamminedichloroplatinum(II) - CDDP) is an anticancer cytotoxic agent classified 
as an alkylating agents and is indicated for the treatment of multiple solid tumors, including 
advanced HNSCC as single agents and in combination with of cytotoxic chemotherapies, 
targeted agents, and checkpoint inhibitors (CPIs). For current information about cisplatin, refer 
to the applicable local or regional prescribing information in the pharmacy binder. Any locally 
available generics for cisplatin may be used.
1.2.2.3.
Information About Carboplatin
Carboplatin is a platinum-based chemotherapy drug that is widely used for the treatment of 
multiple solid tumors, including HNSCC, ovarian, lung, and bladder cancer.
Further information can be found in the current country-specific prescribing information. Any 
locally available generics for carboplatin may be used.
1.2.2.4.
Information About 5-Fluorouracil
5-Fluorouracil is a pyrimidine analog used as a chemotherapy drug and is indicated for the 
treatment of multiple solid tumors, including colorectal, breast, pancreatic, and gastric 
adenocarcinoma. It is also used in combination with platinum-based chemotherapy for the 
treatment of multiple solid tumors, including HNSCC. For current information about 5-FU, refer 


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to the applicable local or regional prescribing information in the pharmacy binder. Any locally 
available generics for 5-FU may be used.
1.2.2.5.
Docetaxel
Docetaxel is an antineoplastic agent which disrupts the microtubular network in cells that is 
essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and 
promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their 
disassembly. This leads to the production of microtubule bundles without normal function and to 
the stabilization of microtubules, which inhibits mitosis in cells. Docetaxel’s binding to 
microtubules does not alter the number of protofilaments in the bound microtubules, a feature 
which differs from most spindle poisons currently in clinical use. Docetaxel is indicated for the 
treatment of multiple solid tumors, including advanced NSCLC, as a single agent. For current 
information about docetaxel, refer to the applicable local or regional prescribing information in 
the pharmacy binder. Any locally available generics for docetaxel may be used.
1.3.
Rationale for This Study
Despite recent therapeutic improvements in the first-line metastatic HNSCC setting, novel 
therapies and combinations are needed to extend survival benefit. Recently, the US Food and 
Drug Administration (FDA) approved pembrolizumab as a monotherapy in subjects whose 
tumors express PD-L1 (CPS ≥ 1) and pembrolizumab in combination with 5-FU and platinum in 
subjects regardless of PD-L1 tumor expression {KEYTRUDA 2021}. These approvals were 
based on an approximately 2 to 3-month survival benefit in both settings, demonstrating the need 
for therapeutic combinations to improve subject benefit. Furthermore, the majority of subjects do 
not respond (primary resistance) or develop resistance after initial tumor regression (acquired 
resistance). This may be due, at least in part, to poor T-cell infiltration into the tumor, which is 
negatively correlated with treatment response. Therefore, the development of novel approaches 
to increase T-cell infiltration within the TME may increase the number of patients benefiting 
from immunotherapy. To this point, evidence indicates critical roles for tumor-residing 
Batf3-dependent cDC1s (migratory CD103+ and lymphoid CD8a+ DCs in mice, and CD141+ 
DCs in humans) in priming and expansion of tumor-specific CD8+ T cells and their recruitment 
to the TME. Although sparse in the TME, cDC1s can be recruited by systemic administration of 
FLT3L  {Hammerich 2019, Hegde 2020}. In this study, GS-3583 is utilized to expand and 
mobilize cDC1s from the hematopoietic progenitors. However, mobilization of cDC1s alone is 
insufficient to generate antitumor T-cell responses in established tumors–immunostimulation in 
the form of intratumoral or systemic administration of toll-like receptor 3 (TLR3) agonists, 
CD40 agonists or radiotherapy, either alone or in combination, is required {Salmon 2016, 
Sanchez-Paulete 2016}. In the current study, immunogenic chemotherapy from the combination 
of 5-FU and a platinum agent is hypothesized to provide such immunostimulation to cDC1 cells 
expanded by GS-3583 which may, in turn, improve the response to immunotherapy.


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Similarly, there remains a high unmet need for novel agents in the treatment of advanced 
NSCLC particularly in subjects who have failed treatment with immune checkpoint inhibitors 
and platinum-based chemotherapy. Even though much progress has been made in the 
development of targeted treatments for specific genomic alterations, eventually most subjects 
have progressive disease on these treatments after which they are treated with platinum 
chemotherapy with or without immune checkpoint inhibitors. Although docetaxel is considered 
standard of care in subjects failing platinum-based regimens and checkpoint inhibitors, novel 
agents remain a significant unmet medical need in subsequent treatment of advanced NSCLC. In 
a study of docetaxel versus best supportive care in relapsed NSCLC, the median PFS was 
approximately 3 months with a median OS of approximately 6 to 8 months {Shepherd 2000}. 
These numbers have been borne out in more contemporaneous studies with docetaxel following 
failure of platinum-based regimens in NSCLC {Horn 2017, Mazieres 2021}. GS-3583 is 
hypothesized to improve the antitumor activity seen with docetaxel in NSCLC based on the 
nonclinical data in syngeneic tumor models (Section 1.3.1). It is postulated that docetaxel 
induces immunogenic cell death which can trigger the activation and maturation of cDC1s 
produced by GS-3583, to present antigen, and prime tumor-specific CD8+ T cells in a manner 
similar to what has been observed with radiotherapy {Demaria 2016, Gupta 2012, Lugade 2005, 
Weichselbaum 2017}.
Part 1 of this study is designed to assess the safety, tolerability, PK, and preliminary efficacy of 
GS-3583 given as a monotherapy and determine the MTD. Part 1 will also explore the PK and 
PK-pharmacodynamic relationship as evaluated by peripheral DC expansion. Once the MTD or 
RP2D of GS-3583 as monotherapy has been determined, Part 2 of the study will explore 
GS-3583 in combination with chemotherapy agents with or without a checkpoint inhibitor in 
NSCLC and HNSCC.
Part 2 of the study utilizes a randomized design in order to assess the contribution of GS-3583 in 
combination with other anticancer therapies. The randomized design also enables the comparison 
of the Treatment Arm, which includes GS-3583, with a contemporaneous Control Arm, 
mitigating the bias associated with historical controls and the need for cross-study comparison.
1.3.1.
Rationale for GS-3583 + Chemotherapy Combination
The mouse surrogate GS-1062398 (mGS-3583) was used to assess combination activity with 
docetaxel in the mouse syngeneic tumor model CT26. Tumor growth inhibition of 50% was 
achieved with mGS-3583 in combination with docetaxel, as compared to 22% growth inhibition 
by either mGS-3583 or docetaxel monotherapies, respectively.
The syngeneic mouse colon tumor model, CT26, is not responsive to docetaxel alone and only 
weakly inhibited by mGS-3583 alone; however, when docetaxel is combined with mGS-3583, 
the tumor growth is significantly inhibited (Figure 1-1).






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cynomolgus monkeys (in terms of cDC1 expansion), GS-3583 doses of 2000 μg may induce 
cDC1 expansion at therapeutically relevant levels and doses of up to 20,000 μg administered 
every 4 weeks may help sustain the peak expansion of cDC1 before returning to the baseline. A 
4-week dosing interval may be suitable for testing the concept of clinical efficacy in subjects 
with solid tumors.
The nonclinical safety profile of GS-3583 has been characterized in a 4-week GLP IV 
repeat-dose toxicity study with 4-week recovery period in cynomolgus monkeys. GS-3583 was 
well tolerated when given IV at doses of up to 10 mg/kg/week for 4 weeks. The no observed 
adverse effect level (NOAEL) in the cynomolgus toxicity study was determined to be 
10 mg/kg/week, corresponding to an average Cmax of 385 μg/mL and AUCtau of 40,100 μg•h/mL 
on Day 22.
On a mg/kg basis, the starting dose of 675 μg GS-3583 in the present study represents a 900-fold 
safety margin relative to the NOAEL in cynomolgus monkeys. Based on the current PK 
projections, GS-3583 675 μg multiple doses are predicted to result in Cmax of 267 ng/mL and 
AUCtau of 9494 ng•h/mL in humans, which correspond to approximately 1440- and 4224-fold 
safety margins, respectively, relative to the Cmax and AUCtau of the 10 mg/kg NOAEL dose in 
cynomolgus monkeys.
The proposed starting dose, dose levels, and dosing frequency of GS-3583 in Part 1 of the 
current study (GS-US-496-5657) may be adjusted based on available data from the 
first-in-human study (GS-US-496-5619) that is currently ongoing in HVs. The first-in-human 
study is investigating the safety, PK, and pharmacodynamics of single ascending doses of 
GS-3583 at 75 g, 225 g, 675 g, and 2000 g. The starting dose of the current study may be 
adjusted such that any dose level that is found to be well tolerated in HVs will not be repeated.
In Part 1, subjects will receive doses of GS-3583 every 2 weeks for the first 3 doses; all 
subsequent doses will be given every 4 weeks for a total of up to 52 weeks (13 cycles). In Part 2, 
subjects will receive GS-3583 every 3 weeks for a total duration of up to 24 weeks (8 cycles). 
The frequency of dosing is supported by the initial 3 dose levels in Part 1 (in which GS-3583 was 
administered every 2 weeks) and based on the lack of significant AEs to date (at doses of up to 
12,000 μg). The dose level selected for Part 2 safety run-in will not exceed the highest dose level 
tolerated during Part 1 of the study. Furthermore, Part 2 safety run-in allows the initial evaluation 
of the safety and tolerability of GS-3583 in combination with other anticancer therapies with the 
option to dose de-escalate, if required, prior to the enrollment of the Randomized Expansion 
cohorts.
For further information on GS-3583, refer to the current IB.
1.5.
Risk/Benefit Assessment for the Study
The proposed Part 1 of the study aims to evaluate GS-3583 in subjects with advanced 
malignancies as a single agent to evaluate safety and to determine the MTD/RP2D. Nonclinical 
investigations provide sufficient evidence that subjects with advanced solid tumors administered 
GS-3583 would not be exposed to unjustifiable risks.


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Based on the nonclinical safety profile of GS-3583, the anticipated risks in subjects will be 
related to FLT3 agonism and may include expansion of cDC1 and cDC2 cell populations, 
peripheral monocytes, lymphocytes, total white blood cells, neutrophils, and eosinophils to a 
lesser degree. There may also be changes in serum cytokine changes that could reflect the change 
in DC populations; however, this is unlikely to lead to acute release of cytokines or cytokine 
storm which has not been observed in cynomolgus monkeys, the most sensitive species in the 
nonclinical toxicology studies.
Part 2 of the study in combination with chemotherapy alone (in NSCLC) or with immunotherapy 
(in HNSCC) will be started after monotherapy dose escalation is complete and the MTD or 
RP2D of GS-3583 has been determined. Based on the safety profile observed from the GS-3583 
nonclinical studies and the clinical experience to date (both in HVs and subjects with advanced 
solid tumors), minimal overlapping toxicities are expected between GS-3583 and other 
combination agents. Nonetheless, to mitigate against any new safety concerns with the proposed 
combinations, both HNSCC and NSCLC cohorts have a dedicated safety run-in with the option 
to dose de-escalate GS-3583 prior to further enrollment. It is worth noting that the recombinant 
FLT3L, CDX-301, has been combined with the immune checkpoint inhibitor pembrolizumab in 
addition to other immunostimulatory agents in ongoing studies {Hammerich 2019}.
There is postulated risk of developing secondary hematological malignancies with FLT3 
activation, based on the observation that aberrant expression of FLT3 is commonly found in 
hematopoietic malignancies, in particular, acute myeloid leukemia. In most cases, this is due to 
activating mutations in the FLT3 gene that promote ligand-independent continuous signaling. 
This theoretical risk has been mitigated by limiting the exposure of subjects to GS-3583 to 
12 months in Part 1 of this study, in which subjects have limited life expectancy due to the 
advanced nature of their malignancies; exposures is further reduced to 24 weeks in Part 2 of the 
study. Moreover, the related recombinant FLT3L (CDX-301) has safely been administered to 
more than 500 patients, including over 300 patients for up to 6 months with cancer with no report 
of secondary leukemia development {Ohri 2018}. There is also theoretical risk of immune 
related adverse events (irAEs) with agents that modulate the immune system and therefore, any 
subjects with a history of active autoimmune diseases will be excluded from the study. Some 
subjects may receive GS-3583 alongside stereotactic body radiation therapy (SBRT) at the 
discretion of the investigator in line with the local protocol. The recombinant FLT3L (CDX-301) 
has been administered in combination with SBRT in patients with NSCLC; this combination has 
been well tolerated.
Subjects may develop ADAs to GS-3583 which may interfere with the physiological actions of 
endogenous FLT3L. Subjects will be monitored for the development of ADAs and any potential 
sequalae throughout their treatment period with GS-3583 and at the end of study. 
Parameters for discontinuation of study drug are defined in Section 6.10.1.
During a pandemic, additional potential risks to subjects may include adequate study drug 
availability, interruptions to the study visit schedule, and adherence to protocol-specified safety 
monitoring or laboratory assessments. Refer to Appendix 2 for further details on the risks and 
risk mitigation strategy.


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There may be no direct benefit to subjects participating in this study; however, data from this 
study will support further development of GS-3583 for the treatment of subjects with advanced 
solid tumors. 
Based on available information, the benefit/risk balance for this study is considered justifiable.
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
2.1.
Objectives: Part 1
The primary objectives of Part 1 are as follows:

To characterize the safety and tolerability of GS-3583 as monotherapy in subjects with 
advanced solid tumors

To determine the MTD or RP2D of GS-3583 as monotherapy in subjects with advanced solid 
tumors
The secondary objectives of Part 1 are as follows:

To characterize the PK of GS-3583 in subjects with advanced solid tumors

To evaluate the immunogenicity of GS-3583 in subjects with advanced solid tumors
The exploratory objectives of Part 1 are as follows: 
2.2.
Objectives: Part 2
The primary objective of Part 2 is as follows:

To assess the safety and tolerability and to determine the RP2D of GS-3583 in combination 
with zimberelimab and platinum (cisplatin or carboplatin) + 5-FU chemotherapy in subjects 
with HNSCC (Cohort A) or in combination with docetaxel in subjects with NSCLC 
(Cohort B)
The secondary objectives of Part 2 are as follows:

To evaluate the investigator-assessed confirmed objective response rate (ORR) with GS-3583 
in combination with zimberelimab and platinum (cisplatin or carboplatin) + 5-FU 
chemotherapy in subjects with HNSCC (Cohort A) or in combination with docetaxel in 
subjects with NSCLC (Cohort B)
CCI


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
To assess the preliminary efficacy of GS-3583 in combination with zimberelimab and 
platinum (cisplatin or carboplatin) + 5-FU chemotherapy versus zimberelimab and platinum 
(cisplatin or carboplatin) + 5-FU chemotherapy alone in subjects with HNSCC (Cohort A) or 
in combination with docetaxel versus docetaxel alone in subjects with NSCLC (Cohort B) as 
determined by PFS, duration of response (DOR), and OS

To evaluate investigator-assessed disease control rate (DCR) with GS-3583 in combination 
with zimberelimab and platinum (cisplatin or carboplatin) + 5-FU chemotherapy in subjects 
with HNSCC (Cohort A) or in combination with docetaxel in subjects with NSCLC 
(Cohort B)

To evaluate the PK of GS-3583 administrated in combination with zimberelimab and 
platinum (cisplatin or carboplatin) + 5-FU chemotherapy in subjects with HNSCC 
(Cohort A) or in combination with docetaxel in subjects with NSCLC (Cohort B)

To evaluate the immunogenicity of GS-3583 administrated in combination with 
zimberelimab and platinum (cisplatin or carboplatin) + 5-FU chemotherapy in subjects with 
HNSCC (Cohort A) or in combination with docetaxel in subjects with NSCLC (Cohort B)
The exploratory objectives of Part 2 are as follows:
CCI


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3.
STUDY DESIGN
3.1.
Endpoints
The endpoints of this study are described in Sections 8.1.2 and 8.1.3.
3.2.
Study Design
3.2.1.
Part 1: Dose Escalation of GS-3583 as Monotherapy
Part 1 is a Phase 1b, open-label study to evaluate the safety, tolerability, PK, and preliminary 
efficacy of GS-3583 in adult subjects with advanced solid tumors to determine the MTD or 
RP2D level of GS-3583 as monotherapy. Below is an overview of the study design (Figure 3-1).
Figure 3-1.
Part 1 Study Schema
DLT = dose-limiting toxicity
3.2.1.1.
Dose Escalation
Subjects with advanced solid tumors who have failed or are intolerant to standard therapy or for 
whom no standard therapy exists will be sequentially enrolled at progressively higher dose levels 
to receive GS-3583 as monotherapy.
Dose escalation will proceed using a standard 3 + 3 design as shown in Figure 3-2. The starting 
dose will be 675 μg and may be modified if the results of the Phase 1a HV study (Study 
GS-US-496-5619) are available prior to the initiation of this study. Subsequent doses of 2000 μg, 
6000 μg, 12,000 μg, and 20,000 μg are planned. Dose level increases will be 3-fold or less 
(Table 3-1). GS-3583 will be administered on Days 1 and 15 of Cycle 1 and on Day 1 of each 
subsequent 4-week/28-day cycle for up to 13 cycles or until the subject meets study treatment 
discontinuation criteria.
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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Table 3-1.
Part 1 Dose Escalation Dose Levels
Dose Level Schema
Cohort
GS-3583 (μg)
Fold Increase
1
675
—
2
2000
≤ 3 ×
3
6000
≤ 3 ×
4
12,000
≤ 2 ×
5
20,000
≤ 1.67 ×  
The safety and tolerability of each dose level will be assessed by the safety review team (SRT) after 
all subjects in the cohort have had 2 doses of GS-3583 and have been followed for at least 28 days 
after the first dose of GS-3583 or if subjects had dose-limiting toxicities (DLTs) during the first 
28 days of study drug dosing. 
The initial block of each dose consists of 3 subjects. Dose escalation will occur if no subjects 
experience a DLT during the first 28 days of study drug dosing. If 1 subject within the initial 
cohort of 3 subjects experiences a DLT during the first 28 days of study drug dosing, an 
additional 3 subjects will be enrolled at the same dose level. If no DLTs are observed in the 
additional 3 subjects, dose escalation will occur. If 2 or more subjects experience DLTs within 
the first 28 days, dose de-escalation to a lower dose will occur. The MTD is the highest dose 
level with a subject incidence of DLTs of < 33% in 6 or more subjects during the first 28 days of 
study drug dosing. A minimum of 6 subjects need to be treated at a dose level before this dose 
level can be deemed as the MTD. A subject who fails to receive all GS-3583 treatments or fails 
to complete all safety assessments in the DLT period for reasons other than DLT will be 
replaced. 
The SRT will review safety and relevant clinical data and make the dose-
escalation/stay/de-escalation decision. Source data verification is not required to be performed 
prior to SRT meetings, as there will be alternative quality control checks implemented. These 
checks will be described in the safety review team charter. The SRT may also add up to 6 
additional subjects to any cohort determined to be safe to collect additional safety and 
PK/pharmacodynamic information. The SRT may also designate intermediate dose levels in 
addition to the ones listed in Table 3-1 after reviewing all the available safety and 
PK/pharmacodynamic information.
The dose of GS-3583 taken forward for Part 2 in combination with other anticancer agents will 
be determined based on all relevant clinical data from all subjects treated in the dose-escalation 
phase. This dose will not exceed the MTD.


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Figure 3-2.
3 + 3 Dose Escalation Scheme
DLT = dose-limiting toxicity; MTD = maximum tolerated dose
3.2.1.1.1.
Dose Escalation Criteria 
For any given cohort in Part 1, the sponsor may elect to hold dosing, select an intermediate dose, 
or stop study enrollment at any time based on review of the preliminary safety data.
Based on review of relevant safety and PK data by the SRT, as specified in Section 3.2.3, and in 
discussion with the investigator, escalation to a higher dose will occur only in the absence of 
DLTs and/or meeting any prespecified stopping criteria. 
3.2.2.
DLT Definition
A DLT is any toxicity defined below occurring during the DLT assessment period considered at 
least possibly related to GS-3583. 

For Part 1, the DLT assessment period is from Day 1 through Day 28.

For Part 2, the DLT assessment period is from Day 1 through Day 21.
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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A DLT may lead to permanent withdrawal of GS-3583 for the subject. The investigator should 
refer to the American Society of Clinical Oncology (ASCO) Toxicity Management Guidelines 
(Appendix 3) and withhold or discontinue GS-3583 accordingly.
Hematologic

Grade ≥ 3 thrombocytopenia with clinically significant bleeding (ie, requires hospitalization, 
transfusion of blood products, or other urgent medical intervention)

Grade ≥ 3 febrile neutropenia (absolute neutrophil count [ANC] < 1.0 × 109/L and fever 
> 101 °F/38.3 °C)

Any Grade 4 hematologic laboratory abnormalities/AEs regardless of duration will be 
considered DLTs with the exception of:
Grade 4 lymphopenia
Grade 4 neutropenia lasting ≤ 7 days that is not associated with fever (the use of growth 
factors is permitted)
Grade 4 anemia explained by underlying disease
Grade 4 thrombocytopenia lasting ≤ 7 days
Nonhematologic

Grade ≥ 3 nonhematologic toxicity, except:
Transient (≤ 3 days) Grade 3 fatigue, local reactions, headache, nausea, emesis, or 
diarrhea that are controlled with medical management and/or resolves to Grade ≤ 1 or 
baseline
Any Grade 3 endocrinopathy that is adequately controlled by hormonal replacement
Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor)
Grade 3 rash for ≤ 7 days
Transient (≤ 3 days) Grade 3 flu-like symptoms or fever, which are controlled with 
medical management
Transient (≤ 3 days) Grade 3 or higher electrolyte abnormality that is not clinically 
complicated and resolves spontaneously or responds to conventional medical 
interventions
An event clearly associated with the underlying disease, progressive disease, a 
concomitant medication, or comorbidity


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
Grade ≥ 2 nonhematologic treatment-emergent adverse event (TEAE) that in the opinion of 
the investigator is of potential clinical significance such that further dose escalation would 
expose subjects to unacceptable risk

Any Grade 3 or Grade 4 elevation in aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) associated with a Grade 2 elevation in bilirubin lasting ≥ 7 days 

Any irAE for which GS-3583 should be permanently discontinued as described in ASCO 
Toxicity Management Guidelines (Appendix 3) (eg, any grade encephalitis, Grade ≥ 3 
myocarditis, reoccurrence of the same Grade 3 adverse reaction) 
Dosing/Procedures-related Toxicities

Part 1 only: Inability to receive the first 2 doses of GS-3583 in Cycle 1 because of related 
toxicity, even if the toxicity does not meet DLT criteria defined above (regardless of dosing 
schedule)
Note: Exceptions include DLT exclusions mentioned above.
Grade 5 Event (ie, Death)
3.2.3.
Part 2: Disease-specific Cohorts of GS-3583 in Combination With Anticancer 
Therapies
Part 2 is a Phase 1b, open-label, multicenter study evaluating GS-3583 in combination with other 
anticancer therapies. There will be 2 cohorts in Part 2, each comprising safety run-in and 
open-label randomized expansion phases. Each safety run-in cohort will enroll 6 to 18 subjects 
based on observed toxicities. Once the SRT reviews each safety run-in cohort and the sponsor 
determines the RP2D for that cohort, randomized expansion cohorts will be enrolled (each 
randomized expansion cohort may commence enrollment based on the results of the 
corresponding safety run-in cohort). Up to 45 subjects will be randomized 2:1 to treatment and 
control arms in each randomized expansion cohort.

Cohort A will enroll subjects with metastatic or unresectable, locally recurrent HNSCC 
regardless of PD-L1 status who have not received previous systemic treatment for metastatic 
disease
Safety Run-in Cohort A: GS-3583 in combination with zimberelimab and platinum 
(cisplatin or carboplatin) + 5-FU chemotherapy
Randomized Expansion Cohort A: 
■
Treatment Arm: GS-3583 in combination with zimberelimab and platinum (cisplatin 
or carboplatin) + 5-FU chemotherapy. No more than 10 subjects with CPS < 1 will be 
enrolled in this arm.


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■
Control Arm: zimberelimab and platinum (cisplatin or carboplatin) + 5-FU 
chemotherapy. No more than 5 subjects with CPS < 1 will be enrolled in this arm.

Cohort B will enroll subjects with locally advanced, unresectable or metastatic NSCLC with 
documented progression on at least one anti-PD-1 or anti-PD-L1 mAb and platinum-based 
chemotherapy given individually or in combination.
Safety Run-in Cohort B: GS-3583 in combination with docetaxel 
Randomized Expansion Cohort B: 
■
Treatment Arm: GS-3583 in combination with docetaxel
■
Control Arm: docetaxel
An overview of the study design for Part 2 is shown in Figure 3-3 and Figure 3-4.
Figure 3-3.
Part 2 Study Schema
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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Figure 3-4.
Part 2 Safety Run-in and Randomized Expansion Phases
a
5-FU = 5-fluorouracil; HNSCC = head and neck squamous cell carcinoma; NSCLC = non–small-cell lung cancer; 
RP2D = recommended Phase 2 dose
3.2.3.1.
Safety Run-in Cohorts
Initially, 6 subjects will be enrolled into the safety run-in for each cohort at the RP2D as 
determined in Part 1. A DLT evaluation period of 1 cycle (21 days) will occur.
To date no dose-dependent toxicities have been observed with GS-3583; however, if DLTs occur 
during the safety run-in, dose de-escalation may take place for GS-3583 using the following 
rules:

If no more than 1 of 6 DLT-evaluable subjects experience a DLT in Cycle 1, enrollment into 
randomized expansion Cohorts A and B may begin at this dose level.

If 2 subjects experienced DLTs, 3 additional subjects may be enrolled into the cohort at the 
same dose level. If no additional DLTs occur in these 3 subjects, the dose level may be 
deemed safe by the SRT. If 1 or more DLTs occur in these 3 subjects, a lower dose cohort 
will be evaluated using the same 6 + 3 de-escalation algorithm to define the recommended 
dose for the combination regimens (Table 3-2).

If 3 or more (> 34%) DLT-evaluable subjects experience a DLT at any time, another 
6 subjects may be enrolled at a lower dose (Table 3-2) and will be evaluated in the same 
manner to define the recommended dose for the combination regimen.
The definitions of hematological and nonhematological toxicities in Section 3.2.2 will be utilized 
for Part 2.
  
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
  
  
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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Table 3-2.
Safety Run-in Cohort A: Dose De-escalation
Dose Schedule 
(Day per 21-Day Cycle)
Dose 
Level
Drug/Dose/Route
Cycle 1
Cycle 2
Cycle 3+
GS-3583 RP2D IV (60 min ± 10 min)
Day 1
Day 1
Day 1
(Maximum of 
8 cyclesa)
Zimberelimab 360 mg IV 
(60 min ± 5 min)
Day 1
Day 1
Day 1
(for up to 
105 weeksb)
5-FU 1000 mg/m2 of BSA/day continuous IV over 
96 hoursc
Days 1-4
Days 1-4
Days 1d-4
Cycles 3-6
(Maximum of 
6 cycles)
Starting 
dose
Cisplatin 100 mg/m2 of BSAe IV (1 hourf)
or
Carboplatin AUC of 5 mg/mL/min (1 hourf)
Day 1
Day 1
Day 1 
Cycles 3-6
(Maximum of 
6 cycles)
GS-3583 Dose Level minus 1g IV (60 min ± 
10 min)
Day 1
Day 1
Day 1
(Maximum of 
8 cyclesa)
Zimberelimab 360 mg IV 
(60 min ± 5 min)
Day 1
Day 1
Day 1
(for up to 
105 weeksb)
5-FU 1000 mg/m2 of BSA/day continuous IV over 
96 hoursc
Days 1-4
Days 1-4
Days 1d-4
Cycles 3-6
(Maximum of 
6 cycles)
Level 
minus 1
Cisplatin 100 mg/m2 of BSAe IV (1 hourf)
or
Carboplatin AUC of 5 mg/mL/min (1 hourf)
Day 1
Day 1
Day 1 
Cycles 3-6
(Maximum of 
6 cycles)
BSA = body surface area; 5-FU = 5-fluorouracil; IV = intravenous; RP2D = recommended Phase 2 dose
a
Subjects will receive GS-3583 for an additional 2 cycles after the completion of chemotherapy. This will amount to a 
maximum of 8 cycles of GS-3583 since there will be a maximum of 6 cycles of chemotherapy. Should the chemotherapy be 
terminated prior to the completion for Cycle 6 (due to reasons other than disease progression), GS-3583 will be continued 
for an additional 2 cycles.
b
Zimberelimab treatment will continue for a maximum of 105 weeks, unless 1 or more criteria for discontinuation are met.
c
l-leucovorin or d,l-leucovorin may be given prior to infusion according to local practice.
d
On Day 1 of each treatment cycle, the 5-FU infusion should be started after completion of all procedures and assessments 
according to the schedule of assessments (Appendix 4).
e
Dosing may be modified based on local/regional label and practice.
f
Or infusion duration according to local practice.
g
Refer to Table 3-1 for GS-3583 dose levels.


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Table 3-3.
Safety Run-in Cohort B: Dose De-escalation
Dose Schedule 
(Day per 21-Day Cycle)
Dose Level
Drug/Dose/Route
Cycle 1
Cycle 2
Cycle 3+
GS-3583 RP2D IV (60 min ± 10 min)
Day 1
Day 1
Day 1a 
(Maximum of 
8 cycles)
Starting 
dose
Docetaxel 75 mg/m2 of BSA IV 
(60 min ± 10 min)b,c
Day 1
Day 1
Day 1
GS-3583 Dose Level minus 1d IV (60 min ± 10 min)
Day 1
Day 1
Day 1a 
(Maximum of 
8 cycles)
Level 
minus 1
Docetaxel 75 mg/m2 of BSA IV 
(60 min ± 10 min)b,c
Day 1
Day 1
Day 1
BSA = body surface area; IV = intravenous; RP2D = recommended Phase 2 dose 
a
GS-3583 will be given for a maximum of 8 cycles. Should docetaxel be terminated prior to Cycle 6 (due to reasons other 
than disease progression), GS-3583 will be continued for an additional 2 cycles.
b
Docetaxel treatment is not limited by number of cycles and will continue until 1 or more criteria for discontinuation are met. 
c
GS-3583 will be administered before the start of the docetaxel infusion.
d
Refer to Table 3-1 for GS-3583 dose levels.
DLT Assessment Period: The DLT assessment period for Part 2 will be the first cycle (21 days) 
and applies to each safety run-in cohort. Subjects will be considered evaluable for assessment of 
DLTs if either of the following criteria is met during the DLT assessment period:

The subject experiences a DLT at any time after initiation of the first infusion of GS-3583.

The subject does not experience a DLT and completes at least 1 infusion of GS-3583 and at 
least 1 dose of zimberelimab, 1 dose of 5-FU, and 1 dose of cisplatin for safety run-in 
Cohort A; at least 1 infusion of GS-3583 and 1 dose of docetaxel for safety run-in Cohort B.
If a subject experiences a DLT during the DLT assessment period, the subject will discontinue 
treatment. Subjects who are not evaluable for DLT assessment in the safety run-in cohorts will 
be replaced.
3.2.4.
Safety Review Team
An SRT will be established to assess safety, review available PK data, make decisions on dose 
escalation, including the decision to dose escalate and the dose to be evaluated, and define the 
DLT and MTD, if applicable. The SRT will consist of at least 1 investigator, a representative 
from Gilead Global Patient Safety (GLPS) and the Gilead medical monitor. Others may be 
invited to participate as members of the SRT if additional expertise is desired (ie, representatives 
from Clinical Operations, Biostatistics, Clinical Pharmacology, and Biomarkers Sciences). The 
medical monitor serves as the chair of the SRT. An SRT charter will be agreed on by all SRT 
members prior to the first SRT meeting. The data reviewed at the SRT meeting to make dose-
escalation decisions will be defined in the SRT charter. The quality control checks performed on 
the data reviewed and used for making dose-escalation decisions will be described in the SRT 
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3.3.
Study Treatments
Details of on-study treatments administered in this study are described in Section 5. Refer to 
Section 5.3 for description of study drug formulation and packaging, Section 5.4 for details on 
planned doses to be administered, timing of doses, and any required pre- or post-medication and 
prophylaxis, Section 5.5 for instructions with regards to dose modifications and treatment 
interruptions, and Section 5.6 for information about prior and concomitant medications.
3.4.
Duration of Treatment
During Part 1 of the study, GS-3583 will be administered for a maximum of 13 cycles.
During Part 2 of the study, GS-3583 will be administered for a maximum of 8 cycles as follows:

In Cohort A (HNSCC), subjects will receive GS-3583 for an additional 2 cycles after the 
completion of chemotherapy. This will amount to a maximum of 8 cycles of GS-3583 since 
there will be a maximum of 6 cycles of chemotherapy. Should the chemotherapy be 
terminated prior to Cycle 6 (due to reasons other than disease progression), GS-3583 will be 
continued for an additional 2 cycles.

In Cohort B (NSCLC), docetaxel will be given until 1 or more criteria for discontinuation are 
met; and not limited by number of cycles. For these subjects, GS-3583 will be given for a 
maximum of 8 cycles. Should docetaxel be terminated prior to Cycle 6 (due to reasons other 
than disease progression), GS-3583 will be continued for an additional 2 cycles.
In Part 2 Cohort A, zimberelimab may be administered for up to 105 weeks.
Subjects will be treated with study drug until they meet discontinuation of study treatment listed 
in Section 6.10.1.
In Part 2, subjects who prematurely discontinue GS-3583 may be able to continue other study 
drugs and remain on the study if they are deemed to continue to derive benefit from those agents. 
However, such cases must be discussed with and approved by the medical monitor.
3.4.1.
Treatment Beyond Initial Progressive Disease
Pseudoprogression has been observed with CPI immunotherapeutic agents such as GS-3583 and 
zimberelimab which can differ from responses seen with cytotoxic agents and can manifest as a 
clinical response after an initial transient increase in tumor burden or appearance of new lesions.
Subjects who experience initial radiologic progressive disease and are clinically worsened will 
discontinue study drug treatment(s) and no further imaging is required.
Subjects who experience initial radiologic progressive disease but improve clinically are 
considered to have initial response evaluation criteria in solid tumors Version 1.1 (RECIST 
V1.1)–defined progressive disease and will be permitted, in consultation with the medical 
monitor, to continue with study drug treatment(s). These subjects will be reevaluated using the 


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same imaging modality no less than 4 weeks later (after the last imaging with initial RECIST 
V1.1–defined progressive disease) to assess whether study drug treatment will be continued. If 
repeat imaging shows a reduction in the tumor burden compared to the initial scan demonstrating 
radiologic progressive disease, treatment may be continued as per treatment calendar. If repeat 
imaging confirms radiologic progressive disease, subjects will be discontinued from study 
therapies. In determining whether or not the tumor burden has increased or decreased, 
investigators should consider all target lesions as well as nontarget lesions.
To continue study drug treatment beyond initial RECIST V1.1–defined progressive disease, 
subjects must meet all the following criteria:

There is investigator-assessed clinical benefit from the study drug treatment

Subject is clinically stable

Subject is tolerating study drug, and

There is an agreement with Gilead
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued study drug treatment. The 
following criteria need to be taken into consideration:

Absence of clinical symptoms and signs (including worsening of laboratory values) 
indicating progressive disease,

No decline in Eastern Cooperative Oncology Group (ECOG) performance status attributed to 
underlying malignancy, and 

Absence of rapid progression of disease or of progressive tumor at critical anatomical sites 
(eg, spinal cord compression) requiring urgent alternative medical intervention.
3.4.2.
Subsequent Anticancer Therapy
The investigator or qualified designee will review all new anticancer therapy initiated after the 
last dose of study treatment. If a subject initiates a new anticancer therapy within 60 days after 
the last dose of study treatment, the 60-day follow-up visit must occur before the first dose of the 
new anticancer therapy.
3.5.
Study Discontinuation Criteria
A subject will be discontinued from the study for any of the following reasons:

Withdrawal of consent

Investigator’s discretion


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
Death

Lost to follow-up

Discontinuation of the study at the request of Gilead, a regulatory agency, or an institutional 
review board (IRB), or independent ethics committee (IEC)
3.6.
End of Study
End of study will be defined as when the last subject reaches the last scheduled follow‑up time 
point (including the 60-day follow-up or survival follow-up, whichever occurs the latest), or is 
lost to follow-up, withdraws from the study, death, or the time at which Gilead closes the study.
3.7.
Poststudy Care 
Upon discontinuation from study treatment, subjects will receive the care upon which they and 
their physician(s) agree. Subjects will be followed for survival and AEs as specified in 
Section 7.3.2 and 7.3.3.
3.8.
Source Data
The source data for this study will be obtained from electronic data capture (EDC), interactive 
voice/web response system (IXRS), central laboratory, and specialty laboratory (for PK, 
immunogenicity and/or pharmacodynamic data).
3.9.
Biomarker Testing 
3.9.1.
Biomarker Samples to Address the Study Objectives 
The following biological specimens will be collected from all subjects who have provided 
consent to participate in this study and may be used to evaluate the association of systemic 
and/or tissue-based biomarkers with study drug response (including efficacy and/or AEs) and 
dose selection, and to better understand the biological pathways involved in response to 
GS-3583, to increase knowledge and understanding of the biology of solid tumors and/or to 
validate a companion diagnostic. Because biomarker science is a rapidly evolving area of 
investigation, and AEs in particular are difficult to predict, it may not be possible to specify 
prospectively all tests that may be done on the specimens provided. The specific analyses will 
include, but may not be limited to, the biomarkers and assays listed below. The testing outlined 
below is based upon the current state of scientific knowledge. It may be modified during or after 
the end of study to remove tests no longer indicated and/or to add new tests based upon new state 
of the art knowledge. 






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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
This study will enroll approximately 150 subjects with advanced solid tumors as follows:
Part 1: 24 subjects
Part 2 Safety Run-in Cohort A: 6 to 18 subjects
Part 2 Safety Run-in Cohort B: 6 to 18 subjects
Part 2 Randomized Expansion Cohort A: approximately 45 subjects (randomized 2:1)
Part 2 Randomized Expansion Cohort B: approximately 45 subjects (randomized 2:1)
4.1.1.
Target Population
Part 1: Adult subjects aged ≥ 18 years with a histologically or cytologically confirmed diagnosis 
of locally advanced or metastatic malignant solid tumor that is refractory to or intolerant of 
standard therapy or for which no standard therapy is available.
Part 2:

Cohort A (HNSCC): Adult subjects aged ≥ 18 years with a histologically or cytologically 
confirmed diagnosis of metastatic HNSCC who have not previously received systemic 
therapy for metastatic disease or with recurrent disease who were considered incurable by 
local therapies.

Cohort B (NSCLC): Adult subjects aged ≥ 18 years with a histologically or cytologically 
confirmed locally advanced or metastatic NSCLC with documented progression on at least 
one anti-PD-1 or anti-PD-L1 mAb and platinum chemotherapy given individually or in 
combination.
4.1.2.
Subject Replacement
During Part 1 and during safety run-in of Part 2, any subject who fails to receive all GS-3583 
treatments or fails to complete all safety assessments in the DLT period for reasons other than 
DLT will be replaced.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in Part 1 
or Part 2 of this study:
1) Voluntarily agree to participate by giving a signed written informed consent


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2) Age ≥ 18 years
3) Have measurable disease on imaging based on RECIST Version 1.1 (Appendix 7). Tumor 
lesions situated in a previously irradiated area are considered measurable if progression has 
been demonstrated in such lesions. Historical images within 28 days of the screening visit 
may be accepted as a screening image if deemed acceptable in the opinion of the investigator.
4) Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 for Part 1 and 
ECOG of 0-1 for Part 2
5) Diagnosis
a) Part 1: Histologically or cytologically confirmed diagnosis of locally advanced or 
metastatic malignant solid tumor that is refractory to or intolerant of standard therapy or 
for which no standard therapy is available
b) Part 2 Cohort A (HNSCC):
i)
Subjects must have histologically or cytologically confirmed recurrent or metastatic 
HNSCC that is considered incurable by local therapies. 
ii) Subjects should not have had prior systemic therapy administered in the recurrent or 
metastatic setting. Systemic therapy which was completed more than 6 months prior 
to signing consent if given as part of multimodal treatment for locally advanced 
disease is allowed.
iii) The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and 
larynx.
iv) Subjects with a primary tumor site of nasopharynx (any histology) are not allowed.
v) Subjects must provide adequate tissue for biomarker analysis at baseline (fine needle 
aspirate [FNA] is not adequate). Repeat samples may be required if adequate tissue is 
not provided. This specimen may be the diagnostic sample for subjects with a new 
diagnosis of metastatic HNSCC. If obtained for a subject with recurrent disease for 
locally advanced disease, then it must be obtained after completion of the previous 
initial management with no other treatment from the time of biopsy until the start of 
study treatment. Subjects must also have a CPS at baseline using a locally available, 
validated test.
Note: In Randomized Expansion Cohort A, no more than 10 subjects with CPS < 1 
will be enrolled in the Treatment Arm and no more than 5 subjects with CPS < 1 will 
be enrolled in the Control Arm (Section 3.2.3).


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vi) Subjects must have results from local testing of HPV for oropharyngeal cancer 
defined as p16 IHC testing using a locally available validated test.
Note: Subjects with oral cavity, hypopharynx, or larynx cancer are not required to 
undergo HPV testing by p16 IHC as by convention they are assumed to be HPV 
negative.
c) Part 2 Cohort B (NSCLC): 
i)
Subjects must have histologically or cytologically confirmed locally advanced, 
unresectable or metastatic NSCLC with documented progression on at least 
1 anti-PD-1 or anti-PD-L1 mAb and platinum-based chemotherapy. Anti-PD-1 or 
anti-PD-L1 mAb and platinum-based chemotherapy may have been given 
individually or in combination.
ii) Includes subjects who received prior platinum-based chemoradiotherapy (with or 
without maintenance anti-PD-L1 antibody) for Stage 3 disease. To be considered to 
have progressed during or after prior treatment with platinum-based chemotherapy, 
subjects should have either received prior platinum-based chemotherapy in the 
recurrent or metastatic setting or have experienced disease progression within 
6 months of last dose of platinum-based chemotherapy administered as part of 
concurrent chemoradiation for Stage 3 disease or as neoadjuvant or adjuvant therapy. 
To be considered to have progressed during or after prior treatment with an anti-PD-1 
or anti-PD-L1 antibody, subjects should have either received this therapy in the 
recurrent or metastatic setting or have experienced disease progression during 
“maintenance” treatment following concurrent chemoradiation for Stage 3 disease.
These subjects must be tested for epidermal growth factor receptor (EGFR), 
anaplastic lymphoma kinase (ALK), ROS1, and PD-L1. Testing for other actionable 
genomic alterations is recommended and to be performed as per local standard of 
care.
iii) Subjects with EGFR, ALK, ROS1, or any other known actionable genomic alterations 
must have also received treatment with at least 1 approved therapy appropriate to the 
genomic alteration, unless these options are not available to the subjects. 
Note: No additional treatments are allowed in the recurrent/metastatic setting for 
subjects with no actionable genomic alterations.
iv) Documented radiographic disease progression while on or after receiving the most 
recent treatment regimen for advanced or metastatic NSCLC.
v) Subjects with mixed small-cell lung cancer and NSCLC histology are not eligible.


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vi) Subjects must provide adequate tissue for biomarker analysis at baseline (FNA is not 
adequate). Repeat samples may be required if adequate tissue is not provided. It must 
be obtained after completion of the previous line of therapy with no other treatment 
from the time of biopsy until the start of study treatment.
6) Life expectancy of ≥ 3 months, in the opinion of the investigator
7) Adequate organ function as assessed by hematological, renal, and hepatic parameters and no 
clinically significant coagulopathy as indicated by the following laboratory values 
(Hematologic laboratory values must be met at screening visit and maintained without 
transfusional or growth factor support within 2 weeks of study drug initiation):
System
Laboratory Valuea
Hematologicalb
Absolute Neutrophil Count (ANC)
≥ 1.5  109/L 
Plateletsc
Part 1 and Part 2 Cohort B (NSCLC): ≥ 100  109/L
Part 2 Cohort A (HNSCC): ≥ 75  109/L
Hemoglobinc
Part 1: ≥ 8 g/dL
 (≥ 9.5 g/dL in subjects with cardiac disease)
Part 2: ≥ 9 g/dL
(≥ 9.5 g/dL in subjects with cardiac disease)
Renal
Creatinine Clearancec
Part 1 and Part 2 Cohort B (NSCLC): ≥ 50 mL/min by the Cockcroft-
Gault method
Part 2 Cohort A (HNSCC): ≥ 60 mL/min by the Cockcroft-Gault method 
Hepatic
Total Bilirubin
≤ 1.5  ULN
AST (SGOT) and ALT (SGPT)c
Part 1 and Part 2 Cohort A (HNSCC): ≤ 3  ULN 
(≤ 5  ULN in subjects with liver metastases)
Part 2 Cohort B (NSCLC): ≤ 2.5  ULN
(≤ 5  ULN in subjects with liver metastases)
Serum albuminc
Part 2 Cohort B (NSCLC) only: > 3 g/dL
Coagulationd
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤ 1.5  ULN unless the subject is receiving anticoagulant therapy
≤ 1.5  ULN unless the subject is receiving anticoagulant therapy
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SGOT = serum glutamic oxaloacetic transaminase; 
SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal
a
All screening laboratory tests must be reviewed by the investigator and be acceptable prior to enrollment. 
b
Hematologic laboratory values must be met at screening visit and maintained without transfusional or growth factor support 
within 2 weeks of study drug initiation.
c
Adequate laboratory values differ by study part and/or cohort due to differences in anticancer agents used in Part 2.
d
Subjects on full-dose oral anticoagulation, must be on a stable dose (minimum duration 14 days prior to the screening visit). 
Subjects on low molecular weight heparin will be allowed. In subjects receiving warfarin, the recommended INR is ≤ 3.0 
with no active bleeding (ie, no bleeding within 14 days prior to first dose of study drug).


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8) A negative serum pregnancy test is required for female subjects (unless permanently sterile 
or greater than 2 years postmenopausal as described in Appendix 5).
9) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol-specified method(s) of contraception and refrain from 
egg or sperm donation as described in Appendix 5.
10) All acute toxic effects of prior antitumor therapy resolved to National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 Grade ≤ 1 before 
the first dose of study drug, with the exception of Grade 2 alopecia and peripheral 
neuropathy.
11) Lactating females must agree to discontinue nursing before the study drug is administered 
until 12 weeks after the last dose of study drug.
12) Able and willing to comply with the protocol requirements 
4.3.
Exclusion Criteria
4.3.1.
General Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not eligible to be enrolled in Part 1 
or Part 2 of this study:
1) Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigation device within 
3 weeks of the first dose of treatment
2) Has received prior systemic cytotoxic chemotherapy, biological therapy, radiotherapy, or 
major surgery within 3 weeks of Cycle 1 Day 1; a 1-week washout is permitted for palliative 
radiation to non–central nervous system (CNS) disease with medical monitor approval
3) Is expected to require any other form of systemic or localized anticancer therapy while on 
study (including maintenance therapy with another agent, and/or surgical resection); for 
subjects enrolled in Part 1 of the study, provision of SBRT per local standard of care is 
acceptable beyond the DLT evaluation period starting at Cycle 2. Hormonal/endocrine 
therapy for prostate cancer or breast cancer is permitted.
4) Has known severe hypersensitivity reactions (NCI CTCAE Grade ≥ 3) to fully human mAb s 
or fusion proteins, GS-3583 formulation excipients, or severe reaction to immuno-oncology 
agents, such as colitis or pneumonitis requiring treatment with corticosteroids, any history of 
anaphylaxis, or uncontrolled asthma
5) Is receiving systemic corticosteroid therapy 1 week prior to the first dose of study treatment 
or receiving any other form of systemic immunosuppressive medication


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Note: The following corticosteroid uses are permitted: use as premedication for known 
hypersensitivity reactions (eg, IV contrast, IV drug infusions); intraocular, intranasal, 
inhaled, and/or topical corticosteroids; and/or prednisone at doses of up to 10 mg per day or 
equivalent. The use of physiologic doses of corticosteroids may be approved after 
consultation with the medical monitor.
6) Has concurrent active malignancy other than nonmelanoma skin cancer, carcinoma in situ of 
the cervix, or superficial bladder cancer who has undergone potentially curative therapy with 
no evidence of disease. Subjects with other previous malignancies are eligible if disease free 
for > 2 years.
7) Previous history of hematological malignancy, monoclonal gammopathy of unknown 
significance (MGUS) or other preleukemic states (Presence of CHIP/age-related clonal 
hematopoiesis [ARCH] is acceptable.)
8) Has a known CNS metastasis(es), unless metastases are treated and stable and the subject 
does not require systemic corticosteroids for management of CNS symptoms at least 1 week 
prior to study treatment. Subjects with history of carcinomatous meningitis are excluded 
regardless of clinical stability.
9) Has active autoimmune disease that requires systemic treatment (ie, with use of 
disease-modifying agents, corticosteroids, or immunosuppressive drugs)
Note: Subjects with diabetes type 1, vitiligo, psoriasis, hypothyroid disease, or hyperthyroid 
disease, not requiring immunosuppressive treatment are eligible.
10) Has had an allogeneic tissue/solid organ transplant
11) Has evidence of active pneumonitis
12) Has a serious systemic fungal, bacterial, viral, or other infection that is not controlled or 
requires IV antibiotics 
13) Previously known or existing FLT3 mutation of any kind
14) Has known active hepatitis B virus (HBV) and/or hepatitis C virus (HCV), and/or HIV
a) Subjects must be negative for hepatitis B surface antigen and total antibody against 
hepatitis B core antigen (anti-HBc). For subjects where total anti-HBc is positive, HBV 
DNA by quantitative polymerase chain reaction will be required. 
b) Subjects must be negative for HCV antibody. For subjects with positive HCV antibody, 
HCV RNA by quantitative polymerase chain reaction will be required. 
c) Subjects must also be negative for HIV at screening.


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15) Subjects with cardiovascular disease/abnormalities will be excluded per the following 
criteria:
a) Has clinically significant (ie, active) cardiovascular disease: cerebral vascular 
accident/stroke or myocardial infarction within 6 months of enrollment, unstable angina, 
congestive heart failure (New York Heart Association class III or IV), or serious 
uncontrolled cardiac arrhythmia requiring medication.
b) Has systolic dysfunction defined as ejection fraction < 45% measured by echocardiogram 
(ECHO) (or multigated acquisition [MUGA] scan). Results from ECHO or MUGA scan 
performed up to 30 days prior to enrollment are acceptable.
16) History or evidence of clinically significant disorder, condition, laboratory abnormality, or 
disease that, in the opinion of the investigator or medical monitor would pose a risk to 
subject safety or interfere with the study evaluations, procedures, or completion 
17) Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the study
18) Is legally incapacitated or has limited legal capacity
19) Uncontrolled intercurrent illness or significant illnesses during the screening period
20) Part 2 Cohort A HNSCC
a) Has disease that is suitable for local therapy administered with curative intent
b) Has progressive disease (PD) within 6 months of completion of curatively-intended 
systemic treatment for locoregionally advanced HNSCC
21) Part 2 Cohort B NSCLC
a) Previously received treatment with docetaxel as monotherapy or in combination with 
other agents
b) NSCLC that is eligible for definitive local therapy alone
22) Have received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu 
and COVID-19 vaccines that do not contain live virus are permitted.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment/Randomization
An IXRS will be employed to manage the conduct of the study. The IXRS will be used to 
maintain a central log documenting enrollment, to assess current inventories of study drug, to 
initiate any necessary resupply of study drug, and to document discontinuation of study drug. 
Subjects who meet eligibility criteria will be enrolled starting on Cycle 1 Day 1 and assigned a 
subject number by IXRS.
For Part 1, no randomization procedures will be applied to treatment assignment.
For Part 2, subjects enrolled in Safety Run-In Cohort A and Safety Run-In Cohort B will not be 
randomized. After the safety run-in, central randomization will be implemented to minimize bias 
in the assignment of subjects to treatment groups for expansion Cohort A and Cohort B, 
respectively. Subjects who meet randomization eligibility criteria will be randomized in a 
2:1 ratio to receive GS-3583 in combination with zimberelimab and platinum (cisplatin or 
carboplatin) + 5-FU chemotherapy or zimberelimab and platinum (cisplatin or carboplatin) + 
5-FU chemotherapy in randomized expansion Cohort A, or to receive GS-3583 in combination 
with docetaxel or docetaxel alone in randomized expansion Cohort B. The IXRS will implement 
a randomization scheme and assign a unique subject number.
5.2.
Blinding
Not applicable.
5.3.
Description and Handling
5.3.1.
GS-3583
5.3.1.1.
Formulation
GS-3583 is supplied in 2 presentations as a liquid or a lyophilized drug product and intended for 
IV administration. For Part 1, GS-3583 is supplied either as a liquid or as a lyophilized drug 
product; for Part 2, GS-3583 is supplied as a liquid drug product. The two formulations are 
detailed below:
1) GS-3583 Injection is formulated as a sterile, clear, preservative-free liquid composed of 
20 mM histidine/histidine-HCl, 263 mM sucrose, and 0.02% (weight-to-volume ratio [w/v]) 
polysorbate 80 at pH 5.9. It is supplied in a 6 mL vial with a deliverable volume of 5 mL 
containing 10 mg of GS-3583 at a concentration of 2 mg/mL.
2) GS-3583 lyophilized powder for reconstitution is composed of 20 mM 
histidine/histidine-HCl, 263 mM sucrose, and 0.02% w/v polysorbate 80 at pH 5.9. It is 
supplied in a 20 mL vial with a deliverable volume after reconstitution with sterile water for 
injection of 5 mL containing 10 mg of GS-3583 at a concentration of 2 mg/mL.


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5.3.1.2.
Packaging and Labeling
GS-3583 will be provided in single-use clear glass vials, closed with coated elastomeric stoppers, 
and sealed with aluminum overseals and polypropylene flip-off caps.
All labels for GS-3583 drug products to be distributed to centers in the US and other 
participating countries shall be labeled to meet applicable requirements of the US FDA, 
European Union (EU) Guidelines to Good Manufacturing Practice, Medicinal Products for 
Human and Veterinary Use, Annex 13 (Investigational Medicinal Products), and/or other local 
regulations.
5.3.1.3.
Storage and Handling
GS-3583 must be stored at 2 °C to 8 °C and protected from light. Storage conditions are 
specified on the study drug label. Until dispensed to the subject, all study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel.
To ensure stability and proper identification, the study drug should be stored in the containers in 
which they were supplied until dosing the subject.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.3.2.
Zimberelimab
5.3.2.1.
Formulation
Zimberelimab is formulated as a sterile, clear, preservative-free liquid intended for IV 
administration containing 20 mM histidine/histidine-HCl buffer solution (pH 5.5), 150 mM 
sucrose, 45 mM sodium chloride, and 0.02% (w/v) polysorbate 80. Each vial is manufactured to 
ensure a deliverable volume of 4 mL containing 120 mg of zimberelimab at a concentration of 
30 mg/mL.
5.3.2.2.
Packaging and Labeling
Zimberelimab is supplied in single-use, 8-mL glass vials with rubber stoppers and aluminum 
crimp overseals with a flip-off cap.  
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the US FDA, EU Guidelines to Good Manufacturing 
Practice, Medicinal Products for Human and Veterinary Use, Annex 13 (Investigational 
Medicinal Products), and/or other local regulations.


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5.3.2.3.
Storage and Handling
Zimberelimab must be stored at 2 °C to 8 °C (36 °F to 46 °F). Zimberelimab should not be 
frozen. Protect from light during storage. Do not shake. Storage conditions are specified on the 
label. Until dispensed to the subject, study drugs should be stored in a securely locked area, 
accessible only to authorized site personnel.
To ensure the stability and proper identification, study drug(s) should not be stored in a container 
other than the container in which they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.3.3.
Cisplatin
5.3.3.1.
Formulation
Cisplatin is commercially sourced. Information regarding the formulation can be found in the 
current prescribing information or summary of product characteristics for each country where the 
study will be conducted.
5.3.3.2.
Packaging and Labeling
Commercial product of cisplatin will be used for this study. Study drug(s) to be distributed to 
centers in the US and other participating countries shall be labeled to meet applicable 
requirements of the US FDA, EU Guidelines to Good Manufacturing Practice, Medicinal 
Products for Human and Veterinary Use, Annex 13 (Investigational Medicinal Products), and/or 
other local regulations.
5.3.3.3.
Storage and Handling
Information regarding the storage and handling of cisplatin can be found in the current 
prescribing information.
5.3.4.
Carboplatin
5.3.4.1.
Formulation
Carboplatin is commercially sourced. Information regarding the formulation can be found in the 
current prescribing information or summary of product characteristics for each country where the 
study will be conducted.


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5.3.4.2.
Packaging and Labeling
Commercial product of carboplatin will be used for this study. Study drug(s) to be distributed to 
centers in the US and other participating countries shall be labeled to meet applicable 
requirements of the US FDA, EU Guidelines to Good Manufacturing Practice, Medicinal 
Products for Human and Veterinary Use, Annex 13 (Investigational Medicinal Products), and/or 
other local regulations.
5.3.4.3.
Storage and Handling
Carboplatin is commercially sourced. Further information regarding storage and handling can be 
found in the current country-specific prescribing information.
5.3.5.
5-Fluorouracil
5.3.5.1.
Formulation
5-FU is commercially sourced. Information regarding the formulation can be found in the current 
prescribing information or summary of product characteristics for each country where the study 
will be conducted.
5.3.5.2.
Packaging and Labeling
Commercial product of 5-FU will be used for this study. Study drug(s) to be distributed to 
centers in the US and other participating countries shall be labeled to meet applicable 
requirements of the US FDA, EU Guidelines to Good Manufacturing Practice, Medicinal 
Products for Human and Veterinary Use, Annex 13 (Investigational Medicinal Products), and/or 
other local regulations.
5.3.5.3.
Storage and Handling
5-FU is commercially sourced. Information regarding the storage and handling can be found in 
the current prescribing information.
5.3.6.
Docetaxel
5.3.6.1.
Formulation
Docetaxel is commercially sourced. Information regarding the formulation can be found in the 
current full prescribing information or summary of product characteristics for each country 
where the study will be conducted.


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5.3.6.2.
Packaging and Labeling
Commercial product of docetaxel will be used for this study where docetaxel is approved for the 
treatment of locally advanced or metastatic NSCLC after platinum therapy failure. Study drug to 
be distributed to centers in other participating countries shall be labeled to meet applicable 
requirements of the US FDA, EU Guidelines to Good Manufacturing Practice, Medicinal 
Products for Human and Veterinary Use, Annex 13 (Investigational Medicinal Products), and/or 
other local regulations.
5.3.6.3.
Storage and Handling
Docetaxel is commercially sourced. Information regarding the storage and handling can be found 
in the current prescribing information.
5.4.
Dosage and Administration
5.4.1.
GS-3583
GS-3583 will be administered as an IV infusion over 60 (± 10) minutes. The proposed doses of 
GS-3583 for Part 1 of the study are 675 μg, 2000 μg, 6000 μg, 12,000 μg, and 20,000 μg; 
intermediate doses within this range may also be evaluated. The recommended dose for Part 2 
will be determined based on the safety, PK, pharmacodynamics, and all other relevant data from 
Part 1 and will not exceed the MTD in Part 1. 
In Part 1, the proposed dosing frequency is GS-3583 administered on Days 1 and 15 of Cycle 1 
and on Day 1 of each subsequent 4-week/28-day cycle; up to a maximum of 13 cycles. 
In Part 2 Safety Run-in Cohorts and Treatment Arms of the Randomized Expansion Cohorts, the 
proposed dosing frequency is GS-3583 administered on Day 1 of each 3-week/21-day cycle up to 
a maximum of 8 cycles (Table 5-1).
Table 5-1.
Proposed Schedule for GS-3583 in Part 1 and Part 2 of the Study
Cycle 1a
Subsequent Cyclesa
Part 1
Days 1 and 15
Day 1 (up to 13 cycles)
Part 2 Cohorts Ab and Bc
Day 1
Day 1 (up to 8 cycles)
a
In Part 1, each cycle is 28 days; in Part 2, each cycle is 21 days.
b
In Part 2 Cohort A (Safety Run-in Cohort and Randomized Expansion Cohort Treatment Arm), subjects will receive 
GS-3583 for an additional 2 cycles after the completion of chemotherapy. This will amount to a maximum of 8 cycles of 
GS-3583 since there will be a maximum of 6 cycles of chemotherapy. Should the chemotherapy be terminated prior to 
Cycle 6 (due to reasons other than disease progression), GS-3583 will be continued for an additional 2 cycles.
c
In Part 2 Cohort B (Safety Run-in Cohort and Randomized Expansion Cohort Treatment Arm), GS-3583 will be given for a 
maximum of 8 cycles. Should docetaxel be terminated prior to Cycle 6 (due to reasons other than disease progression), 
GS-3583 will be continued for an additional 2 cycles.
Premedications should not be administered routinely prior to dosing of GS-3583 unless a 
previous infusion reaction occurred. Refer to Section 5.5.1.3 for subsequent premedication 
recommendations following GS-3583–related infusion reactions.


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GS-3583 should be administered IV over approximately 60 minutes (± 10 minutes) at the 
research clinic by a qualified staff member. Infusions will be followed immediately with a saline 
flush of the IV line, per institutional guidelines. Modifications of the infusion rate due to 
infusion-related reactions are described in Section 5.5.1.3 and Table 5-4. The study drug will be 
administered without regard to food.
Subjects receiving GS-3583 should be monitored for infusion-related reactions. This includes the 
measurement of vital signs prior to each infusion commencing and at the end of each infusion 
(Table 5-2). In Part 1, vital signs will also be measured 1 hour (± 15 minutes) after the end of the 
GS-3583 infusion for the first 2 doses during Cycle 1. Thereafter in subsequent cycles, the 
posttreatment vital signs can be taken 30 minutes (−10/+20 minutes) after the end of the 
GS-3583 infusion. In Part 2 Cohorts A and B, vital signs will also be measured 1 hour 
(± 15 minutes) after the end of the GS-3583 infusion for the first dose during Cycle 1. Thereafter 
in subsequent cycles, the posttreatment vital signs can be taken 30 minutes (−10/+20 minutes) 
after the end of the GS-3583 infusion. Subjects will remain in the clinic under close supervision 
for the duration of this monitoring period.
Table 5-2.
Schedule for Measurement of Vital Signs in Part 1 and Part 2 of the 
Study
Cycle 1a, Day 1
Cycle 1a, Day 15
Subsequent Cyclesa, Day 1
Part 1
preinfusion, end of infusion; 
1 hour (± 15 minutes) 
postinfusion
preinfusion, end of infusion; 
1 hour (± 15 minutes) 
postinfusion
preinfusion, end of infusion; 
30 minutes (−10/+20 minutes) 
postinfusion
Part 2 
Cohorts A 
and B
preinfusion, end of infusion; 
1 hour (± 15 minutes) 
postinfusion
—
preinfusion, end of infusion; 
30 minutes (−10/+20 minutes) 
postinfusion
a
In Part 1, each cycle is 28 days; in Part 2, each cycle is 21 days
5.4.2.
Combination Therapies
Planned dosage and administration of combination therapies is shown in Table 5-3. GS-3583 will 
be administered as described in Section 5.4.1. Further details on dosing, including recommended 
premedications is provided in Sections 5.4.2.1 (zimberelimab), 5.4.2.2 (cisplatin or carboplatin), 
5.4.2.3 (5-FU), and 5.4.2.4 (docetaxel).
On days when GS-3583 is coadministered with other therapies, GS-3583 will be administered 
first. There will be a minimum of 1-hour observation period between the completion of GS-3583 
infusion and the start of the next agent/therapy or their corresponding premedication.


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Table 5-3.
Proposed Dose Levels and Schedules of Combination Therapies for 
Randomized Disease-Specific Expansion Cohorts
Cohort Number
Disease-specific 
Cohort
Drug/Dose/Route
Dose Schedule (Each 
Cycle is 21 Days)
Zimberelimab 360 mg IV infusion 
over 60 min ± 5 min
Day 1 of each cycle
(up to 105 weeks) a 
Cisplatin 100 mg/m² of BSA IV 
infusion over 1 hourb 
Day 1 of each cycle 
(up to 6 cycles)
Carboplatin AUC 5 mg/mL/min IV 
given over 1 hourb
Day 1 of each cycle 
(up to 6 cycles)
Cohort A
Metastatic or 
unresectable, recurrent 
HNSCC
5-FU 1000 mg/m2 of BSA/day 
continuous IV infusion over 
96 hours
Day 1c to Day 4 of 
each cycle (up to 
6 cycles)
Cohort B
Locally advanced, 
unresectable or 
metastatic NSCLCd
Docetaxel 75 mg/m2 of BSA IV 
infusion over 60 min ± 10 min
Day 1 of each cyclee
BSA = body surface area; 5-FU = 5-fluorouracil; HNSCC = head and neck squamous cell carcinoma; IV = intravenous; 
mAb = monoclonal antibody; NSCLC = non–small-cell lung cancer; PD-1 = programmed cell death protein 1; 
PD-L1 = programmed cell death protein 1
a
Zimberelimab treatment will continue for a maximum of 105 weeks, unless 1 or more criteria for discontinuation are met. 
b
Or infusion duration according to local practice.
c
On Day 1 of each treatment cycle, the 5-FU infusion should be started after completion of all procedures and assessments 
according to the Study Procedures Tables (Appendix 4).
d
With documented progression on at least one anti-PD-1 or anti-PD-L1 mAb and cisplatin-based chemotherapy given 
individually or in combination.
e
Docetaxel treatment will continue until 1 or more criteria for discontinuation are met, and not limited by number of cycles.
5.4.2.1.
Zimberelimab
Premedications are recommended for subjects who had infusion-related reactions to a prior 
zimberelimab infusion (Table 5-5). Subjects may be premedicated 1.5 hours (± 30 minutes) prior 
to infusion of zimberelimab with 50 mg diphenhydramine orally (or equivalent dose of 
antihistamine) and/or 500-1000 mg acetaminophen orally (or equivalent dose of antipyretic).
Zimberelimab doses are administered by IV infusion over 60 minutes (± 15 minutes), followed 
by a 30- to 60-minute observation period, on Day 1 of each 21-day cycle for a maximum of 
35 doses. Further guidance and information for the management of zimberelimab is provided in 
the Pharmacy Manual.
5.4.2.2.
Platinum (Cisplatin or Carboplatin)
Subjects may receive adequate pretreatment hydration per institutional guidelines. Premedication 
for prevention of chemotherapy-induced nausea and vomiting is recommended.


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Cisplatin or carboplatin can be administered in Cohort A (Safety Run-in and Randomized 
Expansion) per investigator choice. The platinum dosing regimen for Cohort A (Safety Run-in and 
Randomized Expansion) is presented in Table 5-3.
Cisplatin will be administered on Day 1 of each treatment cycle after completion of all 
procedures and assessments according to the schedule of assessments (Appendix Table 5). 
Cisplatin is given using an infusion duration of 60 minutes (or infusion duration according to 
local practice). Cisplatin can be administered for a maximum of 6 cycles. Subjects receiving 
cisplatin may switch to carboplatin if toxicities occur based on investigator judgment with 
medical monitor approval.
Carboplatin will be administered on Day 1 of each treatment cycle after completion of 
procedures and assessments according to the schedule of assessments (Appendix Table 5). 
Carboplatin is given using an infusion duration of 60 minutes (or infusion duration according to 
local practice). Carboplatin can be administered for a maximum of 6 cycles. Subjects receiving 
carboplatin may switch to cisplatin if toxicities occur based on investigator judgment with 
medical monitor approval.
5.4.2.3.
5-Fluorouracil
Subjects may receive any premedication as indicated per institutional guidelines.
5.4.2.4.
Docetaxel
If necessary, subjects may be premedicated with oral corticosteroids per institutional guidelines 
to reduce the incidence and severity of fluid retention as well as severity of hypersensitivity 
reactions.
5.5.
Dose Modifications and Treatment Delay
If an AE or a laboratory abnormality is attributed to only one study drug, it is at the 
investigator’s discretion to determine if the study drug(s) not attributed to the AE will be 
withheld based on the investigator’s assessment of risk-benefit of withholding one or more study 
drugs. Subjects who have drug-related toxicities that meet the criteria for dose delay should have 
study drug treatment delayed until criteria to resume treatment are met. It is recommended to 
restart study drug treatment at the next scheduled administration. 
Part 2 Cohort A:
For cisplatin, carboplatin, and 5-FU, subjects can have up to 2 dose modifications per agent, for 
toxicities as described in Table 5-9, Table 5-10, Table 5-12, and Table 5-13. If further toxicity 
occurs or the criteria for resuming treatment are not met, the subject may be discontinued from 
that drug, but may continue to participate in the study.
If a subject experiences several toxicities and there are conflicting recommendations, follow the 
most conservative dose adjustment recommended (dose reduction appropriate to the most severe 
toxicity).


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If, in the opinion of the investigator, the toxicity is related to the combination of 2 agents, or if 
the causality is unclear, 1 or both drugs may be reduced or held according to recommended dose 
modifications. Likewise, if, in the opinion of the investigator, the toxicity is related to the 
combination of 3 agents, or the causality is unclear, any 1 or more of the 3 agents may be 
reduced or held according to the recommended dose modifications. If 1 or more study agent(s) 
are held for toxicity, the schedule for restarting the agent(s) should correspond with the next 
treatment cycle once the toxicity has resolved according to the recommended guidelines. 
Subjects who require more than 2 dose modifications as outlined in the corresponding tables 
below to any particular component of the regimen for toxicities may have that agent 
discontinued. Any exception to the above recommendations may only be made with the approval 
of the medical monitor.
Investigators may follow the local label for dose modifications. If a toxicity is not otherwise 
specified, investigators should refer to the label or local standard of care for dose adjustments. 
These dose modification decisions must be documented in the subject’s study records and in the 
case report form.
5.5.1.
GS-3583
5.5.1.1.
Dose Modifications
Intrasubject dose reduction of GS-3583 is not permitted during Part 1 of the study; the need for a 
dose reduction is considered a DLT, and the subject may be discontinued from treatment. 
Intrasubject dose modifications of GS-3583 may be permitted once the MTD has been 
determined and during Part 1 of the study and written approval from the medical monitor should 
be obtained prior to dose modification/reduction. 
For subjects enrolled in Part 2 of the study, dose reductions may be permitted for the treatment of 
AEs. Approval from the medical monitor should be obtained prior to dose 
modification/reduction.
5.5.1.2.
Treatment Delay
Study treatment may be delayed due to any AE, laboratory abnormality, or intercurrent illness 
which, in the judgment of the investigator, warrants a delay.
Subjects who have drug-related toxicities that meet the criteria for dose delay should have study 
drug treatment delayed until criteria to resume treatment are met. Subjects who fail to receive 3 
or more consecutive doses of GS-3583 due to treatment delay may be discontinued from the 
study unless agreed otherwise with the Gilead medical monitor.


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5.5.1.3.
Treatment of Infusion-Related Reactions
Subjects receiving GS-3583 should be monitored for infusion-related reactions. This includes the 
measurement of vital signs (refer to Section 5.4.1 and Table 5-2 for schedule of vital signs 
measurements). Subjects will remain in the clinic under close supervision for the duration of this 
monitoring period. Subjects with mild or moderate infusion-related reactions may receive 
GS-3583 with close monitoring. Premedication with an antipyretic or antihistamine for 
subsequent treatment administration may be considered.
Subjects who do not experience any infusion-related reactions of Grade 1 or higher during or 
after the infusion may be released from monitoring after 1 hour if they are otherwise stable. 
Subjects with any infusion-related reactions must be managed as per the guidelines in Table 5-4, 
and monitoring will continue until any infusion-related reactions have abated to less than 
Grade 1 and at least 1 hour has passed from the completion of the entire infusion and flushing the 
line.
Should infusion-related reactions be considered a significant safety issue by the SRT, the SRT 
may decide to recommend premedication with an antihistamine and acetaminophen 
approximately 30 to 60 minutes before each dose of GS-3583 (eg, 25-50 mg diphenhydramine, 
500-1000 mg acetaminophen or equivalent dose of antipyretic). This regimen may be modified 
based on local treatment standards and guidelines, as appropriate.
All subjects will be given information on and instructions regarding both infusion-related 
reactions (which are expected to be most likely in the hour after completion of the infusion) and 
irAEs before leaving the study site.


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Table 5-4.
GS-3583 Infusion-Related Reactions Management Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dose 
Administration
Grade 1
Mild transient reaction; infusion 
interruption not indicated; 
intervention not indicated.
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion interruption 
but responds promptly to 
symptomatic treatment 
(eg, antihistamines, nonsteroidal 
anti-inflammatory drugs 
[NSAIDs], narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hours.
Stop infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to the following:
- IV fluids
- Antihistamines
- NSAIDs
- Acetaminophen
- Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 50% 
of the original infusion rate. Otherwise, dose 
administration will be held until symptoms resolve, 
and the subject should be premedicated for the next 
scheduled dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug 
administration.
Subject may be premedicated 
prior to infusion with the 
following:
- Diphenhydramine 25-50 mg 
PO (or equivalent dose of 
antihistamine)
- Acetaminophen 
500-1000 mg PO 
(or equivalent dose of 
antipyretic)
Grade 3 or 4
Grade 3
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (eg, renal 
impairment, pulmonary 
infiltrates).
Grade 4
Life-threatening; pressor or 
ventilatory support indicated.
Stop infusion.
Additional appropriate medical therapy may 
include but is not limited to:
- IV fluids
- Antihistamines
- NSAIDs
- Acetaminophen
- Narcotics
- Oxygen
- Pressor
- Corticosteroids
- Epinephrine
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from further 
study drug administration.
No subsequent dosing 
IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; 
NSAID = nonsteroidal anti-inflammatory drug; PO = orally


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5.5.1.4.
Management of Potential Immune-Related Adverse Events
Adverse events (both nonserious and serious) associated with drug exposure and consistent with 
an immune phenomenon may represent an immunologic etiology. Particular attention should be 
paid to AEs that may be suggestive of potential irAEs. These irAEs may be predicted based on 
the nature of the study drug, mechanism of action, and reported experience with 
immunotherapies that have a similar mechanism of action. Immune-related AEs may be 
associated with immuno-oncology agents such as GS-3583. An irAE is defined as an AE of 
unknown etiology, that is potentially associated with study drug exposure and is consistent with 
an immune-mediated phenomenon. Early recognition and management of irAEs may mitigate 
severe toxicity. An irAE can occur any time from shortly after the first dose to several months 
after the last dose of treatment. Such events may consist of persistent rash, diarrhea, colitis, 
autoimmune hepatitis, pneumonitis, encephalitis, arthritis, glomerulonephritis, cardiomyopathy, 
or uveitis and other inflammatory eye conditions.
The investigator should refer to the ASCO Toxicity Management Guidelines (Appendix 3) and 
withhold or discontinue GS-3583 accordingly.
5.5.1.5.
Criteria to Resume Treatment
Subjects may resume treatment with GS-3583 when drug-related AE(s) resolve(s) to Grade 1 or 
baseline value, with the following clarifications and certain exceptions:

Subjects may resume treatment in the presence of Grade 2 fatigue.

Drug-related Grade 2 pulmonary toxicity or colitis must have resolved to baseline before 
treatment is resumed.

Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment. (Exception: Study treatment does not need to be 
delayed/interrupted for subjects who experience immune-related hypothyroidism 
[Grades 1-2].)

Subjects who received systemic corticosteroids for management of any drug-related toxicity 
must be off corticosteroids or have tapered down to an equivalent dose of prednisone 
≤ 10 mg/day.
5.5.2.
Zimberelimab
5.5.2.1.
Dose Modifications
Dose reductions are not permitted. Zimberelimab treatment may be temporarily suspended in 
subjects experiencing toxicity considered to be related to study treatment.


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5.5.2.2.
Treatment Delay
Zimberelimab treatment may be temporarily suspended in subjects experiencing toxicity 
considered to be related to study treatment. If zimberelimab has been withheld for more than 
42 days because of toxicity, the subject should be discontinued from zimberelimab. However, 
zimberelimab can be resumed after being withheld for more than 42 days if the medical monitor 
agrees that the subject is likely to derive clinical benefit.
5.5.2.3.
Treatment of Infusion-related Reactions
Infusion-related reactions may occur during or after administration of zimberelimab. Dose 
reductions, other than a decrease in the infusion rate, are not allowed. Management guidelines 
for infusion reactions are displayed in Table 5-5.
Table 5-5.
Management of Infusion-related Reactions
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing
Grade 1: Mild reaction; 
infusion interruption not 
indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable 
in the opinion of the investigator. 
None 
Grade 2: Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hours 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy may include 
but is not limited to: IV fluids, antihistamines, 
NSAIDs, acetaminophen, and narcotics. 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable 
in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping IP 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 to 50 mL/hour). 
Otherwise, dosing will be held until symptoms 
resolve and the subject should be premedicated for 
the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further IP administration. 
Subject may be premedicated 
1.5 hours (± 30 minutes) prior to 
infusion of zimberelimab with: 

Diphenhydramine 50 mg orally 
(or equivalent dose of 
antihistamine) 

Acetaminophen 500-1000 mg 
orally (or equivalent dose of 
antipyretic) 
Grade 3 or 4 
Grade 3: Prolonged (ie, not 
rapidly responsive to 
symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates) 
Grade 4: Life-threatening; 
pressor or ventilatory support 
indicated 
Stop infusion. 
Additional appropriate medical therapy may include 
but is not limited to: IV fluids, antihistamines, 
NSAIDs, acetaminophen, narcotics, oxygen, pressors, 
corticosteroids, and epinephrine. 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable 
in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further 
IP administration. 
No subsequent dosing 
IP = investigational product; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events; NSAID = nonsteroidal anti-inflammatory drug.


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5.5.2.4.
Management of Potential Immune-related Adverse Events
Treatment modifications of zimberelimab, including dose delays, may be required in the event of 
treatment-related toxicity. Dose reductions are not permitted. Zimberelimab treatment may be 
temporarily suspended in subjects experiencing toxicity considered to be related to study 
treatment. If zimberelimab has been withheld for more than 42 days because of toxicity, the 
subject should be discontinued from zimberelimab. However, zimberelimab can be resumed after 
being withheld for more than 42 days if the medical monitor agrees that the subject is likely to 
derive clinical benefit. Further details on the assessment, evaluation and treatment of toxicities 
associated with anticancer immunotherapy can be found in the National Comprehensive Cancer 
Network (NCCN) Guideline on the Management of Immunotherapy-Related Toxicities. 
Treatment modifications and toxicity management guidelines for zimberelimab are displayed in 
Table 5-6. All toxicities will be graded according to NCI CTCAE v5.0. In case of doubt, the 
investigator should consult with the medical monitor.
Table 5-6.
Toxicity Management Guidelines for Zimberelimab
Adverse Event
NCI CTCAE 
Grade
Action
AE Management
Resumption
Grade 2
Withhold

Resume 
zimberelimab when 
pneumonitis resolves 
to Grade ≤ 1 and 
steroid dose is 
stable/decreasing at 
≤ 10 mg/day 
(prednisone or 
equivalent dose) 
Pneumonitis
Grade 3 or 4 
pneumonitis or 
recurrent Grade 2 
pneumonitis
Permanently 
discontinue

Evaluate subjects with 
suspected pneumonitis 
with radiographic 
imaging 

Administer 
corticosteroids (initial 
dose: 1-2 mg/kg/day 
prednisone or equivalent 
followed by a taper) 

Consider augmentation 
of therapy per NCCN 
guidelines 
(eg, infliximab, 
mycophenolate) if no 
improvement in 48 hours 
NA
Grade 2 or 3
Withhold

Resume 
zimberelimab when 
colitis/diarrhea 
resolves to Grade ≤ 1 
and steroid dose is 
stable/decreasing at 
≤ 10 mg/day 
(prednisone or 
equivalent dose) 
Colitis or Diarrhea
Grade 4
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose: 1-2 mg/kg/day 
prednisone or equivalent 
followed by a taper) 

Loperamide for 2-3 days 

Consider augmentation 
of therapy per NCCN 
guidelines (eg, 
infliximab) if no 
resolution in 7 days 
NA


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Adverse Event
NCI CTCAE 
Grade
Action
AE Management
Resumption
Grade 2
Withhold

Administer 
corticosteroids (initial 
dose: 0.5-1 mg/kg/day 
prednisone or equivalent 
followed by a taper)

Resume 
zimberelimab when 
transaminases return 
to baseline and 
steroid use is 
stable/decreasing at 
≤ 10 mg/day 
(prednisone or 
equivalent) 
Transaminitis without 
elevated bilirubin
Grade 3 or 4
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose: 1-2 mg/kg/day 
prednisone or equivalent 
followed by a taper) 
NA
Grade 1 or 2 
blood bilirubin 
increased
Withhold. 
Discontinue 
any potentially 
hepatotoxic 
medications. If 
no resolution, 
then 
permanently 
discontinue

Evaluate for alternative 
etiology (viral, 
drug-induced) 

Administer 
corticosteroids (initial 
dose: 2 mg/kg/day 
prednisone or equivalent 
followed by a taper) 

Resume 
zimberelimab if, after 
discontinuation of 
any potentially 
hepatotoxic 
medication, 
transaminases return 
to baseline and 
steroid use is 
stable/decreasing at 
≤ 10 mg/day 
(prednisone or 
equivalent) 
Transaminitis with 
elevated bilirubin 
(except in Gilbert’s 
syndrome)
Grade 3 or 4 
blood bilirubin 
increased
Permanently 
discontinue

Evaluate for alternative 
etiology (viral, 
drug-induced)

Administer 
corticosteroids (initial 
dose: 1-2 mg/kg/day 
prednisone or equivalent 
followed by a taper)

Hepatology consultation 
if appropriate
NA


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Adverse Event
NCI CTCAE 
Grade
Action
AE Management
Resumption
Grade 1
Continue

IV hydration 

Investigate other possible 
etiologies of elevated 
amylase/lipase 
NA
Grade 2
Withhold

IV hydration 

Administer 
corticosteroids (initial 
dose: 0.5-1 mg/kg/day 
prednisone or equivalent 
followed by a taper) 
Resume zimberelimab 
when: 

Symptoms no longer 
present 

No radiographic 
evidence of 
pancreatic 
inflammation 

Amylase and lipase 
Pancreatitis
Grade 3 or 4
Permanently 
discontinue

IV hydration 

Administer 
corticosteroids (initial 
dose: 0.5-1 mg/kg/day 
prednisone or equivalent 
followed by a taper) 
NA
Hypothyroidism 
(Grades 1 or 2)
Continue

Consultation with 
endocrinologist

Levothyroxine therapy: 
(1.6 mcg/kg or 75 to 
100 mcg starting dose, 
titrated to TSH level 
within normal limits for 
age)
NA
Thyroid disorders
Hypothyroidism 
(Grades 3 or 4)
Withhold

Withhold until clinically 
stable

Permanently discontinue if 
clinically indicated

If not permanently 
discontinue, resume 
treatment when 
symptoms no longer 
present
Hyperthyroidism 
(Grades 1 or 2)
Withhold if 
symptomatic 
(consider 
continuing if 
asymptomatic)

Consultation with 
endocrinologist

Resume when 
symptoms no longer 
present
Thyroid disorders
Hyperthyroidism 
(Grades 3 or 4)
Withhold

Withhold until clinically 
stable

Permanently discontinue if 
clinically indicated

If not permanently 
discontinue, resume 
treatment when 
symptoms no longer 
present


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Adverse Event
NCI CTCAE 
Grade
Action
AE Management
Resumption
Fasting glucose ≤ 
200 mg/dL
Continue

Consider consultation 
with an endocrinologist 
NA
Hyperglycemia
Fasting glucose > 
200 mg/dL OR 
random glucose 
> 250 mg/dL
Withhold if 
DKA is 
present, 
otherwise 
continue

If DKA, withhold 
immunotherapy and 
implement anti-DKA 
measures 

Resume 
zimberelimab when 
DKA is resolved 
(nonketotic) and in 
consultation with an 
endocrinologist to 
monitor for diabetes 
and related 
complications 
Grade 1
Consider 
withholding

Follow serum creatinine 
NA
Renal dysfunction 
(elevated creatinine)
Grade 2
Withhold

Administer 
corticosteroids (initial 
dose: 0.5-1 mg/kg/day 
prednisone or equivalent 
followed by a taper, if 
other causes of acute 
renal failure 
(dehydration, etc) are 
ruled out 
Resume zimberelimab 
when: 

Renal insufficiency 
resolves to Grade ≤ 1 

Creatinine is stable 

Steroid dose is 
stable/decreasing at 
≤ 10 mg/day 
(prednisone or 
equivalent dose) 
Renal dysfunction 
(elevated creatinine)
Grade 3 or 4
Permanently 
discontinue

Nephrology consultation 

Administer 
corticosteroids (initial 
dose: 1-2 mg/kg/day 
prednisone or equivalent 
followed by a taper) 

Consider augmentation 
of therapy per NCCN 
guidelines 
(eg, azathioprine, 
cyclosporine) is 
> Grade 2 for > 7 days 
NA 
Skin adverse reactions
Refer to Table 5-7 for treatment and management of dermatologic toxicity related to zimberelimab.
Grade 1
Continue

Institute supportive 
measures
NA
Grade 2
Consider 
withholding if 
interfering with 
ADLs

Administer 
corticosteroids based on 
severity of the adverse 
reaction

Resume 
zimberelimab when 
AE is ≤ Grade 1 
Other (may involve any 
organ system)
Grade 3 
recurrence or 
Grade 4
Permanently 
discontinue

Administer 
corticosteroids based on 
severity of the adverse 
reaction 
NA


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Adverse Event
NCI CTCAE 
Grade
Action
AE Management
Resumption

Upon improvement to 
Grade ≤ 1, initiate 
corticosteroid taper and 
continue to taper over 
≥ 1 month 

Systemic 
immunosuppressants 
may be considered for 
subjects whose immune-
related adverse reaction 
could not be controlled 
with corticosteroids 
ADL = activity of daily life; AE = adverse event; DKA = diabetic ketoacidosis; IV = intravenous; IVIG = intravenous 
immunoglobulin; NA = not applicable; NCCN = National Comprehensive Cancer Network; NCI CTCAE = National Cancer 
Institute Common Terminology Criteria for Adverse Events; TSH = thyroid-stimulating hormone; ULN = upper limit of normal.


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Table 5-7.
Treatment Management Guidelines for Dermatologic Toxicity 
Associated With Zimberelimab
Adverse Event
Severity
Assessment
Action Taken
AE Management
Resumption
Grade 1a

Total body skin exam, 
including mucosa

Assess for history of 
prior inflammatory 
dermatologic diseases

Consider biopsy if 
unusual features
Continue

Topical emollient

Oral antihistamine 
for pruritus

Treatment with 
moderate potency 
topical steroids to 
affected areas
NA
Grade 2b

Total body skin exam, 
including mucosa

Assess for history of 
prior inflammatory 
dermatologic diseases

Consider biopsy if 
unusual features

Continue study 
dose with 
intensified 
antipruritic 
therapy

Consider 
holding in 
select cases

Topical emollient

Oral antihistamine 
for pruritus

Treatment with 
moderate to high 
potency topical 
steroids to affected 
areas

If unresponsive to 
topical, consider 
prednisone 
0.5 mg/kg/day
For the select cases 
where treatment is 
held, consider 
resuming after 
symptoms have 
resolved to ≤ Grade 1 
(ie, once skin 
condition is 
mild/localized with 
only topical 
intervention 
indicated).
Grade 3c

Total body skin exam, 
including mucosa

Assess for history of 
prior inflammatory 
dermatologic diseases

Consider biopsy if 
unusual features
Withhold

Treatment with high 
potency topical 
steroids to affected 
areas

Prednisone 05 to 
1 mg/kg/day 
(increase dose up to 
2 mg/kg/day if no 
improvement)

Urgent dermatology 
consultation, 
consider biopsy

Consider in-patient 
care.
Consider resuming 
after symptoms have 
resolved to ≤ Grade 1 
(ie, once skin 
condition is 
mild/localized with 
only topical 
intervention 
indicated).
Dermatologic 
Toxicity (including 
but not limited to rash, 
maculo-papular rash, 
and pruritus)
Grade 4c

Total body skin exam, 
including mucosa

Assess for history of 
prior inflammatory 
dermatologic diseases

Consider biopsy if 
unusual features
Permanently 
discontinue

Treatment with high 
potency topical 
steroids to affected 
areas

Prednisone 05 to 
1 mg/kg/day 
(increase dose up to 
2 mg/kg/day if no 
improvement)

Urgent dermatology 
consultation, 
consider biopsy

Consider in-patient 
care.
Do not resume


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Adverse Event
Severity
Assessment
Action Taken
AE Management
Resumption
Grade 3

Urgent dermatology 
consultation: if 
unavailable, consider 
skin biopsy
Permanently 
discontinue

Prednisone or 
methylprednisolone 
1 to 2 mg/kg/day 
(treat until symptoms 
improve to ≤ Grade 
1 then taper over 4 to 
6 weeks).

Consider IVIG 
(1g/kg/day in divided 
doses per package 
insert for 3 to 4 days)

In-patient care 
required

Urgent dermatology, 
ophthalmology, and 
urology consultation
Do not resume
Dermatologic 
Toxicity: 
Stevens-Johnson 
syndrome (SJS) or 
Toxic epidermal 
necrolysis (TEN)d
Grade 4

Urgent dermatology 
consultation: if 
unavailable, consider
Permanently 
discontinue

Prednisone or 
methylprednisolone 
1 to 2 mg/kg/day 
(treat until symptoms 
improve to ≤ Grade 
1 then taper over 4 to 
6 weeks).

Consider IVIG 
(1 g/kg/day in 
divided doses per 
package insert for 
3 to 4 days)

In-patient care 
required

Urgent dermatology, 
ophthalmology, and 
urology consultation
Do not resume
ADL = activity of daily life; AE = adverse event; BSA = body surface area; DKA = diabetic ketoacidosis; IV = intravenous; 
IVIG = intravenous immune globulin; NA = not applicable; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; 
TSH = thyroid-stimulating hormone; ULN = upper limit of normal.
a.
Macules/papules covering less than 10% BSA with or without symptoms (eg, pruritis, burning, tightness) 
b.
Macules/papules covering 10 to 30% BSA with or without symptoms (eg, pruritis, burning, tightness); limiting instrumental 
ADLs.
c.
Macules/papules covering more than 30% BSA with or without symptoms (eg, pruritis, burning, tightness) limiting ADLs.
d.
SJS, overlapping SJS/TEN, and TEN are characterized by separation of the dermis involving less than 10%, 10 to 30%, and 
more than 30% BSA, respectively. The syndrome is thought to be a hypersensitivity complex affecting the skin and mucous 
membranes. 
Guidelines are referenced from the National Comprehensive Cancer Network (NCCN) Management of Immunotherapy-Related 
Toxicities Version 4.2021 – September 27, 2021
5.5.2.5.
Criteria to Resume Treatment
In the event that zimberelimab is held due to toxicities, criteria for resumption of dosing are 
outlined in Table 5-6.


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5.5.2.6.
Permanent Treatment Discontinuation
Criteria for permanent discontinuation of zimberelimab for toxicities are defined in Table 5-6.
5.5.3.
Dose Modifications for Platinum (Cisplatin or Carboplatin)
Cisplatin is known to cause nephrotoxicity, peripheral neuropathy, nausea and vomiting, 
myelosuppression, ototoxicity, and hypersensitivity reactions. 
Cisplatin or carboplatin dose delays and resumption of treatment as well as dose reductions and 
treatment discontinuation decisions should be conducted in accordance with the current local 
label and treatment guidelines. The cisplatin dose must not be re-escalated following a dose 
reduction. General platinum dose modification guidelines for febrile neutropenia or documented 
infection and drug-related AEs are described in Table 5-8, Table 5-9, and Table 5-10; these 
general guidelines may be overridden by local label and/or treatment guidelines with the 
approval of the medical monitor. If cisplatin or carboplatin is discontinued for reasons other than 
disease progression, the remaining drug(s) in the combination regimen may be continued.
If toxicities occur, investigators may switch subjects from cisplatin to carboplatin and vice versa 
during the course of the study. If the cisplatin dose was modified prior to switching, the subject 
may start at a carboplatin dose of AUC 5 and will be eligible to receive an additional 2 dose 
modifications of carboplatin.
Recommended initial dose and dose reductions for cisplatin and carboplatin are detailed in 
Table 5-8.
Table 5-8.
Platinum Dose Modification Levels
Dose level 0
Dose level −1
Dose level −2
Dose level −3
Cisplatin
100 mg/m2
80 mg/m2
(20% decrease)
64 mg/m2
(20% decrease)
Discontinue
Carboplatin
AUC 5 mg/mL/min
AUC 4 mg/mL/min
(20% decrease)
AUC 3 mg/mL/min
(20% decrease)
Discontinue
Table 5-9.
Platinum Dose Modification Guidelines for Febrile Neutropenia or 
Documented Infection
Adverse Event
Number of Occurrences
Treatment Modification
1
Reduce by 1 dose level
The use of growth factors and antibiotics should be 
considered per local standards
2
Reduce by 1 dose level
Consider prophylactic antibiotics for subsequent cycles
The use of growth factors should be strongly considered 
per local standards
Febrile neutropeniaa
Documented infection
3
Discontinue platinum
a
Absolute neutrophil count < 1000/mm3 (1.0  109/L) and a single temperature > 38.3 °C or sustained temperature ≥ 38 °C 
for > 1 hour.


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Table 5-10.
Platinum Dose Modification Guidelines for Drug-Related Adverse 
Events
Category
Toxicity
Hold 
Platinum 
Treatment 
for Grade
Timing for 
Restarting 
Platinum 
Treatment
Dose for Restarting 
Platinum 
Treatmenta
Discontinue Platinum
3b
Neutrophil 
count resolves 
to ≥ 1000/mm3 
(1.0  109/L)
No reduction
Consider G-CSF
Toxicity does not resolve 
within 12 weeks of last 
infusion or if > 2 dose 
level reductions exceeded
Neutropenia
4b
Neutrophil 
count resolves 
to ≥ 1000/mm3 
(1.0  109/L)
Reduce by 1 dose 
level
Consider G-CSF
Toxicity does not resolve 
within 12 weeks of last 
infusion or if > 2 dose 
level reductions exceeded
2
Platelet count 
resolves to 
≥ 75,000/mm3 
(75  109/L) or 
baseline
No reduction
Toxicity does not resolve 
within 12 weeks of last 
infusion or if > 2 dose 
level reductions exceeded
Hematologic
Thrombocytopenia
3 or 4b
Platelet count 
resolves to 
≥ 75,000/mm3 
(75  109/L) or 
baseline
Reduce by 1 dose 
level
Toxicity does not resolve 
within 12 weeks of last 
infusion or if > 2 dose 
level reductions exceeded
Creatinine 
increased
2 to 4b
Toxicity 
resolves to 
Grade 0 or 1
For subjects taking 
carboplatin, reduce 
by 1 dose level.
For subjects taking 
cisplatin, change 
cisplatin to 
carboplatin.
Toxicity does not resolve 
within 12 weeks of last 
infusion or if > 2 dose 
level reductions exceeded
2
May change cisplatin to carboplatin as per local standards
May continue treatment with carboplatin as per local standards
Ototoxicity or 
sensory 
neuropathy
3 or 4b
May switch cisplatin to carboplatin if resolves to ≤ Grade 2 within 
12 weeks of last infusion
If already using carboplatin, then discontinue
All other 
nonhematologic 
toxicitiesb
3 or 4b
Toxicity 
resolves to 
Grade 0 or 1
Reduce by 1 dose 
level
Toxicity does not resolve 
within 12 weeks of last 
infusion or if > 2 dose 
level reductions exceeded
Nonhematologic
Laboratory 
adverse eventc
4b
Toxicity 
resolves to 
≤ Grade 2 
Reduce by 1 dose 
level
Toxicity does not resolve 
within 12 weeks of last 
infusion or if > 2 dose 
level reductions exceeded
G-CSF = granulocyte colony-stimulating factor
a
Restarting platinum should occur on Day 1 of the next cycle after criteria for restarting has been met.
b
Permanent discontinuation should be considered for any severe or life-threatening event. Consult the sponsor before 
restarting treatment after a Grade 4 drug-related adverse event.
c
Subjects with an intolerable or persistent Grade 2 drug-related adverse event may hold dosing at the physician’s discretion. 
Permanently discontinue platinum for persistent Grade 2 adverse reactions for which treatment has been held and that do not 
improve to Grade 0 or 1 within 12 weeks of the last dose. With investigator and sponsor agreement, subjects with a 
laboratory adverse event still at Grade 2 after 12 weeks may continue in the study only if asymptomatic and the adverse 
event does not worsen.


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5.5.4.
5-Fluorouracil
5-Fluorouracil dose delays and resumption of treatment as well as dose reductions and 
discontinuation decisions should be conducted in accordance with the current local label and 
treatment guidelines. General dose modification guidelines for 5-FU for febrile neutropenia or 
documented infection and drug-related AEs are described in Table 5-11., Table 5-12., and 
Table 5-13.; these general guidelines may be overridden by local label and/or treatment 
guidelines with the approval of the medical monitor. If 5-FU is discontinued for reasons other 
than disease progression, the remaining drug(s) in the combination regimen may be continued.
Table 5-11.
5-Fluorouracil Dose Modification Levels
Dose Level 0
Dose Level −1
Dose Level −2
Dose Level −3
5-FU
1000 mg/m2
800 mg/m2
(20% decrease)
640 mg/m2
(20% decrease)
Discontinue
5-FU = 5-fluorouracil
Table 5-12.
5-Fluorouracil Dose Modification Guidelines for Febrile Neutropenia 
or Documented Infection
Adverse Event
Number of Occurrences
Treatment Modification
1
Reduce by 1 dose level
The use of growth factors and antibiotics should be 
considered per local standards
2
Reduce by 1 dose level
Consider prophylactic antibiotics for subsequent cycles
The use of growth factors should be strongly considered 
per local standards
Febrile neutropeniaa
Documented infection
3
Discontinue 5-FU
5-FU = 5-fluorouracil
a
Absolute neutrophil count < 1000/mm3 (1.0  109/L) and a single temperature > 38.3 °C or sustained temperature ≥ 38 °C 
for > 1 hour.


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Table 5-13.
5-Fluorouracil Dose Modification Guidelines for Drug-Related 
Adverse Events
Category
Toxicity
Hold 5-FU 
Treatment 
for Grade
Timing for 
Restarting 5-FU 
Treatment
Dose for 
Restarting 5-FU 
Treatment
Discontinue 5-FU
3a
Neutrophil count 
resolves to 
≥ 1000/mm3 
(1.0  109/L)
No reduction
Consider G-CSF
Toxicity does not 
resolve within 
12 weeks of last 
infusion or if 
> 2 dose level 
reductions exceeded
Neutropenia
4a
Neutrophil count 
resolves to 
≥ 1000/mm3 
(1.0  109/L)
Reduce by 1 dose 
level
Consider G-CSF
Toxicity does not 
resolve within 
12 weeks of last 
infusion or if 
> 2 dose level 
reductions exceeded
2
Platelet count 
resolves to 
≥ 75,000/mm3 
(75  109/L) or 
baseline
No reduction 
Toxicity does not 
resolve within 
12 weeks of last 
infusion or if 
> 2 dose level 
reductions exceeded
Hematologic
Thrombocytopenia
3 or 4a
Platelet count 
resolves to 
≥ 75,000/mm3 
(75  109/L) or 
baseline
Reduce by 1 dose 
level
Toxicity does not 
resolve within 
12 weeks of last 
infusion or if 
> 2 dose level 
reductions exceeded
Creatinine increased
2 to 4a
Toxicity resolves 
to Grade 0 or 1
No reduction
Toxicity does not 
resolve within 
12 weeks of last 
infusion or if 
> 2 dose level 
reductions exceeded
Mucositis diarrhea
2 to 4a
Toxicity resolves 
to Grade 0 or 1
Reduce by 1 dose 
level
Toxicity does not 
resolve within 
12 weeks of last 
infusion or if 
> 2 dose level 
reductions exceeded
2
Toxicity resolves 
to Grade 0 or 1
No reduction
Toxicity does not 
resolve within 
12 weeks of last 
infusion or if 
> 2 dose level 
reductions exceeded
Nonhematologic
Hand-foot syndrome
3 to 4a
Toxicity resolves 
to Grade 0 or 1
Reduce by 1 dose 
level
Toxicity does not 
resolve within 
12 weeks of last 
infusion or if 
> 2 dose level 
reductions exceeded


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Category
Toxicity
Hold 5-FU 
Treatment 
for Grade
Timing for 
Restarting 5-FU 
Treatment
Dose for 
Restarting 5-FU 
Treatment
Discontinue 5-FU
All other 
nonhematologic 
toxicitiesb
3 to 4a
Toxicity resolves 
to Grade 0 or 1
Reduce by 1 dose 
level
Toxicity does not 
resolve within 
12 weeks of last 
infusion or if 
> 2 dose level 
reductions exceeded
Laboratory adverse 
eventb
4a
Toxicity resolves 
to ≤ Grade 2
Reduce by 1 dose 
level
Toxicity does not 
resolve within 
12 weeks of last 
infusion or if 
> 2 dose level 
reductions exceeded
5-FU = 5-fluorouracil; G-CSF = granulocyte colony-stimulating factor
a
Permanent discontinuation should be considered for any severe or life-threatening event. Consult the sponsor before 
restarting treatment after a Grade 4 drug-related adverse event.
b
Subjects with an intolerable or persistent Grade 2 drug-related adverse event may hold dosing at the physician’s discretion. 
Permanently discontinue 5-FU for persistent Grade 2 adverse reactions for which treatment has been held and that do not 
improve to Grade 0 or 1 within 12 weeks of the last dose. With investigator and sponsor agreement, subjects with a 
laboratory adverse event still at Grade 2 after 12 weeks may continue in the study only if asymptomatic and the adverse 
event does not worsen.
5.5.5.
Docetaxel
Docetaxel is known to cause neutropenia, hepatotoxicity, peripheral neuropathy, fluid retention, 
and hypersensitivity reactions. Subjects with pre-existing effusions should be closely monitored 
from the first dose for the possible exacerbation of the effusions. Subjects developing peripheral 
edema may be treated with standard measures (eg, salt restriction, oral diuretics).
Docetaxel dose delays and resumption of treatment as well as dose reductions and treatment 
discontinuation decisions should be conducted in accordance with the current local docetaxel 
label and treatment guidelines. The docetaxel dose may not be re-escalated following a dose 
reduction.
Recommended initial dose and dose reductions for docetaxel:

Initial dose: 75 mg/m2

First dose level reduction: 55 or 60 mg/m2 (as per local label and guidelines for docetaxel)

Second dose level reduction: Per investigator’s discretion (as per local label and guidelines 
for docetaxel)
Docetaxel should not be administered to subjects who have significant liver dysfunction or a 
neutrophil count of less than 1500 cells/mm3 (refer to local label for liver function requirements 
for dosage and dose modification for hematologic toxicities).


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Subjects who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, 
neutrophils less than 500 cells/mm3 for more than 1 week, severe or cumulative cutaneous 
reactions, or other Grade 3/4 nonhematologic toxicities during docetaxel treatment should have 
treatment withheld until resolution of the toxicity and then resume dosing at the next dose level 
reduction.
General criteria for permanent discontinuation of docetaxel:

Grade 3 or higher peripheral neuropathy

Cystoid macular edema

Severe hypersensitivity reaction to docetaxel

Consider discontinuation for severe cutaneous AEs (eg, Stevens Johnson syndrome)
Docetaxel treatment may be discontinued if there is more than a 5-week dose delay from the last 
dose or failure to resolve a toxicity within 3 weeks of the last dose of docetaxel.
The general guidelines for dose reductions, holds, and discontinuation may be overridden by 
local label and/or treatment guidelines with the approval of the medical monitor.
5.6.
Prior and Concomitant Medications
5.6.1.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the local community standards 
of medical care. Concomitant medications, including all prescription, over-the-counter, herbal 
supplements, and IV medications and fluids received within 30 days before the first dose of 
study treatment through the 60-day follow-up visit should be recorded in the electronic case 
report form (eCRF). If changes occur during the study period, documentation of drug name, 
indication, route, and date will also be included on the eCRF.
Palliative and supportive care is permitted during the course of the study for underlying medical 
conditions and management of symptoms.
Surgery purely for tumor control is not permitted during the study. Palliative radiotherapy is 
permitted to a single lesion if considered medically necessary by the treating physician as long as 
the lesion is not a RECIST V1.1–defined target lesion. During Part 1 of the study, subjects who 
tolerate GS-3583 beyond the DLT evaluation period will have the option to receive SBRT 
starting at Cycle 2 per investigator’s discretion. Selection of subject and provision of SBRT will 
be according to the institution’s own protocol and in line with the local standard of care. In 
subjects receiving radiotherapy, RECIST-designated target lesions will not be subjected to any 
form of radiotherapy including SBRT. In Part 2 of the study, SBRT is not permitted except after 
discontinuation of all study treatment.


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Treatment with GS-3583 may be withheld during the course of palliative radiotherapy or SBRT 
and should be resumed at the next scheduled administration of study therapy when the 
investigator deems it is safe to do so. The specifics of the radiation treatment, including the 
location, will be recorded. Subjects who cannot tolerate GS-3583 following radiotherapy will be 
discontinued from the study.
5.6.1.1.
Rescue Medications and Supportive Care
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below:

Diarrhea: Subjects should be carefully monitored for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). In symptomatic subjects, infectious 
etiologies should be ruled out, and if symptoms are persistent and/or severe, endoscopic 
evaluation should be considered. All subjects who experience diarrhea should be advised to 
drink liberal quantities of clear fluids or rehydration solutions. If sufficient oral fluid intake is 
not feasible, fluid and electrolytes should be substituted via IV infusion.

Anemia: Transfusions may be utilized as clinically indicated for the treatment of anemia but 
should be clearly noted as concurrent medications or in a transfusion page. Consider a 
potential immunologic etiology and follow the ASCO guidelines for use of erythropoietin or 
derivatives.

Neutropenia: Prophylactic use of colony-stimulating factors including granulocyte 
colony‑stimulating factor (G-CSF), pegylated G-CSF, or granulocyte macrophage 
colony‑stimulating factor (GM-CSF) is not allowed in this study. Therapeutic use of G‑CSF 
and GM-CSF are allowed in subjects with Grade 3 to 4 febrile neutropenia. 
(Note: Administration of GM-CSF might affect pharmacodynamic assessments (peripheral 
DC count) and therefore must be appropriately documented in the eCRF). Consider a 
potential immunologic etiology. 

Thrombocytopenia: Transfusion of platelets may be used, if clinically indicated. Immune 
thrombocytopenia purpura should be ruled out before initiation of platelet transfusion.

Anti-infectives: Subjects with suspected or documented infectious complication should 
receive oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard institutional 
practice.

Adverse events with a potential immunologic etiology (irAEs): Follow ASCO or local 
institutional practice guidelines for identification, evaluation, and management of AEs of a 
potential immunologic etiology. Depending on the type and severity of an irAE, oral or IV 
treatment with a corticosteroid should be considered, in addition to appropriate symptomatic 
treatment of a given condition. 


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5.6.1.2.
Stereotactic Body Radiation Therapy (SBRT)
In Part 1 of the study, subjects who tolerate GS-3583 beyond the DLT evaluation period will 
have the option to receive SBRT starting at Cycle 2 per investigator’s discretion. Selection of 
subject and provision of SBRT will be according to the institution’s own protocol and in line 
with the local standard of care. In subjects receiving SBRT, RECIST-designated target lesions 
will not be irradiated. SBRT is not permitted during Part 2 of the study except after 
discontinuation of all study treatment.
5.6.2.
Prohibited and/or Restricted Treatments
Subjects are prohibited from receiving the following therapies and treatments during the study. 
Study treatment will be discontinued in subjects who, in the assessment by the investigator, 
require the use of any of the following therapies and treatments for clinical management:

Immunotherapy not specified in this protocol

Chemotherapy

Investigational agents other than GS-3583 and zimberelimab

Anticancer biologics

Corticosteroids are not permitted with the following exceptions:
As premedication for known hypersensitivity reactions (eg, IV contrast, IV drug 
infusion);
Note: Premedication should not be administered routinely prior to dosing of GS-3583. 
Refer to Section 5.5.1.3 for subsequent premedication recommendations following 
GS‑3583‑related infusion reactions.  
Intraocular, intranasal, inhaled, and/or topical corticosteroids; and/or 
Prednisone at doses of up to 10 mg per day or equivalent
Required dose and schedule for treatment of irAEs
With prior approval from the medical monitor

 Live vaccines within 30 days prior to first dose of study drug through 90 days after the last 
dose of study drug for anti-PD-1- containing regimens. Administration of the COVID-19 
vaccine or inactive influenza vaccinations are permitted (Section 5.7.1).

Surgery for tumor control


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
Any form of radiotherapy for RECIST V1.1–defined target lesion(s)
There are no prohibited therapies during the posttreatment follow-up phase.
5.6.3.
Other Restrictions and Precautions
The following nondrug therapies must not be administered or performed during the study:

Major elective surgery

Herbal remedies with immunostimulating properties (eg, mistletoe extract) or that are known 
to potentially interfere with major organ function (eg, hypericin)

Subjects should not abuse alcohol or other drugs during the study.
In addition to the prohibited medications listed in Section 5.6.2, many herbal and natural 
remedies have effects on the PK of anticancer medicines and should be discouraged. Specific 
medications can be discussed with the medical monitor.
5.6.4.
Cisplatin, Carboplatin, 5-Fluorouracil, and Docetaxel
Refer to the current local prescribing information for cisplatin, carboplatin, 5-FU, and docetaxel 
for permitted and prohibited concomitant medications.
Subjects receiving cisplatin may receive pretreatment hydration per local standards and maintain 
hydration and urinary output for 24 hours after cisplatin administration.
5.6.5.
COVID-19 Vaccine and Prophylaxis
There are no substantial safety data regarding the concurrent administration of the COVID-19 
vaccine and GS-3583, zimberelimab, cisplatin, carboplatin, 5-FU, or docetaxel. Subjects are 
allowed to receive the COVID-19 or influenza vaccines to reduce the risk and complications of 
COVID-19 or influenza infection. The study visits should continue as planned if vaccination 
occurs while the subject is on the study.
Any immunotherapy for the prophylaxis or prevention of COVID-19 infections may be 
administered with the approval of the medical monitor but it is not advisable during the DLT 
evaluation period; subject enrollment into the study should be planned accordingly.
5.7.
Accountability for Investigational Medicinal Product
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug and vials. This includes acknowledgment of receipt of each shipment of study drug 
(quantity and condition).


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Each study site must keep accountability records that capture:

The date received and quantity of study drug vials

The date, subject number, and the study drug kit number dispensed

The date, quantity of used and unused study drug vials, along with the initials of the person 
recording the information
5.7.1.
Timing of Dose Administration
For safety run-in Cohort A and randomized, disease-specific Cohort A treatment arm, GS-3583 
should be administered first before administration of zimberelimab, followed by platinum and 
5-FU.
For randomized, disease-specific Cohort A Control Arm, zimberelimab should be administered 
first, followed by platinum and 5-FU.
For safety run-in Cohort B and randomized, disease-specific Cohort B treatment arm, GS-3583 
should be administered first before administration of docetaxel.
There will be a minimum of 1-hour observation period between the completion of GS-3583 
infusion and the start of next agent/therapy or their corresponding premedication.
All study drugs may be administered up to 3 days before or after the scheduled dosing date for 
administrative reasons per the investigator’s judgment (up to 5 days after randomization is 
permitted). Any deviation from this will require agreement with the medical monitor.
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
(eg, elective surgery, unrelated medical events, subject vacation, and holidays) not related to 
study therapy. Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption. The reason for interruption should be documented in the subject's study record.
5.7.2.
Investigational Medicinal Product Return or Disposal
Gilead recommends that used and unused study drug supplies be destroyed at the 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 electronic master file. If study drug is destroyed at the site, the investigator must maintain 
accurate records for all study drugs destroyed. 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. 


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If the site does not have an appropriate SOP for drug destruction, used and unused study drug 
supplies are to be sent to the designated disposal facility for destruction. The study monitor will 
provide instructions for return.
The study monitor will review study drug supplies and associated records at periodic intervals.
For both disposal options listed above, the study monitor must first perform drug accountability 
during an on-site monitoring visit.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject screened or enrolled in the study are 
presented in tabular form in Appendix 4 and described in the text that follows. 
The investigator must document any deviation from the protocol procedures and notify Gilead or 
the contract/clinical research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
Entry into screening does not guarantee enrollment into the study. In order to manage the total 
study enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or study-wide at any time.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 28 days before enrollment to determine eligibility for 
participation in the study. The following will be performed and documented at screening:

Obtain written informed consent

Review of inclusion/exclusion criteria

Review of medical history, including smoking status and demographics

Review of baseline symptoms

Review of prior and concomitant medications

Obtain cancer disease details and prior treatments

Full physical examination including vital signs, body weight, and height

Perform 12-lead electrocardiogram (ECG)

Perform ECHO or MUGA scan (results from ECHO or MUGA scan performed up to 30 days 
prior to enrollment are acceptable)

Assess ECOG performance status

Obtain blood samples for:
Hematology and serum chemistry




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
Part 2 Cohort B (NSCLC) only: Baseline information on PD-L1 expression level at initial 
diagnosis, EGFR, ALK, ROS1, or any other known actionable genomic alterations using a 
locally validated test

Tumor imaging, unless diagnostic quality tumor imaging is available for exams within 
28 days prior to the first dose of study treatment

Record any serious AEs and all AEs related to protocol-mandated procedures occurring after 
signing of the informed consent form (ICF)
After a subject signs an ICF, the subject will be assigned a unique, sequential subject number. 
Once a number is assigned, it cannot be reassigned if the original subject is found to be ineligible 
or withdraws consent.
Subjects who fulfill all of the inclusion criteria and none of the exclusion criteria will be 
enrolled/randomized into the study within 28 days after screening. Subjects who do not meet the 
inclusion and exclusion criteria will be considered screen fails, and their demographic 
information and reason for screen failure should be documented.
During the screening period, attention must be given to washout periods for prior treatments and 
prohibited medications.
From the time of obtaining informed consent through the first administration of study drug, 
record all serious adverse events (SAEs), as well as any AEs related to protocol-mandated 
procedures on the adverse events eCRF. All other untoward medical occurrences observed 
during the screening period, including exacerbation or changes in medical history, are to be 
considered medical history. See Section 7, Adverse Events and Toxicity Management, for 
additional details.
6.2.2.
Rescreening Criteria
Subjects who do not enroll within 28 days of screening will be screen failed. 
Rescreening may be allowed. Subjects who are rescreened after 28 days must be reconsented 
with a new screening number, and the screening assessments must be repeated. For subjects who 
are rescreened within 28 days, assessments with results that would exclude the subject will need 
to be repeated.
6.2.3.
Medical History and Baseline Assessments
A medical history will be obtained by the investigator or qualified designee. Medical history will 
include all active conditions; history of HBV, HCV, and HIV and any condition diagnosed 
within the prior 10 years that is considered clinically significant by the investigator. Medical 
history will also include an assessment of smoking history.
Baseline symptoms will be assessed for each subject at screening. 


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6.2.3.1.
Cancer Disease Details and Prior Treatment
Cancer disease history will be recorded separately and not listed as medical history. Current 
cancer disease details and prior treatment will be obtained for all subjects including:

Detailed history of the tumor, including histopathological diagnosis, grading, and staging in 
accordance with the eighth edition of the American Joint Committee on Cancer (AJCC-8) 
staging manual tumor node metastasis classification at diagnosis

All therapy used for prior treatment of the tumor (including surgery, radiotherapy, 
chemotherapy, and immunotherapy)

Current cancer signs and symptoms, and side effects from current and/or previous anticancer 
treatments

Smoking history

Tumor markers
For Part 2 Cohort A (HNSCC), baseline CPS and HPV status as outlined under 
Section 6.2.1 will be collected
For Part 2 Cohort B (NSCLC), PD-L1 expression level at diagnosis, presence/absence of 
genomic alterations such as EGFR, ROS1, ALK, or any other known actionable genomic 
alterations will be collected using a locally validated test.
6.3.
Randomization
For Part 1, no randomization procedures will be performed.
For Part 2, after the safety run-in, randomization will occur up to 72 hours prior to the first dose 
of study drug. Please refer to Section 5.1 (Enrollment/Randomization), as needed.
6.4.
Treatment Assessments 
6.4.1.
Baseline/Cycle 1 Day 1 Predose Assessments
The following will be performed and documented prior to study treatment administration:

Review inclusion and exclusion criteria

Review baseline symptoms

Focused physical examination (may be performed within 72 hours prior to the first dose of 
study treatment)

Vital signs (temperature, pulse, respiratory rate, and blood pressure) 


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
Weight

Standard 12-lead ECG 

Assess ECOG performance status (may be performed within 72 hours prior to the first dose 
of study treatment)

Obtain predose blood samples for:
Hematology and serum chemistry (may be performed within 72 hours prior to the first 
dose of study treatment)
GS-3583 PK (< 30 minutes before start of infusion)
GS-3583 immunogenicity assessment (< 30 minutes before start of infusion)
Zimberelimab PK (< 30 minutes before start of infusion) (Part 2 Cohort A)
Zimberelimab immunogenicity assessment (< 30 minutes before start of infusion) (Part 2 
Cohort A)
Whole blood for pharmacodynamic biomarkers (PBMC and plasma). The predose sample 
will be collected any time prior to the start of infusion at the Day 1 visit. An additional 
set of predose samples should be collected up to 72 hours prior to the Cycle 1 Day 1 visit, 
if feasible.
Whole blood for blood cell count. The predose sample will be collected any time prior to 
the start of infusion at the Day 1 visit. An additional set of predose samples should be 
collected up to 72 hours prior to the Cycle 1 Day 1 visit, if feasible.
Whole blood for paxgene RNA
Serum pharmacodynamics for circulating factors


Obtain predose urine samples for:
Urinalysis (may be performed within 72 hours prior to the first dose of study treatment)
Urine pregnancy test for females of childbearing potential (may be performed within 
72 hours prior to the first dose of study treatment)

Obtain predose stool sample for microbiome sequencing. Subjects will collect a sample up to 
72 hours prior to the study visit and be reminded to bring in the sample upon their arrival to 
the clinic.  

Review and record all AEs and concomitant medications
CCI


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Following the completion of the above assessments, the subject will be enrolled and 
administered study drug.
6.4.2.
Cycle 1 Day 1 Postdose Assessments 
The following will be performed and documented after administration of study treatment:

Obtain postdose blood samples for:
 GS-3583 PK (at end of infusion [+ 5 minutes], 2 hours [± 10 minutes], and 6 
hours [± 0.5 hours] after start of infusion) (Part 1 and Part 2 safety run-in Cohort A and 
B)
GS-3583 PK (at end of infusion [+ 5 minutes]) (Part 2 randomized expansion Cohort A 
and B)
Zimberelimab PK (at end of infusion [+ 5 minutes]) (Part 2 Cohort A)
Whole blood for CHIP mutation analysis
Whole blood for TCR sequencing
Whole blood for circulating tumor DNA

Vital signs (temperature, pulse, respiratory rate, and blood pressure; 1 hour [± 15 minutes] 
after end of infusion) 

Standard 12-lead ECG (2 hours [-10/+20 minutes] after end of infusion)

Observation for 1 hour after end of infusion for irAEs 
6.4.3.
Vital Signs, Weight, and Height
The investigator or qualified designee will take vital signs at screening, prior to, and following 
the administration of each dose of study treatment, and throughout the study through the 
follow-up period as specified in the Study Procedures Table (Appendix 4). Vital signs will only 
be measured while the subject is in a sitting, semirecumbent, or supine position. Vital signs 
include temperature, pulse, respiratory rate, and blood pressure. Weight should be assessed as 
specified in Appendix 4 prior to dosing, at the beginning of each cycle, and through the 
follow-up period. Height will be measured at screening only.


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6.4.4.
Physical Examination
6.4.4.1.
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during the 
screening period and at the end of treatment visit as specified in the Study Procedures Table 
(Appendix 4). Clinically significant abnormal findings should be recorded as medical history. 
After consent, new clinically significant abnormal findings should be recorded as AEs as per 
Section 7.3.
6.4.4.2.
Focused Physical Examination
For cycles that do not require a full physical examination as specified in the Study Procedures 
Table (Appendix 4), the investigator or qualified designee will perform a directed physical 
examination as clinically indicated prior to study treatment administration and at the 60-day 
follow-up. New clinically significant abnormal findings should be recorded as AEs.
6.4.4.3.
Eastern Cooperative Oncology Group Performance Status
The ECOG performance status will be assessed at screening, prior to the administration of each 
dose of study treatment, end of treatment (EOT), and at the 60-day  follow-up as specified in 
Appendix 4.
6.4.5.
12-Lead Electrocardiogram (ECG)
A standard 12-lead ECG will be performed using local standard procedures at screening, prior to 
the administration, and following the completion of study treatment on Cycle 1 Day 1, after 
infusion on Cycle 1 Day 15 (Part 1 only), Cycle 2 Day 1, and Day 1 of every odd numbered 
cycle starting at Cycle 3, the end of treatment visit, and the 60-day follow-up as specified in 
Appendix 4. Clinically significant abnormal findings at screening should be recorded as medical 
history.
6.4.6.
Echocardiogram (ECHO) or MUGA Scan
A full standard ECHO evaluation will be performed using local standard procedures at screening 
to establish a baseline. A MUGA scan is also allowed. Results from ECHO or MUGA scan 
performed up to 30 days prior to enrollment are acceptable for establishing a baseline. Clinically 
significant abnormal findings at screening should be recorded as medical history and discussed 
with the medical monitor.
6.4.7.
Prior and Concomitant Medications
Prior medication taken by the subject within 30 days prior to screening visit will be recorded. In 
addition, record all treatments for a prior cancer other than current cancer even if taken greater 
than 30 days prior to screening. Prior treatments for the current cancer will be recorded 
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Concomitant medications, if any, taken by the subject during the study from the date of consent 
through the 60-day follow-up visit will be recorded. After the 60-day follow-up visit, all 
medications related to reportable SAEs will be recorded as defined in Section 7.3.3.
6.4.8.
Clinical Laboratory Assessments
The central laboratory will be responsible for chemistry, hematology, coagulation, endocrine 
function, urinalysis, HIV, HBV and HCV serology, and serum pregnancy testing as well as 
processing and/or storage of other study samples. 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.
If central laboratory results are not available, local laboratories may be used for dosing decisions. 
Local laboratory assessments resulting in a dose change or as part of an AE assessment, which is 
not supported by central laboratory results, will be reported on the eCRF. Gilead’s standard 
reference ranges will be used.
Urine pregnancy tests will be performed locally at the site as shown in Appendix 4. 

For Part 1, following the 60-day follow-up visit, urine pregnancy tests will be performed 
monthly until 12 weeks after the last dose of study drug. 

For Part 2, following the 60-day follow-up visit, urine pregnancy tests will be performed 
monthly until the end of the contraception requirement (Appendix 5).
Laboratory tests for screening should be performed within 28 days prior to the first dose of study 
treatment. Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to the first dose of study treatment. The report of the results must be retained as 
a part of the subject’s medical record or source documents. Blood samples for study-related tests 
will be collected at time points specified in Appendix 4.


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Table 6-1.
Analytes
Chemistry
Urinalysis
Hematology 
Other 
WBC and differential absolute 
count
Basophils
Eosinophils
Lymphocytes
Monocytes
Neutrophils
ANC
Hemoglobin
Hematocrit
Platelet count
MCV
RBC
Albumin
Alkaline phosphatase
ALT 
AST 
Bicarbonate
BUN/total urea
Calcium
Chloride
Serum creatininea
CRP
GGT
Glucose
LDH
Lipase
Cholesterol
Triglycerides
Amylase
Magnesium
Phosphorus/phosphates
Potassium
Sodium
Total bilirubin
Direct bilirubin
Total protein
Uric acid
Color and 
appearance
Specific gravity
pH
Occult blood
Protein
Glucose
Bilirubin
Leukocyte esterase
Nitrite
Urobilinogen
Ketones
Microscopic
Coagulation
Prothrombin time
INR
aPTT
Serum β-hCG or urine 
pregnancy testc
FSH (reflex)
Endocrine Function Tests 
(TSH and free T4d)
Basal cortisol
HIV
HBV and HCV Serologyb
Screening only:
Part 2 Cohort A (HNSCC):
HPV p16 expression testing as 
indicated
CPS
Part 2 Cohort B (NSCLC):
PD-L1 expression at diagnosis 
and other tumor markers per 
Section 6.2.1.
β-hCG = beta-human chorionic gonadotropin; ALT = alanine aminotransferase; ANC = absolute neutrophil count; 
aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CRP = C-reactive 
protein; CPS = combined positive score; FSH = follicle stimulating hormone; GGT = gamma-glutamyltransferase; 
HBV = hepatitis C virus; HCV = hepatitis C virus; HNSCC = head and neck squamous cell carcinoma; INR = international 
normalized ratio; LDH = lactate dehydrogenase; MCV = mean corpuscular volume; NSCLC = National Comprehensive Cancer 
Network; RBC = red blood cell; T4 = thyroxine; TSH = thyroid-stimulating hormone; WBC = white blood cell
a
Estimated creatinine clearance (CLcr)/glomerular filtration rate will be calculated based on the Cockcroft-Gault formula 
using actual body weight: CLcr (mL/min) = (140 − age [years])* weight (kg)/(serum creatinine [mg/dL]*72). If the subject is 
female, multiply the quantity by 0.85.
b
For HBV serology, hepatitis B surface antigen, hepatitis B surface antibody, and total antibody against hepatitis B core 
antigen (anti-HBc). For subjects where total anti-HBc is positive, HBV DNA by quantitative polymerase chain reaction will 
be required. 
For HCV serology, HCV antibody. For subjects with positive HCV antibody, HCV RNA by quantitative polymerase chain 
reaction will be required. 
c
Females of childbearing potential only. Serum pregnancy will be conducted at screening and urine pregnancy test at all other 
indicated visits. 
d
T4 will be tested reflexively based on abnormal TSH results.
6.4.9.
Tumor Biopsies
Part 1: Tumor tissue for biomarker analysis will be collected at the time of screening from an 
archival tumor biopsy, obtained preferably either at the time of or after the diagnosis of advanced 
disease has been made, and from a site not previously irradiated.




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An overview of tumor biopsy requirements in Part 2 is provided in Table 6-2. For additional 
details and instructions regarding tissue requirements, collection, storage, and shipment, refer to 
the study laboratory manual.
Table 6-2.
Part 2 Tumor Biopsy Collection
Safety Run-in Cohorts
Randomized Expansion Cohorts
Archival tumor biopsy
Obtain block, or collect 10 to 
25 slides (archival tumor biopsy 
can be replaced with fresh 
pretreatment biopsy)
Obtain block, or collect 10 to 
25 slides
Mandatory fresh pretreatment 
biopsy
—
Collect (can be replaced with recent 
archival tumor biopsy not older 
than 6 month and obtained after the 
last line of treatment)
Mandatory on-treatment biopsy
—
Collect any time after Day 15 of 
Cycle 2 (only if fresh pretreatment 
biopsy was collected)
EOT = end of treatment
6.4.10.
Testing for HPV Status
In Part 2 Cohort A (HNSCC), subjects with oropharynx cancer must have local assessment of 
HPV status, defined as p16 IHC testing using a locally available validated test, from tumor tissue 
prior to randomization.
Note: Subjects with oral cavity, hypopharynx, or larynx cancer are not required to undergo HPV 
testing by p16 IHC as by convention they are assumed to be HPV negative.
6.5.
Pharmacokinetic, Biomarker, and Immunogenicity Assessments
6.5.1.
Pharmacokinetic Assessments
6.5.1.1.
Pharmacokinetic Parameters
GS-3583 concentrations will be determined by a validated method. The PK parameters to be 
estimated and reported may include, but may not be limited to, Cmax, AUCtau, Ctrough, Tmax, and 
CL. Unresolved missing data may be imputed when analysis integrity is affected. The 
conservative principle will be used for data imputation. Noncompartmental analysis will be used 
to characterize the PK. Compartmental modeling (eg, population PK) analysis may be 
conducted.
CCI


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6.5.1.2.
PK Sample Collection
Blood sample collection for GS-3583 PK characterization will be conducted throughout the 
study. The time for collection of PK blood draws should always be referenced from the start of 
the infusion. It is important to record all infusion start dates/times, infusion end dates/times, 
infusion interruption(s) start and end dates/times, infusion flush end dates/times, and blood 
sample collection dates/times completely and accurately (and to the nearest minute).
Part 1: At Cycles 1 and 3, blood will be collected at predose (< 30 minutes before start of 
infusion), end of infusion (+ 5 minutes), and 2 hours (± 10 minutes), 6 hours (± 0.5 hours), Day 2 
(24 hours [± 2 hours]), Day 3 (48 hours [± 4 hours]), Day 5 (96 hours [± 4 hours]), Day 8 
(168 hours [± 12 hours]), Day 15 (for Cycle 1: pre-Day 15 dose [< 30 minutes before start of 
infusion], end of Day 15 infusion (+ 5 minutes), and 2 hours after start of Day 15 infusion 
(± 10 minutes); for Cycle 3: 336 hours [± 12 hours]), and Day 24 (552 hours [± 12 hours]) after 
start of the Day 1 infusion (Table 6-3). 
In addition, samples will be collected on Day 1 (predose), and Day 15 (336 hours) of Cycles 2, 4, 
and every subsequent even numbered cycle thereafter, and at the 60-day follow-up visit 
(approximately 60 days after last dose). An additional blood sample will be collected at the EOT 
visit if a subject terminates early from study treatment.


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Table 6-3.
Part 1: Schedule of Intensive Pharmacokinetic Assessments
Day 1
Day 2 (24 h)
Day 3 (48 h)
Day 5 (96 h)
Day 8 (168 h)
Day 15 (336 h)
Day 24 (552 h)
Cycles 1 and 3
Predose, end of 
infusion, 2 and 
6 hours
after start of 
infusion
X
X
X
X
Predose, end of infusion, and 
2 hours after start of infusion*
X
Cycles 2, 4, and 
every subsequent 
even cycle
Predose
—
—
—
—
X
—
60-Day 
Follow-up Visit
(60 days after last 
dose)
X
—
—
—
—
—
—
End of Treatment 
(if subject 
terminates early)
X
—
—
—
—
—
—
*
For Cycle 1: pre-Day 15 dose, end of Day 15 infusion, and 2 hours after start of Day 15 infusion; for Cycle 3: 336 hours.


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Part 2 Cohorts A and B
GS-3583 (Safety Run-in Cohorts): At Cycles 1 and 3, blood samples will be collected at 
predose (≤ 30 minutes before start of infusion), end of infusion (+ 5 minutes), and 2 hours 
(± 10 minutes), 6 hours (± 0.5 hours), Day 8 (168 hours [± 12 hours]), and Day 15 (336 hours 
[± 12 hours]) after start of the Day 1 infusion. 
In addition, blood samples will be collected on Day 1 (predose [≤ 30 minutes before start of 
infusion] and end of infusion [+ 5 minutes]) of Cycles 2, 5, and every subsequent odd numbered 
cycle thereafter, and at the 60-day follow-up visit (approximately 60 days after last dose). An 
additional blood sample will be collected at the EOT visit if a subject terminates early from study 
treatment (Table 6-4).
GS-3583 (Randomized Expansion Cohorts Treatment Arms): Blood samples will be 
collected on Day 1 (predose [≤ 30 minutes before start of infusion] and end of infusion 
[+ 5 minutes]) of Cycles 1, 2, 3, and every subsequent odd numbered cycle thereafter, and at the 
60-day follow-up visit (approximately 60 days after last dose). An additional blood sample will 
be collected at the EOT visit if a subject terminates early from study treatment.
Part 2 Cohort A 
Zimberelimab (Safety Run-in Cohort and Randomized Expansion Cohort Control and 
Treatment Arms): Blood samples will be collected on Day 1 (predose [≤ 30 minutes before 
start of infusion] and end of infusion [+ 5 minutes]) of Cycles 1, 2, 3, and every subsequent odd 
numbered cycle thereafter, and at the 60-day follow-up visit (approximately 60 days after last 
dose). An additional blood sample will be collected at the EOT visit if a subject terminates early 
from study treatment (Table 6-4).
Table 6-4.
Schedule of GS-3583 Pharmacokinetic Sample Collection for Part 2 
Cohort A and B (Safety Run-in and Randomized Expansion Cohorts 
[Treatment Arms])
Safety Run-in Cohorts A and B
Sample for
Visit/Cycle
Day 1
Day 8
(168 h)
Day 15
(336 h)
Cycles 1 and 3
Predose, end of 
infusion, 2 and 6 
hours after start of 
infusion
X
X
Cycles 2, 5, and every 
subsequent odd cycle 
(ie, Cycles 7, 9, etc)
Predose and end of 
infusion
—
—
GS-3583
60-Day Follow-up 
Visit
(60 days after last 
dose)
X
—
—


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Safety Run-in Cohorts A and B
Sample for
Visit/Cycle
Day 1
Day 8
(168 h)
Day 15
(336 h)
End of Treatment (if 
subject terminates 
early)
X
—
—
Randomized Expansion Cohorts A and B
Sample for 
Visit/Cycle
Day 1
Day 8 
(168 h)
Day 15
(336 h)
Cycles 1, 2, 3, and 
every subsequent odd 
cycle (ie, Cycles 5, 7, 
etc)
Predose and end of 
infusion
—
—
60-Day Follow-up 
Visit
(60 days after last 
dose)
X
—
—
GS-3583
End of Treatment (if 
subject terminates 
early)
X
—
—
Table 6-5.
Schedule of Zimberelimab Pharmacokinetic Sample Collection for 
Part 2 Cohort A (Safety Run-in and Randomized Expansion Cohorts 
[Control and Treatment Arms])
Sample for 
Visit/Cycle
Day 1
Zimberelimab
Cycles 1, 2, 3, and every 
subsequent odd cycle (ie, Cycles 
5, 7, etc)
Predose and end of infusion
60-Day Follow-up Visit
(60 days after last dose)
X
End of Treatment (if subject 
terminates early)
X
6.5.2.
Biomarker Assessments
6.5.2.1.
Biomarker Sample Collection
Blood samples will be collected from all subjects in the study to assess pharmacodynamic 
responses, immunological response to GS-3583, and correlates of clinical efficacy and/or safety. 
Samples will include:


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Part 1:

Whole Blood for Pharmacodynamic Biomarkers (PBMC and plasma):
Day 1 of Cycle 1 and Cycle 3 at predose, Day 8 (168 hours [± 12 hours]), Day 15 
(336 hours [± 12 hours], must be collected predose at Cycle 1), and Day 24 (552 hours 
[± 12 hours]) after start of the Day 1 infusion. The predose samples will be collected any 
time prior to the start of infusion at the Day 1 visit. However, for Cycle 1 Day 1, an 
additional set of predose samples should be collected up to 72 hours prior to the Cycle 1 
Day 1 visit, if feasible.
Predose on Day 1, and Day 15 (336 hours [± 12 hours]) after start of the Day 1 infusion 
of Cycles 2, 4, and every subsequent even numbered cycle thereafter
End of treatment (for subjects that terminate early from study treatment only)
Sixty-day follow-up visit (approximately 60 days after last dose)
Two 10 mL samples will be collected at all time points except on Days 8 and 24 in 
Cycles 1 and 3, when only 1 sample of 10 mL will be collected.

Whole Blood for Blood Cell Count: at the same time points as the Pharmacodynamic 
Biomarkers (PBMC and plasma) samples above

Whole Blood sample for CHIP mutation analysis: at Screening; anytime on Day 1 of 
Cycles 1, 2, 3, and every subsequent even cycle; and EOT

Whole Blood sample for TCR sequencing: anytime on Day 1 of Cycles 1, 2, 3, and every 
subsequent even numbered cycle; and EOT

Whole Blood for assessing Circulating Tumor DNA: at Screening; anytime on Day 1 of 
Cycles 1, 2, 3, and every subsequent even cycle; and EOT

Whole Blood Paxgene RNA: at predose on Day 1 and Day 15 of Cycle 1, predose on Day 1 
of Cycle 2, predose on Day 1 of Cycle 3, any time on Day 15 of Cycle 3, and predose on 
Day 1 at every subsequent even numbered cycle; and EOT

Serum Pharmacodynamics for Circulating Factors: at predose on Day 1 of Cycles 1, 2, 
and 3; at predose on Day 15 of Cycle 1; any time on Day 8 of Cycle 1; any time on Days 8 
and 15 of Cycle 3; any time on Day 24 of Cycle 1; and EOT

Stool Sample for Microbiome Sequencing: at predose on Day 1 of Cycles 1 and 3, and 
EOT. Subjects will collect a sample up to 72 hours prior to the study visit and be reminded to 
bring in the sample upon their arrival to the clinic.  








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Part 2: Cohort A (Safety Run-in Cohort and Randomized Expansion Cohort: Control and 
Treatment Arms)
Zimberelimab: Subjects will have ADA assessed at predose (< 30 minutes before start of 
infusion) on Day 1 of Cycle 1, 2, 3, 5, 9, and 17; and at 60-day follow-up visit (60 days after last 
dose). An additional blood sample will be collected at the EOT visit if a subject terminates early 
from study treatment.
6.6.
Efficacy Assessments
6.6.1.
Response Assessment
Response assessment will be performed according to RECIST V1.1 {Eisenhauer 2009}. 
For all subjects, tumor response assessment will be performed by computed tomography (CT) 
scan with contrast or magnetic resonance imaging (MRI) of the chest/abdomen/pelvis (plus other 
regions as required for specific tumor types). All scans performed at baseline and other imaging 
performed as clinically required (other supportive imaging) will be repeated at subsequent visits. 
In general, lesions detected at baseline should be followed using the same imaging methodology 
and preferably the same imaging equipment at subsequent tumor evaluation visits.
For each subject, the investigator will designate 1 or more of the following measures of tumor 
status to follow for determining response: CT or MRI images of primary and/or metastatic tumor 
masses, physical examination findings, and results of other assessments. All available images 
collected during the study period will be considered. The most appropriate measures to evaluate 
a subject’s tumor status should be used. Measure(s) chosen for sequential evaluation during the 
study must correspond to measures used to document progressive tumor status that qualifies the 
subject for enrollment.
Subjects who experience initial radiologic progressive disease and are doing well clinically are 
considered to have initial RECIST V1.1-defined progressive disease and will be permitted, with 
Gilead’s approval, to continue with study drug treatment (see Section 3.4.1). These subjects will 
be reevaluated using the same imaging modality no less than 4 weeks later (after the last imaging 
with initial RECIST V1.1-defined progressive disease) to assess whether study drug treatment 
will be continued. If initial progression is based on occurrence of a new lesion in an area not 
scanned at baseline, an on-study scan no less than 4 weeks from initial observation of new lesion 
should be considered before performing the EOT visit.
Tumor responses to treatment will be assigned based on evaluation of response of target, 
nontarget, and new lesions according to RECIST V1.1 (all measurements should be recorded in 
metric notation; see {Eisenhauer 2009}). To assess objective response, tumor burden at baseline 
will be estimated and used for comparison with subsequent measurements. At baseline, tumor 
lesions will be categorized in target and nontarget lesions as described in {Eisenhauer 2009}.


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Results for these evaluations will be recorded with as much specificity as possible so that 
pretreatment and posttreatment results will provide the best opportunity for evaluating tumor 
response.
Any complete response (CR) or partial response (PR) should be confirmed by CT or MRI scan as 
described in {Eisenhauer 2009} no less than 4 weeks after initial assessment. The confirmatory 
scan may replace the next scheduled scan.
The investigator may perform scans in addition to a scheduled study scan for medical reasons or 
if progressive disease is suspected.
Part 1: Subjects who may receive SBRT at investigator’s decision will not have their designated 
target lesion (per RECIST V1.1) subjected to SBRT. 
Part 2: SBRT is not permitted, except after discontinuation of all study treatment.
6.6.2.
Tumor Assessments
6.6.2.1.
Tumor Imaging
Investigator-assessed imaging will be performed at defined time points. The initial tumor 
imaging to establish baseline disease will be performed ≤ 28 days prior to first dose of study 
drug. Scans performed as part of routine clinical management are acceptable for use as screening 
scan if they are of diagnostic quality and ≤ 28 days prior to first dose of study drug. On-study 
imaging as listed in Table 6-6 will be performed as specified below and in Appendix 4.
Table 6-6.
Postbaseline Imaging Schedule
Cohort
Postbaseline Imaging Schedule
Duration of Tumor Imaging 
Assessments
Part 1
Every 8 weeks from the first treatment 
dose (Visit window ± 7 days)
Until progressive disease is assessed by 
investigator, new line of anticancer 
therapy, or 1 year after last treatment 
dose, whichever occurs first
Part 2 (Cohorts A and B)
Every 6 weeks from the first treatment 
dose (Visit window ± 7 days) until 
Week 24, then every 9 weeks thereafter 
starting at Week 33a
Until progressive disease is assessed by 
investigator, new line of anticancer 
therapy, or 1 year after last treatment 
dose, whichever occurs first
Per RECIST V1.1, PR or CR should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date the response was first documented. The scan for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response, or at the 
next scheduled scan (ie, 6 weeks later), whichever is clinically indicated.


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The timing of on-study treatment imaging should follow study calendar days starting from 
Cycle 1 Day 1 and should not be adjusted for delays in treatment administration or for visits. The 
same imaging technique should be used in a subject throughout the study. Tumor imaging may 
be performed by CT or MRI. CT scan is the more commonly used modality and is preferred for 
the majority of subjects. An MRI can be utilized if clinically appropriate. Imaging should include 
the head, neck, chest, abdomen, and pelvis. In general, lesions detected at baseline should be 
followed using the same imaging methodology and preferably the same imaging equipment at 
subsequent tumor evaluation visits. The investigator may perform scans in addition to a 
scheduled study scan for medical reasons or if progressive disease is suspected.
For subjects who permanently discontinued all study drug(s) in the absence of progressive 
disease (eg, experienced unexpected toxicity) and/or start of new anticancer therapy, CT or MRI 
imaging should continue to be performed at the predefined schedule, until documented 
progressive disease, initiation of a new anticancer therapy other than the study treatment, or up to 
1 year after the last dose of study drug, whichever occurs first (see Section 6.8.1.1); and then 
move into survival follow-up for up to 1 year after the completion/discontinuation of tumor 
lesion assessments. 
For subjects who permanently discontinue from the study in the absence of progressive 
disease/or start of a new line of anticancer therapy and will not be continuing tumor imaging 
during the posttreatment period (ie, withdrew consent), additional imaging is recommended at 
the EOT visit if the last imaging was performed more than 30 days prior.
For subjects that met progressive disease clinically, subjects will continue tumor imaging until 
progressive disease is confirmed radiographically or prior to the start of a new line of anticancer 
therapy. As outlined in Section 3.4.1, subjects who experience initial radiologic progressive 
disease but improve clinically are considered to have initial RECIST V1.1-defined progressive 
disease and will be permitted, with Gilead’s approval, to continue with study drug treatment(s). 
These subjects will be reevaluated using the same imaging modality no less than 4 weeks later 
(after the last imaging with initial RECIST V1.1-defined progressive disease) to assess whether 
study drug treatment will be continued.
6.7.
Sample Storage
The stored biological samples may be used by Gilead or its research partner for future testing to 
provide additional data to answer questions that relate to the main study. At the end of this study, 
these samples may be retained in storage by Gilead for a period up to 15 years. If subjects 
provide additional specific consent, residual PK samples may be destroyed no later than 15 years 
after the end of study or per country requirements. 
6.8.
Unscheduled Visits
Unscheduled visits may occur at any time while the subject is enrolled on study. Data generated 
during an unscheduled visit will be collected in subject source documents and captured in the 
eCRFs. Multiple visits occurring during the 28-day screening period are not considered 
unscheduled and all data related should be captured in the screening eCRF.


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6.8.1.
End of Treatment and Posttreatment Visits
6.8.1.1.
End of Treatment Visit
The end of treatment (EOT) visit (refer to Appendix 4, Study Procedures Tables) should occur at 
the time when study drug is permanently discontinued for any reason. If the EOT visit occurs 
60 days from the last dose of study treatment, at the time of the 60-day follow-up visit, then the 
same assessments can be done once and reported under both EOT and 60-day follow-up visits. 
Subjects that terminate early from study treatment will have blood samples collected for PK, 
pharmacodynamic, and immunogenicity assessments at the EOT visit. 
Subjects who discontinue from study treatment for reasons other than progressive disease will 
continue to have tumor imaging at the predefined schedule, until documented progressive 
disease, initiation of a new anticancer treatment, or up to 1 year after the last dose of study drug, 
whichever occurs first (refer to Section 6.6.2.1); and then move into survival follow-up for up to 
1 year. If that is not feasible or acceptable to the subject (ie, subject withdrew consent) additional 
imaging is recommended at the EOT visit if the last imaging was performed more than 30 days 
prior.
6.8.1.2.
Sixty-Day Follow-up Visit
The 60-day  follow-up visit (refer to Appendix 4, Study Procedures Tables) will be conducted for 
all subjects approximately 60 (± 7) days after the last dose of study treatment or before the 
initiation of a new anticancer treatment, whichever comes first. Subjects with an AE of 
Grade > 1 will be further followed until the resolution of the AE to Grade 0 or 1 or until 
initiation of a new anticancer therapy, whichever occurs first.
For all females of childbearing potential in Part 1, urine pregnancy tests will be performed 
monthly until 12 weeks after the last dose of study drug.
For all females of childbearing potential in Part 2, urine pregnancy tests will be performed 
monthly until the end of the contraception requirement (Appendix 5).
6.8.2.
Survival Follow-Up
After the posttreatment 60-day follow-up visit, subjects who present(ed) with progressive disease 
and/or start(ed) a new anticancer therapy will move into survival follow-up. During the survival 
follow-up period, subjects will be contacted by telephone to assess for survival status and any 
new malignancies every 3 months for up to 1 year. No imaging assessment is required for 
survival follow-up. Information about deaths solicited during the survival follow-up period 
should be reported, but will not be considered or reported as SAEs except as those events 
described in Section 7.1.2.2 and 7.3.3. Investigators should abide by the reporting obligations as 
stated in Section 7.


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Subjects who do not present with progressive disease and/or start a new anticancer therapy will 
continue tumor imaging assessments until documented progressive disease, initiation of a new 
anticancer therapy, or up to 1 year after the last dose of study drug, whichever occurs first; and 
then move into the survival follow-up period for up to 1 year.
6.9.
Poststudy Care
Upon withdrawal from study and/or completion of the survival follow-up period, subjects will 
receive the care which they and their physician(s) (investigators) agree upon.
6.10.
Assessments for Early Discontinuation from Study Treatment or Study
If a subject discontinues study dosing (eg, as a result of an AE or other reasons listed in 
Section 6.10.1, Criteria for Discontinuation of Study Treatment), the EOT (Section 6.8.1.1), 
60-day follow-up (Section 6.8.1.2), and survival follow-up visits (Section 6.8.2) will be 
performed, and every attempt should be made to keep the subject in the study to perform the 
required study-related follow-up and procedures. If this is not possible or acceptable to the 
subject or investigator, the subject may be withdrawn from the study. 
Subjects that terminate early from study treatment will have blood samples collected for PK, 
pharmacodynamic, and immunogenicity assessments at the EOT visit. For subjects who 
permanently discontinue from the study in the absence of progressive disease/or start of a new 
line of anticancer therapy and will not be continuing tumor imaging during the posttreatment 
period, additional imaging is recommended at the visit if the last imaging was performed more 
than 30 days prior.
6.10.1.
Criteria for Discontinuation of Study Treatment
Study drug may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree.  

Unacceptable toxicity per ASCO Toxicity Guidelines (Appendix 3), 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

Progressive disease

Initiation of a new anticancer therapy

Death

Lost to follow-up

Subject request to discontinue for any reason


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
Investigator’s discretion

Protocol violation or major protocol deviation

Pregnancy during the study (Appendix 5)

Discontinuation of the study at the request of Gilead, a regulatory agency, or an IRB or IEC
6.11.
End of Study
End of study will be defined as when the last subject reaches the last scheduled follow‑up time 
point (including the 60-day follow-up or survival follow-up, whichever occurs the latest), or lost 
to follow-up, withdraws from the study, death, or the time at which Gilead closes the study.


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events and Serious Adverse Events
7.1.1.
Adverse Events
An AE is any untoward medical occurrence in a clinical study subject administered a study drug, 
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 study drug, whether or not the AE is considered related to the study drug. Adverse events 
may also include pretreatment or posttreatment complications that occur as a result of 
protocol-specified procedures or special situations (Section 7.1.3). 
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an AE and must be reported.

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 (eg, hospitalization for 
elective surgery, social, and/or convenience admissions)

Overdose without clinical sequelae (Section 7.1.3)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed and not related to a protocol-associated procedure is not an AE but 
rather considered to be preexisting and should be documented as medical history.

Disease progression due to underlying disease
Preexisting events that increase in severity or change in nature after study drug initiation or 
during or as a consequence of participation in the clinical study will be considered AEs.
7.1.2.
Serious Adverse Events
An SAE is defined as an event that, at any dose, results in the following:

Death

A life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe.)


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
In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: Such events may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes constituting SAEs. Medical and scientific 
judgment must be exercised to determine whether such an event is a reportable under 
expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse.
7.1.2.1.
Protocol-Specific Serious Adverse Event Definitions
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:

Disease progression due to underlying disease

Death from disease progression due to underlying disease
Disease progression and death from disease progression should be reported as SAEs by the 
investigator, only if it is assessed that the study drug caused or contributed to the disease.
All new malignancies, other than which was being studied during treatment with GS-3583, that 
occur during the study or the posttreatment/survival follow-up period up to 1 year after the 
completion/discontinuation of lesion tumor assessments will be deemed medically important and 
reported as an SAE.
7.1.2.2.
Adverse Events of Special Interest 

All new malignancies, other than which was being studied during treatment with GS-3583, 
that occur during the study or the posttreatment/survival follow-up period will be deemed 
medically important and reported as an SAE.

Following the completion/discontinuation of tumor lesion assessments per the tumor imaging 
schedule outlined in section 6.6.2.1 (as applicable), subjects will be contacted by telephone 
every 3 months for up to 1 year during the survival follow-up period to determine if any new 
malignancies have developed since their last dose of GS-3583.


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7.1.3.
Study Drugs and Gilead Concomitant Therapy Special Situations Reports
Special situation reports (SSRs) include all reports of medication error, abuse, misuse, overdose, 
occupational exposure, drug interactions, exposure via breastfeeding, unexpected benefit, 
transmission of infectious agents via the product, counterfeit of falsified medicine, and 
pregnancy regardless of an associated AE. 
Medication error is any unintentional error in the prescribing, dispensing, preparation for 
administration, or administration of a study drug while the medication is in the control of a 
healthcare professional, subject, or consumer. Medication errors may be classified as a 
medication error without an AE, which includes situations of missed dose, medication error with 
an AE, intercepted medication error, or potential medication error.
Abuse is defined as persistent or sporadic intentional excessive use of a study drug by a subject.
Misuse is defined as any intentional and inappropriate use of a study drug 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 study 
drug given per administration or cumulatively which is above the maximum recommended dose 
as per protocol or in the product labeling (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).
Occupational exposure is defined as exposure to a study drug as a result of one’s professional or 
nonprofessional occupation.
Drug interaction is defined as any drug/drug, drug/food, or drug/device interaction.
Unexpected benefit is defined as an unintended therapeutic effect where the results are judged to 
be desirable and beneficial. 
Transmission of infectious agents is defined as any suspected transmission of an infected agent 
through a Gilead study drug.
Counterfeit or falsified medicine: Any study drug with a false representation of (a) its identity, 
(b) its source, or (c) its history.
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.


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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 using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, preexisting condition, underlying disease, 
intercurrent illness, concomitant medication).

Yes: There is reasonable possibility that the AE may have been caused by the study drug.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE occurred as a result of protocol procedures (eg, venipuncture).
7.2.2.
Assessment of Severity 
The severity of AEs will be graded using the NCI CTCAE toxicity grading scale, Version 5.0. 
For each episode, the highest grade attained should be reported as defined in the Toxicity 
Grading Scale (Appendix 6).
7.3.
Investigator Reporting Requirements and Instructions 
7.3.1.
Requirements for Collection Prior to Study Drug Initiation
After informed consent, but prior to initiation of study medication, the following types of events 
must be reported on the applicable eCRFs: all SAEs and AEs related to protocol-mandated 
procedures.
7.3.2.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 60 days (for Part 1) or 90 days (for Part 2) after the last administration of study drug or start 
of subsequent therapy, whichever occurs first and report them on the eCRFs as instructed.
All AEs and clinically significant laboratory abnormalities should be followed until resolution or 
until the AE is stable, if possible. Gilead may request that certain AEs be followed beyond the 
protocol-defined follow-up period.


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7.3.3.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the ICF) and throughout the duration of the study, including 
the 60 days (for Part 1) or 90 days (for Part 2) after the last dose of study drug, must be reported 
on the applicable eCRFs and GLPS (formerly Gilead Pharmacovigilance and Epidemiology) as 
instructed below in this section. This also includes any SAEs resulting from protocol-associated 
procedures performed after the informed consent form is signed.
Any SAEs and deaths that occur within 90 days of the last dose of study drug, regardless of 
causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after 60 days (for Part 1) or 90 days (for 
Part 2) after the last dose of study drug; however, if the investigator learns of any SAEs that 
occur after the protocol-defined follow-up period has concluded and the event is deemed relevant 
to the use of study drug, the investigator should promptly document and report the event to 
Gilead GLPS.
Instructions for reporting SAEs are described in Section 7.4.1.
7.3.4.
Study Drug Special Situations Reports
All study drug SSRs that occur from study drug initiation and throughout the duration of the 
study, including the posttreatment follow-up, must be reported to Gilead GLPS (Section 7.4.2). 
Adverse events and SAEs resulting from SSRs must be reported in accordance with the AE and 
SAE reporting guidance (Section 7.3).
7.3.5.
Concomitant Therapy Reports
7.3.5.1.
Gilead Concomitant Therapy Special Situations Report
Special situation reports involving a Gilead concomitant therapy (not considered study drug), 
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 60 days (for Part 1) or 90 days (for 
Part 2) after the last dose of study drug, must be reported to Gilead GLPS utilizing the paper SSR 
(Section 7.4.2.2).
7.3.5.2.
Non-Gilead Concomitant Therapy Report
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the SSR 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.


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All clinical sequelae in relation to these SSRs will be reported as AEs or SAEs at the same time 
using the AE eCRF and/or the SAE report form. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available.
7.4.
Reporting Process for Serious Adverse Events and Special Situation Reports
7.4.1.
Serious Adverse Event Reporting Process
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be transmitted by email or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.
Additional information may be requested to ensure the timely completion of accurate safety 
reports.
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the SAE narrative section of the safety report form 
eCRF.
7.4.1.1.
Electronic Serious Adverse Event Reporting Process
Site personnel will record all SAE data on the applicable eCRFs and from there transmit the SAE 
information to Gilead GLPS within 24 hours of the investigator’s knowledge of the event from 
ICF signature throughout the duration of the study, including the protocol-required posttreatment 
follow-up period. 
If it is not possible to record and transmit the SAE information electronically, record the SAE on 
the paper SAE reporting form and transmit within 24 hours:
Gilead GLPS:
Gilead GLPS
Email: 
 
or
Fax: 
If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. If the database is not locked, any SAE reported via paper must be 
transcribed as soon as possible on the applicable eCRFs and transmitted to Gilead GLPS.
C
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7.4.2.
Special Situations Reporting Process
7.4.2.1.
Paper Special Situations Reporting Process for Study Drugs
All SSRs will be recorded on the SSR form and transmitted by emailing or faxing the report 
form within 24 hours of the investigator’s knowledge of the event to the attention of Gilead 
GLPS from study drugs’ initiation throughout the duration of the study, including the protocol 
required posttreatment follow-up period.
Gilead GLPS:
Gilead GLPS
Email: 
 
or
Fax: 
7.4.2.2.
Reporting Process for Gilead Concomitant Medications
Special situations that involve Gilead concomitant medications that are not considered study 
drugs must be reported within 24 hours of the investigator’s knowledge of the event to Gilead 
GLPS utilizing the paper special situations report form to:
Gilead GLPS:
Gilead GLPS
Email: 
 
or
Fax: 
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.
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the SSR form; however, special situations that result in AEs due to a non-Gilead concomitant 
medication, must be reported as an AE.
7.4.2.3.
Pregnancy Reporting Process
The investigator should report pregnancies in female study subjects and/or female partners of 
male subjects that are identified after initiation of study drug and throughout the study until 
6 months after the last dose of study drugs to Gilead GLPS using the pregnancy report form 
within 24 hours of becoming aware of the pregnancy. Contact details for transmitting the 
pregnancy report form are as follows:
Gilead GLPS:
Gilead GLPS
Email: 
 
or
Fax: 
PPD
PPD
PPD
PPD
PPD
PPD


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The pregnancy itself is not considered an AE, nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
All other premature terminations of pregnancy (eg, a spontaneous abortion, an induced 
therapeutic abortion due to complications or other medical reasons) must be reported within 
24 hours as an SAE, as described in Section 7.4.1. The underlying medical reason for this 
procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.4.1. Furthermore, any SAE occurring as an adverse pregnancy outcome after study 
must be reported to Gilead GLPS.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome of the pregnancy/partner pregnancy should be reported to Gilead GLPS 
using the pregnancy outcome report form. If the end of the pregnancy/partner pregnancy occurs 
after the study has been completed, the outcome should be reported directly to Gilead GLPS. 
Gilead GLPS contact information is as follows: email: 
 and fax: 
 
 
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.5.
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 which may be in the form of line-listings, serious 
adverse drug reactions, or suspected unexpected serious adverse reaction (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 IRB/IEC in concerned member states 
of applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB 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. 
PPD
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7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not to be recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, 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, ECG, 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).
Severity should be recorded and graded according to the NCI CTCAE toxicity grading scale, 
Version 5.0. 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.
7.7.
Toxicity Management 
Severity should be recorded and graded according to NCI CTCAE v5.0 (Appendix 6).
Toxicity should be managed according to Sections 5.5.1.3 and 5.5.1.4. Study drug will be 
discontinued for DLT during Part 1 or during safety run-in during Part 2 (Cohorts A and B) as 
defined in Section 3.2.1.1.1. Also refer to the ASCO Toxicity Management Guidelines 
(Appendix 3) and withhold or discontinue GS-3583 accordingly. 
As per Section 5.5.1.1, GS-3583 dose modifications are not permitted in this study. GS-3583 
administration may be delayed due to any AE that warrants a delay, as per Section 5.5.1.2. 
GS-3583 may be resumed as specified in Section 5.5.1.5.


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8.
STATISTICAL CONSIDERATIONS
Details of the statistical methods will be provided in the statistical analysis plan, including any 
deviations from the original statistical analyses planned. 
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The objectives of this study are described in Section 2.
8.1.2.
Endpoints: Part 1
8.1.2.1.
Primary Endpoints

Incidence of DLTs defined in Section 3.2.2.

Incidence of AEs and laboratory abnormalities defined by NCI CTCAE v5.0. 
8.1.2.2.
Secondary Endpoints

GS-3583 PK parameters (AUCtau)

Rate of GS-3583 ADA
8.1.2.3.
Other Endpoints of Interest
The exploratory endpoints of interest for Part 1 are as follows:
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8.1.3.
Endpoints: Part 2
8.1.3.1.
Primary Endpoints
The primary endpoints for Part 2 Cohorts A and B are as follows:

Incidence of DLTs defined in Section 3.2.2.

Incidence of AEs and laboratory abnormalities defined by NCI CTCAE v5.0
8.1.3.2.
Secondary Endpoints
The secondary endpoints for Part 2 Cohorts A and B are as follows:

Confirmed ORR is defined as the percentage of subjects who have achieved confirmed CR or 
confirmed PR according to RECIST V1.1 and assessed by the investigator.

Progression-free survival is the time from date of randomization until disease progression or 
death from any cause, whichever comes first as measured per RECIST V1.1 as assessed by 
the investigator

Duration of response is measured from the time of first response (CR or PR) identified by 
RECIST V1.1 as assessed by the investigator until the date of first documented disease 
progression or death, whichever comes first.

Overall survival is the length of time from date of randomization until the date of death from 
any cause.

Disease control rate is measured by the percentage of subjects with a best overall confirmed 
response of CR or PR or stable disease.

PK parameters (Cmax, Tmax, and AUCtau) for GS-3583

Rate of GS-3583 ADA
8.1.3.3.
Other Endpoints of Interest
CCI
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8.2.
Planned Analyses
8.2.1.
Interim Analysis
8.2.1.1.
Part 1 Dose-Escalation Analysis and Part 2 Safety Run-in Analysis
For the purpose of making the decision whether to escalate to the next dose level/cohort, interim 
analyses of relevant safety and available PK data will be conducted by Gilead after all subjects in 
each cohort have completed dosing and the follow-up period in the DLT period as defined in 
Section 3.2.2. Safety assessments (eg, AEs, ECG, and laboratory results) will be displayed by 
cohort or dose level to facilitate the decision.
8.2.2.
Final Analysis
The final analysis will be performed after all subjects have completed or discontinued from the 
study, outstanding data queries have been resolved or adjudicated as unresolvable, and the data 
have been cleaned and finalized. 
8.3.
Analysis Conventions
8.3.1.
Analysis Sets
8.3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis Set includes all subjects who received a study subject identification 
number. This will be the primary analysis set for by-subject listings.
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8.3.1.2.
DLT Analysis Set
The DLT Analysis Set includes all subjects who were enrolled for dose escalation, received all 
treatments of GS-3583 or combination therapy and completed safety procedures through DLT 
assessment period (inclusive of the last day) or experienced a DLT prior to end of DLT 
assessment period. Determination of MTD or RP2D will be based on the DLT Evaluable 
Analysis Set.
8.3.1.3.
Safety Analysis Set
The Safety Analysis Set will include all subjects who received at least 1 dose of GS-3583 or 
combination therapy. This will be the primary analysis set for safety analysis.
8.3.1.4.
Full Analysis Set
The Full Analysis Set includes all enrolled subjects who received at least 1 dose of GS-3583 or 
combination therapy (Part 1 and Part 2 Safety Run-in Cohorts) or all randomized subjects (Part 2 
Randomized Expansion Cohorts). This will be the primary analysis set for efficacy analyses.
8.3.1.5.
Pharmacokinetics Analysis Set
The PK Analysis Set includes all enrolled subjects who received at least 1 dose of GS-3583 or 
zimberelimab and have at least 1 nonmissing postdose concentration value reported by the PK 
laboratory. This will be the primary analysis set for all PK analyses.
8.3.1.6.
Immunogenicity Analysis Set
The Immunogenicity Analysis Set includes all enrolled subjects who received at least 1 dose of 
GS-3583 or zimberelimab and had at least 1 ADA test. This will be the primary analysis set for 
immunogenicity data analyses.
8.3.1.7.
Biomarker Analysis Set
The Biomarker Analysis Set includes all enrolled subjects who received at least 1 dose of 
GS-3583 or combination therapy and have at least 1 evaluable biomarker measurement available. 
This will be the primary analysis set for all biomarker data analyses.
8.3.2.
Data Handling Conventions
In general, values for missing data will not be imputed. However, a missing pretreatment 
laboratory result would be treated as normal (ie, no toxicity grade) for the laboratory abnormality 
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Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed to the value of the lower or upper limit 
minus or plus 1 significant digit, respectively (eg, if the result of a continuous laboratory test is 
< 20, a value of 19 will be assigned; if the result of a continuous laboratory test is < 20.0, a value 
of 19.9 will be assigned). 
8.4.
Demographic and Baseline Characteristics Analysis
Demographic and baseline measurements will be summarized using standard descriptive 
methods. 
Demographic summaries will include sex, race/ethnicity, and age.
Baseline data will include a summary of body weight, height, and body mass index. 
8.5.
Efficacy Analysis
For Part 1, efficacy analysis will be performed by dose level. For Part 2, efficacy analysis will be 
performed by cohort, dose level (for Safety Run-in Cohorts), or treatment (for Randomized 
Expansion Cohorts).
The ORR, DCR, and the respective corresponding 90% CI based on the Clopper-Pearson exact 
method {Clopper 1934} will be provided. Subjects who do not have sufficient baseline or 
on-study tumor assessment to characterize response will be counted as nonresponders.
PFS, DOR, and OS will be analyzed using Kaplan-Meier (KM) method. The median, 25% and 
75% percentiles will be provided along with the corresponding 90% CI. In addition, the 
estimated rate at selected time point, such as 3 months, 6 months, 12 months, 18 months, and 
24 months will be reported. The detailed censoring rules will be described in the statistical 
analysis plan.
The TTR will be summarized using descriptive statistics.
8.6.
Safety Analysis
For Part 1, safety analysis will be performed by dose level. For Part 2, safety analysis will be 
performed by cohort, dose level (for Safety Run-in Cohorts), or treatment (for Randomized 
Expansion Cohorts).
All safety data collected on or after the date that study drug was first administered up to the last 
dose date plus 90 days will be analyzed according to the study drug received using the Safety 
Analysis Set. 
For categorical safety data including incidence of AEs and categorizations of laboratory data, 
count and percentage of subjects will be summarized. For continuous safety data including 
laboratory data, descriptive summary statistics (mean, standard deviation, minimum, quartiles, 
median and maximum) will be summarized.


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8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug data will be generated from the study drug 
administration data.
8.6.2.
Adverse Events
Clinical and laboratory AEs will be coded using the MedDRA. System organ class, high-level 
group term, high-level term, preferred term, and lower-level term will be attached to the clinical 
database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
AE will be defined as any AE that begins on or after the date of first dose of study drug up to the 
date of last dose of study drug plus 90 days.
Summaries (number and percentage of subjects) of treatment-emergent AEs (by system organ 
class and preferred term) will be provided.
8.6.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the NCI CTCAE v5.0.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
1 toxicity grade from baseline up to and including the date of last dose of study drug plus 90 
days, will be summarized. If baseline data are missing, then any graded abnormality (ie, at least a 
Grade 1) will be considered treatment emergent. 
Laboratory abnormalities that occur before the first dose of study drug or after the subject has 
been discontinued from treatment for at least 90 days will be included in a data listing.
8.6.4.
Other Safety Evaluations
Other safety measures such as vital signs, ECG, etc, will be summarized by treatment group.
8.7.
Pharmacokinetic Analysis
For Part 1, PK analysis will be performed by dose level. For Part 2, PK analysis will be 
performed by cohort, dose level (for Safety Run-in Cohorts), or treatment (for Randomized 
Expansion Cohorts). 


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Serum concentrations for GS-3583 or zimberelimab will be summarized by nominal sampling 
time using descriptive statistics (ie, sample size, arithmetic mean, geometric mean, % coefficient 
of variation, standard deviation, median, minimum, and maximum). Serum concentrations of 
GS-3583 or zimberelimab over time may be plotted in semilogarithmic and linear formats as 
mean ± standard deviation.
Pharmacokinetic parameters (AUCtau, Cmax, Ctrough, Tmax, CL, etc, as appropriate) will be listed 
and summarized using descriptive statistics.
8.8.
Biomarker Analysis
For Part 1, biomarker analysis will be performed by dose level. For Part 2, biomarker analysis 
will be performed by cohort, dose level (for Safety Run-in Cohorts) or treatment (for 
Randomized Expansion Cohorts).
Pharmacodynamics data will be listed and summarized using descriptive statistics. Descriptive 
summaries for change from baseline will also be provided over time. Correlation of 
pharmacodynamic responses, immunologic changes with GS-3583 or combination therapy 
treatment, and other biomarkers with clinical response and/or safety may be explored as 
appropriate.
8.9.
Immunogenicity Analysis
For Part 1, immunogenicity analysis will be performed by dose level. For Part 2, 
immunogenicity analysis will be performed by cohort, dose level (for Safety Run-in Cohorts) or 
treatment (for Randomized Expansion Cohorts).
Immunogenicity to GS-3583 or zimberelimab will be evaluated based upon the incidence of 
ADA formation. Number and percentage of positive or negative ADA results at each specified 
time point will be summarized using the Immunogenicity Analysis Set. Supporting data 
including treatment, nominal sampling day, actual date and time of sampling, and ADA results 
will be included in a listing.
8.10.
Sample Size
A total of approximately 150 subjects will be enrolled.
For Part 1, assuming up to 4 planned dose levels will be tested with 3 DLT-evaluable subjects for 
the first dose level and up to 6 DLT-evaluable subjects per subsequent dose level, 
21 DLT-evaluable subjects will be needed. Assuming 10% are not evaluable, approximately 
24 subjects will be enrolled in Part 1.
For Part 2, a maximum of 63 subjects will be enrolled for each cohort. Six to 18 subjects will be 
evaluated in Safety Run-in Cohorts, and 45 subjects will be enrolled in Randomization 
Expansion Cohorts with 2:1 randomization ratio. The total maximum sample size in Part 2 is 
approximately 126.


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The assessment of efficacy will be based on point estimate of ORR or the difference in ORR 
treatment effect with the confidence intervals. The exact 90% CI for various ORR or the 
differences are provided in Table 8-1 and Table 8-2.
Table 8-1.
Exact 90% CI of ORR for a Sample Size of 30 in GS-3583 
Combination Arm
Observed ORR
Exact 90% CI
20%
(9%, 36%)
30%
(17%, 47%)
40%
(25%, 57%)
50%
(34%, 66%)
ORR = objective response rate
Table 8-2.
Exact 90% CI of Difference in ORR for a Sample Size of 45 with 2:1 
Randomization Ratio
Observed ORR (GS-3583 vs Control) (Difference)
Exact 90% CI
30% vs 20% (10%)
(−15%, 31%)
50% vs 40% (10%)
(−18%, 36%)
40% vs 20% (20%)
(−5%, 41%)
53.3% vs 33.3% (20%)
(−8%, 44%)
ORR = objective response rate


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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 International Council 
for Harmonisation (of Technical Requirements for Pharmaceuticals for Human Use) (ICH) 
E6(R2) addendum to its guideline for GCP and applicable laws and regulations.
9.1.2.
Financial Disclosure
The investigator and subinvestigators will provide prompt and accurate documentation of their 
financial interest or arrangements with Gilead or proprietary interests in the study drug during 
the course of a clinical 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.
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval
The investigator (or Gilead as appropriate according to local regulations) will submit this 
protocol, ICF, 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 IRB/IEC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the 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.
9.1.4.
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 before undertaking any study-related procedures. The investigator 
must use the most current IRB- or IEC-approved informed consent form for documenting written 
informed consent. Each ICF (or assent as applicable) will be appropriately signed and dated by 
the subject or the subject’s legally authorized representative, the person conducting the consent 
discussion, and an impartial witness (if required by IRB or IEC or local requirements). 




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The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification

Documentation that subject meets eligibility criteria, ie, medical 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)

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 AEs and other safety parameters (start and end date, causality and severity), 
and documentation that adequate medical care has been provided for any AE

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 for 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, US, 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, for 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.


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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.
9.1.7.
Case Report 
For each subject consented, an eCRF casebook will be completed by an authorized study staff 
member whose training for this function is completed in the EDC system. The eCRF casebook 
will only capture the data required per the protocol schedule of events and procedures. The 
inclusion/exclusion criteria and enrollment eCRFs should be completed only after all data related 
to eligibility have been received. Data entry should be performed in accordance with the eCRF 
completion guidelines provided by the sponsor. Subsequent to data entry, a study monitor will 
perform source data verification within the EDC system. System-generated or manual queries 
will be issued in the EDC system as data discrepancies are identified by the monitor or Gilead 
staff, who routinely review the data for completeness, correctness, and consistency. The site 
investigator, site coordinator, or other designee is responsible for responding to the queries in a 
timely manner, within the system, either by confirming the data as correct or updating the 
original entry, and providing the reason for the update (eg, data entry error). Original entries as 
well as any changes to data fields will be stored in the audit trail of the system. At a minimum, 
prior to any interim time points or database lock (as instructed by Gilead), the investigator will 
use his/her login credentials to confirm that the forms have been reviewed and that the entries 
accurately reflect the information in the source documents. At the conclusion of the study, Gilead 
will provide the site investigator 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 9.1.6.
9.1.8.
Investigator Inspections
The investigator will make available all source documents and other records for this study to 
Gilead’s appointed study monitors, to IRBs/IECs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies when 
applicable and in accordance with local regulatory requirements. 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. For 
studies with sites in countries following the EU Regulation No. 536/2014, a CSR will be 
submitted within 1 year after the global end of study (as defined in Section 3.6).
Investigators in this study may communicate, orally present, or publish study data in scientific 
journals or other scholarly media in accordance with the Gilead clinical trial agreement.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol (eg, attendance at investigator 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 study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries in the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on-site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or 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.


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9.3.4.
Study Discontinuation
Both Gilead 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 subjects, 
appropriate regulatory authority, IRBs, and ethics committee. In terminating the study, Gilead 
and the investigator will ensure that adequate consideration is given to the protection of the 
subjects’ interests.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Pandemic Risk Assessment and Mitigation Plan
Appendix 3.
American Society of Clinical Oncology (ASCO) Toxicity Management Guidelines
Appendix 4.
Study Procedures Tables
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 6.
NCI CTCAE v5.0 Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities
Appendix 7.
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)


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Appendix 1.
Investigator Signature Page
GILEAD SCIENCES, INC.
333 LAKESIDE DRIVE
FOSTER CITY, CA 94404
STUDY ACKNOWLEDGMENT
A Phase 1b Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary 
Efficacy of GS-3583, a FLT3 Agonist Fc Fusion Protein, as Monotherapy and in 
Combination with Anticancer Therapies in Subjects with Advanced Solid Tumors
GS-US-496-5657, Protocol Amendment 2, 14 April 2022
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval.
[See appended electronic signature]
Name (Printed)
Medical Monitor
Signature
[See appended electronic signature]
Date
INVESTIGATOR STATEMENT
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated.
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study.
Principal Investigator Name (Printed)
Signature
Date
Site Number
PPD


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FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 158
14 April 2022
Appendix 2.
Pandemic Risk Assessment and Mitigation Plan
During an ongoing pandemic, potential risks associated with subjects being unable to attend 
study visits have been identified for this study. 
These risks can be summarized as follows:
1) Study drug supplies to subjects and sites:
a) Subjects may be unable to return to the site for a number of visits to get the study drug, or 
the site may be unable to accept any subject visits. Without study drug, the subject would 
not be able to stay on the study drug as planned per protocol.
Mitigation plan: Since this study is an oncology study the care subjects receive is 
considered essential therefore there should not be an interruption of visits where subjects 
receive study drug due to the pandemic, in most cases.
b) Shipments of study drug could be delayed because of transportation issues. Without study 
drug, subject would not be able to stay on the study drug as planned per protocol.
Mitigation plan: The sites' study drug inventory should be closely monitored. Site staff 
should notify the sponsor or delegate if they foresee shortage in study drug inventory or if 
there is any interruption in local shipping service. The sponsor will continue to monitor 
inventory at the study drug depot and study sites. Manual shipments will be triggered as 
necessary.
2) Subject safety monitoring and follow-up:
a) Subjects may be unable or unwilling to come to the study site for their scheduled study 
visits as required per protocol.
Mitigation plan: For subjects who may be unable or unwilling to visit the study site for 
their scheduled study visits as required per protocol, the principal investigator or 
qualified delegate will conduct a virtual study visit, via phone or video conferencing, to 
assess the subject within target visit window date, whenever possible. During the virtual 
study visit, the following information at minimum will be reviewed: 
i)
Confirm if subject has experienced any adverse events (AEs)/serious adverse events 
(SAEs)/special situations (including pregnancy) and follow-up on any unresolved 
AE/SAEs.
ii) Review current list of concomitant medications and document any new concomitant 
medications.
b) Subjects may be unable or unwilling to travel to the site for planned assessments 
(eg, safety blood draws); hence samples may not be sent for central lab analyses.


GS-3583
Protocol GS-US-496-5657
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Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 159
14 April 2022
Mitigation plan: Local labs may be utilized as appropriate to monitor subject safety until 
the subject can return to the site for their regular follow-up per protocol. Any laboratory 
assessments conducted at a local lab due to the pandemic will be documented 
accordingly. Pregnancy testing may be performed using a home urine pregnancy test if 
local lab pregnancy testing is not feasible.
c) Subjects may be unable or unwilling to attend the study visit to sign an updated informed 
consent form (ICF) version.
Mitigation plan: The site staff will follow their approved consent process and remain in 
compliance with local ethics committee (EC)/ institutional review board (IRB) and 
national laws and regulations. Remote consent will be allowed if it has been approved by 
the local EC/IRB. The consent process will be documented and confirmed by normal 
consent procedure at the earliest opportunity.
3) Protocol and monitoring compliance:
a) Protocol deviations may occur, in case scheduled visits cannot occur as planned per 
protocol.
Mitigation plan: If it is not possible to complete a required procedure, an unscheduled 
visit should be conducted as soon as possible when conditions allow. The situation should 
be recorded and explained as a protocol deviation. Any missed subject visits or deviation 
to the protocol due to the pandemic must be reported in the electronic case report form 
(eCRF) and described in the clinical study report. Any virtual study visits that are 
conducted in lieu of clinic visits due to the pandemic will be documented as a protocol 
deviation related to the pandemic.
b) Monitors may be unable to carry out source data review or source data verification 
(SDV), or study drug accountability or assess protocol and Good Clinical Practice (GCP) 
compliance. This may lead to delays in SDV, an increase in protocol deviations, or under 
reporting of AEs.
Mitigation plan: The study monitor is to remain in close communication with the site to 
ensure data entry and query resolution. In compliance with Gilead policy, remote SDV 
should not be arranged. The study monitor is to reference the study monitoring plan for 
guidance on how to conduct a remote monitoring visit. The study staff is to save and 
document all relevant communication in the study files. The status of sites that cannot 
accept monitoring visits and/or subjects on site, must be tracked centrally and updated on 
a regular basis.
4) Missing data and data integrity:
a) There may be an increased amount of missing data due to subjects missing 
visits/assessments. This could have an impact on the analysis and the interpretation of 
clinical study data. 


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 160
14 April 2022
Mitigation plan: Implications of a pandemic on methodological aspects for the study will 
be thoroughly assessed and documented, and relevant actions will be taken as appropriate 
(ie, modification of the statistical analysis plan) and in compliance with regulatory 
authorities’ guidance. Overall, the clinical study report will describe the impact of the 
pandemic on the interpretability of study data.
5) Concurrent administration of the COVID-19 vaccine:
There may be potential safety issues due to concurrent administration of the COVID-19 
vaccine and study drugs.
Mitigation plan: There is not substantial safety data regarding the concurrent 
administration of the COVID-19 vaccine and zimberelimab, 5-fluorouracil (5-FU), 
cisplatin, carboplatin, and docetaxel. Subjects are allowed to receive the COVID-19 
vaccine to reduce the risk and complications of COVID-19 infection. Investigators and 
study personnel should provide close surveillance of subjects after COVID-19 vaccine 
administration and the institutional guidelines should always be followed. The 
administration of specific COVID-19 vaccine must be documented in the clinical 
database and AEs associated with COVID-19 vaccine administration should be recorded 
in the AE eCRF. The COVID-19 vaccine administration should be recorded in the prior 
or concomitant medication eCRF as appropriate. The study visits should continue as 
planned, if possible, and clinically appropriate if vaccination occurs while the subject is 
on the study.
Risks will be assessed continuously, and temporary measures will be implemented to mitigate 
these risks as part of a mitigation plan, as described above. These measures will be 
communicated to the relevant stakeholders as appropriate and are intended to provide alternate 
methods that will ensure the evaluation and assessment of the safety of subjects who are enrolled 
in this study. 
Since these potential risks are considered mitigated with the implementation of these measures, 
the expected benefit-risk assessment of study drug(s) in study subjects remains unchanged.


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 161
14 April 2022
Appendix 3.
American Society of Clinical Oncology (ASCO) Toxicity Management 
Guidelines
https://ascopubs.org/doi/full/10.1200/JCO.21.01440


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Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 162
14 April 2022
Appendix 4.
Study Procedures Tables
Appendix Table 1.
Part 1 Study Procedures – Screening
Assessment
Administrative Procedures
Day −28 to −1
Informed consent 
X
Review of inclusion/exclusion criteria
X
Review of medical history, including smoking status and demographics
X
Review of baseline symptoms
X
Review of prior and concomitant medications
X
Cancer disease details and prior treatment
X
Enrollmenta
X
Clinical Procedures/Assessments
Day −28 to −1
Review AEsb
X
Full PE
X
Vital signs and weightc
X
Height
X
12-lead ECG
X
Echocardiogram or MUGAd
X
ECOG Performance Status
X
Imaging Assessments
Day −28 to −1
Tumor imaginge
X
Laboratory Procedures/Assessments
Day −28 to −1
Serum chemistry
X
Hematology tests
X
Coagulation tests
X
Endocrine function tests
X
HIV screening
X
HBV & HCV serology 
X
Urinalysis
X
Serum pregnancy test
X
Biomarker Procedures/Assessments
Day −28 to −1
Whole blood for CHIP mutation analysisf
X
Whole blood for circulating tumor DNAf
X
Collection of pretreatment tumor biopsy (archival and fresh)
X
AEs = adverse events; CHIP = clonal hematopoiesis of indeterminate potential; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; HBV = hepatitis B virus; HCV = hepatitis C virus; MUGA = multigated acquisition; 
PE = physical exam; SAE = serious adverse event
a
Subjects who fulfill all of the inclusion criteria and none of the exclusion criteria will be enrolled into the study within 
28 days after screening.
b
After informed consent, but prior to initiation of study medication, all SAEs and AEs related to protocol-mandated 
procedures will be reported on Case Report Forms.
c
Vital signs will only be measured while subject is in sitting, semi-recumbent or supine position.
d
Complete echocardiogram assessment will be conducted at screening to establish a baseline. A MUGA scan is allowed.
e
The initial tumor imaging will be performed within 28 days prior to first dose of study drug. Scans performed as part of 
routine clinical management are acceptable for use as screening scan if they are of diagnostic quality and ≤ 28 days prior to 
first dose of study drug.
f
Biomarker Assays: See details on all biomarker sample collections in Section 6.5.2.1.


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Protocol GS-US-496-5657
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Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 163
14 April 2022
Appendix Table 2.
Part 1 Study Procedures – Treatment Phase
Treatment Phase
Cycle 1
Cycle 2
Cycle 3
Cycle 4 & 
Every Even 
Cycle After
Cycle 5 & 
Every Odd 
Cycle After
Study Visits (Cycle Day)
1
2
3
5
8
15
24
1
15
1
2
3
5
8
15
24
1
15
1
15a
Visit Window (Days)b
—
—
—
—
—
—
—
+ 2
+ 2
+ 2
—
—
—
—
—
—
+ 2
+ 2
+ 2
+ 2
Visit Schedule (Hours Postinfusion)
—
24
48
96
168
336
552
—
336
—
24
48
96
168
336
552
—
336
—
336
Administrative Procedures
Review of inclusion/exclusion criteria
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Review of baseline symptoms
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Review of prior and concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessmentsc
Review AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Focused PE
Xc
—
—
—
—
Xc
—
Xc
—
Xc
—
—
—
—
X
—
Xc
—
Xc
—
Vital signs and weightd
Xd
—
—
—
—
Xd
—
Xd
—
Xd
—
—
—
—
X
—
Xd
—
Xd
—
12-lead ECG
Xe
—
—
—
—
Xf
—
Xf
—
Xf
—
—
—
—
—
—
—
—
Xf
—
ECOG Performance Status
Xc
—
—
—
—
—
—
Xc
—
Xc
—
—
—
—
—
—
Xc
—
Xc
—
Imaging Assessments
Tumor imagingg
Every 8 weeks
Laboratory Procedures/Assessmentsh
Serum chemistry
Xc
—
—
—
X
Xc
—
Xc
X
Xc
—
—
—
—
X
—
Xc
—
Xc
—
Hematology tests
Xc
—
—
—
X
Xc
—
Xc
X
Xc
—
—
—
—
X
—
Xc
—
Xc
—
Coagulation tests
—
—
—
—
—
Xc
—
Xc
—
Xc
—
—
—
—
—
—
Xc
—
Xc
—
Endocrine function tests
—
—
—
—
—
Xc
—
Xc
—
Xc
—
—
—
—
—
—
Xc
—
Xc
—
Urinalysis
Xc
—
—
—
X
Xc
—
Xc
X
Xc
—
—
—
—
X
—
Xc
—
Xc
—
Urine pregnancy testi
Xc
—
—
—
—
Xc
—
Xc
—
Xc
—
—
—
—
—
—
Xc
—
Xc
—
Blood for PK assaysj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
—
Blood for ADA assaysk
X
—
—
—
—
—
—
X
—
X
—
—
—
—
—
—
Xl
—
Xm
—


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 164
14 April 2022
Treatment Phase
Cycle 1
Cycle 2
Cycle 3
Cycle 4 & 
Every Even 
Cycle After
Cycle 5 & 
Every Odd 
Cycle After
Study Visits (Cycle Day)
1
2
3
5
8
15
24
1
15
1
2
3
5
8
15
24
1
15
1
15a
Visit Window (Days)b
—
—
—
—
—
—
—
+ 2
+ 2
+ 2
—
—
—
—
—
—
+ 2
+ 2
+ 2
+ 2
Visit Schedule (Hours Postinfusion)
—
24
48
96
168
336
552
—
336
—
24
48
96
168
336
552
—
336
—
336
Biomarker Procedures/Assessmentsh
Whole blood for pharmacodynamic biomarkers (PBMC 
and plasma)n
Xo
—
—
—
X
Xo
X
Xo
X
Xo
—
—
—
X
X
X
Xo
X
—
—
Whole blood for blood cell countn
Xo
—
—
—
X
Xo
X
Xo
X
Xo
—
—
—
X
X
X
Xo
X
—
—
Whole blood for CHIP mutation analysisn
X
—
—
—
—
—
—
X
—
X
—
—
—
—
—
—
X
—
—
—
Whole blood for TCR sequencingn
X
—
—
—
—
—
—
X
—
X
—
—
—
—
—
—
X
—
—
—
Whole blood for circulating tumor DNAn
X
—
—
—
—
—
—
X
—
X
—
—
—
—
—
—
X
—
—
—
Whole blood for Paxgene RNAn
X
—
—
—
—
X
—
X
—
X
—
—
—
—
X
—
X
—
—
—
Serum pharmacodynamics for circulating factorsn
X
—
—
—
X
X
X
X
—
X
—
—
—
X
X
—
—
—
—
Stool sample for microbiome sequencingn
X
—
—
—
—
—
—
—
—
X
—
—
—
—
—
—
—
—
—
—
Study Drug Administration
GS-3583r
X
—
—
—
—
X
—
X
—
X
—
—
—
—
—
—
X
—
X
—
ADA = antidrug antibody; AEs = adverse events; CHIP = clonal hematopoiesis of indeterminate potential; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EOT = end of treatment; MUGA = multigated acquisition; PBMC = peripheral blood mononuclear cell; PE = physical exam; PK = pharmacokinetic(s); TCR = T-cell 
receptor
a
The Day 15 visit of Cycle 5 and every odd cycle thereafter, including Cycle 13, will be conducted via telephone. However, this visit may be performed in-clinic per the 
investigator's discretion.
b
Treatment administration and associated procedures for a visit may be delayed for treatment-related AEs beyond the window and subsequent schedule adjusted accordingly.
c
On each day of study drug administration, the predose focused PE, ECOG performance status, and safety labs (hematology, chemistry, coagulation [applicable visits], 
endocrine function tests [applicable visits], urinalysis, and urine pregnancy) can be performed within 72 hours prior to each dose of study treatment. 
d
Vital signs will only be measured while subject is in sitting, semi-recumbent or supine position. Vital signs are to be measured prior to each infusion commencing and at the 
end of each infusion. For the first 2 doses during Cycle 1, vital signs will be measured 1 hour (±15 minutes) after the end of the GS-3583 infusion. Thereafter in subsequent 
cycles, the posttreatment vital signs can be taken 30 minutes (-10/+20 minutes) after the end of each GS-3583 infusion. Subjects will remain in the clinic under close 
supervision for the duration of this monitoring period.
e
On Cycle 1 Day 1, 12-lead ECG will be collected before and 2 hours (-10/+20 minutes) after the end of GS-3583 administration.
CCI
CCI




GS-3583
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FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 166
14 April 2022
Appendix Table 3.
Part 1 Study Procedures Table – Posttreatment
End of Treatment
Posttreatment
Survival Follow-Up
Within 7 Days After 
Last Dose of Study 
Treatment or EOT 
Decision
60-day Follow-up 
Visita,b,c
≤ 1 Year From Last 
Doseb
≤ 1 Year From Last 
Tumor Lesion 
Assessmentb,c,d
Visit Window
≤ 7 Days
± 7 Days
± 7 Days
± 7 Days
Administrative Procedures
Review of prior and concomitant medication
X
X
—
—
Subsequent anticancer therapy status
X
X
X
X
Overall survivalb,c,d
—
—
—
X
Clinical Procedures/Assessments
Review AEs
X
X
—
—
Full PE
X
—
—
—
Focused PE
—
X
—
—
Vital signs and weighte
X
X
—
—
12-Lead ECG
X
X
—
—
ECOG Performance Status
X
X
—
—
Imaging Assessments
Tumor imagingf
Every 8 weeks
—
Laboratory Procedures/Assessments
Serum chemistry
X
X
—
—
Hematology tests
X
X
—
—
Coagulation tests
X
X
—
—
Endocrine function tests
X
X
—
—


GS-3583
Protocol GS-US-496-5657
FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 167
14 April 2022
End of Treatment
Posttreatment
Survival Follow-Up
Within 7 Days After 
Last Dose of Study 
Treatment or EOT 
Decision
60-day Follow-up 
Visita,b,c
≤ 1 Year From Last 
Doseb
≤ 1 Year From Last 
Tumor Lesion 
Assessmentb,c,d
Visit Window
≤ 7 Days
± 7 Days
± 7 Days
± 7 Days
Urinalysis
X
X
—
—
Urine pregnancy testg
X
X
Xg
—
Blood for PK assaysh
Xi
X
—
—
Blood for ADA assaysj
Xi
X
—
—
Biomarker Procedures/Assessments
Whole blood for pharmacodynamic biomarkers (PBMC and plasma)k
Xi
X
—
—
Whole blood for blood cell countk
Xi
X
—
—
Whole blood for CHIP mutation analysisk
X
—
—
—
Whole blood for TCR sequencingk
X
—
—
—
Whole blood for circulating tumor DNAk
X
—
—
—
Whole blood for Paxgene RNAk
X
—
—
—
Serum pharmacodynamics for circulating factorsk
X
—
—
—
Stool sample for microbiome sequencingk
X
—
—
—
ADA = antidrug antibody; AEs = adverse events; CHIP = clonal hematopoiesis of indeterminate potential; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EOT = end of treatment; MUGA = multigated acquisition; PBMC = peripheral blood mononuclear cell; PE = physical exam; PK =  pharmacokinetic(s); SAE = serious 
adverse event; TCR = T-cell receptor
a
All subjects who discontinue treatment will have a follow-up visit 60 days (± 7 days) after the last dose of study drug.
b
Subjects who discontinue treatment due to reasons other than progressive disease and/or start of a new line of anticancer therapy will complete the 60-day follow-up and 
continue tumor imaging assessments at the predefined schedule until documented progressive disease, initiation of a new anticancer therapy, or up to 1 year after the last dose 
of study drug, whichever occurs first; and then move into survival follow-up for up to 1 year after the completion/discontinuation of tumor lesion assessments.
c
Subjects who discontinue due to progressive disease and/or start of a new line of anticancer therapy will complete the 60-day follow-up and then enter the survival follow-up 
period for up to 1 year after the completion/discontinuation of tumor lesion assessments.  
d
During the survival follow-up period, subjects will be contacted by telephone to assess for survival status and any new malignancies every 3 months for up to 1 year after the 
completion/discontinuation of tumor lesion assessments. No imaging assessment is required for survival follow-up. Any new malignancies will be reported as SAEs.
CCI




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Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 169
14 April 2022
Appendix Table 4.
Part 2 Study Procedures – Screening
Assessment
Administrative Procedures
Day −28 to −1
Informed consent 
X
Review of inclusion/exclusion criteria
X
Review of medical history, including smoking status and demographics
X
Review of baseline symptoms
X
Review of prior and concomitant medications
X
Cancer disease details and prior treatment
X
Enrollment/Randomizationa
X
Clinical Procedures/Assessments
Day −28 to −1
Review AEsb
X
Full PE
X
Vital signs and weightc
X
Height
X
12-lead ECG
X
Echocardiogram or MUGAd
X
ECOG Performance Status
X
Imaging Assessments
Day −28 to −1
Tumor imaginge
X
Laboratory Procedures/Assessments
Day −28 to −1
Serum chemistry
X
Hematology tests
X
Coagulation tests
X
Endocrine function tests
X
HIV screening
X
HBV & HCV serology 
X
HPV P16 expression testing as indicated (Part 2 Cohort A [HNSCC] subjects only)
X
Baseline combined positive score (CPS) (Part 2 Cohort A [HNSCC] subjects only)
X
Urinalysis
X
Serum pregnancy test
X
Biomarker Procedures/Assessments
Day −28 to −1
Whole blood for CHIP mutation analysisf
X
Whole blood for circulating tumor DNAf
X


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Amendment 2
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Assessment
Collection of pretreatment tumor biopsyg
X
Collection of mandatory fresh baseline tumor biopsy (Randomized Expansion Cohorts only)h
X
Cohort B (NSCLC) only: Baseline information on PD-L1 expression at initial diagnosis, 
EGFR, ALK, ROS1, or any other known actionable genomic alterations
X
AEs = adverse events; ALK = anaplastic lymphoma kinase; CHIP = clonal hematopoiesis of indeterminate potential; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; 
HBV = hepatitis B virus; HCV = hepatitis C virus; HNSCC = head and neck squamous cell carcinoma; HPV = human 
papillomavirus; MUGA = multigated acquisition; PD-L1 = programmed cell death ligand 1; PE = physical exam; SAE = serious 
adverse event
a
Subjects who fulfill all of the inclusion criteria and none of the exclusion criteria will be enrolled/randomized into the study 
within 28 days after screening.
b
After informed consent, but prior to initiation of study medication, all SAEs and AEs related to protocol-mandated 
procedures will be reported on Case Report Forms.
c
Vital signs will only be measured while subject is in sitting, semi-recumbent, or supine position.
d
Complete echocardiogram assessment will be conducted at screening to establish a baseline. A MUGA scan is allowed.
e
The initial tumor imaging will be performed within 28 days prior to first dose of study drug. Scans performed as part of 
routine clinical management are acceptable for use as screening scan if they are of diagnostic quality and ≤ 28 days prior to 
first dose of study drug.
f
Biomarker Assays: See details on all biomarker sample collections in Section 6.5.2.1.
g
Collection of archival tumor biopsy as formalin-fixed paraffin-embedded (FFPE) blocks or 10 to 25 unstained slides. If 
archival tumor tissue is not available or insufficient, collection of fresh tumor biopsy from subjects is strongly preferred. 
Please refer to Section 6.5.2.1
h
Each subject enrolled in the Randomized Expansion Cohorts shall undergo a mandatory tumor biopsy if the investigator 
considers that no undue risk is posed to the subjects due to biopsy related procedures. A fresh archival tumor biopsy 
obtained after the end of the last line of therapy and not older than 6 months may be substituted for the baseline biopsy.


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FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 171
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Appendix Table 5.
Part 2 Study Procedures – Treatment Phase
Treatment Phase
Cycle 1
Cycle 2
Cycle 3
Cycle 4 & Every 
Even Cycle After
Cycle 5 & Every 
Odd Cycle After
Study Visits (Cycle Day)
1
8
12
15
21
1
15
1
8
12
15
21
1
15
1
15a
Visit Window (Days)b
—
—
—
—
—
+ 2
+ 2
+ 2
—
—
—
—
+ 2
+ 2
+ 2
+ 2
Visit Schedule (Hours Postinfusion)
—
168
264
336
—
—
336
—
168
264
336
—
—
336
—
336
Administrative Procedures
Review of inclusion/exclusion criteria
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Review of disease history
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Review of baseline symptoms
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Review of prior and concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessmentsc
Review AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Focused PE
Xc
—
—
—
—
Xc
—
Xc
—
—
—
—
Xc
—
Xc
—
Vital signs and weightd
Xd
—
—
—
—
Xd
—
Xd
—
—
—
—
Xd
—
Xd
—
12-lead ECG
Xe
—
—
—
—
Xf
—
Xf
—
—
—
—
—
—
Xf
—
ECOG Performance Status
Xc
—
—
—
—
Xc
—
Xc
—
—
—
—
Xc
—
Xc
—
Imaging Assessments
Tumor Imagingg
Every 6 weeks (± 7 days) from the first dose of study drug until Week 24, then every 9 weeks thereafter (Week 33, Week 42, 
etc.)
Laboratory Procedures/Assessmentsh
Serum chemistry
Xc
X
—
—
—
Xc
—
Xc
—
—
—
—
Xc
—
Xc
—
Hematology tests
Xc
—
—
—
—
Xc
—
Xc
—
—
—
—
Xc
—
Xc
—
Coagulation tests
—
—
—
—
—
Xc
—
Xc
—
—
—
—
Xc
—
Xc
—
Endocrine function tests
—
—
—
—
—
Xc
—
Xc
—
—
—
—
Xc
—
Xc
—
Urinalysis
Xc
X
—
—
—
Xc
—
Xc
—
—
—
—
Xc
—
Xc
—
Urine pregnancy testi
Xc
—
—
—
—
Xc
—
Xc
—
—
—
—
Xc
—
Xc
—
Blood for PK assaysj (GS-3583) – Safety Run-in Cohorts A and B
X
X
—
X
—
X
—
X
X
—
X
—
—
—
X
—
Blood for PK assaysj (GS-3583) – Randomized Expansion Cohorts 
A and B
X
—
—
—
—
X
—
X
—
—
—
—
—
—
X
—


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Treatment Phase
Cycle 1
Cycle 2
Cycle 3
Cycle 4 & Every 
Even Cycle After
Cycle 5 & Every 
Odd Cycle After
Study Visits (Cycle Day)
1
8
12
15
21
1
15
1
8
12
15
21
1
15
1
15a
Visit Window (Days)b
—
—
—
—
—
+ 2
+ 2
+ 2
—
—
—
—
+ 2
+ 2
+ 2
+ 2
Visit Schedule (Hours Postinfusion)
—
168
264
336
—
—
336
—
168
264
336
—
—
336
—
336
Blood for PK assaysj (zimberelimab) – Safety Run-in and 
Randomized Expansion Cohort A
X
—
—
—
—
X
—
X
—
—
—
—
—
—
X
—
Blood for ADA assaysk
X
—
—
—
—
X
—
X
—
—
—
—
—
—
X
—
Biomarker Procedures/Assessmentsh
Whole blood for pharmacodynamic biomarkers (PBMC and 
plasma)l – Safety Run-in Cohorts A and B
Xm
—
X
X
—
Xm
Xm
Xm
—
X
X
—
Xm
Xm
—
—
Whole blood for pharmacodynamic biomarkers (PBMC and 
plasma)l – Randomized Expansion Cohorts A and B
Xm
—
—
Xm
—
Xm
Xm
Xm
—
—
Xm
—
Xm
Xm
—
—
Whole blood for blood cell countl – Safety Run-in Cohorts A and B
Xm
—
X
X
—
Xm
Xm
Xm
—
X
X
—
Xm
Xm
—
—
Whole blood for blood cell countl – Randomized Expansion Cohorts 
A and B
Xm
—
—
Xm
—
Xm
Xm
Xm
—
—
Xm
—
Xm
Xm
—
—
Whole blood for TCR sequencing
X
—
—
—
—
X
—
X
—
—
—
—
X
—
—
—
Whole blood for CHIP mutation analysis
X
—
—
—
—
X
—
X
—
—
—
—
X
—
—
—
Whole blood for circulating tumor DNA
X
—
—
—
—
X
—
X
—
—
—
—
X
—
—
—
Whole blood for Paxgene RNA
Xm
—
—
X
—
Xm
—
Xm
—
—
X
—
Xm
—
—
—
Serum pharmacodynamics for circulating factors
Xm
—
—
X
—
Xm
—
Xm
—
—
X
—
—
—
—
—
Stool sample for microbiome sequencing
Xm
—
—
—
—
—
—
Xm
—
—
—
—
—
—
—
—
Collection of mandatory on-treatment tumor biopsy (Randomized 
Expansion Cohorts only)o
—
—
—
—
—
—
X
—
—
—
—
—
—
—
—
—
Study drug administration
GS-3583p
X
—
—
—
—
X
—
X
—
—
—
—
X
—
X
—
Cohort A: Zimberelimabq
X
—
—
—
—
X
—
X
—
—
—
—
X
—
X
—
Cohort A: Cisplatinq or Carboplatinq
X
—
—
—
—
X
—
X
—
—
—
—
X (C4, C6)
—
X (C5)
—
Cohort A: 5-FUq
Xr
—
—
—
—
Xr
—
Xr
—
—
—
—
Xr (C4, C6)
—
Xr (C5)
—
Cohort B: Docetaxelq
X
—
—
—
—
X
—
X
—
—
—
—
X
—
X
—
CCI




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Gilead Sciences, Inc. 
Amendment 2
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Appendix Table 6.
Part 2 Study Procedures Table – Posttreatment
End of Treatment
Posttreatment
Survival Follow-up
Within 7 Days After Last 
Dose of Study Treatment 
or EOT Decision
60-Day Follow-up 
Visita,b,c
≤ 1 year from last 
doseb
≤ 1 year from last tumor 
lesion assessmentb,c,d
Visit Window
≤ 7 Days
± 7 Days
± 7 Days
± 7 Days
Administrative Procedures
Review of prior and concomitant 
medication
X
X
—
—
Subsequent anticancer therapy status
X
X
X
X
Clinical Procedures/Assessments
Review AEs
X
X
—
—
Full physical examination
X
—
—
—
Focused physical exam
—
X
—
—
Vital signs and weighte
X
X
—
—
12-Lead ECG
X
X
—
—
ECOG Performance Status
X
X
—
—
Imaging Assessments
Tumor Imagingf
Every 6 weeks (± 7 days) from the first treatment dose until Week 24, then every 9 
weeks thereafter starting at Week 33
—
Laboratory Procedures/Assessments
Serum chemistry
X
X
—
—
Hematology tests
X
X
—
—
Coagulation tests
X
X
—
—
Endocrine function tests
X
X
—
—
Urinalysis
X
X
—
—
Urine pregnancy testg
X
X
Xg
—
Blood for PK assaysh (GS-3583) – Safety Run-in 
Cohorts A and B
Xi
X
—
—


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End of Treatment
Posttreatment
Survival Follow-up
Within 7 Days After Last 
Dose of Study Treatment 
or EOT Decision
60-Day Follow-up 
Visita,b,c
≤ 1 year from last 
doseb
≤ 1 year from last tumor 
lesion assessmentb,c,d
Visit Window
≤ 7 Days
± 7 Days
± 7 Days
± 7 Days
Blood for PK assaysh (GS-3583) – Randomized 
Expansion Cohorts A and B
Blood for PK Assaysh 
(GS-3583) – Safety Run-in 
Cohorts A and B
X
—
—
Blood for PK assaysh (zimberelimab) – Safety 
Run-in and Randomized Expansion Cohort A 
Xi
X
—
—
Blood for ADA assaysj
Xi
X
—
—
Biomarker Procedures/Assessments
Whole blood for Pharmacodynamic 
Biomarkers (PBMC and plasma)k
Xi
X
—
—
Whole blood for blood cell countk
Xi
X
—
—
Whole blood for CHIP mutation analysisk
X
—
—
—
Whole blood for TCR sequencingk
X
—
—
—
Whole blood for circulating tumor DNAk
X
—
—
—
Whole blood for Paxgene RNAk
X
—
—
—
Serum pharmacodynamics for circulating 
factorsk
X
—
—
—
Stool sample for microbiome sequencingk
X
—
—
—
Overall survivalb,c,d
—
—
—
X
ADA = antidrug antibody; AEs = adverse events; CHIP = clonal hematopoiesis of indeterminate potential; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EOT = end of treatment; MUGA = multigated acquisition; PBMC = peripheral blood mononuclear cell; PE = physical exam; PK = pharmacokinetic(s); SAEs = serious 
adverse events; TCR = T-cell receptor
a
All subjects who discontinue treatment will have a follow-up visit 60 days (± 7 days) after the last dose of study drug. Collect all AEs, regardless of cause or relationship, 
until 90 days after the last dose of study drug (Section 7.3).
b
Subjects who discontinue treatment due to reasons other than progressive disease and/or start of a new line of anticancer therapy will complete the 60-day follow-up and 
continue tumor imaging assessments at the predefined schedule until documented progressive disease, initiation of a new anticancer therapy, or up to 1 year after the last dose 
of study drug, whichever occurs first; and then move into survival follow-up for up to 1 year after the completion/discontinuation of tumor lesion assessments
CCI


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c
Subjects who discontinue due to progressive disease and/or start of a new line of anticancer therapy will complete the 60-day follow-up and then enter the survival follow-up 
period for up to 1 year after the completion/discontinuation of tumor lesion assessments.  
d
During the survival follow-up period, subjects will be contacted by telephone to assess for survival status and any new malignancies every 3 months for up to 1 year after the 
completion/discontinuation of tumor lesion assessments. No imaging assessment is required for survival follow-up. Any new malignancies will be reported as SAEs.
e
Vital signs will only be measured while subject is in sitting, semi-recumbent, or supine position.
f
On-study imaging will be performed every 6 weeks from first treatment dose and will continue until progressive disease as assessed by the investigator, a new line of 
anticancer therapy is initiated, or up to 1 year after the last dose of study drug, whichever occurs first. For subjects who permanently discontinue from the study in the absence 
of progressive disease/or start of a new line of anticancer therapy and will not be continuing tumor imaging during the posttreatment period, additional imaging is 
recommended at the EOT visit if the last imaging was performed more than 30 days prior. For subjects that met progressive disease clinically, subjects will continue tumor 
imaging until progressive disease is confirmed radiographically or prior to the start of a new line of anticancer therapy. The timing of on-study treatment imaging should 
follow calendar days and should not be adjusted for delays in treatment administration or for visits. 
g
Urine pregnancy tests will be performed locally at each site. After the 60-day follow-up visit, urine pregnancy tests will be performed monthly until the end of the 
contraception requirement (Appendix 5).
h
PK Assays: See details of all PK sample collections in Section 6.5.1.2, Table 6-4, and Table 6-5.
i
Blood samples will only be collected at the EOT visit for subjects that terminate early from study treatment.
j
ADA Assays: Assessed at the 60-day follow-up visit (approximately 60 days after the last dose of study drug). An additional blood sample will be collected at the EOT visit if 
a subject terminates early from study treatment.
k
Biomarker Assays: See details on all biomarker sample collections in Section 6.5.2.1.
l
CCI


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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 postmenopausal unless the 
subject is permanently sterile or has 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 < 54 years of age with amenorrhea of ≥ 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b)
Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless the subject is permanently sterile by bilateral orchidectomy or medical 
documentation.
2)
Contraception Requirements for Female Subjects
a)
Study Drug Effects on Pregnancy and Hormonal Contraception
GS-3583 is contraindicated in pregnancy as a malformation effect has been 
demonstrated/suspected or is unknown, taking into consideration class effects and/or a strong 
suspicion of human teratogenicity/fetotoxicity in early pregnancy based on nonclinical data. 
For GS-3583, there is no anticipated PK interaction with progestin or other steroids based on the 
distinct clearance pathways. Refer to the latest version of the investigator’s brochure (IB) for 
additional information.
Based on its mechanism of action and consistent with the risks identified for the approved 
anti-programmed cell death protein 1 (PD-1) agents, nivolumab and pembrolizumab, 
zimberelimab may cause fetal harm when administered to a pregnant woman. No 
contraindication to hormonal contraception is described in the zimberelimab IB. Refer to the 
latest version of the IB for additional information.


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Gilead Sciences, Inc. 
Amendment 2
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Based on the mechanism of action, 5-fluorouracil (5-FU) can cause fetal harm when 
administered to a pregnant woman. In animal studies, administration of 5-FU at doses lower than 
a human dose of 12 mg/kg caused teratogenicity. If this drug is used during pregnancy or if the 
subject becomes pregnant while taking this drug, the subject should be apprised of the potential 
hazard to a fetus. There is no contraindication to hormonal contraception according to the 5-FU 
prescribing information.
Based on human data from published literature, cisplatin for injection can cause fetal harm when 
administered to pregnant women. Data demonstrate transplacental transfer of cisplatin. Exposure 
of pregnant women to cisplatin-containing chemotherapy has been associated with 
oligohydramnios, intrauterine growth restriction, and preterm birth. Cases of neonatal acute 
respiratory distress syndrome, cytopenias, and hearing loss have been reported. Cisplatin for 
injection administration to animals during and after organogenesis resulted in teratogenicity. 
There is no contraindication to hormonal contraception according to the cisplatin prescribing 
information.
Based on the mechanism of action and findings in animals, docetaxel can cause fetal harm when 
administered to a pregnant woman. Women of childbearing potential should be advised to use 
effective contraception and avoid becoming pregnant during therapy with docetaxel. If the 
subject becomes pregnant while receiving docetaxel, the subject should be apprised of the 
potential hazard to the fetus. There is no contraindication to hormonal contraception according to 
the docetaxel prescribing 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 with a failure rate of < 1% per year. They must have a negative serum 
pregnancy test at screening and a negative urine pregnancy test at each Day 1 visit of every cycle 
prior to enrollment/study drug administration. Pregnancy tests will be performed at monthly 
intervals thereafter until 12 weeks after the last dose of study drug for subjects in Part 1 and until 
the end of the contraception requirement for subjects in Part 2.
Duration of required contraception for female subjects in this clinical study should start from 
Screening visit until 6 months after last dose of study drug unless there is a longer time 
requirement described in the country-specific prescribing information. If the duration of 
contraception differs by study drug, the longest effective duration of contraception should be 
observed.
Female subjects must agree to one of the following contraceptive methods:
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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Amendment 2
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Consistent and correct use of 1 of the following methods of birth control listed below: 

Non-hormonal intrauterine device (IUD) 

Bilateral tubal occlusion (upon medical assessment of surgical success)

Vasectomy in the male partner (upon medical assessment of surgical success)
Or
Female subjects of childbearing potential who wish to use a hormonally based method must use 
it in conjunction with a barrier method, preferably a male condom. Hormonal methods are 
restricted to those associated with the inhibition of ovulation. Hormonally based contraceptives 
and barrier methods permitted for use in this protocol are as follows:

Hormonal methods (each method must be used with a barrier method, preferably male 
condom)
Oral contraceptives (either combined or progesterone only)
Injectable progesterone
Transdermal contraceptive patch
Contraceptive vaginal ring
Subdermal contraceptive implant
Hormonal intrauterine device (IUD)

Barrier methods (each method must be used with a hormonal method)
Male condom (with or without spermicide)
Female condom (with or without spermicide)
Diaphragm with spermicide
Cervical cap with spermicide
Sponge with spermicide
Inclusion of methods of contraception in this list of permitted methods does not imply that the 
method is approved in any country or region. Methods should only be used if locally approved. 
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until the end of contraceptive requirement. If needed, female subjects of childbearing 


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Gilead Sciences, Inc. 
Amendment 2
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potential should be advised to seek advice about egg donation and cryopreservation of germ cells 
before treatment.
3)
Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration of study drug may be achieved 
in a female partner from exposure of the male subject’s seminal fluid and poses a potential risk 
to an embryo/fetus. Male subjects with female partners of childbearing potential must use 
condoms during treatment and until 6 months after last dose of study drug unless there is a 
longer time requirement described in the country-specific prescribing information. If the duration 
of contraception differs by study drug, the longest effective duration of contraception should be 
observed. If the female partner of childbearing potential is not pregnant, additional contraception 
recommendations should also be considered.
Male subjects must also refrain from sperm donation during treatment and until the end of 
contraceptive requirement. If needed, male subjects should be advised to seek advice about 
sperm donation and cryopreservation of germ cells before treatment.
4)
Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method. A female condom and a male condom should not be used 
together.
5)
Procedures to be Followed in the Event of Pregnancy
Female subjects will be instructed to notify the investigator if they become pregnant or suspect 
they are pregnant at any time from start of the study to 6 months after last study drug dose. Study 
drug must be discontinued immediately. 
Male subjects whose partner has become pregnant or suspects she is pregnant from start of study 
to 6 months of last the study drug dose must also report the information to the investigator. 
Instructions for reporting pregnancy and pregnancy outcome are outlined in Section 7.4.2.3.


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Gilead Sciences, Inc. 
Amendment 2
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Appendix 6.
NCI CTCAE v5.0 Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf


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Appendix 7.
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)
Measurability of tumor at baseline
Definitions: At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows:
Measurable Tumor lesions: Must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of:
10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm).
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable).
20 mm by chest X-ray.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and at follow-up, only the short axis will 
be measured and followed. See also notes below on ‘Baseline documentation of target and 
non-target lesions’ for information on lymph node measurement.
Non-measurable: All other lesions, including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
Bone lesions:
Bone scan, positron emission tomography (PET) scan or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used to confirm 
the presence or disappearance of bone lesions.
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or magnetic resonance 
imaging (MRI) can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above.
Blastic bone lesions are non-measurable.
Cystic lesions:
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts.


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‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if noncystic lesions are 
present in the same subjects, these are preferred for selection as target lesions.
Lesions with prior local treatment:
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such lesions 
would be considered measurable.
Baseline documentation of ‘target’ and ‘non-target’ lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where subjects have only one or 2 organ sites involved a maximum of 2 and 
4 lesions respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the image 
is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, sagittal or coronal). The smaller of these measures is the short axis. For example, 
an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.


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Gilead Sciences, Inc. 
Amendment 2
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All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required, and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’).
Tumor response evaluation
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
Evaluation of non-target lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression).
Also refer to Section 3.4.1 of the protocol for additional information regarding treatment beyond 
initial progressive disease.


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FINAL
Gilead Sciences, Inc. 
Amendment 2
CONFIDENTIAL
Page 185
14 April 2022
Table 11-1.
Time Point Response: Subjects with Target (+/- Non-target) Disease
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-progressive 
disease
No
PR
CR
Not evaluated
No
PR
PR
Non-progressive disease or not 
all evaluated
No
PR
SD
Non-progressive disease or not 
all evaluated
No
SD
Not all evaluated
Non-progressive disease
No
NE
Progressive disease
Any
Yes or No
Progressive disease
Any
Progressive disease
Yes or No
Progressive disease
Any
Any
Yes
Progressive disease
CR = complete response; PR = partial response; SD = stable disease; NE = not evaluable
Table 11-2.
Time Point Response: Subjects with Non-target Disease Only
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-progressive disease
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal progressive disease
Yes or No
Progressive disease
Any
Yes
Progressive disease
CR = complete response; NE = not evaluable
a
‘Non-CR/non-PD’ is preferred over ‘SD’ for non-target disease since SD is increasingly used as endpoint for assessment of 
efficacy in some studies so to assign this category when no lesions can be measured is not advised.


Prot GS-US-496-5657 amd-2
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned
19-Apr-2022
00:41:40
PPD

SAP_001.pdf: 
GS-3583
GS-US-496-5657
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 1
13 June 2023
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 1b Study to Evaluate the Safety, Tolerability,
Pharmacokinetics, and Preliminary Efficacy of GS-3583, a 
FLT3 Agonist Fc Fusion Protein, as Monotherapy and in 
Combination With Anticancer Therapies in Participants With 
Advanced Solid Tumors 
Name of Test Drug:
GS-3583
Study Number:
GS-US-496-5657
Protocol Version (Date):
Amendment 2 (14 April 2022)
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
13 June 2023
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
 
 
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF IN-TEXT FIGURES........................................................................................................................................4
LIST OF ABBREVIATIONS.........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS.................................................................................................................7
1.
INTRODUCTION..................................................................................................................................................8
1.1.
Study Objectives and Endpoints................................................................................................................8
1.2.
Study Design ...........................................................................................................................................10
1.3.
Sample Size and Power ...........................................................................................................................12
2.
TYPE OF PLANNED ANALYSIS......................................................................................................................14
2.1.
Interim Analyses......................................................................................................................................14
2.1.1.
Part 1 Dose-Escalation Analysis and Part 2 Safety Run-in Analysis....................................14
2.2.
Final Analysis..........................................................................................................................................14
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................15
3.1.
Analysis Sets ...........................................................................................................................................15
3.1.1.
All Enrolled Analysis Set ......................................................................................................15
3.1.2.
DLT Evaluable Analysis Set .................................................................................................15
3.1.3.
Safety Analysis Set................................................................................................................15
3.1.4.
Full Analysis Set....................................................................................................................15
3.1.5.
Pharmacokinetic Analysis Set ...............................................................................................15
3.1.6.
Immunogenicity Analysis Set................................................................................................16
3.1.7.
Biomarker Analysis Set.........................................................................................................16
3.2.
Participant Grouping ...............................................................................................................................16
3.3.
Strata and Covariates...............................................................................................................................16
3.4.
Examination of Participant Subgroups....................................................................................................16
3.5.
Adjustment for Multiplicity.....................................................................................................................16
3.6.
Missing Data and Outliers.......................................................................................................................16
3.6.1.
Missing Data..........................................................................................................................16
3.6.2.
Outliers ..................................................................................................................................16
3.7.
Data Handling Conventions and Transformations ..................................................................................17
3.8.
Assessment of COVID-19 Impact...........................................................................................................18
4.
PROTOCOL DEVIATIONS................................................................................................................................19
5.
PARTICIPANT INFORMATION.......................................................................................................................20
5.1.
Participant Enrollment and Disposition...................................................................................................20
5.2.
Extent of Study Treatment Exposure ......................................................................................................20
5.3.
Demographics and Baseline characteristics ............................................................................................20
5.4.
Medical History.......................................................................................................................................21
5.5.
Prior and Concomitant Medications........................................................................................................21
5.5.1.
Prior Medications ..................................................................................................................21
5.5.2.
Concomitant Medications......................................................................................................21
5.6.
Post Treatment Anti-cancer Therapies ....................................................................................................22
6.
EFFICACY ANALYSES.....................................................................................................................................23
6.1.
Efficacy Endpoints ..................................................................................................................................23
6.1.1.
Definition of the Efficacy Endpoints.....................................................................................23


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6.1.2.
Analysis of the Efficacy Endpoint.........................................................................................25
6.2.
Changes From Protocol-Specified Efficacy Analyses ............................................................................26
7.
SAFETY ANALYSES.........................................................................................................................................27
7.1.
Adverse Events and Deaths.....................................................................................................................27
7.1.1.
Adverse Event Dictionary .....................................................................................................27
7.1.2.
Adverse Event Severity .........................................................................................................27
7.1.3.
Relationship of Adverse Events to Study Treatment ............................................................27
7.1.4.
Serious Adverse Events.........................................................................................................27
7.1.5.
Treatment-Emergent Adverse Events....................................................................................27
7.1.6.
Summaries of Adverse Events and Deaths............................................................................28
7.1.7.
Additional Analysis of Adverse Events ................................................................................29
7.2.
Laboratory Evaluations ...........................................................................................................................29
7.2.1.
Summaries of Numeric Laboratory Results ..........................................................................29
7.2.2.
Graded Laboratory Values ....................................................................................................29
7.3.
Body Weight and Vital Signs..................................................................................................................30
7.4.
Electrocardiogram Results.......................................................................................................................30
7.5.
Other Safety Measures ............................................................................................................................31
7.5.1.
Echocardiogram.....................................................................................................................31
7.5.2.
Surgeries and Procedures ......................................................................................................31
7.6.
Changes From Protocol-Specified Safety Analyses................................................................................31
8.
PHARMACOKINETIC (PK) AND IMMUNOGENICITY ANALYSES..........................................................32
8.1.
PK Sample Collection .............................................................................................................................32
8.2.
PK Analyses Related to Intensive PK Sampling.....................................................................................33
8.2.1.
Estimation of PK Parameters.................................................................................................33
8.2.2.
PK Parameters .......................................................................................................................33
8.3.
Immunogenicity analysis.........................................................................................................................34
9.
BIOMARKER ANALYSIS .................................................................................................................................36
10.
REFERENCES.....................................................................................................................................................37
11.
SOFTWARE.........................................................................................................................................................38
12.
SAP REVISION...................................................................................................................................................39
13.
APPENDIX 1 RECIST 1.1-BASED ASSESSMENTS - OVERALL VISIT RESPONSE.................................40


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LIST OF IN-TEXT TABLES
Table 6-1.
Rule for PFS Calculation.........................................................................................................24
Table 8-1.
PK Parameters for Each Analyte.............................................................................................33
Table A2-13-1.
Overall Visit Response ..........................................................................................................40
LIST OF IN-TEXT FIGURES
Figure 1-1.
Part 2 Study Schema................................................................................................................12
Figure 1-2.
Part 2 Safety Run-in and Randomized Expansion Phases.......................................................12


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LIST OF ABBREVIATIONS
AE
adverse event
ADA
anti-drug antibody
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under curve
BICR
blinded independent central review
BLQ
below the limit of quantitation
BMI
body mass index
BoR
best overall response
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatine kinase
CRF
case report form
CR
complete response
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DILI
drug-induced liver injury
DLT
dose limiting toxicity
DMC
data monitoring committee
DOR
duration of response
ECG
electrocardiogram
EOT
end of treatment
FAS
Full Analysis Set
Hb
hemoglobin
HLT
high-level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
IRR
infusion-related reactions
ITT
intent to treat
LTT
lower-level term
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
NE
not evaluable
ORR
objective response rate
OS
overall survival
PD
progressive disease


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PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
Participant reported outcome 
PT
preferred term
Q1, Q3
first quartile, third quartile
QRS
electrocardiographic deflection between the beginning of the Q wave and termination of the 
S wave representing time for ventricular depolarization
QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave representing the time for both ventricular depolarization and repolarization to occur
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RP2D
recommended Phase 2 dose
RR
electrocardiographic interval representing the time measurement between the R wave of one 
heartbeat and the R wave of the preceding heartbeat
SAP
statistical analysis plan
SD
Stable Disease
SE
standard error
StD
standard deviation
SI (units)
international system of units
SOC
system organ class
SRT
safety review team
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
TTR
time to response
ULN
upper limit of normal
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum quantifiable concentration of the drug 
Ctau
observed drug concentration at the end of the dosing interval
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 
2 by the terminal elimination rate constant (z)
Tmax
time (observed time point) of Cmax


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and defines key 
elements including variable definitions for analysis of data of Study GS-US-496-5657 in support 
of the clinical study report (CSR). This SAP is based on the study protocol Amendment 2 dated 
14 April 2022. Any changes made after the finalization of the SAP will be documented in the 
CSR.
Since the study was terminated prematurely and no participants were enrolled in Part 2, the 
analysis methods and the key elements for data analysis outlined in this SAP will solely pertain 
to Part 1. Analysis methods specified in this document take precedence over those described in 
protocol should there be any difference.
1.1.
Study Objectives and Endpoints
Primary Objective(s)
Primary Endpoint(s)
Safety
Part 1
•
To characterize the safety and tolerability of GS-
3583 as monotherapy in participants with 
advanced solid tumors
•
To determine the maximum tolerated dose (MTD) 
or recommended Phase 2 dose (RP2D) of GS-
3583 as monotherapy in participants with 
advanced solid Tumors
Part 2
•
To assess the safety and tolerability and to 
determine the RP2D of GS-3583 in combination 
with zimberelimab and platinum (cisplatin or 
carboplatin) + 5-FU chemotherapy in participants 
with HNSCC (Cohort A) or in combination with 
docetaxel in participants with NSCLC (Cohort B)
Part 1
•
Incidence of dose limiting toxicities (DLTs)
•
Incidence of AEs and laboratory abnormalities
Part 2
•
Incidence of DLTs
•
Incidence of AEs and laboratory abnormalities
Secondary Objective(s)
Secondary Endpoint(s)
Efficacy/Safety/PK delineate objectives and endpoints as appropriate.
Part 1
•
To characterize the PK of GS-3583 as 
monotherapy in participants with advanced solid 
tumors
•
To evaluate the immunogenicity of GS-3583 as 
monotherapy in participants with advanced solid 
tumors
Part 2
•
To evaluate the investigator-assessed confirmed 
objective response rate (ORR) with GS-3583 in 
Part 1
•
GS-3583 PK parameters (Cmax, Tmax, and AUC) 
Rate of GS-3583 antidrug antibody (ADA)
Part 2
•
Confirmed ORR is defined as the percentage of 
participants who have achieved confirmed CR or 


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Primary Objective(s)
Primary Endpoint(s)
combination with zimberelimab and platinum 
(cisplatin or carboplatin) + 5-FU chemotherapy in 
participants with HNSCC (Cohort A) or in 
combination with docetaxel in participants with 
NSCLC (Cohort B)
•
To assess the preliminary efficacy of GS-3583 in 
combination with zimberelimab and platinum 
(cisplatin or carboplatin) + 5-FU chemotherapy 
versus zimberelimab and platinum (cisplatin or 
carboplatin) + 5-FU chemotherapy alone in 
participants with HNSCC (Cohort A) or in 
combination with docetaxel versus docetaxel alone 
in participants with NSCLC (Cohort B) as 
determined by PFS, duration of response (DOR), 
and OS
•
To evaluate investigator-assessed disease control 
rate (DCR) with GS-3583 in combination with 
zimberelimab and platinum (cisplatin or 
carboplatin) + 5-FU chemotherapy in participants 
with HNSCC (Cohort A) or in combination with 
docetaxel in participants with NSCLC (Cohort B)
•
To evaluate the PK of GS-3583 administrated in 
combination with zimberelimab and platinum 
(cisplatin or carboplatin) + 5-FU chemotherapy in 
participants with HNSCC (Cohort A) or in 
combination with docetaxel in participants with 
NSCLC (Cohort B)
•
To evaluate the immunogenicity of GS-3583 
administrated in combination with zimberelimab 
and platinum (cisplatin or carboplatin) + 5-FU 
chemotherapy in participants with HNSCC 
(Cohort A) or in combination with docetaxel in 
participants with NSCLC (Cohort B)
confirmed PR according to RECIST V1.1 and 
assessed by the investigator.
•
Progression-free survival is the time from date of 
randomization until disease progression or death 
from any cause, whichever comes first as 
measured per RECIST V1.1 as assessed by the 
investigator
•
Duration of response is measured from the time of 
first response (CR or PR) identified by RECIST 
V1.1 as assessed by the investigator until the date 
of first documented disease progression or death, 
whichever comes first.
•
Overall survival is the length of time from date of 
randomization until the date of death from any 
cause.
•
Disease control rate is measured by the percentage 
of participants with a best overall confirmed 
response of complete response (CR) or partial 
response (PR) or stable disease.
•
PK parameters (Cmax, Tmax, and AUC) for GS-
3583
•
Rate of GS-3583 ADA
Exploratory Objective(s)
Exploratory Endpoint(s)
CCI


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Primary Objective(s)
Primary Endpoint(s)
correlation with clinical response in participants 
with advanced solid tumors
Part 2
•
To evaluate the pharmacodynamics of GS-3583 
administrated in combination with zimberelimab 
and platinum (cisplatin or carboplatin) + 5-FU 
chemotherapy in participants with HNSCC 
(Cohort A) or in combination with docetaxel in 
participants with NSCLC (Cohort B) in blood and 
tumor samples
•
To evaluate the PK of zimberelimab administrated 
in combination with GS-3583 and platinum 
(cisplatin or carboplatin) + 5-FU chemotherapy in 
participants with HNSCC (Cohort A)
•
To evaluate the immunogenicity of zimberelimab 
administrated in combination with GS-3583 and 
platinum (cisplatin or carboplatin) + 5-FU 
chemotherapy in participants with HNSCC 
(Cohort A)
•
To explore biomarkers that may predict activity or 
response to GS-3583
•
Time to response (TTR), defined as the interval 
from start of treatment to the first documentation 
of CR or PR that is subsequently confirmed
•
Overall survival (OS), defined as the time from the 
first dose date of GS-3583 to death from any cause
•
Changes in pharmacodynamic markers of GS-
3583 (eg, changes in the number of cDC1s, 
cDC2s, plasmacytoid DCs and other cell types as 
determined by flow, IHC, imaging, or RNA 
sequencing)
•
Other PK parameters of interest, if applicable
•
Correlations between GS-3583 PK and 
pharmacodynamics
Part 2
•
Changes in pharmacodynamic markers of GS-
3583 (eg, changes in the number of cDC1s, 
cDC2s, plasmacytoid DCs and other cell types as 
determined by flow, IHC, imaging, or RNA 
sequencing) in blood and tumor tissue
•
PK parameters (Cmax, Tmax, and Ctrough) for 
zimberelimab
•
Rate of zimberelimab ADA
•
Baseline levels of GS-3583 biomarkers (eg, 
number of cDC1s, cDC2s, plasmacytoid DCs, and 
other cell types, gene expression levels, and 
cytokine levels as determined by flow, IHC, 
imaging, enzyme-linked immunosorbent assay, or 
RNA sequencing at baseline) in blood and tumor 
tissue
1.2.
Study Design
Part 1 is a Phase 1b, open-label study to evaluate the safety, tolerability, PK, and preliminary 
efficacy of GS-3583 in adult participants with advanced solid tumors to determine the MTD or 
RP2D level of GS-3583 as monotherapy. 
Dose escalation will proceed using a standard 3 + 3 design. Doses of 675 μg, 2000 μg, 6000 μg, 
12,000 μg, and 20,000 μg are planned. GS-3583 will be administered on Days 1 and 15 of Cycle 
1 and on Day 1 of each subsequent 4-week/28-day cycle for up to 13 cycles or until the 
participant meets study treatment discontinuation criteria.
The safety and tolerability of each dose level will be assessed by the safety review team (SRT) 
after all participants in the cohort have had 2 doses of GS-3583 and have been followed for at 


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least 28 days after the first dose of GS-3583 or if participants had DLTs during the first 28 days 
of study drug dosing.
The initial block of each dose consists of 3 participants. Dose escalation will occur if no 
participants experience a DLT during the first 28 days of study drug dosing. If 1 participant 
within the initial cohort of 3 participants experiences a DLT during the first 28 days of study 
drug dosing, an additional 3 participants will be enrolled at the same dose level. If no DLTs are 
observed in the additional 3 participants, dose escalation will occur. If 2 or more participants 
experience DLTs within the first 28 days, dose de-escalation to a lower dose will occur. The 
MTD is the highest dose level with a participant incidence of DLTs of < 33% in 6 or more 
participants during the first 28 days of study drug dosing. A minimum of 6 participants need to 
be treated at a dose level before this dose level can be deemed as the MTD. A participant who 
fails to receive all GS-3583 treatments or fails to complete all safety assessments in the DLT 
period for reasons other than DLT will be replaced.
The SRT will review safety and relevant clinical data and make the dose 
escalation/stay/de-escalation decision. Source data verification is not required to be performed 
prior to SRT meetings, as there will be alternative quality control checks implemented. These 
checks will be described in the safety review team charter. The SRT may also add up to 6 
additional participants to any cohort determined to be safe to collect additional safety and 
PK/pharmacodynamic information. The SRT may also designate intermediate dose levels in 
addition to the ones listed in protocol after reviewing all the available safety and 
PK/pharmacodynamic information.
The dose of GS-3583 taken forward for Part 2 in combination with other anticancer agents will 
be determined based on all relevant clinical data from all participants treated in the 
dose-escalation phase. This dose will not exceed the MTD.
Part 2 is a Phase 1b, open-label, multicenter study evaluating GS-3583 in combination with other 
anticancer therapies. There will be 2 cohorts in Part 2, each comprising safety run-in and 
open-label randomized expansion phases. Each safety run-in cohort will enroll 6 to 18 
participants based on observed toxicities. Once the SRT reviews each safety run-in cohort and 
the sponsor determines the RP2D for that cohort, randomized expansion cohorts will be enrolled 
(each randomized expansion cohort may commence enrollment based on the results of the 
corresponding safety run-in cohort). Up to 45 participants will be randomized 2:1 to treatment 
and control arms in each randomized expansion cohort.
An overview of the study design for Part 2 is shown in Figure 1-1 and Figure 1-2.


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Figure 1-1.
Part 2 Study Schema
Figure 1-2.
Part 2 Safety Run-in and Randomized Expansion Phases
1.3.
Sample Size and Power
A total of approximately 150 participants will be enrolled.
For Part 1, assuming up to 4 planned dose levels will be tested with 3 DLT-evaluable 
participants for the first dose level and up to 6 DLT-evaluable participants per subsequent dose 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
    
 
  
  
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
  
 
  
 


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level, 21 DLT-evaluable participants will be needed. Assuming 10% are not evaluable, 
approximately 24 participants will be enrolled in Part 1.
For Part 2, a maximum of 63 participants will be enrolled for each cohort. Six to 18 participants 
will be evaluated in Safety Run-in Cohorts, and 45 participants will be enrolled in 
Randomization Expansion Cohorts with 2:1 randomization ratio. The total maximum sample size 
in Part 2 is approximately 126.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
2.1.1.
Part 1 Dose-Escalation Analysis and Part 2 Safety Run-in Analysis
For the purpose of making the decision whether to escalate to the next dose level/cohort, interim 
analyses of relevant safety and available PK data will be conducted by Gilead after all 
participants in each cohort have completed dosing and the follow-up period in the DLT period as 
defined in protocol. Safety assessments (eg, AEs, ECG, and laboratory results) will be displayed 
by cohort or dose level to facilitate the decision.
2.2.
Final Analysis
The final analysis will be performed after all participants have completed or discontinued from 
the study, outstanding data queries have been resolved or adjudicated as unresolvable, and the 
data have been cleaned and finalized.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of participants in each category will be presented; for continuous 
variables, the number of participants (n), mean, standard deviation (StD) or standard error (SE), 
median, first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
3.1.
Analysis Sets
A listing of reasons for exclusion from analysis sets will be provided by participant.
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all participants who received a study participant identification 
number in the study after screening.
The All Enrolled Analysis Set will be used for data listings, unless otherwise specified.
3.1.2.
DLT Evaluable Analysis Set
The DLT Evaluable Analysis Set includes all participants who were enrolled for dose escalation, 
received all prescribed treatments and completed safety procedures through DLT assessment 
period (from Day 1 through Day 28 inclusive of the last day) or experienced a DLT prior to end 
of DLT assessment period as specified in protocol. Determination of MTD or RP2D will be 
based on the DLT Evaluable Analysis Set. 
3.1.3.
Safety Analysis Set
The Safety Analysis Set will include all participants who received at least 1 dose of study drug. 
This will be the primary analysis set for safety analysis.
3.1.4.
Full Analysis Set
The Full Analysis Set includes all enrolled participants who received at least 1 dose of study 
drug (Part 1 and Part 2 Safety Run-in Cohorts) or all randomized participants (Part 2 
Randomized Expansion Cohorts). This will be the primary analysis set for efficacy analyses.
3.1.5.
Pharmacokinetic Analysis Set
The PK Analysis Set includes all enrolled participants who received at least 1 dose of study drug 
and have at least 1 nonmissing postdose concentration value reported by the PK laboratory. This 
will be the primary analysis set for all PK analyses.




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3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:
•
If only month and year of birth is collected, then “15” will be imputed as the day of birth
•
If only year of birth is collected, then “01 July” will be imputed as the day and month of birth
•
If year of birth is missing, then date of birth will not be imputed.
In general, age collected at Day 1 (in years) will be used for analyses and presented in listings. If 
age at Day 1 is not available for a participant, then age derived based on date of birth and the 
Day 1 visit date will be used instead. If an enrolled participant was not dosed with any study 
drug, the enrollment date will be used instead of the Day 1 visit date. For screen failures, the date 
the first informed consent was signed will be used for the age derivation. Age required for 
longitudinal and temporal calculations and analyses (e.g., estimates of creatinine clearance, age 
at date of AE) will be based on age derived from date of birth and the date of the measurement or 
event, unless otherwise specified.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:
•
A value that is 1 unit less than the lower LOQ at the same precision level of the originally 
reported value will be used to calculate descriptive statistics if the datum is reported in the 
form of “ x” (where x is considered the lower 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 upper LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the upper LOQ). Values 
with decimal points will follow the same logic as above.
•
The lower or upper 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 lower or upper LOQ, 
respectively).
Sparse PK concentration values that are below the limit of quantitation (BLQ) will be presented 
as “BLQ” in the data listing.
Natural logarithm transformation will be used for analyzing concentrations and PK parameters in 
intensive PK samples. Concentration values that are BLQ will be presented as “BLQ” in the 
concentration data listing. Values that are BLQ will be treated as 0 at predose time points, and 
one-half the value of the LOQ at postdose time points for summary purposes.


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The following conventions will be used for the presentation of summary and order statistics for 
intensive PK concentrations: 
•
If at least 1 participant has a concentration value of BLQ for the time point, the minimum 
value will be displayed as “BLQ.”
•
If more than 25% of the participants 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 participants 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 participants 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 participants 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.”
PK parameters that are BLQ will be imputed as one-half LOQ before log transformation or 
statistical model fitting.
3.8.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (COVID-19) pandemic which has an 
impact on the study conduct. Some participants were unable to attend onsite visits due to shelter 
in place guidelines, site closures, or other reasons. The following special situations due to 
COVID-19 will be handled in the analysis:
•
Study treatment or study discontinuation due to COVID-19
•
Protocol deviations due to COVID-19
•
Missed and Virtual Visits due to COVID-19
•
Adverse events due to COVID-19
•
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4.
PROTOCOL DEVIATIONS 
Participants 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-participant 
listing will be provided for those participants 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 participants did not meet and related comments, if collected.
Protocol deviations occurring after participants entered the study are documented during routine 
monitoring. Important protocol deviations will be listed by participant for All Enrolled Analysis 
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5.
PARTICIPANT INFORMATION
5.1.
Participant Enrollment and Disposition
Key study dates (i.e.,first participant screened, first participant enrolled, last participant enrolled, 
last participant last visit for the primary endpoint, and last participant last visit for the clinical 
study report) will be provided.
A summary of participant enrollment will be provided by treatment group for each investigator 
within a country and overall. 
A summary of participant disposition will be provided by treatment group based on the All 
Enrolled Analysis Set. This summary will present the number of participants screened and the 
number of participants in each of the categories listed below:
•
Safety Analysis Set 
•
DLT Evaluable Analysis Set
•
Full Analysis Set
•
Pharmacokinetic Analysis Set
•
Immunogenicity Analysis Set
•
Discontinued study drug with reasons for discontinuation of study drug
•
Discontinued the study with reasons for discontinuation of study
5.2.
Extent of Study Treatment Exposure 
Extent of exposure to study treatment will be summarized using descriptive statistics for total 
duration of exposure to each study drug, total number of doses received, total number of cycles 
and total cumulative dose administered. 
Duration of treatment (in days) will be calculated as (the last dose date - the first dose date + 1). 
Cumulative dosage (mg/kg) received for each participant is defined as the sum of all delivered 
dosages (mg/kg) of all infusions the participant received in the study.
5.3.
Demographics and Baseline characteristics 
Participant demographics and baseline characteristics will be summarized with descriptive 
statistics by treatment arm for Safety Analysis Set, which include
•
Age


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•
Gender
•
Race
•
Ethnicity
•
Weight 
•
Height 
•
Body mass index (BMI)
•
ECOG status
5.4.
Medical History
General medical history data will be collected at screening and listed only. General medical 
history data will not be coded.
Disease-specific medical history including disease-specific prior anticancer therapies and 
radiotherapy will be listed by participant.
5.5.
 Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary.
5.5.1.
Prior Medications
Prior medications are defined as any medications taken before a participant took the first study 
drug. Prior medication data will be reported by a by-participant listing only. 
5.5.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a participant took study 
treatment. For the purposes of analysis, any medications with a start date prior to or on the first 
dosing date of study treatment 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 treatment 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 treatment will also be considered concomitant. 
Medications with a stop date prior to the date of first dosing date of study treatment or a start 
date after the last dosing date of study treatment will not be considered as concomitant 
medications. Medications with partially or completely missing start and stop dates will be 
considered concomitant medication, unless the partial missing date suggested otherwise. 
Concomitant medication data will be reported by a by-participant listing only. 


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5.6.
Post Treatment Anti-cancer Therapies
All post treatment anti-cancer therapies (other than those allowed per-protocol) will be provided 
in a by-participant listing sorted by participant ID number and administration date in 
chronological order.


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6.
EFFICACY ANALYSES
6.1.
Efficacy Endpoints
6.1.1.
Definition of the Efficacy Endpoints
Best overall response (BoR)
Best overall response (BoR) is calculated based on the overall visit responses from each RECIST 
assessment including unscheduled visits. It is the best response a participant has had from the 
start of treatment until objective documentation of PD (per RECIST v1.1 in Appendix 1), or 
participant withdrawn from the study, or participant started new anticancer therapy, whichever 
occurs first. Categorization of BoR will be based on RECIST v1.1 using the following response 
categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive 
Disease (PD) and Not Evaluable (NE). 
A BoR of CR or PR must be confirmed. A CR/PR requires confirmation no less than 4 weeks 
(28 days) after the first response criterion was met and with no evidence of progression between 
the initial and CR/PR confirmation visit. Participants who responded with an unconfirmed 
CR/PR at the time of data cutoff will be reported as unconfirmed CR/PR under the SD category 
provided the minimum criteria for SD duration are met, otherwise this will be reported under the 
NE category.
For determination of a BoR of SD, the earliest timepoint SD can be recorded will be at the time 
of the first scheduled scan (8 weeks) minus any applicable window (minus 1 week) after the first 
dosing date. For the determination of BoR, an overall visit response with “Non-CR/non PD” is 
considered as SD. 
For participants who die with no evaluable RECIST assessments, if the death occurs ≤9 weeks 
(i.e. 8 weeks + 1 week to allow for a late assessment within the assessment window) after the 
first dosing date, then BoR will be assigned to the progression (PD) category. For participants 
who die with no evaluable RECIST assessments, if the death occurs > 9 weeks after the first 
dosing date then BoR will be assigned to the NE category.
Objective response rate (ORR)
ORR is defined as the proportion of all enrolled participants who achieve the best overall 
response of CR or PR as determined by investigator. Tumor response assessments after the date 
of participants receiving new anticancer therapy will be excluded from the analysis. The 
response definition of each response category is based on RECIST 1.1. Participants who do not 
have baseline or on-study response status assessment or received new anticancer therapy prior to 
achieving CR or PR, will be considered as non-responders. 


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Progression-free survival (PFS)
PFS is defined as the interval from the first dosing date of study treatment to the earlier date of 
the first documentation of objective disease progression by investigator or death from any cause. 
Disease progression is determined based on RECIST 1.1, as defined in protocol Appendix 7. 
PFS in months = (Date of event/censoring – Date of first dosing date + 1)/30.4375.
Table6-1.
Rule for PFS Calculation
Situation
Outcome
Date of Event/Censoring
No disease assessment at baseline or 
post-baseline*
Censored
Date of first dosing date 
No documented PD or death
Censored
Date of last evaluable disease assessment
Documented PD
Event
Date of first documented PD
Death without any documented PD 
Event
Date of death 
Death within 2 disease assessments 
window and no baseline or post-baseline 
assessment
Event
Date of death 
PD or death after ≥ 2 consecutively 
missed or NE disease assessments
Censored
Date of last evaluable assessment prior to missed or 
NE assessments
Subsequent anticancer therapy initiated 
prior to PD or death 
Censored
Date of last evaluable assessment prior to subsequent 
anticancer therapy
*Baseline tumor assessment should be performed no more than 28 days before the start of study drug. 
Duration of response (DOR) 
DOR is defined for confirmed responders as duration of time from the date of initial response to 
the date of first documentation of disease progression or the date of death due to any cause, 
whichever occurs first.
DOR in months = (Date of disease progression/death or censoring – Date of initial response + 1) 
/ 30.4375.
Date of initial response is the date of first response achieved and then confirmed by a subsequent 
disease assessment conducted prior to or at the initiation of the next line of anticancer therapy. 
For responders, DOR will use the PFS censoring time. DOR will not be defined for those 
participants who do not have documented responses.
Time to response (TTR)
Time to response (TTR) will be summarized with descriptive statistics only for confirmed 
responders (PR or better) based on disease assessments conducted prior to or at the initiation of 
the next line of anticancer therapy.


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TTR will be calculated as the time from the first dosing date of study treatment to date of first 
documented response.
TTR in months = (Date of response - date of the first dosing date + 1)/30.4375
Overall survival (OS)
OS is defined as the interval from first dosing date of study treatment to death from any cause. 
For participants who were not known to have died at the time of the analysis, OS data will be 
censored at the last date that they were known to be alive. In the event that the participant has 
withdrawn consent, the vital status of the participant can be obtained by site personnel from 
publicly available resources under applicable local laws. 
OS in months = (date of event/censoring – date of first dose of study drug + 1) / 30.4375. 
Disease Control Rate (DCR)
DCR is defined as the proportion of participants with best response of CR, PR, or SD. 
Change from Baseline in Tumor Lesions
For participants with solid tumors, the percent change from baseline in the sum of diameters of 
target lesions as documented radiographically will be determined for each postbaseline 
assessment. The baseline sum of the diameters will be the value of last target lesion assessment 
prior to the start of treatment.
Waterfall plots for the percent change from baseline in the sum of diameters of target lesions for 
BoR of each individual participant will be generated.
The details of tumor lesion assessments by visit will be listed by cohort and participant ID 
number in ascending order, including target and non-target lesions, any new lesions, percent 
change from baseline, and percent change from nadir in sum of diameters of target lesions.
6.1.2.
Analysis of the Efficacy Endpoint
For each treatment arm BoR will be summarized by n (%) for each category (CR, PR, SD, PD 
and NE). No formal statistical analyses are planned for BoR. 
ORR and the corresponding 90% confidence intervals based on Clopper-Pearson method of each 
treatment group will be presented. 
DCR along with the 2-sided 90% exact CIs (using the same methods as for ORR) will be 
presented.
By-participant listings of objective response, DOR, TTR, PFS and OS will be provided by 
participant ID number in ascending order.


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6.2.
Changes From Protocol-Specified Efficacy Analyses
Due to the early termination of the study, analyses on PFS, DOR and OS using Kaplan-Meier 
(KM) method specified in the protocol will not be included in the analysis plan. No analyses will 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA. 
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to CTCAE 
Version 5.0. 
7.1.3.
Relationship of Adverse Events to Study Treatment
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Drug Safety and 
Public Health Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events 
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as any events not present prior to the 
study treatment, or any events already present but worsening in either intensity or frequency 
following exposure to the study treatment. 
The TEAE reporting period is defined as the period from the date of the first dose of study 
treatment up to 90 days after the date of the last dose of study treatment or the day before 
initiation of subsequent therapy, whichever comes first. 
7.1.5.2.
Missing or incomplete Dates
If there was a missing or incomplete date for the start date or stop date of an AE, the most 
conservative approach was used for analysis. An AE with a complete missing onset date but a 
resolution date after initiation of study treatment will be considered treatment-emergent unless 
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7.1.6.
Summaries of Adverse Events and Deaths
A brief, high-level summary of the number and percentage of participants who experienced at 
least 1 TEAE in the categories described below will be provided by treatment group. All deaths 
observed in the study will also be included in this summary.
The number and percentage of participants who experienced at least 1 TEAE will be provided 
and summarized by SOC, PT, and treatment group: 
•
TEAEs
•
TEAEs by maximum severity 
For the AE categories described below, summaries will be provided by SOC, PT, and treatment 
group:
•
TEAEs with Grade 3 or higher 
•
TE treatment-related AEs
•
TE treatment-related AEs by maximum severity 
•
TE treatment-related AEs with Grade 3 or higher 
•
TE SAEs
•
TE AEs leading to death 
Multiple events will be counted only once per participant 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 grade, the most severe grade will be 
used for those AEs that occurred more than once in an individual participant during the study. 
In addition to the above summary tables, all TEAEs and TE SAEs will be summarized by PT 
only, in descending order of total frequency.
In addition, data listings will be provided for the following:
•
All AEs, indicating whether the event is treatment emergent
•
All SAEs
•
All Deaths


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A summary (number and percentage of participants) of deaths will be provided by treatment 
group. Summary will include the following categories:
•
All deaths
•
Deaths within 90 days of the last dosing of study treatment
•
Deaths beyond 90 days of the last dosing of study treatment
7.1.7.
Additional Analysis of Adverse Events
7.1.7.1.
Dose Limiting Toxicity (DLT)
For each cohort being evaluated for safety and tolerability based on DLT assessment, DLT 
evaluable participants are identified as those who were enrolled for dose escalation, either 
experienced a DLT any time during the DLT assessment period or completed all treatments of 
study drug and completed safety procedures during the DLT assessment period. 
A listing of the DLT AEs will be provided by cohort including cohort number with dose level, 
participant identification, actual dose amount prior to or on the start date of the AE, DLT term 
from investigator as well as CTCAE term and associated severity grade, if available.
7.1.7.2.
Infusion-related Reactions (IRR)
Infusion-related reactions will be collected on the CRF. A listing of IRR AEs will be provided in 
a by-participant listing sorted by participant ID number and administration date in chronological 
order. 
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 during the treatment-emergent period. The 
analysis will be based on values reported in conventional units.
7.2.1.
Summaries of Numeric Laboratory Results
Spaghetti plots for white blood cells and monocytes of individual participants will be provided. 
By-participant listings of results of laboratory tests will be provided for All Enrolled Analysis 
Set by participant ID number and visit in chronological order.
7.2.2.
Graded Laboratory Values
The CTCAE Version 5.0 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 (i.e., increased, decreased) will be presented separately. 


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7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point up to 90 days after the date of the 
last dose of study treatment or the day before initiation of subsequent therapy, whichever comes 
first. If the relevant baseline laboratory value is missing, any abnormality of at least Grade 1 
observed within the time frame specified above will be considered treatment emergent.
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities
Treatment-emergent marked laboratory abnormalities are defined as values that increase from 
baseline by at least 2 toxicity grades at any postbaseline time point during treatment-emergent 
period. If the relevant baseline laboratory value is missing, any Grade 3 or 4 values observed 
within the timeframe specified above will be considered treatment-emergent marked 
abnormalities.
7.2.2.3.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of participants) for treatment-emergent 
laboratory abnormalities will be provided by lab test and dose cohort within each treatment 
group; participants will be categorized according to the most severe postbaseline abnormality 
grade for a given lab test:
•
laboratory abnormalities (Grade 1 to 4 separately)
•
Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of participants in 
the safety analysis set. By-participant listings will be provided for treatment-emergent laboratory 
abnormalities and Grade 3 or 4 laboratory abnormalities by participant ID number in 
chronological order.
7.3.
Body Weight and Vital Signs
A by-participant listing will be provided for body weight, height, BMI, blood pressure, heart 
rate, temperature, and respiratory rate by participant ID number in chronological order.
7.4.
Electrocardiogram Results
A by-participant listing will be provided for electrocardiogram results by participant ID number 
in chronological order.


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7.5.
Other Safety Measures
7.5.1.
Echocardiogram
A by-participant listing will be provided for echocardiogram and multigated acquisition 
(MUGA) scan results by participant ID number in chronological order.
7.5.2.
Surgeries and Procedures
A by-participant listing will be provided for prior and on-study surgeries and procedures by 
participant ID number in chronological order.
7.6.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC (PK) AND IMMUNOGENICITY 
ANALYSES
8.1.
PK Sample Collection
Blood sample collection for GS-3583 PK characterization will be conducted at protocol specified 
time points. 
Part 1: 
At Cycles 1 and 3, blood will be collected at predose (< 30 minutes before start of infusion), end 
of infusion (+ 5 minutes), and 2 hours (± 10 minutes), 6 hours (± 0.5 hours), Day 2 (24 hours [± 
2 hours]), Day 3 (48 hours [± 4 hours]), Day 5 (96 hours [± 4 hours]), Day 8 (168 hours [± 12 
hours]), Day 15 (for Cycle 1: pre-Day 15 dose [< 30 minutes before start of infusion], end of Day 
15 infusion (+ 5 minutes), and 2 hours after start of Day 15 infusion (± 10 minutes); for Cycle 3: 
336 hours [± 12 hours]), and Day 24 (552 hours [± 12 hours]) after start of the Day 1 infusion.
In addition, samples will be collected on Day 1 (predose), and Day 15 (336 hours) of Cycles 2, 4, 
and every subsequent even numbered cycle thereafter, and at the 60-day follow-up visit 
(approximately 60 days after last dose). An additional blood sample will be collected at the end 
of treatment (EOT) visit if a participant terminates early from study treatment.
Part 2 Cohorts A and B
GS-3583 (Safety Run-in Cohorts): At Cycles 1 and 3, blood samples will be collected at predose 
(≤ 30 minutes before start of infusion), end of infusion (+ 5 minutes), and 2 hours (± 10 
minutes), 6 hours (± 0.5 hours), Day 8 (168 hours [± 12 hours]), and Day 15 (336 hours [± 12 
hours]) after start of the Day 1 infusion.
In addition, blood samples will be collected on Day 1 (predose [≤ 30 minutes before start of 
infusion] and end of infusion [+ 5 minutes]) of Cycles 2, 5, and every subsequent odd numbered 
cycle thereafter, and at the 60-day follow-up visit (approximately 60 days after last dose). An 
additional blood sample will be collected at the EOT visit if a participant terminates early from 
study treatment.
GS-3583 (Randomized Expansion Cohorts Treatment Arms): Blood samples will be collected on 
Day 1 (predose [≤ 30 minutes before start of infusion] and end of infusion [+ 5 minutes]) of 
Cycles 1, 2, 3, and every subsequent odd numbered cycle thereafter, and at the 60-day follow-up 
visit (approximately 60 days after last dose). An additional blood sample will be collected at the 
EOT visit if a participant terminates early from study treatment.


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Part 2 Cohort A
Zimberelimab (Safety Run-in Cohort and Randomized Expansion Cohort Control and Treatment 
Arms): Blood samples will be collected on Day 1 (predose [≤ 30 minutes before start of infusion] 
and end of infusion [+ 5 minutes]) of Cycles 1, 2, 3, and every subsequent odd numbered cycle 
thereafter, and at the 60-day follow-up visit (approximately 60 days after last dose). An 
additional blood sample will be collected at the EOT visit if a participant terminates early from 
study treatment.
8.2.
PK Analyses Related to Intensive PK Sampling
8.2.1.
Estimation of PK Parameters
PK parameters will be estimated using Phoenix WinNonlin® software using standard 
noncompartmental methods. The linear/log trapezoidal rule will be used in conjunction with the 
appropriate noncompartmental model, with input values for dose level, dosing time, plasma 
concentration, and corresponding real-time values, based on drug dosing times whenever 
possible.
All predose sample times before time-zero will be converted to zero.
For area under the curve (AUC), samples that are BLQ of the bioanalytical assays occurring 
prior to the attainment of the first quantifiable concentration will be assigned a concentration 
value of zero to prevent overestimation of the initial AUC. Samples that are BLQ at all other 
time points will be treated as missing data in WinNonlin. The nominal time point for a key event 
or dosing interval (τ) may be used to permit direct calculation of AUC over specific time 
intervals. The appropriateness of this approach will be assessed by the PK scientist on a 
profile-by-profile basis.
Pharmacokinetic parameters such as AUCinf, λz, and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of the drug. The appropriateness of calculating these 
parameters will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK 
scientist.
8.2.2.
PK Parameters
PK parameters will be generated for all participants in the PK Analysis Set. The analytes and 
parameters presented in Table 8-1 will be used to evaluate the PK objectives of the study. The 
primary PK parameters are [AUClast, AUCtau, and Cmax] of GS-3583. The PK parameters to be 
estimated in this study are listed and defined in the PK Abbreviations section.
Table 8-1.
PK Parameters for Each Analyte
Analyte
Parameters
GS-3583
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Individual PK parameter data listings and summaries will include all participants for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of participants with nonmissing data for that PK parameter.
8.3.
Immunogenicity analysis
The immunogenicity analyses will use the Immunogenicity Analyses Set. The following 
measures of anti GS-3583 antibody positivity will be reported: ADA prevalence rate, ADA 
incidence rate (i.e. sum of Treatment-Induced and Treatment-Boosted ADA rate), ADA 
transience/persistence rate, and anti-body prevalence rate. 
ADA Prevalence Rate: the proportion of participants who had at least one positive ADA sample 
based on the Immunogenicity Analysis Set. 
Treatment-Boosted ADA Rate: the proportion of participants who had positive baseline ADA 
sample and at least one positive post-treatment ADA sample and the (max titer of the 
posttreatment ADA) / (titer of baseline ADA) >= 9 based on the Immunogenicity Analyses Set.
Treatment-Induced ADA Rate: the proportion of participants who had negative baseline ADA 
sample and at least one positive post-treatment ADA sample based on participants who had both 
non-missing baseline and at least one post-treatment ADA result reported. 
ADA incidence (treatment-emergent ADA): is the sum of both treatment-induced and 
treatment boosted ADA-positive participants as a proportion of the evaluable participant 
population.
Transient ADA is defined as: a) Treatment-Induced ADA detected only at one sampling time 
point during the treatment or follow-up observation period (excluding the last sampling time 
point, which ought to be considered persistent unless shown to be undetectable at a later time). or 
b) Treatment-Induced ADA detected at two or more sampling time points during the treatment 
(including follow-up period if any), where the first and last ADA-positive sample (irrespective of 
any negative samples in between) are separated by a period less than 16 weeks, and the 
participant’s last sampling time point is ADA-negative. 
ADA Transience Rate: the proportion of participants who had transient ADA based on the 
Immunogenicity Analyses Set. 
Persistent ADA is defined as a) Treatment-Induced ADA detected at two or more sampling time 
points during the treatment (including follow-up period if any), where the first and last 
ADA-positive sample (irrespective of any negative samples in between) are separated by a 
period of 16 weeks or longer. or b) Treatment-Induced ADA only in the last sampling time point 
of the treatment study period or at a sampling time point with less than 16 weeks before an 
ADA-negative last sample.


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ADA Persistence Rate: the proportion of participants who had persistent ADA based on the 
Immunogenicity Analyses Set. 
The following ADA categories will be summarized by treatment arms. 
•
ADA prevalence
•
ADA positive post-baseline and positive at baseline
•
ADA not detected post-baseline and positive at baseline
•
ADA incidence
•
Treatment-induced ADA
•
Treatment-boosted ADA
•
Persistent ADA
•
Transient ADA
ADA titers and positive ADA values will be summarized by visits and treatment arms. A 
by-participant listing for ADA status at each time point, along with treatment, visit, ADA sample 
collection status, reason of sample not collected, ADA result, and titer for participants with 
positive ADA status will be provided by participant ID number and time point in chronological 
order.


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9.
BIOMARKER ANALYSIS
Biomarker analyses will be described in the biomarker analysis plan.


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10.
REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New Response 
Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (Version 1.1). Eur J Cancer 
2009;45 (2):228-47.


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


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12.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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13.
APPENDIX 1
RECIST 1.1-BASED ASSESSMENTS - 
OVERALL VISIT RESPONSE
The RECIST tumor response data will be used to determine each participant’s visit response 
according to RECIST version 1.1. At each visit, participants will be assigned a RECIST 1.1 visit 
response of CR, PR, SD or PD, using the information from TLs, non-target lesions (NTLs) and 
new lesions and depending on the status of their disease compared with baseline and previous 
assessments. If a participant has had a tumor assessment which cannot be evaluated, then the 
participant will be assigned a visit response of NE. For participants with no disease at baseline 
(i.e. no TLs and no NTLs), evaluation of overall visit responses will be based on 
absence/presence of new lesions. If no TLs and no NTLs are recorded at a visit, both the TL and 
NTL visit response will be recorded as NA and the overall visit response will be no evidence of 
disease (NED). If a new lesion is observed then the overall visit response will be PD. 
Table A2-13-1 summarizes overall visit response given the visit responses from TL and NTL are 
combined with new lesion.
Table A2-13-1.
Overall Visit Response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR or NA
No
CR
CR
Non CR/Non PD or NE
No
PR
PR
Non PD or NE or NA
No
PR
SD 
Non PD or NE or NA
No
SD
NE
Non PD or NE or NA
No
NE
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
NA
CR
No
CR
NA
Non CR/Non PD
No
SD
NA
NE
No
NE
NA
NA
No
NED
CR Complete response, NA Not applicable, PR Partial response, SD Stable disease, PD Progression of disease, NE Not 
evaluable, NED No evidence of disease.


SAP GS-US-496-5657
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Development
eSigned
15-Jun-2023
15:05:55
Biostatistics eSigned
15-Jun-2023
21:58:49
PPD
PPD